EA040588B1 - VIRAL REPLICATION INHIBITORS - Google Patents

Description

The field of technology to which the invention belongs

The invention relates to a number of compounds, a method for the prevention (prevention) or treatment of viral infections in animals using compounds and to these compounds for use as a drug, more preferably for use as a drug for the treatment or prevention of viral infections, especially RNA- viral infections, more specifically infections of viruses belonging to the Flavivirus family, and even more specifically dengue virus infections. In addition, the invention relates to pharmaceutical compositions of the compounds, compositions or preparations for use as a drug, more preferably for the prevention or treatment of viral infections. The invention also relates to methods for preparing compounds.

Background of the Invention

Flaviviruses, which are carried by mosquitoes or itchworms, cause life-threatening infections in humans, such as encephalitis and hemorrhagic fever. There are four distinct but closely related dengue flavivirus serotypes (DENV-1, -2, -3 and -4). Dengue is endemic in most tropical and subtropical regions around the world, predominantly in urban and semi-urban areas. According to the World Health Organization (WHO), 2.5 billion people, of which 1 billion children, are at risk of DENV infection (WHO, 2002). Approximately 50 to 100 million cases of dengue fever [DF], half a million cases of acute dengue disease (i.e. dengue hemorrhagic fever [DHF] and dengue hemorrhagic fever shock [DSS]) and more occur each year worldwide than 20,000 deaths. DHF has become a major cause of hospitalization and death among children in epidemic areas. Overall, dengue is the most common cause of arbovirus disease. Due to recent large outbreaks in countries located in Latin America, Southeast Asia and the Western Pacific (including Brazil, Puerto Rico, Venezuela, Cambodia, Indonesia, Vietnam, Thailand), the number of cases of dengue has increased greatly in recent years . Not only is the number of cases of dengue on the rise as the disease spreads to new areas, but outbreaks tend to be more severe.

For the prevention and/or control of dengue disease, the only methods currently available are mosquito extermination strategies to control the vector. While advances are being made in the development of dengue vaccines, there are also many challenges. They provide for the existence of a phenomenon called antibody dependent enhancement (ADE).

Cure from infection with one serotype confers lifelong immunity against that serotype, but provides only partial and temporary protection against subsequent infection with one of the other three serotypes. After infection with another serotype, the previous heterologous antibodies form complexes with the newly infecting dengue virus serotype, but do not neutralize the pathogen. Instead, it was believed that the entry of the virus into the cells is facilitated, which leads to uncontrolled viral replication and a higher peak in virus titers. In both primary and secondary infections, higher viral titers are associated with more severe dengue virus disease. Because maternal antibodies can easily pass to the baby through breastfeeding, this may be one reason why children are more susceptible to serious dengue disease than adults.

In locations with two or more serotypes spreading at the same time, also called hyperendemic areas, the risk of serious dengue disease is substantially higher due to the increased risk of exposure to a secondary, more severe infection. Moreover, in a hyperendemic situation, more virulent strains are more likely to emerge, which in turn increases the likelihood of dengue haemorrhagic fever (DHF) or dengue haemorrhagic fever shock.

Mosquitoes that carry dengue, including Aedes aegypti and Aedes albopictus (yellow fever mosquito), are moving north. According to the US Centers for Disease Control and Prevention (CDC), both mosquito species are currently present in south Texas. The northward spread of dengue-carrying mosquitoes is not limited to the US, they have also been observed in Europe.

Despite great efforts over the past 3 decades, there is currently no vaccine suitable to protect against dengue virus disease. The main challenge is to develop a vaccine that offers protection against all four serotypes (a quadrivalent vaccine) to the same extent. Moreover, no specific antiviral drugs are currently available to treat or prevent dengue virus infection. Clearly, there is still a great need for therapy for the prevention or treatment of viral infections in animals, more specifically humans, and especially viral infections caused by flaviviruses, more specifically dengue virus. Therapies with good efficacy, with no or low levels of minor side effects, with a broad spectrum of activity against many dengue virus serotypes, with low toxicity and/or good pharmacokinetic or dynamic properties are highly welcome. The present invention provides compounds with activity against flaviviruses, including dengue virus. The prior art does not lead the person skilled in the art either to the compounds of the present invention or to their use as antiviral compounds.

Brief summary of the invention

The present invention is based on the unexpected discovery that at least one of the above problems can be solved with a new class of compounds.

The present invention provides compounds that have been shown to have antiviral activity. Moreover, the present invention provides that these compounds effectively inhibit the proliferation of viruses, especially flaviviruses, more specifically dengue virus (DENV) and yellow fever virus (YFV). Therefore, these compounds constitute a useful class of effective compounds that can be used in the treatment and/or prevention of viral infections in animals, mammals and humans, more specifically for the treatment and/or prevention of infections with viruses that belong to the flavivirus family, and more specifically infections with viruses. dengue or yellow fever virus.

In addition, the present invention relates to the use of such compounds as medicines and to their use in the manufacture of medicaments for the treatment and/or prevention of viral infections, more specifically viruses that belong to the flavivirus family, and even more specifically infections with dengue virus or virus yellow fever, in animals or mammals, more specifically in humans. The present invention also relates to methods for preparing all such compounds and to pharmaceutical compositions which contain them in an effective amount.

The present invention also relates to a method of treating or preventing viral infections in humans by administering one or more such compounds to a patient in need thereof. In particular, the present invention also relates to a method of treating or preventing viral infections, especially flavivirus infections, in humans by administering an effective amount of one or more such compounds, or a pharmaceutically acceptable salt thereof, to a patient in need thereof. More specifically, the present invention also relates to a method of treating or preventing dengue virus or yellow fever virus infections in humans by administering an effective amount of one or more such compounds, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

One aspect of the present invention are compounds of formula (B)

where fragment is selected from

where the wavy line (—) denotes the point of attachment to the carbonyl of the main formula (B), where the specified fragment is unsubstituted;

cycle B is selected from

- 2 040588

where the wavy line (—) denotes the point of attachment to the carbon atom of the basic formula (B) and where the depicted cycles may be optionally substituted by one, two or three Z ^1a ;

R ¹ is selected from C _3-7 cycloalkyl, aryl, heterocycle;

and wherein said C _3-7 cycloalkyl, aryl and heterocycle are optionally substituted with one, two or three Z ^1b ;

R ² is hydrogen;

each Z ^1a is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ ² , -OC(=O)Z ³ , =O, -SZ ² , =S, -S(=O)Z ² , -S (=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethoxy, nitro, -NZ4Z ⁵ , -NZ ⁴ S(=O)2Z ² , -NZ4C(=O)Z ² , -NZ4C(= O)NZ4Z ⁵ , cyano, -C(=O)Z ³ , -C(=O)OZ ² , -C(=O)NZ4Z ⁵ , -C(=O)H, heteroC^alkyl, aryl, heterocycle and heterocycle-C ₁ -6 alkyl;

and where is the specified heteroCl. ₆ alkyl, aryl, heterocycle and heterocycle-C ₁ - ₆ alkyl are optionally substituted with one, two or three substituents selected from hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -OCF3, -O-C(O) Me, cyano, nitro, -C(O)OH, -C(O)OC1.6 alkyl, -NH2, -NHCH3; -N(CH3)2, -NHС(=O)O-С ₁ . ₄ alkyl; -S(O) ₂ C ₁ - ₄ alkyl and -O-C ₁ . ₆ alkyl;

each Z ^1b is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ ² , -OC(=O)Z ³ , =O, -SZ ² , =S, -S(=O)Z ² , -S (=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethyl, trifluoromethoxy, nitro, -NZ4Z ⁵ , -NZ4C(=O)NZ4Z ⁵ , cyano, -C(=O)Z ³ , -C (=O)H, C1. ₆ alkyl, heteroCl. ₆ alkyl, aryl and heterocycle;

and where specified C1. ₆ alkyl, heteroC^alkyl, aryl and heterocycle are optionally substituted with one, two or three substituents selected from hydroxyl, halogen, -SH, =S, trifluoromethyl, -OCF ₃ , -O-C(O)Me, cyano, nitro, -C (O) OH, -C (O) OS ₁ . ₆ alkyl, -NH ₂ , -NHCH3; -N(CH ₃ ) ₂ , -NH-C(=O)O-C ₁ . ₄ alkyl; -S (O) ₂ C ₁ . ₄ alkyl and -O-C ₁ . ₆ alkyl;

each Z ² is independently selected from C1. ₆ alkyl, aryl and heterocycle;

where specified C1. ₆ alkyl, aryl and heterocycle are optionally substituted with one, two or three substituents selected from hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, difluoromethyl, -O-C ₁₆ alkyl, -OCF3, -S(=O) ₂ C ₁ . ₄ alkyl, cyano, nitro, -C(=O)OH, -C(=O)O-C ₁ . ₄ alkyl, -NH2 and -N(CH ₃ ) ₂ , pyrrolidinyl, piperidinyl and piperazinyl;

each Z ³ is independently selected from hydroxyl, C1. ₆ alkyl, aryl and heterocycle; where specified C1. ₆ alkyl, aryl and heterocycle are optionally substituted with one, two or three substituents selected from C1. ₆ alkyl and -N(CH ₃ ) ₂ ;

each Z ⁴ and Z ⁵ is independently selected from hydrogen, C1. ₆ alkyl, aryl, C ₃ . ₇ cycloalkyl and heterocycle;

or 1-(1H-indol-4-yl)-2-(3-methoxyanilino)-2-phenylethanone;

or 1-(4-isoquinolyl)-2-(3-methoxyanilino)-2-phenylethanone;

or 1-(1H-indol-3-yl)-2-(3-methoxy-N-methylanilino)-2-phenylethanone;

or 3-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-N,N-dimethylbenzamide;

or 2-[2-furylmethyl (methyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone;

or N-[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]-2-(dimethylamino)-N-(3-methoxyphenyl)acetamide;

and its stereoisomers or tautomers or pharmaceutically acceptable salts,

- 3 040588 where the term heteroalkyl as used herein refers to an acyclic alkyl in which one or more carbon atoms are replaced by an oxygen, nitrogen or sulfur atom, provided that the specified chain may not contain two adjacent O atoms or two adjacent S atoms;

where the term heterocycle means a saturated, unsaturated or aromatic ring system of 3-18 atoms, including at least one N, O, S or P;

the term aryl means an aromatic hydrocarbon radical of 6 to 20 carbon atoms formed by removal of a hydrogen from a carbon atom of the parent aromatic ring system, provided that the compound of formula (B) is not itself

3-(2-(1H-indol-3-yl)-2-oxo-1-phenylethylamino)benzenesulfonamide (CAS number 1211427-21-2);

2-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylamino)-1-(1H-indol-3-yl)-2-phenylethanone (CAS No. 1090733-87- 1);

1-(III-indol-3-yl)-2-phenyl-2-(m-tolylamino)ethanone (CAS number 1252467-88-1);

2-(4-ethoxy-3-(hydroxymethyl)phenylamino)-1-(1 H-indol-3-yl)-2-phenylethanone (CAS number 1241127-58-1);

1-(III-indol-3-yl)-2-[(6-methoxy-3-pyridinyl)amino]-2-phenylethanone (CAS number 1181884-55-8);

1-(1H-indol-3-yl)-2-[(1-methyl-1H-pyrazol-3-yl)amino]-2-phenylethanone (CAS number 1134766-19-0);

2-[(3,5-dimethoxyphenyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone (CAS number 1030232-46-2);

1-(1H-indol-3-yl)-2-phenyl-2-(phenylamino)ethanone (CAS number 1030214-83-5);

1-(III-indol-3-yl)-2-[[6-(4-morpholinyl)-3-pyridinyl]amino]-2-phenylethanone (CAS number 103021241-9);

2-(3-(difluoromethoxy)-4-methoxyphenylamino)-1-(1H-indol-3-yl)-2-phenylethanone (CAS number 1015662-06-2);

1-(1H-indol-3-yl)-2-phenyl-2-[(3,4,5-trimethoxyphenyl)amino]ethanone (CAS number 1014535-82-0);

2-[(4-fluorophenyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone (CAS number 1014493-63-0);

2-[(4-ethoxy-3-methoxyphenyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone (CAS number 1014422-80-0);

1-[4-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-2-methoxyphenyl]-2-pyrrolidinone (CAS number 1011119-79-1);

2-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)amino]-1-(1H-indol-3-yl)-2-phenylethanone (CAS number 949443-90-7);

1-(1H-indol-3-yl)-2-phenyl-2-[(1-propyl-4-piperidinyl)amino]ethanone (CAS number 941047-24-1);

2-(cyclopentylamino)-1-(1H-indol-3-yl)-2-phenylethanone (CAS number 931079-25-3);

1-(III-indol-3-yl)-2-[(4-methylphenyl)amino]-2-phenylethanone (CAS number 931016-79-4);

2-(cyclopropylamino)-1-(1H-indol-3-yl)-2-phenylethanone (CAS number 931000-99-6);

2-[(3,4-dihydro-2H-1-benzothiopyran-4-yl)amino]-1-(1H-indol-3-yl)-2-phenylethanone (CAS number 924713-60-0);

2-[(3,4-dimethoxyphenyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone (CAS number 924712-67-4);

2-ethoxy-5-[[2-(III-indol-3-yl)-2-oxo-1-phenylethyl]amino]-N,N-dimethylbenzenesulfonamide (CAS number 920883-17-6);

6-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-2-methyl-2H-1,4-benzoxazin-3(4H)-one (CAS No. 920834- 07-7);

2-[(3,4-dihydro-2H-1-benzopyran-4-yl)amino]-1-(1H-indol-3-yl)-2-phenylethanone (CAS number 920819-87-0);

4-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]benzolacetonitrile (CAS number 920669-36-9);

1-(1H-indol-3-yl)-2-[(4-methoxyphenyl)amino]-2-phenylethanone (CAS number 920601-77-0);

1-(1H-indol-3-yl)-2-phenyl-2-(1,1-dioxotetrahydrothiophen-3-ylamino)ethanone (CAS number 87861992-2);

2-[[3-(hydroxymethyl)phenyl]amino]-1-(1H-indol-3-yl)-2-phenylethanone (CAS number 875166-36-2);

2-[(2,3-dihydro-1,4-benzodioxin-6-yl)amino]-1-(1H-indol-3-yl)-2-phenylethanone (CAS No.

874669-99-5);

1-(1H-indol-3-yl)-2-(morpholino(phenyl)methylamino)-2-phenylethanone;

2-(4-(dimethylamino)benzylamino)-1-(1H-indol-3-yl)-2-phenylethanone;

1-(1H-indol-3-yl)-2-(2-methoxybenzylamino)-2-phenylethanone;

1-(1H-indol-3-yl)-2-(3-methoxybenzylamino)-2-phenylethanone;

2-(2-(dimethylamino)-1-phenylethylamino)-1-(1H-indol-3-yl)-2-phenylethanone;

2-(3,4-dimethoxyphenethylamino)-1-(1H-indol-3-yl)-2-phenylethanone;

1-(1H-indol-3-yl)-2-(1-(2-methoxyphenyl)ethylamino)-2-phenylethanone;

1-(1H-indol-3-yl)-2-(4-methoxybenzylamino)-2-phenylethanone;

2-(benzylamino)-1-(1 H-indol-3-yl)-2-phenylethanone;

2-[4-[[2-(III-indol-3-yl)-2-oxo-1-phenylethyl]amino]phenyl]-N,N-dimethylacetamide;

4-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-1,5-dimethyl-2-phenylpyrazol-3-one;

(2S)-2-(1,3-benzodioxol-5-ylamino)-1-(1 H-indol-3-yl)-2-phenylethanone;

(2S)-2-(2,3-dihydro-1,4-benzodioxin-6-ylamino)-1-(1 H-indol-3-yl)-2-phenylethanone;

- 4 040588 (2S)-2-anilino-1-(1H-indol-3-yl)-2-phenylethanone;

(2S)-1-(1H-indol-3-yl)-2-(3-methylanilino)-2-phenylethanone;

(2S)-1-(1H-indol-3-yl)-2-(3-methoxyanilino)-2-phenylethanone;

(2S)-1-(1H-indol-3-yl)-2-(4-methylanilino)-2-phenylethanone;

(2S)-1-(1H-indol-3-yl)-2-(4-methoxyanilino)-2-phenylethanone;

methyl 4-[[(^)-2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]benzoate;

(2S)-1-(1H-indol-3-yl)-2-phenyl-2-(3,4,5-trimethoxyanilino)ethanone;

(2S)-2-(4-ethoxy-3-methoxyanilino)-1-(1H-indol-3-yl)-2-phenylethanone;

2-[4-[[(1 S)-2-( 1 H-indol-3 -yl)-2-oxo-1-phenylethyl] amino] phenyl] acetonitrile;

(2S)-2-(4-fluoroanilino)-1-(1H-indol-3-yl)-2-phenylethanone;

(2R)-2-[(1-acetyl-2,3-dihydroindol-5-yl)amino]-1-(1H-indol-3-yl)-2-phenylethanone;

(2S)-2-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylamino)-1-(1H-indol-3-yl)-2-phenylethanone;

(2R)-2-(4-fluoroanilino)-1-(1H-indol-3-yl)-2-phenylethanone;

3,4-dihydro-6-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-2(1H)quinolinone (CAS number

1277962-26-1);

2-[(3-(hydroxymethyl)-4-methoxyphenyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone;

2-(1,3-benzodioxol-5-ylamino)-1-(1 H-indol-3-yl)-2-phenylethanone; or n

about Ph Me

G ii il ^{11 1 1}

С—С—N—С--- ^{n n n} 1 l

Another aspect of the invention are compounds of formula (B)

where fragment is selected from

where the wavy line (—) denotes the point of attachment to the carbonyl of the basic formula (B); moreover, the specified fragment is optionally substituted with one or two Z ¹ ;

cycle B is selected from

- 5 040588

where the wavy line (—) denotes the point of attachment to the carbon atom of the basic formula (B) and where the depicted cycles are unsubstituted;

R ¹ is selected from C _3-7 cycloalkyl, aryl, heterocycle;

and wherein said C _3-7 cycloalkyl, aryl and heterocycle are optionally substituted with one, two or three Z ^1b ;

R ² is hydrogen;

each Z ¹ is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ ² , -OC(=O)Z ³ , =O, -SZ ² , =S, -S(=O)Z ² , -S (=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethyl, trifluoromethoxy, nitro, -NZ4Z ⁵ , -NZ ⁴ S(=O)2Z ² , -NZ4C(=O)Z ² , -NZ4C (=O)-OZ ² , -NZ ⁴ C(=O)NZ ⁴ Z ⁵ , cyano, -C(=O)Z ³ , -C(=O)OZ ² , -C(=O)NZ ⁴ Z ⁵ , -C(=O)H, C1-6alkyl, _{heteroC1-6alkyl} , aryl, heterocycle, and heterocycle- _C1-6alkyl ;

and wherein said C _1-6 alkyl, heteroC _1-6 alkyl, aryl, heterocycle and heterocycle-C _1-6 alkyl are optionally substituted with one, two or three substituents selected from hydroxyl, ═O, halogen, —SH, ═S, trifluoromethyl, -OCF3, -O-C(O)Me, cyano, nitro, -C(O)OH, -C(O)OC _1-6 alkyl, -NH ₂ , -NHCH3; -N(CH ₃ ) ₂ , -NH-C(=O)O-C _1-4 alkyl; -S(O) ₂ C _1-4 alkyl and -O-C _1-6 alkyl;

each Z ^1b is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ ² , -OC(=O)Z ³ , =O, -SZ ² , =S, -S(=O)Z ² , -S (=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethyl, trifluoromethoxy, nitro, -NZ4Z ⁵ , -NZ ⁴ C(=O)NZ ⁴ Z ⁵ , cyano, -C(=O)Z ³ , -C(=O)OZ ² , -C(=O)H, ^^alkyl, heteroC^alkyl, aryl and heterocycle;

and wherein said C _1-6 alkyl, heteroC _1-6 alkyl, aryl and heterocycle are optionally substituted with one, two or three substituents selected from hydroxyl, halogen, -SH, =S, trifluoromethyl, -OCF ₃ , -O-C( O)Me, cyano, nitro, -C(O)OH, -C(O)OC _1-6 alkyl, -NH ₂ , -NHCH3; -N(CH ₃ ) ₂ , -NH-C(=O)O-C _1-4 alkyl; -S(O) ₂ C _1-4 alkyl, and -O-C _1-6 alkyl;

each Z ² is independently selected from C _1-6 alkyl, aryl, heterocycle, and heterocycle-C _1-6 alkyl;

where the specified C _1-6 alkyl, aryl, heterocycle and heterocycle-C _1-6 alkyl are optionally substituted with one, two or three substituents selected from hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, difluoromethyl, -O- C _1-6 alkyl, -OCF3, -S (= O) ₂ C _1-4 alkyl, cyano, nitro, -C (= O) OH, -C (= O) O-C _1-4 alkyl, -NH ₂ and -N(CH ₃ ) ₂ , pyrrolidinyl, piperidinyl and piperazinyl;

each Z ³ is independently selected from hydroxyl, C _1-6 alkyl, aryl, and heterocycle; wherein said C _1-6 alkyl, aryl and heterocycle are optionally substituted with one, two or three substituents selected from C _1-6 alkyl and -N(CH ₃ ) ₂ ;

each Z ⁴ and Z ⁵ is independently selected from hydrogen, C _1-6 alkyl, aryl, C _3-7 cycloalkyl, and heterocycle;

or 1-(1H-indol-3-yl)-2-(3-methoxy-N-methylanilino)-2-phenylethanone;

or 3-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-N,N-dimethylbenzamide;

or 2-[2-furylmethyl (methyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone;

or N-[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]-2-(dimethylamino)-N-(3-methoxyphenyl)acetamide;

and its stereoisomers or tautomers or pharmaceutically acceptable salts;

- 6 040588 where the term heteroalkyl as used herein refers to an acyclic alkyl in which one or more carbon atoms are replaced by an oxygen, nitrogen or sulfur atom, provided that the specified chain may not contain two adjacent O atoms or two adjacent S atoms;

where the term heterocycle means a saturated, unsaturated or aromatic ring system of 3-18 atoms, including at least one N, O, S or P;

the term aryl means an aromatic hydrocarbon radical of 6 to 20 carbon atoms formed by removal of a hydrogen from a carbon atom of the parent aromatic ring system, provided that the compound of formula (B) is not itself

N-(5-(2-(7-ethyl-1H-indol-3-yl)-2-oxo-1-phenylethylamino)-2-methoxyphenyl)methanesulfonamide;

3-(2-(1H-indol-3-yl)-2-oxo-1-phenylethylamino)benzenesulfonamide;

2-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylamino)-1-(1H-indol-3-yl)-2-phenylethanone;

-(7-ethyl-1H-indol-3-yl)-2-[(1-methyl-1H-pyrazol-3-yl)amino]-2-phenylethanone;

1-(7-ethyl-1H-indol-3-yl)-2-phenyl-2-[(3,4,5-trimethoxyphenyl)amino]ethanone;

2-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)amino]-1-(7-ethyl-1H-indol-3-yl)-2-phenylethanone;

,4-dihydro-6-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-2(1H)-quinolinone;

1-(1H-indol-3-yl)-2-phenyl-2-(m-tolylamino)ethanone;

2-(4-ethoxy-3-(hydroxymethyl)phenylamino)-1-(1H-indol-3-yl)-2-phenylethanone;

2-[(1-acetyl-4-piperidinyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone;

-1-(1H-indol-3-yl)-2-[(6-methoxy-3-pyridinyl)amino]-2-phenylethanone;

1-(1H-indol-3-yl)-2-[(1-methyl-1H-pyrazol-3-yl)amino]-2-phenylethanone;

2-[(3,5-dimethoxyphenyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone;

1-(1H-indol-3-yl)-2-phenyl-2-(phenylamino)ethanone;

1-(1H-indol-3-yl)-2-[[6-(4-morpholinyl)-3-pyridinyl]amino]-2-phenylethanone;

2-(3-(difluoromethoxy)-4-methoxyphenylamino)-1-(1 H-indol-3-yl)-2-phenylethanone;

1-(1H-indol-3-yl)-2-phenyl-2-[(3,4,5-trimethoxyphenyl)amino]ethanone;

2-[(4-fluorophenyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone;

2-[(4-ethoxy-3-methoxyphenyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone;

1-[4-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-2-methoxyphenyl]-2-pyrrolidinone (CAS number 1011119-79-1);

2-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)amino]-1-(1H-indol-3-yl)-2-phenylethanone;

1-(1H-indol-3-yl)-2-phenyl-2-[(1-propyl-4-piperidinyl)amino]ethanone;

2-(cyclopentylamino)-1-(1 H-indol-3-yl)-2-phenylethanone;

1-(1H-indol-3-yl)-2-[(4-methylphenyl)amino]-2-phenylethanone;

2-(cyclopropylamino)-1-(1 H-indol-3-yl)-2-phenylethanone;

2-[(3,4-dihydro-2H-1-benzothiopyran-4-yl)amino]-1-(1H-indol-3-yl)-2-phenylethanone;

2-[(3,4-dimethoxyphenyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone;

2-ethoxy-5-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-N,N-dimethylbenzenesulfonamide;

6-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-2-methyl-2H-1,4-benzoxazin-3(4H)-one;

2-[(3,4-dihydro-2H-1-benzopyran-4-yl)amino]-1-(1H-indol-3-yl)-2-phenylethanone;

4-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]benzolacetonitrile;

1-(1H-indol-3-yl)-2-[(4-methoxyphenyl)amino]-2-phenylethanone;

1-(1H-indol-3-yl)-2-phenyl-2-(1,1-dioxotetrahydrothiophen-3-ylamino)ethanone;

2-[[3-(hydroxymethyl)phenyl]amino]-1-(1H-indol-3-yl)-2-phenylethanone;

2-[(2,3-dihydro-1,4-benzodioxin-6-yl)amino]-1-(1H-indol-3-yl)-2-phenylethanone;

1-(1H-indol-3-yl)-2-(morpholino(phenyl)methylamino)-2-phenylethanone;

N-[5-[[2-(7-ethyl-1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-2-methylphenyl]methanesulfonamide;

N-[5-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-2-methoxyphenyl]methanesulfonamide;

2-[4-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]phenyl]-N,N-dimethylacetamide;

4-[[2-(7-ethyl-1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-1,5-dimethyl-2-phenylpyrazol-3-one;

4-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-1,5-dimethyl-2-phenylpyrazol-3-one;

(2S)-2-(1,3-benzodioxol-5-ylamino)-1-(1 H-indol-3-yl)-2-phenylethanone;

(2S)-2-(2,3-dihydro-1,4-benzode ioxyn-6-ylamino)-1-(1 H-indol-3-yl)-2-phenylethanone;

(2S)-2-anilino-1-(1H-indol-3-yl)-2-phenylethanone;

(2S)-1-(1H-indol-3-yl)-2-(3-methylanilino)-2-phenylethanone;

(2S)-1-(1H-indol-3-yl)-2-(3-methoxyanilino)-2-phenylethanone;

(2S)-1-(1H-indol-3-yl)-2-(4-methylanilino)-2-phenylethanone;

(2S)-1-(1H-indol-3-yl)-2-(4-methoxyanilino)-2-phenylethanone;

Methyl 4-[[(1 S)-2-(1 H-indol-3-yl)-2-oxo-1-phenylethyl]amino]benzoate;

(2S)-1-(1H-indol-3-yl)-2-phenyl-2-(3,4,5-trimethoxyanilino)ethanone;

(2S)-2-(4-ethoxy-3-methoxyanilino)-1-(1 H-indol-3-yl)-2-phenylethanone;

2-[4-[[(1S)-2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]phenyl]acetonitrile;

(2S)-2-(4-fluoroanilino)-1-(1 H-indol-3-yl)-2-phenylethanone;

- 7 040588 (2R)-2-[(1-acetyl-2,3-dihydroindol-5-yl)amino]-1-(1H-indol-3-yl)-2-phenylethanone;

(2S)-1-(7-ethyl-1H-indol-3-yl)-2-phenyl-2-(3,4,5-trimethoxyanilino)ethanone;

(2S)-2-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylamino)-1-(1H-indol-3-yl)-2-phenylethanone;

N-[4-[[(1R)-2-(7-ethyl-1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]phenyl]ethanesulfonamide;

5-[[(1R)-2-(7-ethyl-1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-3H-1,3-benzoxazol-2-one;

(2R)-2-(4-fluoroanilino)-1-(1H-indol-3-yl)-2-phenylethanone;

N-[5-[[(1R)-2-(7-ethyl-1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-2-methoxyphenyl]methanesulfonamide;

3,4-dihydro-6-[[2-( 1 H-indol-3 -yl)-2-oxo-1-phenylethyl] amino]-2( 1 H)-quinolinone (CAS number

1277962-26-1);

2-[(3-(hydroxymethyl)-4-methoxyphenyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone;

2-(1,3-benzodioxol-5-ylamino)-1-(1H-indol-3-yl)-2-phenylethanone;

-(7-ethyl-1H-indol-3-yl)-2-[3-(hydroxymethyl)anilino]-2-phenylethanone;

1-(7-ethyl-1H-indol-3-yl)-2-[3-(hydroxymethyl)-4-methoxyanilino]-2-phenylethanone;

Another aspect of the present invention are compounds of formula (B) where the moiety is selected from

where the wavy line (—) denotes the point of attachment to the carbonyl of the basic formula (B); moreover, the specified fragment is substituted by one or two Z ¹ ; cycle B is selected from

- 8 040588

where the wavy line (—) denotes the point of attachment to the carbon atom of the basic formula (B) and where the indicated cycles are substituted by one, two or three Z ^1a ;

R ¹ is selected from C _3-7 cycloalkyl, aryl, heterocycle;

and where the specified C _3-7 cycloalkyl, aryl and heterocycle are unsubstituted;

R ² is hydrogen;

each Z ¹ is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ ² , -OC(=O)Z ³ , =O, -SZ ² , =S, -S(=O)Z ² , -S (=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethyl, trifluoromethoxy, nitro, -NZ4Z ⁵ , -NZ ⁴ S(=O)2Z ² , -NZ4C(=O)Z ² , -NZ4C (=O)-OZ ² , -NZ4C(=O)NZ4Z ⁵ , cyano, -C(=O)Z ³ , -C(=O)OZ ² , -C(=O)NZ4Z ⁵ , -C(= O)H, C1-6alkyl, _{heteroC1-6alkyl} , aryl, heterocycle and heterocycle- _C1-6alkyl ;

and wherein said C _1-6 alkyl, heteroC _1-6 alkyl, aryl, heterocycle and heterocycle-C _1-6 alkyl are optionally substituted with one, two or three substituents selected from hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -OCF3, -O-C(O)Me, cyano, nitro, -C(O)OH, -C(O)OC1-6 alkyl, -NH ₂ , -NHCH3; -N(CH ₃ )2, -NH-C(=O)O-C _1-4 alkyl; -S(O) ₂ C _1-4 alkyl and -O-C _1-6 alkyl;

each Z ^1a is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ ² , -OC(=O)Z ³ , =O, -SZ ² , =S, -S(=O)Z ² , -S (=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethoxy, nitro, -NZ4Z ⁵ , -NZ ⁴ S(=O)2Z ² , -NZ4C(=O)Z ² , -NZ4C(= O)-OZ ² , -NZ4C(=O)NZ4Z ⁵ , cyano, -C(=O)Z ³ , -C(=O)OZ ² , -C(=O)NZ4Z ⁵ , -C(=O) H, C1-6alkyl, _{heteroC1-6alkyl} , aryl, heterocycle and heterocycle- _C1-6alkyl ;

and where said C _1-6 alkyl, heteroC _1-6 alkyl, aryl, heterocycle and heterocycle-C _1-6 alkyl are optionally substituted with one, two or three substituents selected from hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -OCF3, -OC(O)Me, cyano, nitro, -C(O)OH, -C(O)OC1-6alkyl, -NH2, -NHCH3; -N(CH ₃ )2, -NH-C(=O)O-C _1-4 alkyl; -S(O) ₂ C _1-4 alkyl and -O-C _1-6 alkyl;

each Z ² is independently selected from C _1-6 alkyl, aryl, heterocycle, and heterocycle-C _1-6 alkyl;

where the specified C _1-6 alkyl, aryl, heterocycle and heterocycle-C _1-6 alkyl are optionally substituted with one, two or three substituents selected from hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, diphthomethyl, -O- C _1-6 alkyl, -OCF3, -S (= O) ₂ C _1-4 alkyl, cyano, nitro, -C (= O) OH, -C (= O) O-C _1-4 alkyl, -NH2 and -N(CH3)2, pyrrolidinyl, piperidinyl and piperazinyl;

each Z ³ is independently selected from hydroxyl, C _1-6 alkyl, aryl, and heterocycle; where the specified C 1-6 alkyl, aryl and heterocycle optionally substituted with one, two or three substituents selected from C _1-6 alkyl and-N(CH ₃ ) ₂ ;

each Z ⁴ and Z ⁵ is independently selected from hydrogen, C _1-6 alkyl, aryl, C _3-7 cycloalkyl, and heterocycle;

or 1-(indolin-1-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;

and its stereoisomers or tautomers or pharmaceutically acceptable salts, where the term heteroalkyl as used herein refers to an acyclic alkyl in which one or more carbon atoms are replaced by an oxygen, nitrogen or sulfur atom, provided that said chain may not contain two adjacent O atoms or two neighboring S atoms;

where the term heterocycle means a saturated, unsaturated or aromatic ring system of 3-18 atoms, including at least one N, O, S or P;

the term aryl means an aromatic hydrocarbon radical of 6-20 carbon atoms formed by the removal of a hydrogen from a carbon atom of the parent aromatic ring system.

Detailed disclosure of graphic material

The figure shows a Kapalan-Meier plot of dengue virus causing mortality/euthanasia in AG129 mice and the effect of treatment with Celgosivir and CPD-242. The red dotted line means the end of treatment.

Detailed disclosure of the invention

The invention will be described with respect to specific embodiments, but the invention is not limited thereto.

The first embodiment of the present invention relates to a compound of formula (B)

where is the snippet

- 9 040588 selected from

where the wavy line (—) denotes the point of attachment to the carbonyl of the main formula (B), where the specified fragment is unsubstituted;

cycle B is selected from

where the wavy line (—) denotes the point of attachment to the carbon atom of the basic formula (B) and where the depicted cycles may be optionally substituted by one, two or three Z ^1a ;

R ¹ is selected from C _3-7 cycloalkyl, aryl, heterocycle;

and wherein said C _3-7 cycloalkyl, aryl and heterocycle are optionally substituted with one, two or three Z ^1b ;

R ² is hydrogen;

each Z ^1a is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ ² , -OC(=O)Z ³ , =O, -SZ ² , =S, -S(=O)Z ² , -S (=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethoxy, nitro, -NZ ⁴ Z ⁵ , -NZ ⁴ S(=O)2Z ² , -NZ ⁴ C(=O)Z ² , -NZ ⁴ C(=O)NZ ⁴ Z ⁵ , cyano, -C(=O)Z ³ , -C(=O)OZ ² , -C(=O)NZ ⁴ Z ⁵ , -C(=O) H, heteroC _1-6 alkyl, aryl, heterocycle and heterocycle-C _1-6 alkyl;

and where said heteroC _1-6 alkyl, aryl, heterocycle and heterocycle-C _1-6 alkyl are optionally substituted with one, two or three substituents selected from hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -OCF ₃ , -O-C(O)Me, cyano, nitro, -C(O)OH, -C(O)OC _1-6 alkyl, -NH ₂ , -NHCH ₃ ; -N(CH ₃ ) ₂ , -NHC(=O)O-C _1-4 alkyl; -S(O) ₂ C _1-4 alkyl and -O-C _1-6 alkyl;

each Z ^1b is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ ² , -OC(=O)Z ³ , =O, -SZ ² , =S, -S(=O)Z ² , -S (=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethyl, trifluoromethoxy, nitro, -NZ ⁴ Z ⁵ , -NZ ⁴ C(=O)NZ ⁴ Z ⁵ , cyano, -C(=O )Z ³ , -C(=O)H, C _1-6 alkyl, heteroC _1-6 alkyl, aryl and heterocycle;

and wherein said C _1-6 alkyl, heteroC _1-6 alkyl, aryl and heterocycle are optionally substituted with one, two or three substituents selected from hydroxyl, halogen, -SH, =S, trifluoromethyl, -OCF ₃ , -O-C( O)Me, cyano, nitro, -C(O)OH, -C(O)OC1-6alkyl, -NH2, -NHCH3; -N(CH ₃ )2, -NH-C(=O)O-C1-4 alkyl; -S(O) ₂ C _1-4 alkyl and -O-C _1-6 alkyl;

each Z ² is independently selected from C _1-6 alkyl, aryl, and heterocycle;

- 10 040588 wherein said _C1-6 alkyl, aryl and heterocycle are optionally substituted with one, two or three substituents selected from hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, difluoromethyl, -O-C1.

₆ alkyl, -OCF3, -S(=O) ₂ C _1-4 alkyl, cyano, nitro, -C(=O)OH, -C(=O)O-C _1-4 alkyl, -NH2 and -N (CH ₃ ) ₂ , pyrrolidinyl, piperidinyl and piperazinyl;

each Z ³ is independently selected from hydroxyl, C _1-6 alkyl, aryl, and heterocycle; where the specified C _1-6 alkyl, aryl and heterocycle is optionally substituted with one, two or three substituents selected from C _1-6 alkyl and -N(CH ₃ )2;

each Z ⁴ and Z ⁵ is independently selected from hydrogen, C _1-6 alkyl, aryl, C ₃ -7 cycloalkyl, and heterocycle;

or 1-(1H-indol-4-yl)-2-(3-methoxyanilino)-2-phenylethanone;

or 1-(4-isoquinolyl)-2-(3-methoxyanilino)-2-phenylethanone;

or 1-(1H-indol-3-yl)-2-(3-methoxy-N-methylanilino)-2-phenylethanone;

or 3-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-N,N-dimethylbenzamide;

or 2-[2-furylmethyl (methyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone;

or N-[2-(1 H-indol-3-yl)-2-oxo-1-phenylethyl]-2-(dimethylamino)-N-(3-methoxyphenyl)acetamide;

and its stereoisomers or tautomers or pharmaceutically acceptable salts;

where the term heteroalkyl as used herein refers to an acyclic alkyl in which one or more carbon atoms are replaced by an oxygen, nitrogen or sulfur atom, provided that said chain may not contain two adjacent O atoms or two adjacent S atoms;

where the term heterocycle means a saturated, unsaturated or aromatic ring system of 3-18 atoms, including at least one N, O, S or P;

the term aryl means an aromatic hydrocarbon radical of 6 to 20 carbon atoms formed by removal of a hydrogen from a carbon atom of the parent aromatic ring system, provided that the compound of formula (B) is not itself

3-(2-(1H-indol-3-yl)-2-oxo-1-phenylethylamino)benzenesulfonamide (CAS number 1211427-21-2);

2-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylamino)-1-(1H-indol-3-yl)-2-phenylethanone (CAS No. 1090733-87- 1);

1-(1H-indol-3-yl)-2-phenyl-2-(m-tolylamino)ethanone (CAS number 1252467-88-1);

2-(4-ethoxy-3-(hydroxymethyl)phenylamino)-1-(1 H-indol-3-yl)-2-phenylethanone (CAS number 1241127-58-1);

1-(1H-indol-3-yl)-2-[(6-methoxy-3-pyridinyl)amino]-2-phenylethanone (CAS number 1181884-55-8);

1-(1H-indol-3-yl)-2-[(1-methyl-1H-pyrazol-3-yl)amino]-2-phenylethanone (CAS number 1134766-19-0);

2-[(3,5-dimethoxyphenyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone (CAS number 1030232-46-2);

1-(1H-indol-3-yl)-2-phenyl-2-(phenylamino)ethanone (CAS number 1030214-83-5);

1-(1H-indol-3-yl)-2-[[6-(4-morpholinyl)-3-pyridinyl]amino]-2-phenylethanone (CAS number 103021241-9);

2-(3-(difluoromethoxy)-4-methoxyphenylamino)-1-(1 H-indol-3-yl)-2-phenylethanone (CAS No.

1015662-06-2);

1-(1H-indol-3-yl)-2-phenyl-2-[(3,4,5-trimethoxyphenyl)amino]ethanone (CAS number 1014535-82-0);

2-[(4-fluorophenyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone (CAS number 1014493-63-0);

2-[(4-ethoxy-3-methoxyphenyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone (CAS number 1014422-80-0);

1-[4-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-2-methoxyphenyl]-2-pyrrolidinone (CAS number 1011119-79-1);

2-[(1-Acetyl-2,3-dihydro-1H-indol-5-yl)amino]-1-(1H-indol-3-yl)-2-phenylethanone (CAS No.

949443-90-7);

1-(1H-indol-3-yl)-2-phenyl-2-[(1-propyl-4-piperidinyl)amino]ethanone (CAS number 941047-24-1);

2-(cyclopentylamino)-1-(1H-indol-3-yl)-2-phenylethanone (CAS number 931079-25-3);

1-(1H-indol-3-yl)-2-[(4-methylphenyl)amino]-2-phenylethanone (CAS number 931016-79-4);

2-(cyclopropylamino)-1-(1H-indol-3-yl)-2-phenylethanone (CAS number 931000-99-6);

2-[(3,4-dihydro-2H-1-benzothiopyran-4-yl)amino]-1-(1H-indol-3-yl)-2-phenylethanone (CAS number 924713-60-0);

2-[(3,4-dimethoxyphenyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone (CAS number 924712-67-4);

2-ethoxy-5-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-N,N-dimethylbenzenesulfonamide (CAS number 920883-17-6);

6-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-2-methyl-2H-1,4-benzoxazin-3(4H)-one (CAS No. 920834- 07-7);

2-[(3,4-dihydro-2H-1-benzopyran-4-yl)amino]-1-(1H-indol-3-yl)-2-phenylethanone (CAS No.

920819-87-0);

4-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]benzolacetonitrile (CAS number 920669-36-9);

1-(1H-indol-3-yl)-2-[(4-methoxyphenyl)amino]-2-phenylethanone (CAS number 920601-77-0);

1-(1H-indol-3-yl)-2-phenyl-2-(1,1-dioxotetrahydrothiophen-3-ylamino)ethanone (CAS number 87861992-2);

2-[[3-(hydroxymethyl)phenyl]amino]-1-(1H-indol-3-yl)-2-phenylethanone (CAS number 875166-36-2);

- 11 040588

2-[(2,3-dihydro-1,4-benzodioxin-6-yl)amino]-1-(1H-indol-3-yl)-2-phenylethanone (CAS No.

874669-99-5);

1-(1H-indol-3-yl)-2-(morpholino(phenyl)methylamino)-2-phenylethanone;

2-(4-(dimethylamino)benzylamino)-1-(1H-indol-3-yl)-2-phenylethanone;

1-(1H-indol-3-yl)-2-(2-methoxybenzylamino)-2-phenylethanone;

1-(1H-indol-3-yl)-2-(3-methoxybenzylamino)-2-phenylethanone;

2-(2-(dimethylamino)-1-phenylethylamino)-1-(1 H-indol-3-yl)-2-phenylethanone;

2-(3,4-dimethoxyphenethylamino)-1-(1H-indol-3-yl)-2-phenylethanone;

1-(1H-indol-3-yl)-2-(1-(2-methoxyphenyl)ethylamino)-2-phenylethanone;

1-(1H-indol-3-yl)-2-(4-methoxybenzylamino)-2-phenylethanone;

2-(benzylamino)-1-(1 H-indol-3-yl)-2-phenylethanone;

2-[4-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]phenyl]-N,N-dimethylacetamide;

4-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-1,5-dimethyl-2-phenylpyrazol-3-one;

(2S)-2-(1,3-benzodioxol-5-ylamino)-1-(1H-indol-3-yl)-2-phenylethanone;

(28)-2-(2,3-dihydro-1,4-benzodioxin-6-ylamino)-1-(1H-indol-3-yl)-2-phenylethanone;

(28)-2-anilino-1-(1H-indol-3-yl)-2-phenylethanone;

(28)-1-(1H-indol-3-yl)-2-(3-methylanilino)-2-phenylethanone;

(28)-1-(1H-indol-3-yl)-2-(3-methoxyanilino)-2-phenylethanone;

(28)-1-(1H-indol-3-yl)-2-(4-methylanilino)-2-phenylethanone;

(28)-1-(1H-indol-3-yl)-2-(4-methoxyanilino)-2-phenylethanone;

Methyl 4-[[(1S)-2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]benzoate;

(2S)-1-(1H-indol-3-yl)-2-phenyl-2-(3,4,5-trimethoxyanilino)ethanone;

(28)-2-(4-ethoxy-3-methoxyanilino)-1-(1H-indol-3-yl)-2-phenylethanone;

2-[4-[[(1S)-2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]phenyl]acetonitrile;

(28)-2-(4-fluoroanilino)-1-(1 H-indol-3-yl)-2-phenylethanone;

(2R)-2-[(1-acetyl-2,3-dihydroindol-5-yl)amino]-1-(1H-indol-3-yl)-2-phenylethanone;

(28)-2-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylamino)-1-(1H-indol-3-yl)-2-phenylethanone;

(2R)-2-(4-fluoroanilino)-1-(1H-indol-3-yl)-2-phenylethanone;

3,4-dihydro-6-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-2(1H)-quinolinone (CAS number 1277962-26-1);

2-[(3-(hydroxymethyl)-4-methoxyphenyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone;

2-(1,3-benzodioxol-5-ylamino)-1-(1H-indol-3-yl)-2-phenylethanone; or

According to the second embodiment, the compounds are characterized by the structural formula (B) where the moiety is selected from

where the wavy line (—) denotes the point of attachment to the carbonyl of the basic formula (B); and

- 12 040588 said fragment is optionally substituted with one or two Z ¹ ; cycle B is selected from

where the wavy line (—) denotes the point of attachment to the carbon atom of the basic formula (B) and where the depicted cycles are unsubstituted;

R ¹ is selected from C _3-7 cycloalkyl, aryl, heterocycle;

and wherein said C _3-7 cycloalkyl, aryl and heterocycle are optionally substituted with one, two or three Z ^1b ;

R ² is hydrogen;

each Z ¹ is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ ² , -OC(=O)Z ³ , =O, -SZ ² , =S, -S(=O)Z ² , -S (=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethyl, trifluoromethoxy, nitro, -NZ ⁴ Z ⁵ , -NZ ⁴ S(=O)2Z ² , -NZ ⁴ C(=O)Z ² , -NZ ⁴ C(=O)-OZ ² , -NZ ⁴ C(=O)NZ ⁴ Z ⁵ , cyano, -C(=O)Z ³ , -C(=O)OZ ² , -C( =O)NZ ⁴ Z ⁵ , -C(=O)H, C _1-6 alkyl, heteroC _1-6 alkyl, aryl, heterocycle and heterocycle-C _1-6 alkyl;

and wherein said C _1-6 alkyl, heteroC _1-6 alkyl, aryl, heterocycle and heterocycle-C _1-6 alkyl are optionally substituted with one, two or three substituents selected from hydroxyl, ═O, halogen, —SH, ═S, trifluoromethyl, -OCF ₃ , -O-C(O)Me, cyano, nitro, -C(O)OH, -C(O)OC _1-6 alkyl, -NH ₂ , -NHCH ₃ ; -N(CH ₃ ) ₂ , -NH-C(=O)OC _1-4 alkyl; -S(O) ₂ C _1-4 alkyl and -O-C _1-6 alkyl;

each Z ^1b is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ ² , -OC(=O)Z ³ , =O, -SZ ² , =S, -S(=O)Z ² , -S (=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethyl, trifluoromethoxy, nitro, -NZ ⁴ Z ⁵ , -NZ ⁴ C(=O)NZ ⁴ Z ⁵ , cyano, -C(=O )Z ³ , -C(=O)OZ ² , -C(=O)H, C1-6αkyl, heteroC1-6alkyl, aryl and heterocycle;

and wherein said C _1-6 alkyl, heteroC _1-6 alkyl, aryl and heterocycle are optionally substituted with one, two or three substituents selected from hydroxyl, halogen, -SH, =S, trifluoromethyl, -OCF3, -O-C(O )Me, cyano, nitro, -C(O)OH, -C(O)OC1-6alkyl, -NH2, -NHCH3; -N(CH3^, -NH-C(=O)O-C1-4 alkyl; -S(O) ₂ C _1-4 alkyl, and -OC _1-6 alkyl;

each Z ² is independently selected from C _1-6 alkyl, aryl, heterocycle, and heterocycle- _C1-6 alkyl;

where specified C _1-6 alkyl, aryl, heterocycle and heterocycle- _C1-6 alkyl are optionally substituted with one, two or three substituents selected from hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, difluoromethyl, -O-C _1-6 alkyl, -OCF ₃ , -S(=O) ₂ C _1-4 alkyl, cyano, nitro, -C(=O)OH, -C(=O)O-Cl _-4 alkyl, -NH ₂ and -N(CH ₃ ) ₂ , pyrrolidinyl, piperidinyl and piperazinyl;

each Z ³ is independently selected from hydroxyl, C _1-6 alkyl, aryl, and heterocycle; wherein said C _1-6 alkyl, aryl and heterocycle are optionally substituted with one, two or three substituents selected from C _1-6 alkyl and -N(CH ₃ ) ₂ ;

each Z ⁴ and Z ⁵ is independently selected from hydrogen, C _1-6 alkyl, aryl, C _3-7 cycloalkyl, and heterocycle;

or 1-(1H-indol-3-yl)-2-(3-methoxy-N-methylanilino)-2-phenylethanone;

or 3-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-N,N-dimethylbenzamide;

- 13 040588 or 2-[2-furylmethyl (methyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone;

or N-[2-(1 H-indol-3-yl)-2-oxo-1-phenylethyl]-2-(dimethylamino)-N-(3-methoxyphenyl)acetamide;

and its stereoisomers or tautomers or pharmaceutically acceptable salts, where the term heteroalkyl as used herein refers to an acyclic alkyl in which one or more carbon atoms are replaced by an oxygen, nitrogen or sulfur atom, provided that said chain may not contain two adjacent O atoms or two neighboring S atoms;

where the term heterocycle means a saturated, unsaturated or aromatic ring system of 3-18 atoms, including at least one N, O, S or P;

the term aryl means an aromatic hydrocarbon radical of 6 to 20 carbon atoms formed by removal of a hydrogen from a carbon atom of the parent aromatic ring system, provided that the compound of formula (B) is not itself

N-(5-(2-(7-ethyl-1H-indol-3-yl)-2-oxo-1-phenylethylamino)-2-methoxyphenyl)methanesulfonamide;

3-(2-(1H-indol-3-yl)-2-oxo-1-phenylethylamino)benzenesulfonamide;

2-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylamino)-1-(1H-indol-3-yl)-2-phenylethanone;

-(7-ethyl-1H-indol-3-yl)-2-[(1-methyl-1H-pyrazol-3-yl)amino]-2-phenylethanone;

1-(7-ethyl-1H-indol-3-yl)-2-phenyl-2-[(3,4,5-trimethoxyphenyl)amino]ethanone;

2-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)amino]-1-(7-ethyl-1H-indol-3-yl)-2-phenylethanone;

,4-dihydro-6-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-2(1H)-quinolinone;

1-(1H-indol-3-yl)-2-phenyl-2-(m-tolylamino)ethanone;

2-(4-ethoxy-3-(hydroxymethyl)phenylamino)-1-(1H-indol-3-yl)-2-phenylethanone;

2-[(1-acetyl-4-piperidinyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone;

- 1-(1H-indol-3-yl)-2-[(6-methoxy-3-pyridinyl)amino]-2-phenylethanone;

1-(1H-indol-3-yl)-2-[(1-methyl-1H-pyrazol-3-yl)amino]-2-phenylethanone;

2-[(3,5-dimethoxyphenyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone;

1-(1H-indol-3-yl)-2-phenyl-2-(phenylamino)ethanone;

1-(1H-indol-3-yl)-2-[[6-(4-morpholinyl)-3-pyridinyl]amino]-2-phenylethanone;

2-(3-(difluoromethoxy)-4-methoxyphenylamino)-1-(1 H-indol-3-yl)-2-phenylethanone;

1-(1H-indol-3-yl)-2-phenyl-2-[(3,4,5-trimethoxyphenyl)amino]ethanone;

2-[(4-fluorophenyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone;

2-[(4-ethoxy-3-methoxyphenyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone;

1-[4-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-2-methoxyphenyl]-2-pyrrolidinone (CAS number 1011119-79-1);

2-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)amino]-1-(1H-indol-3-yl)-2-phenylethanone;

1-(1H-indol-3-yl)-2-phenyl-2-[(1-propyl-4-piperidinyl)amino]ethanone;

2-(cyclopentylamino)-1-(1 H-indol-3-yl)-2-phenylethanone;

1-(1H-indol-3-yl)-2-[(4-methylphenyl)amino]-2-phenylethanone;

2-(cyclopropylamino)-1-(1 H-indol-3-yl)-2-phenylethanone;

2-[(3,4-dihydro-2H-1-benzothiopyran-4-yl)amino]-1-(1H-indol-3-yl)-2-phenylethanone;

2-[(3,4-dimethoxyphenyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone;

2-ethoxy-5-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-N,N-dimethylbenzenesulfonamide;

6-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-2-methyl-2H-1,4-benzoxazin-3(4H)-one;

2-[(3,4-dihydro-2H-1-benzopyran-4-yl)amino]-1-(1H-indol-3-yl)-2-phenylethanone;

4-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]benzolacetonitrile;

1-(1H-indol-3-yl)-2-[(4-methoxyphenyl)amino]-2-phenylethanone;

1-(1H-indol-3-yl)-2-phenyl-2-(1,1-dioxotetrahydrothiophen-3-ylamino)ethanone;

2-[[3-(hydroxymethyl)phenyl]amino]-1-(1H-indol-3-yl)-2-phenylethanone;

2-[(2,3-dihydro-1,4-benzodioxin-6-yl)amino]-1-(1H-indol-3-yl)-2-phenylethanone;

1-(1H-indol-3-yl)-2-(morpholino(phenyl)methylamino)-2-phenylethanone;

N-[5-[[2-(7-ethyl-1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-2-methylphenyl]methanesulfonamide;

N-[5-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-2-methoxyphenyl]methanesulfonamide;

2-[4-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]phenyl]-N,N-dimethylacetamide;

4-[[2-(7-ethyl-1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-1,5-dimethyl-2-phenylpyrazol-3-one;

4-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-1,5-dimethyl-2-phenylpyrazol-3-one;

(2S)-2-(1,3-benzodioxol-5-ylamino)-1-(1 H-indol-3-yl)-2-phenylethanone;

(2S)-2-(2,3-dihydro-1,4-benzode ioxyn-6-ylamino)-1-(1 H-indol-3-yl)-2-phenylethanone;

(2S)-2-anilino-1-(1H-indol-3-yl)-2-phenylethanone;

(2S)-1-(1H-indol-3-yl)-2-(3-methylanilino)-2-phenylethanone;

(2S)-1-(1H-indol-3-yl)-2-(3-methoxyanilino)-2-phenylethanone;

(2S)-1-(1H-indol-3-yl)-2-(4-methylanilino)-2-phenylethanone;

(2S)-1-(1H-indol-3-yl)-2-(4-methoxyanilino)-2-phenylethanone;

methyl 4-[[(1 S)-2-( 1 H-indol-3-yl)-2-oxo-1-phenylethyl]amino]benzoate;

(2S)-1-(1H-indol-3-yl)-2-phenyl-2-(3,4,5-trimethoxyanilino)ethanone;

- 14 040588 (2S)-2-(4-ethoxy-3-methoxyanilino)-1-(1 H-indol-3-yl)-2-phenylethanone;

2-[4-[[(1S)-2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]phenyl]cetonitrile;

(2S)-2-(4-fluoroanilino)-1-(1H-indol-3-yl)-2-phenylethanone;

(2R)-2-[(1-acetyl-2,3-dihydroindol-5-yl)amino]-1-(1H-indol-3-yl)-2-phenylethanone;

(2S)-1-(7-Ethyl-1H-indol-3-yl)-2-phenyl-2-(3,4,5-trimethoxyanilino)ethanone;

(2S)-2-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylamino)-1-(1H-indol-3-yl)-2-phenylethanone;

N-[4-[[(1R)-2-(7-ethyl-1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]phenyl]ethanesulfonamide;

5-[[(1R)-2-(7-ethyl-1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-3H-1,3-benzoxazol-2-one;

(2R)-2-(4-fluoroanilino)-1-(1H-indol-3-yl)-2-phenylethanone;

N-[5-[[(1R)-2-(7-ethyl-1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-2-methoxyphenyl]methanesulfonamide;

3,4-dihydro-6-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-2(1H)-quinolinone (CAS number

1277962-26-1);

2-[(3-(hydroxymethyl)-4-methoxyphenyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone;

2-(1,3-benzodioxol-5-ylamino)-1-(1H-indol-3-yl)-2-phenylethanone;

1-(7-ethyl-1H-indol-3-yl)-2-[3-(hydroxymethyl)anilino]-2-phenylethanone;

1-(7-ethyl-1H-indol-3-yl)-2-[3-(hydroxymethyl)-4-methoxyanilino]-2-phenylethanone;

According to the third embodiment, the compounds are characterized by the structural formula (B)

where is the snippet

selected from

means the point of attachment to the carbonyl of the basic formula (B); moreover, the specified fragment is substituted by one or two Z ¹ ; cycle B is selected from where the wavy line (-)

- 15 040588

where the wavy line (^) denotes the point of attachment to the carbon atom of the basic formula (B) and where the indicated cycles are replaced by one, two or three Z ^1a ;

R ¹ is selected from C _3-7 cycloalkyl, aryl, heterocycle;

and where the specified C _3-7 cycloalkyl, aryl and heterocycle are unsubstituted;

R ² is hydrogen;

each Z ¹ is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ ² , -OC(=O)Z ³ , =O, -SZ ² , =S, -S(=O)Z ² , -S (=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethyl, trifluoromethoxy, nitro, -NZ4Z ⁵ , -NZ ⁴ S(=O)2Z ² , -NZ4C(=O)Z ² , -NZ4C (=O)-OZ ² , -NZ4C(=O)NZ4Z ⁵ , cyano, -C(=O)Z ³ , -C(=O)OZ ² , -C(=O)NZ4Z ⁵ , -C(= O)H, C _1-6 alkyl, heteroC _1-6 alkyl, aryl, heterocycle and heterocycle-C _1-6 alkyl;

and wherein said C _1-6 alkyl, heteroC _1-6 alkyl, aryl, heterocycle and heterocycle-C _1-6 alkyl are optionally substituted with one, two or three substituents selected from hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -OCF3, -O-C(O)Me, cyano, nitro, -C(O)OH, -C(O)OC1-6 alkyl, -NH2, -NHCH3; -N(CHs)2, -NH-C(=O)O-C _1-4 alkyl; -S(O) ₂ C _1-4 alkyl and -O-C _1-6 alkyl;

each Z ^1a is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ ² , -OC(=O)Z ³ , =O, -SZ ² , =S, -S(=O)Z ² , -S (=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethoxy, nitro, -NZ ⁴ Z ⁵ , -NZ ⁴ S(=O)2Z ² , -NZ ⁴ C(=O)Z ² , -NZ ⁴ C(=O)-OZ ² , -NZ ⁴ C(=O)NZ ⁴ Z ⁵ , cyano, -C(=O)Z ³ , -C(=O)OZ ² , -C(=O )NZ ⁴ Z ⁵ , -C(=O)H, C1-6alkylα, heteroC _1-6 alkyl, aryl, heterocycle and heterocycle-C _1-6 alkyl;

and where the specified C ₁ _ ₆ alkyl, heteroC ₁ _ ₆ alkyl, aryl, heterocycle and heterocycle-C ₁ . ₆ alkyl optionally substituted with one, two or three substituents selected from hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -OCF ₃ , -O-C(O)Me, cyano, nitro, -C(O) OH, -C(O)OC ₁ _ ₆ alkyl, -NH ₂ , -NHCH ₃ ; -N(CH ₃ ) ₂ , -NH-C(=O)O-C ₁ _ ₄ alkyl; -S(O) ₂ C _1-4 alkyl and -O-C _1-6 alkyl;

each Z ² is independently selected from C _1-6 alkyl, aryl, heterocycle, and heterocycle-C _1-6 alkyl;

where the specified C _1-6 alkyl, aryl, heterocycle and heterocycle-C _1-6 alkyl are optionally substituted with one, two or three substituents selected from hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, diphthomethyl, -O- C _1-6 alkyl, -OCF ₃ , -S(=O) ₂ C _1-4 alkyl, cyano, nitro, -C(=O)OH, -C(=O)O-C _1-4 alkyl, - NH ₂ and -N(CH ₃ ) ₂ , pyrrolidinyl, piperidinyl and piperazinyl;

each Z ³ is independently selected from hydroxyl, C _1-6 alkyl, aryl, and heterocycle; where the specified C _1-6 alkyl, aryl and heterocycle optionally substituted with one, two or three substituents selected from C _1-6 alkyl and-N(CH ₃ ) ₂ ;

each Z ⁴ and Z ⁵ is independently selected from hydrogen, C _1-6 alkyl, aryl, C _3-7 cycloalkyl, and heterocycle;

or 1-(indolin-1-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone;

and its stereoisomers or tautomers or pharmaceutically acceptable salts;

where the term heteroalkyl as used herein refers to an acyclic alkyl in which one or more carbon atoms are replaced by an oxygen, nitrogen or sulfur atom, provided that said chain may not contain two adjacent O atoms or two adjacent S atoms;

where the term heterocycle means a saturated, unsaturated or aromatic ring system of 3-18 atoms, including at least one N, O, S or P;

the term aryl means an aromatic hydrocarbon radical of 6-20 carbon atoms formed by the removal of a hydrogen from a carbon atom of the parent aromatic ring system.

According to a fourth embodiment, the present invention relates to a compound according to the first embodiment, wherein each Z ^1a is independently selected from the group consisting of halogen, hydroxyl, -OZ ² , -OC(=O)Z ³ , =O, -S(=O )2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethoxy, -NZ ⁴ Z ⁵ , -NZ ⁴ C(=O)Z ² , -NZ ⁴ C(=O)-OZ ² , cyano, -C (=O)Z ³ , -C(=O)OZ ² , -C(=O)NZ4Z ⁵ , heteroC _1-6 alkyl, aryl, heterocycle and heterocycle-C _1-6 alkyl;

- 16 040588 and wherein said aryl and heterocycle are optionally substituted with one, two or three substituents selected from hydroxyl, =O, -O-C(O)Me, cyano, -C(O)OH, -C(O)OC1- ₆ alkyl, -NH2, -NHCH3;

-N(CH ₃ )2, -NH-C(=O)O-C ₁ . ₄ αlkulα; -S (O) ₂ C ₁ . ₄ alkyl and -O-C1_ ₆ alkyl;

each Z ^1b is independently selected from the group consisting of halogen, hydroxyl, -OZ ² , -OC(=O)Z ³ , =O, -S(=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethyl, trifluoromethoxy, -NZ ⁴ Z ⁵ , cyano, -C(=O)Z ³ , C _1-6 alkyl, heteroC _1-6 alkyl, aryl and heterocycle;

and wherein said _{C1_6} alkyl, aryl and heterocycle are optionally substituted with one, two or three substituents selected from hydroxyl, -O-C(O)Me, cyano, -C(O)OH, -C(O)OC ₁ . ₆ αkyl, -NH2, -NHCH ₃ ; -N(CH ₃ )2, -NH-C(=O)O-C ₁ . ₄ alkyl; -S(O) ₂ C1- _{4 4} alkyl and -O-C1_ ₆ alkyl;

each Z ² is independently selected from _C1-6 alkyl and aryl;

where the specified _C1-6 alkyl and aryl are optionally substituted with one, two or three substituents selected from hydroxyl, halogen, difluoromethyl, -O-C1_ ₆ alkyl, -S(=O) ₂ C ₁ . ₄ αalkyl, -C(=O)OH, -C(=O)O- _C1-4 alkyl, -NH2 and -N(CH ₃ )2, pyrrolidinyl, piperidinyl and piperazinyl;

each Z ³ is independently selected from hydroxyl, _C1-6 alkyl and heterocycle;

where the specified C1_ ₆ alkyl and heterocycle optionally substituted with one, two or three substituents selected from C1_ ₆ alkyl and-N(CH ₃ )2;

each Z ⁴ and Z ⁵ is independently selected from hydrogen, _{C1_6} alkyl, and _{C3_7cycloalkyl} ; and its stereoisomers or tautomers or pharmaceutically acceptable salts. According to a fifth embodiment, the present invention relates to a compound according to a second embodiment, wherein each Z ¹ is independently selected from the group consisting of halogen, hydroxyl, -OZ ² , -OC(=O)Z ³ , =O, -S(=O )2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethyl, trifluoromethoxy, -NZ ⁴ Z ⁵ , -NZ ⁴ C(=O)Z ² , -NZ ⁴ C(=O)-OZ ² , cyano, -C(=O)Z ³ , -C(=O)OZ ² , -C(=O)NZ ⁴ Z ⁵ , C ₁ . ₆ alkyl, _heteroC1-6 alkyl, aryl, heterocycle and heterocycle- _C1-6 alkyl;

and wherein said _C1-6 alkyl, aryl and heterocycle are optionally substituted with one, two or three substituents selected from hydroxyl, =O, -O-C(O)Me, cyano, -C(O)OH, -C(O) _OC1-6 alkyl, -NH2, -NHCH ₃ ; -N(CH ₃ )2, -NH-C(=O)O-C ₁ . ₄ alkyl; -S(O) ₂ C1_ ₄ alkyl and -O-C1_ ₆ alkyl;

each Z ^1b is independently selected from the group consisting of halogen, hydroxyl, -OZ ² , -OC(=O)Z ³ , =O, -S(=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethyl, trifluoromethoxy, -NZ ⁴ Z ⁵ , cyano, -C(=O)Z ³ , -C(=O)OZ ² , _{C1_6} alkyl, _{heteroC1_6} alkyl, aryl and heterocycle;

and wherein said _{C1_6} alkyl, aryl and heterocycle are optionally substituted with one, two or three substituents selected from hydroxyl, -O-C(O)Me, cyano, -C(O)OH, -C(O)OC ₁ . ₆ αkyl, -NH2, -NHCH ₃ ; -N(CH ₃ )2, -NH-C(=O)O-C ₁ . ₆ alkyl; -S(O) _{2 C1-4} alkyl and -O- _C1-6 alkyl;

each Z ² is independently selected from _C1-6 alkyl, aryl, and heterocycle- _C1-6 alkyl; where the specified _C1-6 alkyl and aryl are optionally substituted with one, two or three substituents selected from hydroxyl, halogen, difluoromethyl, -O-C1-6 alkyl, -S(=O) ₂ C ₁ . ₄ αalkyl, -C(=O)OH, -C(=O)O- _C1-4 alkyl, -NH2, -N(CH3)2, pyrrolidinyl, piperidinyl and piperazinyl;

each Z ³ is independently selected from hydroxyl, _C1-6 alkyl and heterocycle;

where the specified C1_ ₆ alkyl and heterocycle optionally substituted with one, two or three substituents selected from C1_ ₆ alkyl and-N(CH ₃ )2;

each Z ⁴ and Z ⁵ is independently selected from hydrogen, _{C1_6} alkyl, and _{C3_7} cycloalkyl. According to a sixth embodiment, the present invention relates to a compound according to a third embodiment, wherein each Z ¹ is independently selected from the group consisting of halogen, hydroxyl, -OZ ² , -OC(=O)Z ³ , =O, -S(=O )2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethyl, trifluoromethoxy, -NZ ⁴ Z ⁵ , -NZ ⁴ C(=O)Z ² , -NZ ⁴ C(=O)-OZ ² , cyano, -C(=O)Z ³ , -C(=O)OZ ² , -C(=O)NZ ⁴ Z ⁵ , _C1-6 alkyl, _heteroC1-6 alkyl, aryl, heterocycle and heterocycle- _C1-6 alkyl;

and wherein said _C1-6 alkyl, aryl and heterocycle are optionally substituted with one, two or three substituents selected from hydroxyl, =O, -O-C(O)Me, cyano, -C(O)OH, -C(O) _OC1-6 alkyl, -NH2, -NHCH ₃ ; -N(CH ₃ )2, -NH-C(=O)O-C ₁ . ₄ alkyl; -S(O) ₂ C1_ ₄ alkyl and -O-C1_ ₆ alkyl;

each Z ^1a is independently selected from the group consisting of halogen, hydroxyl, -OZ ² , -OC(=O)Z ³ , =O, -S(=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethoxy, -NZ ⁴ Z ⁵ , -NZ ⁴ C(=O)-OZ ² , cyano, -C(=O)Z ³ , -C(=O)OZ ² , C1_ ₆ alkyl, heteroC1_ ₆ alkyl, aryl, heterocycle and heterocycle- _{C1_6} alkyl;

and wherein said _{C1_6} alkyl, aryl and heterocycle are optionally substituted with one, two or three substituents selected from hydroxyl, -O-C(O)Me, cyano, -C(O)OH, -C(O) _{OC1_6} alkyl, -NH2, _-NHCH3 ; -N(CH ₃ )2, -NH-C(=O)O-C ₁ . ₄ alkyl; -S(O) _{2 C1-4} alkyl and -O- _C1-6 alkyl;

each Z ² is independently selected from C ₁ . ₆ αalkyl, aryl and heterocycle- _C1-6 alkyl; where specified C ₁ . ₆ αalkyl and aryl are optionally substituted with one, two or three substituents selected from hydroxyl, halogen, difluoromethyl, -O-C1-6 alkyl, -S(=O) ₂ C ₁ . ₄ alkyl, -C(=O)OH, -C(=O)O- _C1-4 alkyl, -NH2, -N(CH ₃ )2, pyrrolidinyl, piperidinyl and piperazinyl;

each Z ³ is independently selected from hydroxyl, C1_ ₆ alkyl and heterocycle;

where said _{C1_6} alkyl and heterocycle are optionally substituted with one, two or three substituents selected from _C1-6 alkyl and -N(CH ₃ )2;

each Z ⁴ and Z ⁵ is independently selected from hydrogen, C _1-6 alkyl and C _3-7 cycloalkyl. According to the seventh embodiment, the present invention relates to the compound according to the first embodiment, in which the fragment

where the specified fragment is unsubstituted; cycle B is selected from

where the wavy line ( ) denotes the point of attachment to the carbon atom of the basic formula (B) and where the depicted cycles may be optionally substituted with one, two or three Z ^1a ;

R ¹ is a fragment selected from

moreover, the fragment is optionally substituted with one, two or three Z ^1b ;

Z ^1b is selected from the group consisting of halogen, hydroxyl, -OZ2, =O, -S(=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethyl, trifluoromethoxy, -NZ4Z ⁵ , cyano, -C(=O)Z ³ , C _1-6 alkyl, aryl and heterocycle;

and where said C _1-6 alkyl, aryl and heterocycle are optionally substituted with one, two or three substituents selected from hydroxyl, -O-C(O)Me, cyano, -C(O)OH, -NHCH ₃ ; -N(CH ₃ )2, -S(O) ₂ C _1-4 alkyl and -O-C _1-6 alkyl;

R ² is hydrogen;

each Z ^1a is independently selected from the group consisting of halogen, hydroxyl, -OZ ² , -OC(=O)Z ³ , =O, -S(=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethoxy, -NZ4Z ⁵ , -NZ ⁴ C(=O)Z ² , cyano, -C(=O)Z ³ , -C(=O)OZ ² , -C(=O)NZ ⁴ Z ⁵ , heteroC] _ ₆ alkyl, aryl, heterocycle and heterocycle-C1_ ₆ alkyl;

where the specified aryl and heterocycle are optionally substituted with one, two or three substituents selected from hydroxyl, =O, -O-C(O)Me, cyano, -C(O)OH, -C(O)OC _1-6 alkyl, -NH2, -NHCH3; -N(CH ₃ ) ₂ , -NH-C(=O)O-C _1-4 alkyl, morpholinyl, -S(O) ₂ C _1-4 alkyl and -O-C _1-6 alkyl;

Z ² is independently selected from C _1-6 alkyl and aryl;

where said C _1-6 alkyl and aryl are optionally substituted with one, two or three substituents selected from hydroxyl, halogen, difluoromethyl, -O-C1-6 alkyl, -S(=O) ₂ C _1-4 alkyl, -C( =O)OH, -C(=O)O-C _1-4 alkyl, -NH2 and -N(CH ₃ ) ₂ , pyrrolidinyl, piperidinyl and piperazinyl;

Z ³ is independently selected from hydroxyl, C _1-6 alkyl and heterocycle;

where the specified C _1-6 alkyl and heterocycle optionally substituted with one, two or three substituents selected from C _1-6 alkyl and-N(CH ₃ ) ₂ ;

each Z ⁴ and Z ⁵ is independently selected from hydrogen, C _1-6 alkyl and C _3-7 cycloalkyl.

According to an eighth embodiment, the present invention relates to a compound according to a second embodiment, wherein the moiety

moreover, the specified fragment is optionally substituted with one or two Z ¹ ; cycle B is selected from

- 19 040588 where the wavy line (—) denotes the point of attachment to the carbon atom of the basic formula (B) and where the depicted cycles are unsubstituted;

R ¹ is a fragment selected from

moreover, the fragment is optionally substituted with one, two or three Z ^1b ;

R ² is hydrogen;

each Z ¹ is independently selected from the group consisting of halogen, hydroxyl, -OZ ² , -OC(=O)Z ³ , =O, -S(=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethyl, trifluoromethoxy, -NZ4Z ⁵ , -NZ4C(=O)Z ² , -NZ4C(=O)-OZ ² , cyano, -C(=O)Z ³ , -C(=O)OZ ² , -C( =O)NZ4Z ⁵ , C _1-6 alkyl, heteroC _1-6 alkyl, aryl, heterocycle, and heterocycle-C _1-6 alkyl;

where the specified C _1-6 alkyl, aryl and heterocycle are optionally substituted with one, two or three substituents selected from hydroxyl, =O, -O-C(O)Me, cyano, -C(O)OH, -C(O) OC _1-6 alkyl, -NH2, -NHCH ₃ ; -N(CH ₃ ) ₂ , -NH-C(=O)O-C _1-4 alkyl, morpholinyl, -S(O) ₂ C _1-4 alkyl and -O-C _1-6 alkyl;

each Z ^1b is independently selected from the group consisting of halogen, hydroxyl, -OZ ² , -OC(=O)Z ³ , =O, -S(=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethyl, trifluoromethoxy, -NZ4Z ⁵ , cyano, -C(=O)Z ³ , -C(=O)OZ ² , C _1-6 alkyl, heteroC _1-6 alkyl, aryl and heterocycle;

and where said C _1-6 alkyl, aryl and heterocycle are optionally substituted with one, two or three substituents selected from hydroxyl, -O-C(O)Me, cyano, -C(O)OH, -C(O)OC _{1 -6} alkyl, -NH2, -NHCH ₃ ; -N(CH ₃ ) ₂ , -NH-C(=O)OC _1-4 alkyl; morpholinyl, -S(O) ₂ C _1-4 alkylα and -O-C _1-6 alkyl;

Z ² is independently selected from C _1-6 alkyl, aryl and heterocycle-C _1-6 alkyl;

where said C _1-6 alkyl and aryl are optionally substituted with one, two or three substituents selected from hydroxyl, halogen, difluoromethyl, -OC _1-6 alkyl, -S(=O) ₂ C _1-4 alkyl, -C(= O)OH, -C(=O)O-C _1-4 alkyl, -NH2 and -N(CH ₃ ) ₂ , pyrrolidinyl, piperidinyl and piperazinyl;

Z ³ is independently selected from hydroxyl, C _1-6 alkyl and heterocycle;

where the specified C _1-6 alkyl and heterocycle optionally substituted with one, two or three substituents selected from C _1-6 alkyl and-N(CH ₃ ) ₂ ;

each Z ⁴ and Z ⁵ is independently selected from hydrogen, C _1-6 alkyl and C _3-7 cycloalkyl.

According to a ninth embodiment, the present invention relates to a compound according to a third embodiment, wherein the moiety

selected from

moreover, the specified fragment is substituted by one or two Z ¹ ; cycle B is selected from

- 20 040588

where the wavy line (—) denotes the point of attachment to the carbon atom of the basic formula (B) and where the depicted cycles are replaced by one, two or three Z ^1a ;

R ¹ is a fragment selected from

wherein the fragment is unsubstituted;

R ² is hydrogen;

each Z ¹ is independently selected from the group consisting of halogen, hydroxyl, -OZ ² , -OC(=O)Z ³ , =O, -S(=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethyl, trifluoromethoxy, -NZ ⁴ Z ⁵ , -NZ ⁴ C(=O)Z ² , -NZ ⁴ C(=O)-OZ ² , cyano, -C(=O)Z ³ , -C(=O) OZ ² , -C(=O)NZ ⁴ Z ⁵ , C _1-6 alkyl, heteroC _1-6 alkyl, aryl, heterocycle and heterocycle-C _1-6 alkyl;

where the specified C _1-6 alkyl, aryl and heterocycle are optionally substituted with one, two or three substituents selected from hydroxyl, =O, -O-C(O)Me, cyano, -C(O)OH, -C(O) OC _1-6 alkyl, -NH ₂ , -NHCH ₃ ; -N(CH ₃ ) ₂ , -NH-C(=O)O-C _1-4 alkyl, morpholinyl, -S(O) ₂ C _1-4 alkyl and -O-C _1-6 alkyl;

each Z ^1a is independently selected from the group consisting of halogen, hydroxyl, -OZ ² , -OC(=O)Z ³ , =O, -S(=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethoxy, -NZ ⁴ Z ⁵ , -NZ ⁴ C(=O)-OZ ² , cyano, -C(=O)Z ³ , -C(=O)OZ ² , -C(=O)NZ ⁴ Z ⁵ , C _1-6 alkyl, heteroC _1-6 alkyl, aryl, heterocycle and heterocycle-C _1-6 alkyl;

and wherein said C _1-6 alkyl, aryl and heterocycle are optionally substituted with one, two or three substituents selected from hydroxyl, =O, -O-C(O)Me, cyano, -C(O)OH, -C(O )OC _1-6 alkyl, -NH ₂ , -NHCH ₃ ; -N(CH ₃ ) ₂ , -NH-C(=O)O-C _1-4 alkyl; morpholinyl, -S(O) ₂ C _1-4a alkyl and -O-C _1-6 alkyl;

Z ² is independently selected from C _1-6 alkyl, aryl and heterocycle-C _1-6 alkyl;

where the specified C _1-6 alkyl and aryl are optionally substituted with one, two or three substituents selected from hydroxyl, halogen, difluoromethyl, -O-C _1-6 alkyl, -S (=O) ₂ C _1-4 alkyl, -C (=O)OH, -C(=O)O-C _1-4 alkyl, -NH ₂ and -N(CH ₃ ) ₂ , pyrrolidinyl, piperidinyl and piperazinyl;

Z ³ is independently selected from hydroxyl, C _1-6 alkyl and heterocycle;

where the specified C _1-6 alkyl and heterocycle optionally substituted with one, two or three substituents selected from C _1-6 alkyl and-N(CH ₃ ) ₂ ;

each Z ⁴ and Z ⁵ is independently selected from hydrogen, C _1-6 alkyl and C _3-7 cycloalkyl.

- 21 040588

According to a tenth embodiment, the present invention relates to a compound according to any one of the first or fourth embodiments, wherein the compound has the structure of formula (G)

where ring B, R ¹ , R ² , X ¹ and Z ¹ are the same as defined in any of claims 1 or 4, R ⁴ is hydrogen and X ¹ is N or CH, and n is 0.

According to an eleventh embodiment, the present invention relates to a compound according to any of the second or fifth embodiments, wherein the compound has the structure of formula (G)

where cycle B, R ¹ , R ² , X ¹ and Z ¹ are defined in any of paragraphs 2 or 5, R ⁴ is hydrogen and X ¹ is N or CH and n is selected from 0; 1; and 2.

According to a twelfth embodiment, the present invention relates to a compound according to any of the third or sixth embodiments, wherein the compound has the structure of formula (G)

where cycle B, R ¹ , R ² , X ¹ and Z ¹ are defined in any of paragraphs 3 or 6, R ⁴ is hydrogen and X ¹ is N or CH, and n is selected from 1; and 2.

According to a thirteenth embodiment, the present invention relates to a compound according to any one of the first or fourth embodiments, wherein the compound is characterized by the structure of formula (H) wherein

cycle B, each Z ¹ independently and each Z ^1b independently are the same as defined in any one of claims 1 or 4;

m is selected from 0, 1, 2 and 3;

n is 0; and where X ² is NH and X ¹ is CH or N, or

X ² is S and X ¹ is CH, or X ² is O and X ¹ is N.

According to a fourteenth embodiment, the present invention relates to a compound according to any of the second or fifth embodiments, wherein the compound is characterized by the structure of formula (H) wherein

(H), cycle B, each Z ¹ independently and each Z ^1b independently, are defined in any one of claims 2 or 5, m is selected from 0, 1, 2 and 3; n is selected from 0, 1 and 2; And

- 22 040588 where X ² is NH and X ¹ is CH or N, or X ² is S and X ¹ is CH, or X ² is O and X ¹ is N.

According to a fifteenth embodiment, the present invention relates to a compound according to any of the third or sixth embodiments, wherein the compound is characterized by the structure of formula (H) wherein

loop B, each Z ¹ independently and each Z ^1b independently as defined in any one of claims 3 or 6, m is 0;

n is selected from 1 and 2; and where X ² is NH and X ¹ is CH or N, or

X ² is S and X ¹ is CH, or X ² is O and X ¹ is N.

According to a sixteenth embodiment, the present invention relates to a compound according to any of the first or fourth embodiments, characterized by the structure of formula (I), where

independently each Z ¹ and independently each Z ^1b cycle B is defined in any one of claims 1 or 4;

n is 0; and m is selected from 0, 1, 2 and 3.

the same as defined in any of claims 1 or 4;

According to a seventeenth embodiment, the present invention relates to a compound according to any of the second or fifth embodiments, wherein the compound has the structure of formula (I)

where, each Z ¹ independently and each Z ^1b independently defined in any of paragraphs.2 or 5;

cycle B is defined in any of claims 2 or 5; n is selected from 0, 1 and 2; and m is selected from 0, 1, 2 and 3.

According to an eighteenth embodiment, the present invention relates to a compound according to any of the third or sixth embodiments, wherein the compound is characterized by the structure of formula (I) wherein

each Z ¹ is independently and each Z ^1b is independently defined in any one of claims 3 or 6;

cycle B is defined in any of claims 3 or 6;

n is selected from 1 and 2; and m is 0.

According to a nineteenth embodiment, the present invention relates to a compound according to any one of the first to third embodiments, wherein the fragment

- 23 040588

According to a twentieth embodiment, the present invention relates to a compound according to any one of the first to third embodiments, wherein the compound has the structure of formula (F1) is

and the bicyclic fragment is chosen from

According to a twenty-first embodiment, the present invention relates to a compound according to any of the preceding embodiments, wherein the carbon atom substituted with the B ring is in the R configuration.

According to a twenty-second embodiment, the present invention relates to a compound according to any of the preceding embodiments, wherein the carbon atom substituted with the B ring is in the S configuration.

Furthermore, the present invention relates to a medicament for the prevention or treatment of a flavivirus infection in an animal, which contains an effective amount of a compound of the preceding embodiments.

In one embodiment, the invention relates to a medicament wherein said animal is a mammal.

In another embodiment, the invention relates to a medicament wherein said mammal is a human.

In another embodiment, the invention relates to a medicament wherein the flavivirus infection is an infection with dengue virus or yellow fever virus.

In addition, the present invention relates to the use of a compound of the preceding embodiments for the manufacture of a medicament for the treatment or prevention of a flavivirus infection.

Furthermore, the present invention relates to the use of the medicament of the preceding embodiments for the treatment or prevention of a flavivirus infection.

In addition, the present invention relates to the use of a compound of the preceding embodiments for the treatment or prevention of a flavivirus infection.

In one embodiment, the invention relates to a use wherein the flavivirus infection is a dengue or yellow fever virus infection.

According to another embodiment, the invention relates to a use wherein the flavivirus infection is a dengue virus or yellow fever virus infection.

In addition, the present invention relates to a pharmaceutical composition containing a pharmaceutically acceptable carrier and, as an active ingredient, an effective amount of a compound of the preceding embodiments or a pharmaceutically acceptable salt thereof.

In addition, the present invention relates to a method for preparing the compound of the preceding embodiments, comprising the steps of:

reaction of a compound of formula (X1) with an amine R ¹ R ² NH in a suitable solvent, with ring A corresponding to the fragment

- 24 040588

formula (B) as defined in claims 1 to 20, cycle B, R ¹ and R ² have the meaning of the preceding embodiments and LG is a leaving group

where the leaving group is selected from a halogen atom or a sulfonate.

According to one embodiment, the invention relates to a process wherein the leaving group is selected from chlorine, bromine and iodine.

In addition, the present invention relates to a method for preparing a compound of the preceding embodiments, the method comprising the steps of reacting an imine of formula (X2) with an aldehyde of formula (X3) in the presence of a catalyst and a suitable solvent to obtain a compound of formula (A1), where the ring A of formula

cycle B and R ¹ are characterized by the meaning of the preceding embodiments and provided that in cycle A of formulas (X3) and (A1) the carbon atom is bonded to a carbonyl

In addition, the present invention relates to a method for treating or preventing flavivirus infections in humans by administering an effective amount of a compound of the preceding embodiments, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

In one embodiment, the invention relates to a method wherein the flavivirus infection is a dengue virus or yellow fever virus infection.

As used herein, the term treat or treatment is intended to refer to administering a compound or composition of the present invention to a subject for the purpose of producing a therapeutic or prophylactic effect by inhibiting a viral infection. Treatment involves changing, ameliorating, alleviating, inhibiting progress, alleviating or preventing a disease, disorder or condition, or one or more symptoms of such disease, disorder or condition, mediated by inhibition of viral infection. The term subject refers to an animal or mammal in need of such treatment, such as a human.

It will be noted that the term "comprising" used in the claims should not be interpreted as limiting the meanings listed below; it does not exclude other elements or steps.

Reference throughout the description to one embodiment or embodiment means that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment of the present invention. Thus, occurrences of phrases according to one embodiment or according to an embodiment in various places throughout the application do not necessarily all refer to the same embodiment, but may. Moreover, specific features, structures, or characteristics may be combined in any suitable manner, as will be apparent to those skilled in the art from this disclosure, in accordance with one or more embodiments. The use of singular forms is intended to include the plural form of that noun, unless specifically noted otherwise.

Similarly, it should be noted that when describing illustrative embodiments of the present invention, various features of the invention are sometimes grouped together in one embodiment, figure, or description thereof, for the purpose of simplifying the description and aiding understanding of one or

- 25 040588 several different aspects of the invention.

In each of the following definitions, the number of carbon atoms represents the maximum number of carbon atoms that is generally optimally present in a substituent or linker; it is understood that if otherwise noted in this application, the number of carbon atoms represents the optimal maximum number of carbon atoms for such a particular substituent or linker.

As used herein, the term "leaving group" or "LG" means a chemical group that is susceptible to displacement by a nucleophile, or is cleaved off or hydrolyzed under basic or acidic conditions. In a particular embodiment, the leaving group is selected from a halogen atom (eg Cl, Br, I) or a sulfonate (eg mesylate, tosylate, triflate).

The term protecting group refers to a fragment of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole. The chemical substructure of the protecting group varies widely. One function of the protecting group is to serve as intermediates in the synthesis of the parent drug. Chemical protecting groups and protection/deprotection principles are well known in the art. See Protective Groups in Organic Chemistry, Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991). The protecting groups of the moiety are used to mask the reactivity of certain functional groups, to promote the effectiveness of desired chemical interactions, for example, the formation and breaking of chemical bonds in an orderly and intended manner. Protecting the functional groups of a compound alters other physical properties other than the reactivity of the protected functional group, such as polarity, lipophilicity (hydrophobicity), and other properties that can be determined by conventional analytical devices. Chemically protected intermediates may themselves be biologically active or inactive.

Protected compounds may also exhibit altered and, in some cases, optimized in vitro and in vivo properties, such as passage through cell membranes and resistance to enzymatic degradation or sequestration. In this role, protected compounds with putative therapeutic effects may be referred to as prodrugs. Another function of the protecting group is to convert the parent drug into a prodrug, whereby the parent drug is released upon conversion of the prodrug in vivo. Because active prodrugs may be absorbed more efficiently than the parent drug, prodrugs may be more effective in vivo than the parent drug. The protecting groups were removed either in vitro for chemical intermediates or in vivo for prodrugs. With chemical intermediates, it is not particularly important that the resulting deprotected products, eg alcohols, be physiologically acceptable, although it is generally more desirable if the products are pharmacologically safe.

As used herein, the term hydrocarbyl, C _1-18 hydrocarbyl, hydrocarbyl group, or C ₁ . ₁₈ hydrocarbyl group refers to C ₁ -C ₁₈ normal, secondary, tertiary, unsaturated or saturated, non-aromatic, acyclic or cyclic hydrocarbons and combinations thereof. Thus, the term includes alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl.

As used herein, the terminology is heterohydrocarbyl, heteroC ₁ - ₁₈ hydrocarbyl, heterohydrocarbyl group, heteroC ₁ - ₁₈ hydrocarbyl group, or hydrocarbyl group which optionally includes one or more heteroatoms, said heteroatoms being selected from the atoms consisting of O, S and N refers to a hydrocarbyl group in which one or more carbon atoms have been replaced by oxygen, nitrogen or sulfur atom(s), and thus includes heteroalkyl, heteroalkenyl, heteroalkynyl and non-aromatic heterocycle. Thus, this term includes, by way of example, alkoxy, alkenyloxy, C _w alkyl-O-C ₁₈ . _w alkyl, C _w αlkenyl-O-alkyl, C _w αkyl-NH-C ₁₈ . _w is alkenyl, inter alia, where w is selected from any number from 1 to 18.

Used in the present description, the term alkyl or C ₁ . ₁₈ αkyl means C ₁ -C ₁₈ normal, secondary or tertiary, straight or cyclic (or a combination of straight and cyclic), branched or unbranched hydrocarbon without a section of unsaturation. Examples are methyl, ethyl, 1-propyl (n-propyl), 2-propyl (iso-Pr), 1-butyl, 2-methyl-1-propyl (iso-Vi), 2-butyl (sec-Bu), 2-dimethyl-2-propyl (tert-Bu), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3methyl-2-butyl, 3-methyl-1- butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3- pentyl, 2-methyl-3-pentyl, cyclopropylethylene, methylcyclopropylene, 2,3-dimethyl-2-butyl, cyclopentylmethylene, 3,3-dimethyl-2-butyl, n-heptyl, n-octyl, nononyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, ngeptadecyl, n-octadecyl, n-nonadecyl, n-isocyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. According to a particular embodiment, the term alkyl refers to C-hydrocarbons, even more specifically to C ₁ . ₆ hydrocarbons, even more specifically C ₁ . ₃ hydrocarbons, as further defined above. Preferred alkyl is C ₁ . ₆ alkyl. Another preferred alkyl is C ₁ _ ₄ alkyl.

- 26 040588

Used in the present description, the term acyclic alkyl or straight alkyl means C ₁ -C ₁₈ non-cyclic normal, secondary or tertiary, straight, branched or straight hydrocarbon without a section of unsaturation. Examples are methyl, ethyl, 1-propyl, 2-propyl (iso-Pr), 1-butyl, 2-methyl-1-propyl (iso-Bu), 2-butyl (sec-Bu), 2-methyl-2-propyl (tert-Bu), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl -1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3methyl-3-pentyl, 2-methyl -3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl n-heptyl, n-octyl, nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, ngeptadecyl, n-octadecyl, n-nonadecyl and n-isocil.

Unless otherwise noted, as used herein, the term cycloalkyl or C ₃ - ₁₈ cycloalkyl means a saturated hydrocarbon monovalent radical containing from 3 to 18 carbon atoms, including or containing C ₃ . ₁ monocyclic or _{C7_18} polycyclic saturated hydrocarbon such as, for example, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclopentylmethylene, cyclopropylethylene, methylcyclopropylene, cyclohexyl, cycloheptyl, cyclooctyl, isopropylcyclooctyl, cyclooctylmethylene, norbornyl, fenchyl, trimethyltricycloheptyl, decalinyl, adamantyl, etc. P. For the avoidance of doubt and by way of example, cyclopentylmethylene refers to \ whereby the methyl group on cyclopentyl is bonded to another group. Moreover, for the avoidance of doubt and by way of example, methylcyclopropylene is referred to as ''G'' ⁵ ', whereby methylcyclopropyl's cyclopropyl is linked to another group. The preferred cycloalkyl is C ₃ _7 cycloalkyl.

As used herein, the term alkenyl or C _2-18 alkenyl means C ₂ -C ₁₈ normal, secondary or tertiary, straight or cyclic, branched or straight hydrocarbon with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely carbon-carbon, sp2 double bond. Examples include, without limitation: ethylene or vinyl (-CH=CH ₂ ), allyl (-CH ₂ CH=CH ₂ ), cyclopentenyl (-C5H7), cyclohexenyl (-C ₆ H ₉ ), cyclopentenylpropylene, methylcyclohexenylene, and 5- hexenyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH=CH ₂ ). The double bond may be in the cis or trans configuration. In a specific embodiment, the term alkenyl refers to Cm2 hydrocarbons, even more specifically to ^^ hydrocarbons, as further defined above. The preferred alkenyl is C ₂ _ ₆ alkenyl.

As used herein, the term acyclic alkenyl or linear alkenyl refers to a C ₂ -C ₁₈ non-cyclic normal, secondary or tertiary, straight, branched or straight hydrocarbon with at least one site (typically 1 to 3, preferably 1) of unsaturation, namely carbon-carbon, sp2 double bond. Examples include, without limitation: ethylene or vinyl (-CH=CH ₂ ), allyl (-CH ₂ CH=CH ₂ ) and 5-hexenyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH=CH ₂ ). The double bond may be in the cis or trans configuration.

As used herein, the term cycloalkenyl refers to a non-aromatic hydrocarbon radical containing 3 to 18 carbon atoms with at least one site (typically 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp2 double bond, and comprising in itself or containing C ₃ _ ₁₀ monocyclic or C7_ ₁₈ polycyclic hydrocarbon. Examples include, without limitation: cyclopentenyl (-C5H7), cyclopentenylpropylene, methylcyclohexenylene, and cyclohexenyl (-C ₆ H ₉ ). The double bond may be in the cis or trans configuration.

As used herein, the term alkynyl or C _2-18 alkynyl refers to a C ₂ -C ₁₈ normal, secondary, tertiary, straight or cyclic, branched or straight hydrocarbon with at least one site (typically 1 to 3, preferably 1) of unsaturation , namely carbon-carbon, sp triple bond. Examples include, without limitation: ethynyl (-C^CH), 3-ethyl-cyclohept-1-ynylene, 4-cyclohept-1-inmethylene, and 1-propynyl (propargyl, -CH ₂ C^CH). In a specific embodiment, the term alkenyl refers to C ₁ - ₁₂ hydrocarbons, even more specifically C ₁ . ₆ hydrocarbons, as further defined above. Preferred alkynyl is C ₂ _ ₆ alkynyl.

As used herein, the term acyclic alkynyl or straight alkynyl refers to a C ₂ -C ₁₈ non-cyclic normal, secondary, tertiary, straight, branched or straight hydrocarbon with at least one site (typically 1 to 3, preferably 1) of unsaturation, namely carbon-carbon, sp triple bond. Examples include, without limitation: ethynyl (-C^CH) and 1-propynyl (propargyl, -CH ₂ C^CH).

As used herein, the term cycloalkynyl refers to a non-aromatic hydrocarbon radical containing from 3 to 18 carbon atoms with at least one site (typically 1 to 3, preferably 1) of unsaturation, namely carbon-carbon, sp triple bond, and including in itself or containing C ₃ - ₁₀ monocyclic or C7 - ₁₈ polycyclic hydrocarbon. Examples include, without limitation: cyclohept-1-yne, 3-ethylcyclohept-1-ynylene, 4-cyclohept-1inmethylene, and ethylenecyclohept-1-yne.

- 27 040588

As used herein, each term alkylene refers to a saturated, branched or straight chain hydrocarbon radical with 1-18 carbon atoms (more specifically C ₁ _ ₁₂ or C 1-6 carbon atoms) and with two monovalent radical centers obtained by removing two atoms hydrogen from the same or two different carbon atoms of the original alkane. Exemplary alkylene radicals include, without limitation: methylene (-CH2-), 1,2-ethyl (-CH2CH2-), 1,3-propyl (-CH2CH2CH2-), 1,4-butyl (-CH2CH2CH2CH2-) and t .P.

As used herein, each term alkenylene refers to a branched or straight chain hydrocarbon radical of 2-18 carbon atoms (more specifically _C2-12 or C2-6 carbon atoms) with at least _one site (typically 1 to 3, preferably 1) unsaturation, namely carbon-carbon, sp2 double bond, and with two monovalent radical centers obtained by removing two hydrogen atoms from the same or two different carbon atoms of the original alkene.

As used herein, each term alkynylene refers to a branched or straight chain hydrocarbon radical of 2 to 18 carbon atoms (more specifically C ₂ to ₁₂ or C 2 to 6 carbon atoms) with at least one site (typically 1 to 3, preferably 1) unsaturation, namely carbon-carbon, sp triple bond, and with two monovalent radical centers obtained by removing two hydrogen atoms from the same or two different carbon atoms of the original alkyne.

As used herein, the term heteroalkyl refers to an acyclic alkyl where one or more carbon atoms have been replaced by an oxygen, nitrogen, or sulfur atom, provided that said chain may not contain two adjacent O atoms or two adjacent S atoms. This means that one or several -CH ₃ of said acyclic alkyl may be replaced by -NH2 and/or that one or more -CH ₂ - of said acyclic alkyl may be replaced by -NH-, -O- or -S-. The S atoms in these chains may optionally be oxidized with one or two oxygen atoms to give sulfoxides and sulfones, respectively. Moreover, the heteroalkyl groups in the compounds of the present invention may contain an oxo or thio group at any carbon atom or heteroatom resulting in a stable compound. Typical heteroalkyl groups include, without limitation, alcohols, alkyl ethers, primary, secondary, and tertiary alkylamines, amides, ketones, esters, alkyl sulfides, and alkyl sulfones.

As used herein, the term heteroalkenyl refers to an acyclic alkenyl in which one or more carbon atoms have been replaced by an oxygen, nitrogen, or sulfur atom, provided that said chain may not contain two adjacent O atoms or two adjacent S atoms. This means that one or more _-CH3 of said acyclic alkenyl may be replaced by -NH2, that one or more -CH2- of said acyclic alkenyl may be replaced by -NH-, -O or -S- and/or that one or more -CH= of said acyclic alkenyl may be be replaced by -N=. The S atoms in these chains may optionally be oxidized with one or two oxygen atoms to give sulfoxides and sulfones, respectively. Moreover, the heteroalkyl groups in the compounds of the present invention may contain an oxo or thio group at any carbon atom or heteroatom resulting in a stable compound. Thus, the term heteroalkenyl includes imines, -O-alkenyl, -NH-alkenyl, -N(alkenyl) ₂ , -M(alkyl)(alkenyl) and -S-alkenyl.

As used herein, the term heteroalkynyl refers to an acyclic alkynyl where one or more carbon atoms have been replaced by an oxygen, nitrogen, or sulfur atom, provided that said chain may not contain two adjacent O atoms or two adjacent S atoms. This means that one or several -CH3 of said acyclic alkynyl may be replaced by -NH2, that one or more -CH2- of said acyclic alkynyl may be replaced by -NH-, -O- or -S-, that one or more -CH= of said acyclic alkynyl may be replaced -N= and/or that one or more of said acyclic alkynyl may be replaced by ^= ^N

The S atoms in these chains may optionally be oxidized with one or two oxygen atoms to give sulfoxides and sulfones, respectively. Moreover, the heteroalkynyl groups in the compounds of the present invention may contain an oxo or thio group at any carbon atom or heteroatom, resulting in a stable compound. Thus, the term heteroalkynyl includes -O-alkynyl, -NH-alkynyl, -N(alkynyl) ₂ , -N(alkyl)(alkynyl), N(alkenyl)(alkynyl), and -Salkynyl.

As used herein, the term heteroalkylene refers to an alkylene where one or more carbon atoms have been replaced by an oxygen, nitrogen, or sulfur atom, provided that said chain may not contain two adjacent O atoms or two adjacent S atoms. This means that one or more -CH3 of said alkylene may be replaced by -NH2 and/or that one or more -CH ₂ -of said alkylene may be replaced by -NH-, -O- or -S-. The S atoms in these chains may optionally be oxidized with one or two oxygen atoms to give sulfoxides and sulfones, respectively. Moreover, the heteroalkylene groups in the compounds of the present invention may contain an oxo or thio group at any carbon atom or heteroatom, resulting in a stable compound.

- 28 040588

As used herein, the term heteroalkenylene refers to alkenylene where one or more carbon atoms have been replaced by an oxygen, nitrogen, or sulfur atom, provided that said chain may not contain two adjacent O atoms or two adjacent S atoms. This means that one or more _-CH3 of said alkenylene may be replaced by -NH2, that one or more -CH2 of said alkenylene may be replaced by -NH-, -O- or -S- and/or that one or more -CH= of said alkenylene may be replaced by - N=. The S atoms in these chains may optionally be oxidized with one or two oxygen atoms to give sulfoxides and sulfones, respectively. Moreover, the heteroalkenylene groups in the compounds of the present invention may contain an oxo or thio group at any carbon atom or heteroatom, resulting in a stable compound.

As used herein, the term heteroalkynylene refers to alkynylene where one or more carbon atoms have been replaced by an oxygen, nitrogen, or sulfur atom, provided that said chain may not contain two adjacent O atoms or two adjacent S atoms. This means that one or more _-CH3 of said alkynylene may be replaced by -NH2, that one or more -CH2 of said alkynylene may be replaced by -NH-, -O- or -S-, that one or more -CH= of said alkynylene may be replaced by -N= and/or that one or more ^= ⁿ of said alkynylene may be replaced by ^= ^N

The S atoms in these chains may optionally be oxidized with one or two oxygen atoms to give sulfoxides and sulfones, respectively. Moreover, the heteroalkynylene groups in the compounds of the present invention may contain an oxo or thio group at any carbon atom or heteroatom, resulting in a stable compound.

As used herein, the term aryl means an aromatic hydrocarbon radical of 6-20 carbon atoms obtained by removing a hydrogen from a carbon atom of the parent aromatic ring system. Exemplary aryl groups include, without limitation, 1 ring, or 2 or 3 rings fused together, radicals derived from benzene, naphthalene, anthracene, biphenyl, and the like. The term parent aromatic ring system means a monocyclic aromatic ring system or bi- or tricyclic a ring system in which at least one ring is aromatic. Thus, according to the present embodiment, exemplary aryl groups include, without limitation, 1 ring, or 2 or 3 rings fused together, radicals derived from benzene, naphthalene, anthracene, biphenyl, 2,3-dihydro-Shindenyl, 5,6, 7,8-tetrahydronaphthalene, 1,2,6,7,8,8a-hexahyroacenaphthylene, 1,2-dihydroacenaphthylene, and the like. Specific aryl groups are phenyl and naphthyl, especially phenyl.

As used herein, the term arylalkyl or arylalkyl- refers to an acyclic alkyl radical in which one of the hydrogen atoms that is bonded to a carbon atom, typically a terminal or sp3 carbon atom, has been replaced by an aryl radical. Exemplary arylalkyl groups include, without limitation, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2naphthylethyl, and the like. An arylalkyl group contains from 6 to 20 carbon atoms, for example, the alkyl moiety of an arylalkyl group contains from 1 to 6 carbon atoms and the aryl moiety contains from 5 to 14 carbon atoms.

As used herein, the term arylalkenyl or arylalkenyl- refers to an acyclic alkenyl radical in which one of the hydrogen atoms that is bonded to a carbon atom has been replaced by an aryl radical. The arylalkenyl group contains from 6 to 20 carbon atoms, for example, the alkenyl moiety of the arylalkenyl group contains from 1 to 6 carbon atoms and the aryl moiety contains from 5 to 14 carbon atoms.

As used herein, the term arylalkynyl or arylalkynyl- refers to an acyclic alkynyl radical in which one of the hydrogen atoms that is bonded to a carbon atom has been replaced by an aryl radical. The arylalkynyl group contains from 6 to 20 carbon atoms, for example, the alkynyl moiety of the arylkynyl group contains from 1 to 6 carbon atoms and the aryl moiety contains from 5 to 14 carbon atoms.

As used herein, the term arylheteroalkyl or arylheteroalkyl- refers to a heteroalkyl radical in which one of the hydrogen atoms that is bonded to a carbon atom, typically a terminal or sp3 carbon atom, has been replaced by an aryl radical. An arylheteroalkyl group contains 6 to 20 carbon atoms, for example, the heteroalkyl moiety of an arylheteroalkyl group contains 1 to 6 carbon atoms and the aryl moiety contains 5 to 14 carbon atoms.

As used herein, the term arylheteroalkenyl or arylheteroalkenyl- refers to a heteroalkenyl radical in which one of the hydrogen atoms that is bonded to a carbon atom has been replaced by an aryl radical. The arylheteroalkenyl group contains 6 to 20 carbon atoms, for example, the heteroalkenyl moiety of the arylheteroalkenyl group contains 1 to 6 carbon atoms and the aryl moiety contains 5 to 14 carbon atoms.

As used herein, the term arylheteroalkynyl or arylheteroalkynyl- refers to a heteroalkynyl radical in which one of the hydrogen atoms that is bonded to a carbon atom has been replaced by an aryl radical. The arylheteroalkynyl group contains 6 to 20 carbon atoms, for example the heteroalkynyl moiety of the arylheteroalkynyl group contains 1 to 6 carbon atoms and the aryl moiety contains 5 to 14 carbon atoms.

As used herein, the term heterocycle means a saturated, unsaturated, or aromatic ring system of 3 to 18 atoms, including at least one N, O, S, or P. Thus, a heterocycle includes heteroaryl groups. As used herein, the heterocycle includes, by way of example and not limitation, those heterocycles as described in Paquette, Leo A. Principles of Modern Heterocyclic Chemistry (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6 , 7 and 9; The Chemistry of Heterocyclic Compounds, A series of Monographs (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19 and 28; Katritzky, Alan R., Rees C.W. and Scriven E. Comprehensive Heterocyclic Chemistry (Pergamon Press, 1996); and J. Am. Chem. soc. (1960) 82:5566. In a specific embodiment, the term means pyridyl, dihydropyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl , 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, bistetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H-1H ,5,2-dithiazinyl, thiangtrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3Nindolyl, 1H-indazolyl, purinyl, 4H-quinolisinyl, phthalazinyl, naphthyridinyl , quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, пиримидинил, фенантролинил, феназинил, фенотиазинил, фуразанил, феноксазинил, изохроманил, хроманил, имидазолидинил, имидазолинил, пиразолидинил, пиразолинил, пиперазинил, индолинил, изоиндолинил, хинуклидинил, морфолинил, оксазолидинил, бензотриазолил, бензизоксазолил, оксиндолил, бензоксазолинил, бензотиенил, бензотиазолил и изатиноил.

The term heteroaryl means an aromatic ring system of 5 to 18 atoms, including at least one N, O, S or P, and thus refers to aromatic heterocycles. Examples of heteroaryl include, without limitation, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, sectriazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, fural, thienyl, and pyrrolyl.

As used herein, the term non-aromatic heterocycle means a saturated or unsaturated non-aromatic ring system of 3 to 18 atoms, including at least one N, O, S, or P.

As used herein, the term heterocyclyl or heterocyclyl- refers to an acyclic alkyl radical in which one of the hydrogen atoms that is bonded to a carbon atom, typically a terminal or sp3 carbon atom, has been replaced by a heterocyclic radical. An example of a heterocyclyl group is 2-pyridylmethylene. The heterocyclyl group contains 6 to 20 atoms, for example the alkyl moiety of the heterocyclyl group contains 1 to 6 carbon atoms and the heterocyclic moiety contains 3 to 14 atoms.

As used herein, the term heterocyclalkenyl or heterocyclalkenyl- refers to an acyclic alkenyl radical in which one of the hydrogen atoms that is bonded to a carbon atom has been replaced by a heterocyclic radical. The heterocyclalkenyl group contains 6 to 20 atoms, for example the alkenyl moiety of the heterocyclalkenyl group contains 1 to 6 carbon atoms and the heterocyclic moiety contains 3 to 14 atoms.

As used herein, the term heterocyclalkynyl or heterocyclalkynyl- refers to an acyclic alkynyl radical in which one of the hydrogen atoms that is bonded to a carbon atom has been replaced by a heterocyclic radical. The heterocyclalkynyl group contains 6 to 20 atoms, for example the alkynyl moiety of the heterocyclalkynyl group contains 1 to 6 carbon atoms and the heterocyclic moiety contains 3 to 14 atoms.

As used herein, the term heterocyclheteroalkyl or heterocyclheteroalkyl- refers to a heteroalkyl radical in which one of the hydrogen atoms that is bonded to a carbon atom, typically a terminal or sp3 carbon atom, has been replaced by a heterocyclic radical. The heterocyclic heteroalkyl group contains 6 to 20 atoms, for example the heteroalkyl moiety of the heterocyclheteroalkyl group contains 1 to 6 carbon atoms and the heterocyclic moiety contains 3 to 14 atoms.

As used herein, the term heterocyclheteroalkenyl or heterocyclheteroalkenyl- refers to a heteroalkenyl radical in which one of the hydrogen atoms that is bonded to a carbon atom has been replaced by a heterocyclic radical. The heterocycleheteroalkenyl group contains 6 to 20 atoms, for example the heteroalkenyl moiety of the heterocycleheteroalkenyl group contains 1 to 6 carbon atoms and the heterocyclic moiety contains 3 to 14 atoms.

As used herein, the term heterocyclheteroalkynyl or heterocyclheteroalkynyl- refers to a heteroalkynyl radical in which one of the hydrogen atoms that is bonded to a carbon atom has been replaced by a heterocyclic radical. The heterocyclic heteroalkynyl group contains 6 to 20 atoms, for example the heteroalkynyl moiety of the heterocyclheteroalkynyl group contains 1 to 6 carbon atoms and the heterocyclic moiety contains 3 to 14 atoms.

As used herein, the term heteroarylalkyl or heteroarylalkyl- refers to an acyclic alkyl radical in which one of the hydrogen atoms that is bonded to a carbon atom, typically a terminal or sp3 carbon atom, has been replaced by a heteroaryl radical. An example of a heteroarylalkyl group is 2-pyridylmethylene. The heteroarylalkyl group contains 6 to 20 atoms, for example, the alkyl moiety of the heteroarylalkyl group contains 1 to 6 carbon atoms and the heteroaryl moiety contains 5 to 14 atoms.

As used herein, the term heteroarylalkenyl or heteroarylalkenyl- refers to an acyclic alkenyl radical in which one of the hydrogen atoms that is bonded to a carbon atom has been replaced by a heteroaryl radical. The heteroarylalkenyl group contains 6 to 20 atoms, for example, the alkenyl moiety of the heteroarylalkenyl group contains 1 to 6 carbon atoms and the heteroaryl moiety contains 5 to 14 atoms.

As used herein, the term heteroarylalkynyl or heteroarylalkynyl- refers to an acyclic alkynyl radical in which one of the hydrogen atoms that is bonded to a carbon atom has been replaced by a heteroaryl radical. The heteroarylalkynyl group contains 6 to 20 atoms, for example, the alkynyl moiety of the heteroarylalkynyl group contains 1 to 6 carbon atoms and the heteroaryl moiety contains 5 to 14 atoms.

As used herein, the term heteroarylheteroalkyl or heteroarylheteroalkyl- refers to a heteroalkyl radical in which one of the hydrogen atoms that is bonded to a carbon atom, typically a terminal or sp3 carbon atom, has been replaced by a heterocyclic radical. The heteroarylheteroalkyl group contains 6 to 20 atoms, for example, the heteroalkyl moiety of the heteroarylheteroalkyl group contains 1 to 6 carbon atoms and the heteroaryl moiety contains 5 to 14 atoms.

As used herein, the term heteroarylheteroalkenyl or heteroarylheteroalkenyl- refers to a heteroalkenyl radical in which one of the hydrogen atoms that is bonded to a carbon atom has been replaced by a heteroaryl radical. The heteroarylheteroalkenyl group contains 6 to 20 atoms, for example the heteroalkenyl moiety of the heteroarylheteroalkenyl group contains 1 to 6 carbon atoms and the heteroaryl moiety contains 5 to 14 atoms.

As used herein, the term heteroarylheteroalkynyl or heteroarylheteroalkynyl- refers to a heteroalkynyl radical in which one of the hydrogen atoms that is bonded to a carbon atom has been replaced by a heteroaryl radical. The heteroarylheteroalkynyl group contains 6 to 20 atoms, for example, the heteroaryl moiety of the heteroarylheteroalkynyl group contains 1 to 6 carbon atoms and the heteroaryl moiety contains 5 to 14 atoms.

As used herein, the term non-aromatic heterocyclalkyl or non-aromatic heterocyclyl- refers to an acyclic alkyl radical in which one of the hydrogen atoms that is bonded to a carbon atom, typically a terminal or sp3 carbon atom, has been replaced by a non-aromatic heterocyclic radical. A non-aromatic heterocyclyl group contains 6 to 20 atoms, for example, the alkyl moiety of a non-aromatic heterocyclyl alkyl group contains 1 to 6 carbon atoms and a non-aromatic heterocyclic moiety contains 3 to 14 atoms.

As used herein, the term non-aromatic heterocyclalkenyl or non-aromatic heterocyclalkenyl- refers to an acyclic alkenyl radical in which one of the hydrogen atoms that is bonded to a carbon atom has been replaced by a non-aromatic heterocyclic radical. A non-aromatic heterocyclalkenyl group contains 6 to 20 atoms, for example, an alkenyl moiety of a non-aromatic heterocyclalkenyl group contains 1 to 6 carbon atoms and a non-aromatic heterocyclic moiety contains 3 to 14 atoms.

As used herein, the term non-aromatic heterocyclalkynyl or non-aromatic heterocyclalkynyl- refers to an acyclic alkynyl radical in which one of the hydrogen atoms that is bonded to a carbon atom has been replaced by a non-aromatic heterocyclic radical. The non-aromatic heterocyclalkynyl group contains 6 to 20 atoms, for example the alkynyl moiety of the non-aromatic heterocyclalkenyl group contains 1 to 6 carbon atoms and the non-aromatic heterocyclic moiety contains 3 to 14 atoms.

As used herein, the term non-aromatic heterocyclheteroalkyl or non-aromatic heterocyclheteroalkyl- refers to a heteroalkyl radical in which one of the hydrogen atoms that is bonded to a carbon atom, typically a terminal or sp3 carbon atom, has been replaced by a heterocyclic radical. A non-aromatic heterocyclheteroalkyl group contains from 6 to 20 atoms, for example, a heteroalkyl moiety of a non-aromatic heterocyclheteroalkyl group contains from 1 to 6 carbon atoms and a non-aromatic heterocyclic moiety contains from 3 to 14 atoms.

As used herein, the term non-aromatic heterocyclheteroalkenyl or

- 31 040588 non-aromatic heterocycloheteroalkenyl- refers to a heteroalkenyl radical in which one of the hydrogen atoms that is bonded to a carbon atom is replaced by a non-aromatic heterocyclic radical. A non-aromatic heterocyclheteroalkenyl group contains from 6 to 20 atoms, for example, a heteroalkenyl moiety of a non-aromatic heterocyclheteroalkenyl group contains from to 6 carbon atoms and a non-aromatic heterocyclic moiety contains from 3 to 14 atoms.

As used herein, the term non-aromatic heterocyclheteroalkynyl or non-aromatic heterocyclheteroalkynyl refers to a heteroalkynyl radical in which one of the hydrogen atoms that is bonded to a carbon atom has been replaced by a non-aromatic heterocyclic radical. The non-aromatic heterocyclheteroalkynyl group contains 6 to 20 atoms, for example, the heteroalkynyl moiety of the non-aromatic heterocyclheteroalkynyl group contains 1 to 6 carbon atoms and the non-aromatic heterocyclic moiety contains 3 to 14 atoms.

By way of example, carbon-linked heterocyclic rings are those linked at the 2, 3, 4, 5 or 6 position of pyridine, at the 3, 4, 5 or 6 position of pyridazine, at the 2, 4, 5 or 6 position of pyrimidine, at position 2, 3, 5 or 6 pyrazine, 2, 3, 4 or 5 position of furan, tetrahydrofuran, thiophene, pyrrole or tetrahydropyrrole, 2, 4 or 5 position of oxazole, imidazole or thiazole, 3, 4 or 5 position of isoxazole, pyrazole or isothiazole, at position 2 or 3 of aziridine, at position 2, 3 or 4 of azetidine, at position 2, 3, 4, 5, 6, 7 or 8 of quinoline, or at position 1, 3, 4, 5, 6, 7 or 8 isoquinoline. More typical carbon-linked heterocycles are 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5 -pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl. By way of example, nitrogen-linked heterocyclic rings are those linked at the 1-position of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole; at position 2 of isoindole or isoindoline, at position 4 of morpholine, and at position 9 of carbazole or β-carboline. More typical nitrogen-linked heterocycles are 1-aziridyl, 1-azetidyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

Unless otherwise noted, as used herein, the terms alkoxy, cycloalkoxy, aryloxy, arylalkyloxy, heterocycloxy, alkylthio, cycloalkylthio, arylthio, arylalkylthio, and heterocyclthio refer to substituents wherein the alkyl group is, respectively, cycloalkyl, aryl, arylalkyl, or heterocycle (each defined herein) are attached to an oxygen atom or a sulfur atom via a single bond, such as but not limited to methoxy, ethoxy, propoxy, butoxy, thioethyl, thiomethyl, phenyloxy, benzyloxy, mercaptobenzyl, and the like. The same definitions will apply to alkenyl and alkynyl radicals instead of alkyl. Preferred alkoxy is C ₁ . ₆ alkoxy; another preferred alkoxy is C _1-4 alkoxy.

Unless otherwise noted, the term halogen as used herein means any atom selected from the group consisting of fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

Unless otherwise noted, as used herein with respect to a substituent group, the terms substituted, for example, in substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl, substituted heterocycle, substituted arylalkyl, substituted heterocyclyl, and the like, refer to the chemical structures defined in the present description, and where the specified hydrocarbyl, heterohydrocarbyl group and/or the specified aryl or heterocycle may be optionally substituted with one or more substituents (preferably 1, 2, 3, 4, 5 or 6), this means that one or more of each atoms hydrogen are independently replaced by a substituent. Exemplary substituents include, without limitation, and in a particular embodiment, said substituents independently selected from the group consisting of halo, amino, hydroxyl, sulfhydryl, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heterocyclalkenyl and heterocyclalkynyl, -X, -Z, -O ^- , -OZ, =O, -SZ, -S ^- , =S, -NZ2, - N ⁺ Z ₃ , =NZ, =N-OZ, -CX ₃ (for example, trifluoromethyl), -CN, -OCN, -SCN, -N=C=O, -N=C=S, -NO, -NO2 , =N ₂ , -N ₃ , -NZC(O)Z, -NZC(S)Z, -NZC(O)O', -NZC(O)OZ, -NZC(S)OZ, -NZC(O) NZZ, NZC(NZ)Z, NZC(NZ)NZZ, -C(O)NZZ, -C(NZ)Z, -S(O) ₂ O', -S(O) ₂ OZ, -S(O) ₂ Z, -OS(O) ₂ OZ, -OS(O)2Z, -OS(O)2O ^- , -S(O)2NZ, -S(O)Z, -OP(O)(OZ)2, -P(O)(OZ)2, -P(O)(O ^- )2, -P(O)(OZ)(O ^- ), -P(O)(OH)2, -C(O)Z , -C(O)X, -C(S)Z, -C(O)OZ, -C(O)O ^- , -C(S)OZ, -C(O)SZ, -C(S)SZ , -C(O)NZZ, -C(S)NZZ, -C(NZ) NZZ, -OC(O)Z, -OC(S)Z, -OC(O)O ^- , -OC(O)OZ, -OC(S)OZ, where each X is independently a halogen selected from F, Cl, Br or I; and each Z is independently -H, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, protecting group, or prodrug moiety, while two Zs attached to a nitrogen atom may be taken together with a nitrogen atom to which they are bonded to form a heterocycle. Alkyl(ene), alkenyl(ene) and alkynyl(ene) groups may also be substituted in a similar manner.

Any substituent designation that is found on more than one site of a compound of the present invention must be independently selected.

- 32 040588

Substituents are optionally indicated with or without bonds. Regardless of the bond designations, if a substituent is multivalent (based on its position in the referenced structure), then any and all possible orientations of the substituent are contemplated.

As used herein, the term heteroatom(s) means an atom selected from nitrogen, which may be quaternized; oxygen and sulfur, including sulfoxide and sulfone.

As used herein, the term hydroxy means -OH.

As used herein, the term carbonyl means a carbon atom bonded to an oxygen by a double bond, i.e. C=O.

As used herein, the term amino means an -NH2 group.

The compounds of the present invention have been used to treat or prevent viral infections, more specifically flavivirus infections.

Flavivirus is a species of the Flavivirus family. This species includes West Nile virus, dengue virus, tick-borne encephalitis virus, yellow fever virus, and other serious viruses that can cause encephalitis. Flaviviruses share common size (40-65 nm), symmetry (enveloped icosahedral nucleocapsid), nucleic acid (positively polar, single-stranded RNA approximately 10,000-11,000 bases), and electron microscope appearance. These viruses are transmitted by the bite of an infected arthropod (mosquito or itch).

The compounds of the present invention are particularly active against dengue virus replication. There are four distinct but closely related dengue flavivirus serotypes (DENV-1, -2, -3 and 4). Dengue is endemic in most tropical and subtropical regions around the world, predominantly in urban and semi-urban areas. According to the World Health Organization (WHO), 22.5 billion people, of which 1 billion children, are at risk of DENV infection (WHO, 2002). Approximately 50 to 100 million cases of dengue fever [DF], half a million cases of acute dengue disease (i.e. dengue hemorrhagic fever [DHF] and dengue hemorrhagic fever shock [DSS]) and more occur each year worldwide than 20,000 deaths. DHF has become a major cause of hospitalization and death among children in epidemic areas. Overall, dengue is the most common cause of arbovirus disease. Due to recent large outbreaks in countries located in Latin America, Southeast Asia and the Western Pacific (including Brazil, Puerto Rico, Venezuela, Cambodia, Indonesia, Vietnam, Thailand), the number of cases of dengue has increased greatly in recent years . Not only is the number of dengue cases increasing as the disease spreads to new areas, but outbreaks tend to be more severe.

To prevent and/or control the disease caused by dengue, the only methods currently available are mosquito extermination strategies to control the vector. While advances are being made in the development of dengue vaccines, there are also many challenges. They provide for the existence of a phenomenon called antibody dependent enhancement (ADE). Cure from infection with one serotype confers lifelong immunity against that serotype, but provides only partial and temporary protection against subsequent infection with one of the other three serotypes. After infection with another serotype, the previous heterologous antibodies form complexes with the newly infecting dengue virus serotype, but do not neutralize the pathogen. Instead, it was believed that the entry of the virus into the cells is facilitated, which leads to uncontrolled viral replication and a higher peak in virus titers. In both primary and secondary infections, higher viral titers are associated with more severe dengue disease. Because maternal antibodies can easily pass to the baby through breastfeeding, this may be one reason why children are more susceptible to serious dengue disease than adults.

In locations with two or more serotypes spreading at the same time, also called hyperendemic areas, the risk of serious dengue disease is substantially higher due to the increased risk of exposure to a secondary, more severe infection. Moreover, in a hyperendemic situation, more virulent strains are more likely to emerge, which in turn increases the likelihood of dengue haemorrhagic fever (DHF) or dengue haemorrhagic fever shock.

When using one or more of the compounds of the present invention or the formulas defined herein, the compound(s) may be administered to the animal or mammal (including human) being treated by any method well known in the art, i.e. e. orally, intranasally, subcutaneously, intramuscularly, intradermally, intravenously, intra-arterially, parenterally or by catheterization;

the therapeutically effective amount of the compound(s) obtained, especially for the treatment of viral infections in humans and other mammals, is preferably a flavivirus replication inhibitory amount of the formulas defined herein and corresponds to an amount that provides a plasma level between 1 μg/ml and 100 mg/ml, optionally 10 mg/ml.

In addition, the present invention relates to a method for preventing or treating viral infections in a subject or patient by administering to a patient in need thereof a therapeutically effective amount of the compounds of the present invention. A therapeutically effective amount of the compound(s), especially for the treatment of viral infections in humans and other mammals, is preferably a flavivirus replication inhibitory amount. A suitable dosage is generally in the range of 0.001 to 60 mg, optionally 0.01 to 10 mg, optionally 0.1 to 1 mg per day per kg body weight of humans. Depending on the condition being treated and the condition of the patient, said effective amount may be divided into several subunits per day or may be administered at intervals of more than one day.

In a more general sense, the present invention relates to compounds of formula (B) and (G), and all of its options for implementation, applicable as agents with biological activity (in particular with antiviral activity) or as diagnostic agents. Any of the uses mentioned in relation to the present invention may be limited to non-medical use, non-therapeutic use, non-diagnostic use, or exclusively in vitro use, or use associated with cells distant from the animal.

In a more general sense, the present invention relates to compounds of formula (B), (G) and (H), and all of its variants of implementation, applicable as agents with biological activity (in particular with antiviral activity) or as diagnostic agents. Any of the uses mentioned in relation to the present invention may be limited to non-medical use, non-therapeutic use, non-diagnostic use, or exclusively in vitro use, or use associated with cells distant from the animal.

Those skilled in the art will also recognize that the compounds of the present invention may exist in many different protonation states depending, among other things, on the pH of their environment. While the structural formulas presented herein represent compounds in only one of several possible protonation states, it will be understood that these structures are illustrative only and that the present invention is not limited to any particular protonation state - it is intended that any and all protonated forms of the compounds fall within the scope of scope of the present invention.

Used in the present description, the term pharmaceutically acceptable salts means therapeutically active non-toxic salt forms, which are able to form compounds of the formulas specified in the present description. Thus, the compounds of the present invention optionally include salts of the present compounds, especially pharmaceutically acceptable non-toxic salts containing, for example, Na ⁺ , Li ⁺ , K ⁺ , NH4 ⁺ , Ca ²⁺ and Mg ²⁺ . Such salts may include salts that are derived from the combination of appropriate cations such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions with an anionic acid moiety, typically a carboxylic acid. The compounds of the present invention may carry several positive or negative charges. The net charge of the compounds of the present invention may be either positive or negative. Generally, any bound counterions are due to the synthetic and/or isolation methods by which the compounds were prepared. Representative counterions include, without limitation, ammonium, sodium, potassium, lithium, halides, acetate, trifluoroacetate, etc., and mixtures thereof. It will be understood that the identity of any associated counterion is not a critical feature of the present invention and that the present invention encompasses compounds in association with any type of proionion. Moreover, since compounds can exist in many different forms, the present invention is intended to cover not only forms of compounds that are bound to counterions (e.g., dry salts), but also forms that are not bound to counterions (e.g., aqueous or organic solutions). Typically, metal salts have been prepared by reacting a metal hydroxide with a compound of the present invention. Examples of metal salts which have thus been obtained are salts containing Li ⁺ , Na ⁺ and K ⁺ . A less soluble metal salt can be precipitated from a solution of a more soluble salt by adding an appropriate metal compound. In addition, salts can be formed from the acidic addition of certain organic and inorganic acids to basic centers, typically amines, or to acidic groups. Examples of such suitable acids include, for example, inorganic acids such as hydrohalic acids, such as hydrochloric or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, 2hydroxypropanoic, 2-oxopropanoic, lactic, pyruvic, oxalic (i.e., ethanedioic), malonic, succinic (i.e., butanedioic acid), maleic, fumaric , malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, para-toluenesulfonic, cyclohexane sulfonic, salicylic (i.e. 2-hydroxybenzoic), para-aminosalicylic, etc. In conclusion, it should be understood that the compositions presented herein contain the compounds of the present invention in their non-ionized as well as zwitterionic form and combinations with stoichio

- 34 040588 metric quantities of water, as in hydrates.

Also included within the scope of the present invention are salts of the parent compounds with one or more amino acids, especially naturally occurring amino acids, found as protein components. Typically, an amino acid is an acid carrying a side chain with a basic or acidic group, such as lysine, arginine, or glutamic acid, or a neutral group, such as glycine, serine, threonine, alanine, isoleucine, or leucine.

The compounds of the present invention also include their physiologically acceptable salts. Examples of physiologically acceptable salts of the compounds of the present invention include salts derived from a suitable base, e.g. alkali metal (e.g. sodium), alkaline earth (e.g. magnesium), ammonium, and NX4+ (wherein X is C1- _C4 alkyl) . Physiologically acceptable salts of the hydrogen atom or amino group include salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids. Physiologically acceptable salts of a compound containing hydroxyl groups include the anion of said compound in combination with a suitable cation such as Na ⁺ and NX4 ⁺ (where X is typically independently selected from H or a C1-C4 alkyl group). However, salts of acids or bases that are not physiologically acceptable can also be used, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived from a physiologically acceptable acid or base, are within the scope of the present invention.

Preferred anions for the formation of pharmaceutically acceptable acid addition salts are acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate/diphosphate , polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, theoclate, triethiodide, and the like.

Preferred cations for the formation of pharmaceutically acceptable basic salts are benzathine, chlorprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, and the like; and those formed from metal cations such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and the like.

Used in the present description, and unless otherwise noted, the term enantiomer means each individual optically active form of the compounds of the present invention with an optical purity or enantiomeric excess (as determined by standard methods of the known art) of at least 80% (i.e. by at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98%.

As used herein, the term isomers means all possible isomeric forms, including tautomeric and stereochemical forms, that compounds of the formulas of the present invention may have, but not including positional isomers. Generally, the structures presented herein are examples of only one tautomeric or resonance form of the compounds, but corresponding alternative configurations are also contemplated. Unless otherwise noted, the chemical designation of compounds denotes a mixture of all possible stereochemical isomeric forms, said mixtures contain all diastereomers and enantiomers (as compounds of the formulas of the present invention may contain at least one chiral center) of the main molecular structure, as well as stereochemically pure or enriched compounds . More specifically, the stereogenic centers may be in either the R or S configuration, and the multiple bonds may be in either the cis or trans configuration.

Pure isomeric forms of these compounds are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure. In particular, the term stereoisomeric pure or chirally pure refers to compounds with a stereoisomeric excess of at least about 80% (i.e. at least 90% of one isomer and at most 10% of other possible isomers), preferably at least 90%, more preferably at least 94% and most preferably at least 97%. The terms enantiomerically pure and diastereomerically pure should be understood in a similar way, considering the enantiomeric excess, respectively, the diastereomeric excess, of the mixture in question.

The separation of stereoisomers was performed by standard methods known to those skilled in the art. One enantiomer of a compound of the present invention may be separated in a substantially free manner from its opposite enantiomer, such as dia

- 35 040588 stereomers using optically active resolving agents (Stereochemistry of Carbon Compounds, (1962) E.L. Eliel, McGraw Hill; Lochmuller, C.H., (1975) J. Chromatogr., 113:(3) 283-302). Separation of isomers in a mixture can be carried out by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of diastereomers and conversion to pure enantiomers , or (3) enantiomers can be separated directly under chiral conditions. In method (1), diastereomeric salts can be formed by reacting enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a-methyl-b-phenylethylamine (amphetamine) and the like with asymmetric compounds bearing acidic functional groups such as carboxylic acid and sulfonic acid. Diastereomeric salts can be provoked to separation by fractional crystallization or ion chromatography. To separate the optical isomers of amino compounds, the addition of chiral carboxylic or sulfonic acids such as camphorsulfonic acid, tartaric acid, mandelic acid or lactic acid can lead to the formation of diastereomeric salts. Alternatively, by method (2), the cleavable substrate may be reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel E. and Wilen S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., p. 322). Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents such as mental derivatives, followed by separation of diastereomers and hydrolysis to give free, enantiomerically enriched xanthene. A method for determining optical purity involves the formation of chiral esters such as a menthyl ester or a Mosher ester, a-methoxy-a-(trifluoromethyl)phenylacetate (Jacob III. (1982) J. Org. Chem. 47:4165), racemic mixture and analysis of the NMR spectrum for the presence of two atropisomeric diastereomers. Stable diastereomers can be separated and isolated by normal- and reverse-phase chromatography, followed by separation methods for atropisomeric naphthylisoquinolines (Noye T., WO 96/15111). In method (3), a racemic mixture of two asymmetric enantiomers was separated by chromatography using a chiral stationary phase. Suitable chiral stationary phases are, for example, polysaccharides, in particular cellulose or amylose derivatives. Commercially available chiral polysaccharide stationary phases are ChiralCeI™ CA, OA, OB5, OC5, OD, OF, OG, OJ and OK and Chiralpak™ AD, AS, OP(+) and OT(+). Appropriate eluents or mobile phases for use in combination with said polysaccharide chiral stationary phases are hexane and the like modified with an alcohol such as ethanol, isopropanol and the like. (Chiral Liquid Chromatography (1989) W.J. Lough, Ed. Chapman and Hall, New York; Okamoto, (1990) Optical resolution of dihydropyridine enantiomers by High-performance liquid chromatography using phenylcarbamates of polysaccharides as a chiral stationary phase, J. of Chromatogr. 513:375-378).

The terms cis- and trans- are used herein according to Chemical Abstract Service nomenclature and include reference to the positions of substituents on the ring moiety. The absolute stereochemical configuration of the compounds of formula (1) can be readily determined by those skilled in the art using well-known methods such as, for example, X-ray diffraction.

The compounds of the present invention may be formulated with conventional carriers and excipients, which may be selected according to standard practice. Tablets will contain excipients, glidants, fillers, binders, and the like. Aqueous formulations are prepared in sterile form, and if intended to be delivered by a route other than oral administration, they will generally be isotonic. The formulations optionally contain excipients as set forth in the Handbook of Pharmaceutical Excipients (1986) and include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, and the like.

Further, as used in the present invention, the term pharmaceutically acceptable carrier means any material or substance with which an active ingredient is formulated for the purpose of facilitating its application or distribution to the locus being treated, for example, by dissolving, dispersing or dispersing said composition, and/or for the purpose of facilitate its storage, transport or handling without compromising its effectiveness. The pharmaceutically acceptable carrier may be in solid form, or in liquid form, or in gaseous form which has been compressed to form a liquid, i.e. the compositions of the present invention may suitably be used as concentrates, emulsions, solutions, granulates, dusts, sprays, aerosols, suspensions, ointments, creams, tablets, pellets or powders.

Suitable pharmaceutical carriers for use in certain pharmaceutical compositions and formulations thereof are well known to those skilled in the art and there is no particular limitation as to their choice within the scope of the present invention. Also they

- 36 040588 may include additives such as wetting agents, dispersants, adhesives, adhesives, emulsifiers, solvents, coatings, antibacterial and antifungal agents (eg phenol, sorbic acid, chlorobutanol), isotonic agents (such as sugars or chloride sodium), etc., provided that they are in accordance with pharmaceutical practice, i.e. carriers and additives that do not cause irreversible damage to mammals. Pharmaceutical compositions of the present invention may be prepared by any known method, for example, uniform mixing, coating and/or milling of the active ingredients in one or more step procedures with the carrier material of choice and, if necessary, with other additives such as surface active agents. They can also be obtained by micronization, for example, in order to obtain them in the form of microspheres, usually characterized by a diameter of from about 1 to 10 gm, namely for the manufacture of microcapsules for controlled or delayed release of active ingredients.

Used in the pharmaceutical compositions of the present invention, suitable surface active agents, also known as emulsifier or emulsifier, are non-ionic, cationic and/or anionic substances with good emulsifying, dispersing and/or wetting properties. Suitable anionic surfactants include both water-soluble soaps and water-soluble synthetic surfactants. Suitable soaps are alkali or alkaline earth metal salts, unsubstituted or substituted ammonium salts of higher fatty acids (C ₁₀ -C ₂₂ ), such as sodium or potassium salts of oleic or stearic acid, or natural fatty acid mixtures derived from coconut oil or tall oil. Synthetic surfactants include sodium or calcium salts of polyacrylic acids; fatty acid sulfonates and sulfates; derivatives of sulfonated benzimidazoles and alkylarylsulfonates. Fatty acid sulfonates or sulfates are generally in the form of alkali or alkaline earth metal salts, unsubstituted ammonium salts or ammonium salts substituted with a C8-C22 alkyl or acyl radical, for example the sodium or calcium salt of lignosulfonic acid or dodecylsulfonic acid, or a mixture of an alcohol derived from natural fatty acids, alkali or alkaline earth metal salts of sulfuric or sulfonic acid esters (eg sodium lauryl sulfate) and sulfonic acids of fatty alcohol/ethylene oxide adducts. Suitable sulfonated benzimidazole derivatives preferably contain 8-22 carbon atoms. Examples of alkylarylsulfonates are the sodium, calcium or amino alcohol salts of dodecylbenzenesulfonic acid or dibutylnaphthalenesulfonic acid or the naphthalenesulfonic acid/formaldehyde condensate. Also suitable are the corresponding phosphates, for example phosphoric acid ester salts and the adduct of para-nonylphenol with ethylene and/or propylene oxide, or phospholipids. Suitable phospholipids for this purpose are natural (derived from animal or plant cells) or synthetic phospholipids of the cephalin or lecithin type, such as, for example, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, lysolecithin, cardiolipin, dioctanylphosphatidylcholine, dipalmitoylphosphatidylcholine and mixtures thereof.

Suitable nonionic surfactants include polyethoxylated and polypropoxylated derivatives of alkylphenols, fatty alcohols, fatty acids, aliphatic amines or amides containing at least 12 carbon atoms per molecule, alkylarenesulfonates and dialkylsulfosuccinates such as polyglycol ether derivatives of aliphatic and cycloaliphatic alcohols, saturated and unsaturated fatty acids and alkylphenols, and these derivatives preferably contain 3-10 glycol ether groups and 8-20 carbon atoms in the (aliphatic) hydrocarbon fragment and 6-18 carbon atoms in the alkyl fragment of the alkylphenol. Additional suitable non-ionic surfactants are water-soluble adducts of polyethylene oxide with polypropylene glycol, ethylenediaminopolypropylene glycol containing from 1 to 10 carbon atoms in the alkyl chain, the adducts of which contain from 20 to 250 ethylene glycol ether groups and/or from 10 to 100 propylene glycol ether groups. . Typically, such compounds contain from 1 to 5 ethylene glycol units per unit of propylene glycol. Typical examples of nonionic surfactants are nonylphenol polyethoxyethanol, castor oil polycolic esters, polypropylene/polyethylene oxide adducts, tributylphenoxypolyethoxyethanol, polyethylene glycol and octylphenoxypolyethoxyethanol.

Polyethylene sorbitan fatty acid esters (such as polyoxyethylene sorbitan trioleate), glycerin, sorbitan, sucrose, and pentaerythritol are also suitable non-ionic surfactants.

Suitable cationic surfactants include quaternary ammonium salts, in particular halides containing 4 hydrocarbon radicals optionally substituted with halogen, phenyl, substituted phenyl or hydroxy; for example, quaternary ammonium salts containing at least one C8-C22 alkyl radical as an N-substituent (for example, cetyl, lauryl, palmityl, myristyl, oleyl, etc.) and, as additional substituents, unsubstituted nye or halogenated lower alkyl, benzyl and/or hydroxy-lower alkyl radicals.

A more detailed description of surface active agents suitable for this purpose can be found, for example, in McCutcheon's Detergents and Emulsifiers Annual (MC Publishing Crop., Ridgewood, New Jersey, 1981), Tensid-Taschenbucw, 2d ed. (Hanser Verlag, Vienna, 1981) and Encyclopaedia of

Surfactants, (Chemical Publishing Co., New York, 1981).

The compounds of the present invention and their physiologically acceptable salts (hereinafter collectively referred to as active ingredients) may be administered by any route suitable for the condition being treated, suitable routes include oral, rectal, nasal, topical (including ophthalmic, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural). The preferred route of administration may vary with, for example, the condition of the recipient.

While it is possible for the active ingredients to be administered separately, it is preferable to provide them as pharmaceutical formulations. The compositions for both veterinary and human use of the present invention contain at least one active ingredient as described above, together with one or more pharmaceutically acceptable carriers, respectively, and optionally other therapeutic ingredients. The carrier(s) is(are) optionally acceptable(s) in the sense that they are compatible(s) with the other ingredients of the formulation and not harmful to their recipient. The compositions contain carriers which are suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, formulations are prepared by uniformly and directly bringing into association the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product.

Formulations of the present invention which are suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; in the form of powder or granules; as a solution or suspension in an aqueous liquid or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be present as a bolus, electuary or paste.

The tablet may be obtained by crushing or compressing, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable device the active ingredient in free-flowing form, for example powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersing agent. Compressed tablets may be prepared by compressing in a suitable apparatus a mixture of a powdered compound moistened with an inert liquid diluent. Tablets may optionally be coated or roughened, and may be formulated to provide slow or controlled release of the active ingredient therein. For eye infections or infections of other external tissues, such as the mouth and skin, the formulations are optionally applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, from 0.075 to 20% w/w. (including active ingredient(s) ranging from 0.1 and 20% in 0.1% w/w increments, e.g. 0.6% w/w, 0.7% w/w . etc.), preferably from 0.2 to 15% wt./wt. and most preferably 0.5 to 10% w/w. When formulated as an ointment, the active ingredients can be used with either a paraffinic or water-miscible ointment base. Alternatively, the active ingredients may be formulated as a cream with an oil-in-water cream base. If necessary, the aqueous phase of the cream base may include, for example, at least 30% wt./wt. polyhydric alcohol, i.e. alcohol with two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerin and polyethylene glycol (including PEG400) and mixtures thereof. Topical formulations may desirably include a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs.

The oil phase of the emulsions of the present invention may be formulated from known ingredients in a known manner. While the phase may contain only an emulsifier (otherwise known as an emulsifier), it is desirable to contain a mixture of at least one emulsifier with fat or oil, or with fat and oil. Optionally, a hydrophilic emulsifier is included with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both oil and fat. Together, the emulsifier(s), with or without stabilizer(s), constitute the so-called emulsifying wax, and the wax, together with oil and fat, constitute the so-called emulsifying ointment base, which forms the oily dispersed phase of cream formulations.

The selection of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most of the oils likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream need not be a non-greasy, non-staining, rinse-off product of suitable consistency to avoid leakage from tubes or other containers. Straight or branched mono or dibasic alkyl esters such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut oil fatty acids, isopropyl myristate, decyloleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a mixture of branched chain esters known in the art can be used. like Crodamol CAP, the last three were the preferred esters. They can be used singly or in combination depending on the desired properties. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical application to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is optionally present in such compositions at a concentration of from about 0.5 to 20%, preferably from 0.5 to 10%, in particular about 1.5% w/w. Formulations suitable for topical use in the mouth include lozenges containing the active ingredient in a flavored base, typically sucrose and gum arabic or gum tragacanth; lozenges containing the active ingredient in an inert base such as gelatin and glycerin, or sucrose and gum arabic; and mouthwashes containing the active ingredient in a suitable liquid carrier.

Compositions for rectal administration may be presented as a suppository with a suitable base containing, for example, cocoa butter or salicylate. Formulations suitable for nasal administration when the carrier is a solid include a coarse powder with a particle size, for example, in the range of 20 to 500 µm (including a particle size in the range of 20 to 500 µm in 5 µm increments, for example 30 , 35 µm, etc.), which were administered in a manner that used inhalation, for example, by rapid inhalation through the nasal passage from a powder container held close to the nose. Suitable formulations, wherein the carrier is a liquid, for administration as, for example, a nasal spray or nasal drops, include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol administration may be prepared by conventional means and may be delivered with other therapeutic agents.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing, in addition to the active ingredient, such carriers as are known in the art to be suitable.

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, bacteriostats, and liquid phases that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickeners. Formulations may be presented in single-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored under a freeze-drying (lyophilization) condition that requires only the addition of a sterile liquid carrier, such as water for injection, immediately prior to use. Non-injectable solutions and suspensions can be prepared from sterile powders, granules and tablets of the kind previously described.

Preferred dosage units are those containing the daily dose or daily sub-dose unit as described above, or a suitable fraction thereof, of the active ingredient.

It should be understood that, in addition to the ingredients specifically mentioned above, the formulations of the present invention may include other agents conventional in the art, taking into account the type of formulation in question, for example, those suitable for oral administration may include flavorings.

The compounds of the present invention can be used to prepare pharmaceutical controlled release formulations containing as an active ingredient one or more compounds of the present invention (controlled release formulations) in which the release of the active ingredient can be controlled and controlled to allow less frequent dosing or to improve pharmacokinetics. profile or toxicity profile of the compound of the present invention. Controlled release formulations adapted for oral administration, in which discrete units contain one or more compounds of the present invention, can be prepared by conventional methods.

Additional ingredients may be included to control the duration of action of the active ingredient in the composition. Thus, controlled release compositions

- 39 040588 can be obtained by selecting suitable polymeric carriers such as, for example, polyesters of polyamic acids, polyvinylpyrrolidone, copolymers of ethylene and vinyl acetate, methylcellulose, carboxymethylcellulose, protamine sulfate, and the like. The drug release rate and duration of action can also be controlled by incorporating active ingredient, eg microcapsules, polymeric material such as hydrogels, polylactic acid, hydroxymethyl cellulose, polymethyl methacrylate and other polymers described above into the particles. Such methods include colloidal drug delivery systems such as liposomes, microspheres, microemulsions, nanoparticles, nanocapsules, and the like. Protective coatings may be necessary depending on the route of administration of the pharmaceutical composition. Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for their non-intended preparation. Thus, typical carriers for this purpose include biocompatible aqueous buffers, ethanol, glycerol, propylene glycol, polyethylene glycol, and the like, and mixtures thereof.

Given that if several active ingredients are used in combination they do not necessarily produce their combined therapeutic effect directly at the same time in the mammal being treated, the appropriate composition may also be in the form of a medical kit or pack containing the two ingredients separately, but adjacent storage areas or compartments. Thus, according to the latter context, each active ingredient may be formulated in some way suitable for the route of administration which is different for the other ingredient, for example, one of them may be in the form of an oral or parenteral formulation, while the other is in the form of an intravenous ampoule. injection or aerosol.

Compounds of the present invention are optionally covalently bonded to an insoluble matrix and are useful for affinity chromatography (separations depending on the nature of the compound groups, e.g. aryl pendant compounds are useful in hydrophobic affinity chromatography separations.

The compounds of the present invention can be prepared using a number of chemical reactions well known to those skilled in the art, totaling the process for preparing said compounds, and they are presented below. The additionally described methods are intended as examples only and are not intended to limit the scope of the present invention.

Compounds of the present invention can be obtained according to the general procedure presented in the following schemes.

Scheme 1

Scheme 1: all B, R ¹ , R ² , X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ , X ⁹ , X ¹⁰ , p, q and LG are the same, as described for the compounds of the present invention and its embodiments and formulas.

Derivatives of general formula 1 (commercially available or synthesized by procedures known to those skilled in the art) can react with intermediates of formula 2 (commercially available or synthesized by procedures known to those skilled in the art) wherein LG is independently selected from chlorine, bromine, and iodine (more preferably chlorine) in an aprotic solvent (eg toluene, dichloromethane, dichloroethane, etc.) at a temperature raised from 0 to 100° C. to give intermediates of formula 3. In the case of X ¹⁰ = C or CH, a catalyst may be required (eg AlCl ₃ , Et ₂ AlCl, ZrCl ₄ etc.) or a base (eg pyridine, DBN, DMAP etc.). More information can be found in the following references: Tetrahedron 29, 971-976, 1973; Org. Lett., Vol. 12, no. 24, 2010; J. Org. Chem. 2011, 76, 4753-4758. In the case of X ¹⁰ =N, compounds of formula 1 can be converted to compounds of formula 3 by reacting with intermediates of formula 2 following standard amide coupling conditions. The leaving group (LG) from formula 3 intermediates can be displaced with amines of formula R1R2NH (commercially available or synthesized) following procedures known to those skilled in the art or as set forth in the examples below to give the desired compounds of formula 4.

Alternatively, the compounds of the present invention can also be obtained according to the general procedure presented in the following scheme.

- 40 040588

Scheme 2

Scheme 2: all B, R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ , X ⁹ , X ¹⁰ , p and q are the same as described for compounds according to the present invention and its embodiments and formulas.

Aldehydes of general formula 5 can be reacted with amines of formula R1NH2 to give imines of general formula 6 which can be reacted with intermediates of formula 7 (commercially available or synthesized by procedures known to those skilled in the art or as set forth in the examples below), where X ¹⁰ represents represents a carbon atom, in the presence of a catalyst such as 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-th chloride, to give the desired compounds of formula 8. More details can be found in Chem. Commun., 2007, 852-854.

According to another embodiment, the compounds of the present invention can also be synthesized according to the general procedure outlined in the following scheme.

Scheme 3

Scheme 3: all B, R ¹ , R ² , X ¹ , X 2 , X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ , X ⁹ , ^{X 10 ,} p, q and LG are the same, as described for the compounds of the present invention and its embodiments and formulas.

Derivatives of general formula 1, where X ¹⁰ is selected only from C or CH (commercially available or synthesized by procedures known to specialists in this field of technology), can interact with intermediate compounds of formula 11 (commercially available or synthesized by procedures known to specialists in this field of technology), where LG is a leaving group such as chlorine, bromine and iodine under Friedel-Crafts conditions to give formula 10 intermediates. Weinreb amide) as known to those skilled in the art. These formula 10 intermediates can be converted to formula 3 intermediates wherein LG is a halogen such as chlorine, bromine, or iodine following reactions known to those skilled in the art or as set forth in the examples below. Formula 10 intermediates where B is selected from aryl or heteroaryl only can be prepared by α-arylation of a formula 12 ketone with haloaryl or haloheteroaryl in the presence of a catalyst (e.g., Pd ₂ dba ₃ , Pd(OAc) ₂ , Pd(dba), etc.). .p.), a ligand (eg BINAP, Xantphos, PtBu ₃ etc.) and a base (eg NaOtBu, K ₃ PO ₄ etc.). More information can be found at the following links: J. Am. Chem. soc. 1997, 11108-11109 and J. Am. Chem. soc. 1999, 1473-1478. Al- 41 040588 Alternatively, formula 9 intermediates can also be prepared from aldehydes of formula

7, where X ¹⁰ is selected only from C or CH, and reagents of general formula 8, where M is Li or

MgCl or MgBr, after an oxidation reaction known to those skilled in the art. Compounds of interest with general formula 4 can be prepared from intermediates 3 as described in Scheme 1.

The following are abbreviations used in the description, in particular in the diagrams and examples: BOC - tert-butyloxycarbonyl;

DBU - 1,8-diazabicyclo[5.4.0]undec-7-ene;

DBN - 1,5-diazabicyclo[4.3.0]non-5-ene;

DIPEA - diisopropylethylamine;

DMAP - 4-dimethylaminopyridine;

DMF - N,N-dimethylformamide;

DMSO - dimethyl sulfoxide;

e.i. - enantiomeric excess;

equiv. - equivalent;

h - hour;

HATU - O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate;

HPLC - high performance liquid chromatography;

min - minutes;

NMP - N-methyl-2-pyrrolidone;

TBDMSCl - tert-butyldimethylchlorosilane;

THF - tetrahydrofuran;

TLC - thin layer chromatography;

t _r - retention time.

Examples

The following examples are provided for the purpose of illustrating the present invention and should in no way be interpreted as limiting the scope of the present invention.

Part A is the preparation of compounds (intermediates and finished compounds), while part B is pharmacological examples.

- 42 040588

Table 1 Compound Structures of Examples of the Invention and Their Corresponding Codes

Code Structure Code Structure Code Structure CPD-001 ABOUT o G nJ L^A-ome L N jJ ρ |Γ> OMe n CPD-011 Su Alu° T| CPD-021 \ ° . ^s -'o o J ί jT y ome CPD-002 y) OME I | G y OMe CPD-012 Vj ^0We O ) |J\ ^N nJ x'BH n ^A || G u__ OME vJ hl CPD-022 O ^N 'C _L / ⁴ Ν-ΧΧ ΓΎλ ^η hi CPD-003 LJJ A CPD-013 Su ΓΙ A/o ο Ξ° Φ CPD-023 α 0 / r-<4 |jJj ^Η OMe x Jn Η CPD 004 GL _L / NJ ί Il T y OMe huM n CPD 014 Ο Λ' 0 J f^\ ^χ.^/ ^4Ν nJ 1 J7 o ^Mg hl CPD 024 V ^s Μ ΛΑ / Ν JJ ΙίητΑ ¹⁴ ome Η CPD-005 o O rfx _A NJJ z\J n ^Ά. || G ? o°^ Η CPD-015 0 ^f °\ JJ\ [| U OMe H CPD-025 Λθ Jn CH-Q H ome Ν Η CPD-006 O O /==\ _L ml J ί G? ^C1 H CPD-016 O ⁰ AChg-A h ί T> χ.ί^Ν H CPD-026 Su । \ Ζ £ A' S f CPD-007 eff UL CPD-017 O ⁰ / r=^ / N _L / nA a o3 ⁿ hl CPD-027 J ^s about G || jTJ OMe Η CPD-008 O J CPD-018 O 0 AA ^x_(^ ^N AJ || Jj ^Z OMe hl CPD-028 He <\ Г ||YJ ^h ОМe x^N Η CPD-009 O O rfk _L J rv> ^{n cRz} AJ' N N CPD-019 ⁿ JQ AA η ν—\ || G X OMe hl CPD-029 'Ν Ά 0 / ΐ=\ yAd || ^0Μθ H CPD-010 O O ^m vj ^N OMe nJ N CPD-020 About J || | y OMe J- _Ί rt CPD-030 o jXq Η Ά | Gu ome ⁴ ' Jrj H

- 43 040588

Code Structure Code Structure Code Structure CPD-031 ABOUT 0 VA/n [ |G he H CPD-041 O'™ v€q Il G OMe H CPD-051 oS^O' h CPD-D32 O ID O H CPD-D42 ⁿ 'N ^x || | at ^OMe Oi^N H CPD D52 o 0 ) rf, Tn -LE ^H 0 W CPD D33 O ABOUT SgG'L H CPD D43 NH y O O >—X _l nQ Γ| Γ'7OMe CPD D53 ch ? wop । / n-U ί And [U ome y^^N H CPD-034 Oh oh co H CPD-044 Ο gPg > ^η Ο -'^Ν Ο ⁴ Η CPD-054 U o gl / nAJ ouu ^N OMe ΓίΑ-Ν N CPD-035 ABOUT 0, J? l=^ Г if 7 CM Ol Η CPD-045 Ο 0 / V—\ / Ν _Λ / Ν^\„ ft to I [V> OMe Η CPD-D55 OMv O^N 0 / r—\ [fOMe O^N H CPD-036 CN fS 0 J .^. ^14'nU ? if])) H OMe O- N H CPD-046 ο 0 _s / ^00 yOO r o Η CPD-05S O 0,) /=\ . n-4j ,ί,^ι n ^-Α 017 ohm® CPD-037 Nt*\ -J O' ⁴ 0 _v ) N'F Г |T x> OMe Oyj H CPD-047 N==\^ Q) AND ABOUT No. G/ ^OMe CPD-057 Ο °ν° /=He. ji P ⁿ n CPD-038 ^ν Ά· _/ r^rA. ^H /— PJ / MeO NH CPD-048 N^\ f N ABOUT O-Q || Ίρ y Οί^Ν Η CPD-058 o _l jOQ eh? ^{n rJ} n H ^Ν <1Ζ ^Ν CPD-039 ΐ OMe 4¾ |Ι .χ 2 MeO H CPD-049 V? uh g f CPD-D59 oS^O Η Ν CPD-D4D O 0 ) rf, O Z ri Y^X I A / OM II^JL, / MeO H CPD-D5D [I G y Os^N Η CPD-060 Oh 'C ⁿ n ome

- 44 040588

Code Structure Code Structure Code Structure CPD-061 CN ABOUT 0A, V4J? N Il ome H CPD-071 ώ^4™ Η CPD-081 4> Ξ O CPD-062 pl H CPD-072 O O / Ν=Ν ΆΛ / n _ / nW ti || |A OM UCH H CPD-082 A V,N °u π _j ΐΓ^ΓΑ ^h ome matin' H CPD-063 he f' N VJ o / CHN-O ^H OMe Η CPD-073 o 0 / a-ch j 'n _l / na y || G A OMe CI-'^Ai^N CPD-083 A nM M AmQ ZA4 h ^^=А || | ome H CPD-064 p νΆ / ν [| Tae ome CPD-074 A yA Il G A O Me N H CPD-084 CP A _l / NA J || TA OMe V^N T h 01 CPD-065 O^H Η CPD-075 “Ar-fl TA OMe c^.G'- N ^r H CPD-085 O AAq n |i T \> ome MaO'JL^Af/ if H 0 CPD-066 o 0 N=N ^N '\ 4 [l Г OMe Η CPD-076 rs mA _l Г nA y iWAy'A h N Г \> OMe MaO'Aj^h CPD-086 o _cl ^AyQ OMe H CPD-067 cf ^ιζ ΑΟ GL U ζ s It \ CPD-077 About 0. / ACH-g-A h n | ome MaO'^Aji^rj CPD-087 X-ss/ ^OMe o. jn=4 VA / n 4 ^N KhmD || ^0MexAn H CPD-068 Sr^H H CPD-078 cs MeO ^^4 n \^H P P? ome H CPD-088 MF ΝΆ Cm o G [| T> ^h 0Me Η CPD-069 p \,N O G UCH / n _ / nA o il Tv OMe Cl-^N CPD-079 About %-ΑΑ ^ν P | w ome MaO.LD/ T h 0 CPD-089 o %^-Ζ ^Ν=ί \ _Λ / nA J αΑ-τ-Α η ν Ά ί ] ΟΜβ Η CPD-070 O ^{N s} /4:4^HN O Me ί H CPD-08D Z^o V o / ^N CZ? ιΑΑ'Ά h JI 1 y Ome Αί^Ν H CPD-090 F Ο o g-a uCh Γ Ν J ^Ν \^4 1 ^0Me 44^ Ν Η

- 45 040588

Code Structure Code Structure Code Structure CPD-091 F θ Wow J? N i| ome CPD-101 HA y A J ^Ν χίΛ ί^ΓΛ ^H ^OMe AjsA'N T h Cl CPD-111 O 0 IlTz ^{H 0Me} Κί^-Ν oA 0 CPD-092 A MeO h '^ _s J| ΎΑOMe AiA^ N H CPD-102 N 0 JJ . N't) Г^т-Л H A || | at OMe Wa 4 H CPD-112 / ABOUT ABOUT _ M'ChhU Α4νΛ n ^Ά [I tou ome A? Am Η CPD-093 y Un _A / nA , АУ-A Η ί 1 OMe NcAA N CPD-103 y 0 . N-O FROM? OM® ^-4H CPD-113 ο <\ / f=^\ Y^ ^Ν χ^Λ l^jAy ^Η ^ΌΜθ OEt CPD-094 ABOUT Oh G /A-A/ gLg-L. H -4 Il Г at OMe nA^n CPD-104 c 0 ₄ ff^\ ^N Ax-A i^ lT^y ^H ° ^Me Λ' N ^bn CPD-114 Ο o Y Λ ⁵ ^, Ν-^Λ Γ|ΓΛ. ^Η °Me ΑχΑ|/ / CFD 095 N У yA JT m /AL η al 1] I у OMe AA^N CFD 105 c °4 f r^jpy ^H OMe H>x-^K nh ₂ CPD 115 Q νΔ 7 Η 'sx^oMe Λθ Α° CPD-096 0 Vn O J ^s, A>i ||^Ay ¹⁴ OMe H CFD-100 o 0 (j -sl C|G> ^H OMe ^Y ⁰ OH CPD-116 ο^Λ V °>Α/l nA< ί '1 Y OMe _C |xO-H CPD-097 ^NH ABOUT o G UL/N χ-χ. J[| jy-ome A^N H CPD-107 \ % I 0 x= _x ACH^L H'^A [| Woo ome n CPD-117 ο^χ ^H L AW y 1 y OMe Aj^N CPD-098 b at N [| G A OM H CPD-108 \siN O G x-sy UL / N / nA if i^<rA ^H ^A Π T Y OMe AsA-m n CPD-118 A AMA 7 nA Λ iAAr-Α h 0 I y ^0Μβ CI^A^h CPD-099 rs vOy CL xs. L Y ) T\) OMe LA _H CFD-109 ^F xA ^ν Ά y 0 Г x->Y^ ^{4 N} aJ i| ^y ^H _0Me AsA^M n CPD-119 A AAL F.x--^Z N Ay y jy OMe Αΐ-μ H CPD-100 ΓΑ “Lla / ^N Λ ||TL ^AND OMe Α/Ά CPD-110 o Г N'Aj γ^4ί-A ^h ^-a || Г y OMe AsA^NH CPD-120 Chi o o / rA.. x^J^N 'C? [| yA> OMe A/A _n T n Cl

- 46 040588

Code Structure Code Structure Code Structure CPD-121 O ⁰ \ / N l n-Aw ifjy ome Dd^I S*o 0 > CPD-131 A> *?dd SA Oh ha Ξ η CPD-141 O 0 _ 'y'N'aJ dA^-A n ^A Π Τ A OMe ^no ^ _o AAd ^U Η CPD 122 O ..4 hDa 7 | G7, OMe CPD 132 GN Dd “L I^PCA ^and ome YES n CPD 142 A T1D ⁿ om. Dd^m H CPD-123 ABOUT °h / /==\ ^Yes ^D p ipA ome A% CPD-133 dd YES ⁰ tg L zLn Ξ 4 CPD-143 A a>VQ ^HO ^|^TD) ^H °Me Dg^b H CPD-124 / < ^N o O. ^ r A*\ PPP yTR) ^H OMe DdD/ n CPD-134 ABOUT 0 ) . vα? AA n ^-A t| [ D OME CPD-144 ^p DD °\-D AD . /n-4x? Α4νΆ n A Π [ 7 OMe Dd^n n CPD 125 4/ ' \ ° IZ λΧ # AdD ² & S * \ CPD 135 O O) rf=\ _ K|DD _D 1-^Th-A n P G OMe HOOC'^^^N CPD 145 O 0 Ίζ ^0Me Dd^s ? o ( 0 / CPD-126 O C,D no l .τ' and Al. D| J D OMe D;-N H CPD-136 dd y-dd ₍ ^: ° « \ D^gl 0 O £ Cfr CPD-146 o ⁰ A\ ^N 'A_? E|Td> OMe Dd^D ? He CPD 127 BUT ABOUT 0 ) 1| Dd^n n CPD 137 About F.l. J, ^H OMe D>^M V CPD 147 \3 OMe o Χι ||Jy ^H OMe Dd^n r 0 < 0 / CPD-128 f Ξ O %A \_J CPD-138 O r^\ ¹⁴ || [D OMe Dd ^ n CPD-148 D_D °Me ⁰ X/ /^\ ^ν Ά^Χ |AA ^{H 0Me} Dd^u ? He CPD-129 about 1 about / J d p-S AAA H'^A o u [A ome Dd^s n CPD-139 O n'd^D 1| OME Dd^m n CFD-149 F θ 0 Xf Α%-Α ⁿ A Η [A OMe Dd^y n CPD-130 o _l ^DD ΆΑ n ^^A T [A ome Dd^m n CPD-140 about 0l^\ 7^ mH? /^sv-A n ^-A P G A OMe ^HO -^AAD n CPD-150 P VN o G ^d ⁴ yDd 1| Ar A OMe CI^A^N

- 47 040588

Code Structure Code Structure Code Structure CPD-151 C/ ^k 0 rfix F / ⁴ T j/ T| G x Ome WH CPD-161 A, H CPD-171 Oh oh CXn F-O CPD-152 ABOUT . N-Λ? P 7 OMe _F ^r H CPD-162 O 0 /Ή'-χ Α γ7, n U===\ UQ O n G Meo CPD-172 /A T-O' L O CPD-153 o . n4? z'^r-A h '-A P[ X OMa T H F CPD-163 ABOUT .-. 1 ΝΆ - TmCh ⁿ MeO-\=/ CPD-173 o °vD ^J TLp ⁰⁰ _l G ktt gAT \ n 'A G G \> OMe T-T CPD-154 OMe ζΤ 0 rfx F _l / ⁴ T / ^h '^A4rT n ''A Ί| T A OMe Ν Η CPD-164 f S o R CPD-174 tt / of o CPD-155 ΟΜβ γ\ ⁰ ΑΆ j Υ5 OMe ΤΙ F CPD-165 tt mgL ⁰ T- N N CPD-175 O TTO L O H CPD-156 \Ρ ome ⁰ 2 Ρ\ _F 7^ ^ν Ad ^Η OMe On J CPD-166 Oh oh A'Tv Ν T\ CO C} n OMe CPD-176 °^L R CPD-157 o o ^N . Ν-Λ? n ⁴ 'Ά P 7 A OMe P-TTn ^{r n} CPD-167 » o ^ϋ o ⁹ ' CPD-177 O °ρτρ° _l / N-\ J From? ⁿ n CPD-158 OMa O' ° V1 a ⁿ l Ν'Λ C || T V OMe n CPD-168 ^-Gu O x^'Tch / ^•n Ζ CPD-178 ijj o o o C ^g ο ^ζ ^\ VP CPD-159 CN O o jf ⁴ νΆτ Ρ jT OMe Η CPD-169 o o / N\ pL ⁴ o N \=*A N CPD-179 oA but CPD-160 0 °Λ ν</T η ^ CD Α'- Ν Η CPD-170 oll n \ CPD-180 OD? n

- 48 040588

Code Structure Code Structure Code Structure CPD-181 0 O Co ⁿ o n CPD-191 0¾ H CPD-201 About Ag-A ^{4 0Me} and CPD-182 ¢4¾ CPD-192 §δA <yyvy CPD-202 O 0 _/ l₽^\ xCo gM G || 0 Ome CPD-183 O O ΛΊ _ / N—\ 1 Co ^h H CPD-193 O 0 / MA j /hgA H [ι T/ome AA CPD-203 y_? .T £It- CPD-184 O O G G uA L fA / mA / So ⁿ N CPD-194 about AAO Il GO ome A- h CPD-2D4 about 0 || Gu$ ^Me ? NH °=< Ύ CPD-185 yo ^1'n CPD-195 O ΑΑ ,m 7 || J0 OMV n CPD-205 o mOp J ^N A^U A'jCy ⁿ ome F CPD-186 0 Г lX Н ν-Α π Am qT’^o^ Vh CPD-196 to A % CPD-206 OMe ° ^ua v/L FJ ^N AA. A i ^; j ^{H 4} ° ^M0 NH CPD-187 oac AVA ⁿ A ⁰ ί ί > ^s 0 NH ₂ n ^g CPD-197 U A CPD-207 ABOUT °vA / nA, J! H with L O Η CPD 188 νΑη r r > 4.--N H CPD 198 O ΟΓ-Q s''Ά And Tn ome C^- h n CPD 208 A AcAr AO ° M ° VA CPD 189 O o'j 00Ά H CPD 199 R ⁰ T f^=\ U-Ch. / N _ / O\ fj rG^rA ⁿ 1 [o ^0Mθ CPD 209 A , G \\ ^{gm 7} ° )—( ° VA CPD-190 Λ ^AA CXa ^t o^cr vy CPD-2D0 4 oCHO ¹ o ^=2 CPD-210 ί / OMe mA G h AjA CAA ^{n 0Me} AAn

- 49 040588

Code Structure Code Structure Code Structure CPD-211 ABOUT °PA P CPD-221 VVQ ^Η ϊ A ” UL n HCl CPD-231 O fj N'-yy ^{H ΟMβ} Η CPD 212 У yyy FJ ^N xL ^{h 0Me} UL^ ~-0 °L CPD 222 y °Zy rYy ^h om® G h OMe CPD 232 GL __U OMe ΛηΖ ίΐ Ίζ ^{Η 0Ua} CPD-213 OMe j ^N xL LUL. ^H θ ^Μβ pA/V ^h H CPD-223 U . llb ]j>| ^H ΟΜε \ CPD-233 CN CJ 0 ^Us ν<Л г ^ν ΆΑ ^Η ° ^Μβ hLi Η CPD 214 L V-f ppp about CPD 224 At CPD 234 \)OMe C ΛΛ ΟΜθ L-^s n CPD-215 Ny MaO'AL vZΖΛ G ^N LL. LUU ^H '°Ua UL^ CPD-225 ZvQ ίιΤζ ⁿ ° ^Ma -^M^H Ν n CPD-235 F e / ohm vzS J ^Ν Ά;Α. ^{n h} ° ^iv V^N H CPD-216 y st Λ ^Ν ' ^Λ \ίί=< UL^ ^r b CPD-226 o ^APP o o f CPD-236 Ν (< „ OMe °uL gLgl ^{n OMv} LLi n CPD-217 A LLL Lu> ^H om _e 4-Ά _h *o °CH CPD-227 'Ίι ° ^My ^gg^s ^N n CPD-237 RU Z—x -O CPD-218 O m 2TL ^H ^OUa H CPD-228 V °^Cr ^z yy Z ώ ⁴ 5 CPD-238 rum lll ΓιΤΛ ^{n Olule} n CPD-219 I about z? A s CPD-229 y ¹ V yy o. /<l/o CPD-239 NMe ₂ C ^ ^N °, d rx 1 ^N x ^ L ^N ome UL N N CPD-220 at 1 0 A A L JI . JnA# /UU ''U-L h U । T| NOM X, N \ CPD-230 A ^F Y Ί G N'-yy [Zr? ^{n 0Ma} CPD-240 OMe V ^m uGu G ^N xL. ^N OMv st N N

- 50 040588

Code Structure Code Structure Code Structure CPD-241 OMe C) / lL F ^N N-D ⁿ OMe NA/ H CPD-251 A V CPD-261 ABOUT ^2 oh Ar A Ξ and F I f CPD 242 OMe A^N AOA ^h om» pO'^N ^r Η CPD 252 AA is V _z ° o D CPD 262 Ah” o ⁿ * CPD-243 O. J /=^ Jc ⁿ o>a AVA ^H OMe H CFD-253 Ο P'No/ AA ^L || OM H CPD-263 FROM ⁴ CPD-244 ABOUT O 'j Η -Ά P G OMe '? CPD-254 \ 3 ^oei AA pjTA ^H Owe 4/^NH CPD-2G4 OMe C^ ^N °oo OL ^{n oma} \ CPD 245 n J ^H OMe ? He CPD 255 A) °X-OH Cl / g=A. ^N nA ^{h OMe} AAn H CPD 265 $ ) OMe V l At ⁿ ° ^m = \ CPD-246 w O 2 11 θ_3 ^χ O^C Y o CPD-256 O' A ¹ I CPD-266 l G ^Ν ν^α Pjp _N ^H om» MeO'>' CPD-247 A UGA ^m h^A. ί^νΑ ⁴ ^OiPr Η CPD-257 oh oh J ^N ' ^: VA ^{H OMe} ΑΑή H CPD-26? Us ViN ml? ^{n Olu,s} n CPD-248 A V lCh ^t ASr o CPD-258 o V< r ^N o^> ^ν Ά^α Г ΐΓζ ^H ' CPD-268 OiPr Λ^Ν S-^ °OjZ J ^Ν ΆίΑ Aur ⁿ Άωβ CPD 249 OME Aj VAQ 0a ⁿ ™' CPD 259 About o A s On ^{H om} \u003d AA'N CPD 269 θΟ= ATO o CPD 250 OEt C^ ^N °uA/L luA ⁿ ome ν ^ζ Η CPD 269 CN 0 °A /L G ^Ν x-A Prm ⁿ CPD 270 l _F /whisker YVn ⁿ ™ ^a H' N \

- 51 040588

Code Structure Code Structure Code Structure CPD-271 NHMe ° Η /b ⁿ OH0 Ν Η CPD-281 GL UL J ^N HpN ^{H 0Ua} CPD-291 OME Vj/ .°^on o. G N OJ? ⁿ ^ ^ohm n CPD-272 ΟΜβ And „ vr / e AL ⁿ ™ ^a Ch-N \ CPD-282 4- CPD-292 OME schn CPD-273 O \ ^ N m / l Pgch ^{n 0ME} H- k CPD-283 OMe 4' OQ ^{h OMe} CPD-293 o An Vu R ^Ma I II 2 ohm CPD-274 <4 “L Och ^° ^mv CPD-284 OMe C^ ^N h D rY\ ^H owe '4-- / CPD-294 ΟΜβ ΗOMe 4- CPD-275 η mTp '44 CPD-285 “Ж ,Χ” “ ^r H CPD-295 OMe Μ JX >< ^ίίΧ νΑ ^Η ΟΜβ Ch^ m Η CPD-276 O NJ 4 ULL [Hh ^{H oua} \ CPD-286 n γΓη fT ^NH ™° CPD-296 -Ж ^ρ χχ> ⁿ ™ ^a Η CPD-277 O CJ [ 7^n4 i ^HN ° ^m ® 4^- N H CPD-287 O %2r n4 i ^{HN 0Ms} _F ^r H CPD-297 OMe ό WQ ^H ΟΜβ ρ' Η CPD 278 Q r ^m 05" CPD 288 ome JU H CPD 298 O O\_on ChgCh γΥΛ ^0Me Ύΐ\ CPD 279 Γ ^Ν _l .. K it OMe v<rS m ^H ° ^ua \ CPD 289 o /4 ^OH Γ'Ύ^ί ^OMe H CPD 299 η 0 4 4 ρ] Ύ Г 1Γ2 ^0Μβ kA _H enantiomer 1 t _r = 6 7 min CPD-28D r\ ^{H N} QUe 4-N CPD-290 O _l r\D J r^bgch. ^{H ν} Ά IF ^0Me ^Ch-'A-m n CPD-30D G5 /R/ hD r |GA ^Om ® M- _th enantiomer 2 t _r = 12 1 min

- 52 040588

Code Structure Code Structure Code Structure CPD-301 4 ΗζΠ 99 CPD-311 °9 ¥N Cha Vi-Q om& chl^m^ And CPD-321 Q x^HH X' 0 I CPD-3D2 4=( o ¥ Q i CPD-312 o ^x OGO I xxx X' π CPD-322 OM a s. / g. "j Ν"Ά. -c ° ^Me HH ~ m n enantiomer 1 : _r = 9 7 min CPD 303 ¥ uso g over gogom ^{n 0Me} 44~ _N ? He CPD 313 So oG ^yMia n CPD 323 OM a x g h\ ₽ 9^ ^w Ή9 С |ГЧ ^0Me Ch-Chts n enantiomer 2 t _r = 12 5 min CPD 304 O °^0 L O ) psX '4 pLJ ^f r^Thm-4 ⁿ | 1 A OMe ¥> N CPD 314 CN 7 N OsJ Χ44\ ⁿ Chme 40^ N n CPD 324 О An V ^N GO [Γθ> ^0Me enantiomer 1 t _r = 9 3 min CPD-305 (J “'Von Οχ / 1^\ ^N Hd, Ch|GF> ^H OMe Ch-Ch N \ CPD-315 CF ^, Ui Co ¹ V 'GD G CPD-325 Oh An \*N .ΖηΌ. ⁿ ome Ch^h ν n (Enantiomer 2 |t _r = 12 9 min CPD-306 o9h. CPD-316 g o? 1"X Ο-? ^ξι O' CPD-32G // / Ome J "44 Hit? ^{n 0Μβ} H.Chm n enantiomer 1 t _r = 8 1 min CPD 307 Q/ ouch. A CPD 317 O CPD 327 U / OMe ds pCh^Chh ^H OMe 44-1/ n enantiomer 2 t _r = 17 9 min CPD 308 3.9-0, V^N^^OMe SO CPD 318 Cl g ™ vCq Po ⁴ ™ ^e 4Ο^Ν 1 ⁿ CPD 328 aCh °' ^ί μ9 ^Ι o CPD 309 ¥ Xx AJ CPD 319 ί / OMe J ^M \s=4 ^{4 0M8} 40 Ν N CPD 329 Π 4v r<r4 η ¥ I II at OME 1 H CPD-310 OMe O\^N °O year Τ ^N '4 _S J HHH' ^N Chma 44*Ή n CPD-320 Oh Oh Cha Ch-Chi n CPD-330 4 1 12 ° Vj ο

- 53 040588

Code Structure Code Structure Code Structure CPD 331 Ον Γ ^HOMe Η CPD 341 F e / OMa vxS J ^N / ^H / N I ^H CPD 351 S / OMe VrS J ^N Χίί=\ H OMa H ΟΡΟ 332 OMe XUQ /^'|/Y> QMa T ^H CPD 342 V ⁷ ?^O / ⁰ f^\ rXJ || [ X ome /?y CPD 352 ί J ^0Me but °,j 1 n /УУ ^h ° ^Ms X'4 H CPD-333 F О r ^m €) / ,^X J/ ^h Hell _: ^H OMe H CPD-343 ^N yj/ ^xch ^O v / Г^Х ^H OMa H CPD-353 I o'C? //-o o CPD 334 J/” F. J PI *—N X—X ^M O ^Ma NH CPD 344 s I US L=1 1 iyy CPD 354 -GU ?^Vc 7 o F /Mu ^H ux%t-Ch H ^-. Il I 7 ^{0 Me} H CPD-335 OMe Cjf ^N ° ^ua UG Λ U]// ^H OMa '4-· Ν Η CPD-345 ii / OMe vQ5 j ⁴ x=X YY'y ^H fJOM® H CPD-355 O °^OH 0./^ /=*U _F Jt* r TS ^H ° ^Μ6 X-.Un' H CPD 336 Ο Λ ^ν Cn 0 Γ pjys ^{Η Ume} 4^Ν Η CPD 346 N u OMa v+rS J ^{N H 4} ° ^Me 4' NH CPD 356 °y/ry ^F J ^Ν NsX YU / ^H ° ^Me H CPD-337 P / OMe vuS j ^N AL ^H ° ^Me 'X^N T ^H CFD-347 ) OMe Ayi/ ^Chm U' H CPD-357 ^HO x, C 7 OMe \ Hn 1 JN ' ^J Xs=Z ^{H 0We} v4 H CPD-338 4 / OMe YU / ^H ohm CPD-348 // °pY/ ⁴ ^OMa 4-· N H CPD-358 \X OMe r$ >4^7^ ^'xU Γ^ΐΓ ^- ^ ^H Vx JA OH CPD-339 P / OMe UTL J ^N \U, ^H OMe / An 1 ^H OH CPD-349 F С/ P'^o / o y / ^h рХ( l| θΜ® CPD-359 ί } ^0H CJ f rsX\ N xU Y'U/. ^{H O Me} H CPD 340 F P ) OMa M/0 s/L ⁱ /An A CPD 350 F /j ?V-on €) / j^X N^VX / ^{H 0Me} VYg/ H CPD 360 2 O o / OU/ //

- 54 040588

Code Structure Code Structure Code Structure CPD 361 CPD 370 4 o 0 CPD 379 Y% O 7^ Y^~ i|T^S ^{n OMe} T ⁿ Ύ CPD-362 0f S 1 CPD-371 F #A \A OMe 0 }'"U ....., 7 ' ii Jy ome T ^H OH CPD-38O ° —/ ^ν Ά»/ [11^, OMe T ⁿ OH CPD-363 O 0 7^ N / n || G A OMe T ^H 0.^0 CPD-372 O o G L D »-0 1 T/ome H CPD-381 ABOUT 0_J/S.N n I] || Ta ome About LA/ n CPD-364 About ⁰ d' || T/om® T ⁿ OH CPD-373 O O _ _ _ )n-4 7 ^N QMa Η CPD-382 O y'sd II | OME n CPD 365 z—, □—. τζ^Λ ⁰ 7? £ Ф » 1 CPD 374 F SD R'H-on o G j Tj ^QMe CPD 383 OMb c5 o 7^ λ \u003d ^ν O / ⁴ νΆ "V P 11 Ta OMe O Vw CPD 366 About [G^g? ⁿ he and CPD 375 OME ⁰ || 1^4 OMe Yll ^t° CPD 384 OMe ^w 0 ^N o 7^ HO h'CR || A, OMe H CPD 367 O 0^ O-gl COOEt . 7^ nAs 7 || Tu ome '-A-N Η CPD 376 OME ^Μ ύ ^{Ν 0} 'f || OMe T ^H OH CPD 385 n \=N O J χτ& ^Ν Π II Ta omeon CPD-368 ci ,°Ά-0 / ί r^\ ^^_7^ n N-A || ome %^hl H CPD-377 O > ^m \^N 0 G - \u003d. B . Wee-L? n N || G OMe% ^ ^ 1 ⁿ CPD-386 o o Z f CPD-369 ci °\_ _O n 0 Г 7^n-4, 7 r^sv-A h -Ά fi | A, OM H CPD-378 O Gm \<.Ν O K rS.^ _L 7^ν-Λ7 n -A [| G A Om® T ⁿ he CPD-387 A _L O ^7-0

- 55 040588

Code Structure Code Structure Structure Structure CPD-388 j T } ome X ⁱ OH CPD-397 F \J OMe 0. ,/ ί^\ ,Γ''' NAJ “'^TTlA ^{H 0Ms} AjA^n Η CPD-406 n^n γ,Ν C / OMa O /ί=Α ^w n x-A Ρ G / ^0Μβ ApfA'N Τ η ⁴ νη ₂ CPD-389 O □ /V\ COOH (GA ^H OMe A' Ν Η CPD-398 F O o V ° χΆ Λ > IJ _{A A l G} nA # ^H ^Ame A^n n CPD-4D7 Qo \=Ν Ρ ^Μ = y TA OMe Af^N Τ ^{Η h} he CPD-39D A Dm C _N OMe 0 G” “DA CHAL Π T PM OM® 0 W n CPD-399 F ABOUT ABOUT ) N-Xv 7 n TERMS 0 Α° Vn , ^0Ma o G h Ad II I / ^OMe dAm n CPD-391 o An XN OMe O _y __G but,., „ 'chAl [I H OMe N CPDA00 F fS ohm ° hA/ Ύ ohm AfA-N n SROLOE \ And 0 ™θ o G and Hell T| TG OMe CPD-392 p A GG >N o G ? va N _{A l} ... / nA y '° A ^{n sh} AdA n URGENT g 8 O A 'oAA ¹ <7 CPD-4W A VAA hAh _o D-h n CPD-393 o An^ o UA X ? ^H °^TGT? ^H ^OMe ^h CPDA02 HO X ^N L^X O 50 _g Me xN <-4 n χΆ Π G X ome AsAN Η CPD-411 ζ) N J ^NHMe V=N / O G rfi< / ⁴ N Ax / AA n h G 7 SdAm n CPD 394 OMe ^Ν ό ^Ν o G - ^{Ί 0} v4 G l A G NA J ⁿ * CPDA03 Ζο < 1 ΟΜθ ⁰ /^\ ₽ / nA. ΰ Τ Ί 7 ^ΟΜβ 4ίΑ-Μ ^Ζ 1 ^1-1 he CPDA12 AT / on ° / 1^\ ^nj 4J |АЧгА Н h Г 7 ^0Μ3 Η CPD-395 Ome %5 ° nY ? ^{Yu N} ЪMe A - N CPD-404 Λ° А__/ ОМе ν4<7 ^Μθ ^γργ5 ⁿ ome Α<Α-ν CPD^13 A Ν Τ η—. Ο Λ rf=< τ^ ⁴ νAh ? AChg-A ^η Ρ ί 7 ^0Ma AdA _g Η CPD-396 GA \ / OMe 0 J rL··. Ome AAT T ⁴ SO ₂ Me CPDA05 /° N “AkJJ OMe 0 ^N x>_? NΗ ⁴ ' ^, Ά 1 Tl Τ ζ ^ΟΜβ Η SRSL14 0 g? /Αν Hell\ o^Tj ¹ YES

- 56 040588

Code Structure Code Structure Code Structure CPD-415 O An oh,_G "a ? [AL l| OCHFj HA H CPD-421 р VN ,°^\^SO _z Me CPD-427 F \^/ Oma ]| T U OMe -.an X SRMS'6 S T t| | A ome CPD422 y 4? 4 y [A OMe vAn n CPD428 F o G . τ'vA? Π Γ _Ν om® ΑΑν \ CPD-417 f^\ ^NH i nAd [(DD OMe H CPD423 x^/ ^OM0 LoA 012 OMe υί he CPD-429 0 Ο /Α CPD-418 Vn A ^h Ά _γ . ₁₆ CAN CPD-424 F ?Άοη 444 ί Gr OMe T^n CH CPD430 F ° 7*^ Ι| ΓρOMe Η CPD-419 D-n Cn ° ^Me _L / ⁴ νΆ ί P G OMe T ^{n 4} nh ₅ CPD-425 About RFA il'M t Tre ome n CPD431 -Ώ l g-AgR Η Τ 7 ome YES-μ I ^Η % O ₂ Me CPD420 nl N Hell T ΎΛ AA n SR0L26 F R? Oma ^]|TD OMe X-Aj n CPD432 Vn ™ ^a O G lA noos , _z -., _z .4 / C BH U T) Omen n

Part A.

All preparative HPLC purifications mentioned in this experimental part were performed on the following system: Waters 2489 UV/Vis detector, Waters 2545 dual channel gradient pump, Waters III fraction collector, and Waters dual Flex Injector.

Separations were performed on an XBridge Prep C18 column (19x100 mm; 5 μm) equipped with an XBridge C18 guard column (19x10 mm; 5 μM) or a SunFire Prep C18 ODB column (19x100 mm; 5 μm) equipped with a SunFire C18 guard column (19x10 mm; 5 µm).

Elutions were performed using the methods described in the following tables, and detection wavelengths were fixed at 210 and 254 nm.

Method 1

Time (min) Flow rate (ml/min) Solvent A (%) Solvent B (%) 0 20 50 50 2.00 20 50 50 9.00 20 10 90 11.00 20 10 90 11.20 20 50 50 16.00 20 50 50

Solvent A: 0.1% formic acid purity by LC-MS in milliQ water.

Solvent B: HPLC grade of acetonitrile.

- 57 040588

Method 2

Time (min) Flow rate (ml/min) Solvent A (%) Solvent B (%) 0 20 80 20 2.00 20 80 20 8.00 20 10 90 10.80 20 10 90 11.00 20 80 20 16.00 20 80 20

Solvent A: 0.1% formic acid purity by LC-MS in milliQ water

Solvent B: HPLC grade of acetonitrile.

Method 3

Time (min) Flow rate (ml/min) Solvent A (%) Solvent B (%) 0 20 95 5 2.00 20 95 5 8.00 20 50 50 9.00 20 10 90 11.80 20 10 90 12.00 20 95 5 16.00 20 95 5

Solvent A: 0.1% formic acid purity by LC-MS in milliQ water.

Solvent B: HPLC grade of acetonitrile.

Method 4

Time (min) Flow rate (ml/min) Solvent A (%) Solvent B (%) 0 20 50 50 2.00 20 50 50 9.00 20 10 90 11.00 20 10 90 11.20 20 50 50 16.00 20 50 50

Solvent A: 10 mM ammonium acetate, analytical grade. for HPLC in milliQ water adjusted to pH 10 with analytical ammonium hydroxide. for HPLC.

Solvent B: HPLC grade of acetonitrile.

Method 5

Time (min) Flow rate (ml/min) Solvent A (%) Solvent B (%) 0 20 80 20 2.00 20 80 20 8.00 20 10 90 10.80 20 10 90 11.00 20 80 20 16.00 20 80 20

Solvent A: 10 mM ammonium acetate, analytical grade. for HPLC in milliQ water adjusted to pH10 with analytical ammonium hydroxide. for HPLC.

Solvent B: HPLC grade of acetonitrile.

All enantiomeric separations mentioned in this Experimental Part were performed on the following system: Waters 2489 UV/Visible Detector, Waters 2545 Dual Channel Gradient Pump, Waters III Fraction Collector, and Waters Dual Channel Flex Injector. Separations were performed on a ChiralPak IC column (20x250 mm; 5 μm) equipped with a ChiralPak IC guard column (10x20 mm; 5 μM). Elutions were performed using the isocratic methods described below, and detection wavelengths were fixed at 210 and 254 nm.

Method 6.

Eluant: acetonitrile/diethylamine: 100/0.1.

Flow rate: 20 ml/min.

Method 7.

Eluant: n-heptane/dichloromethane/ethanol/diethylamine: 50/50/1/0.1.

Flow rate: 20 ml/min.

General procedures used in the synthesis of the compounds of the present invention.

General procedure a.

To a solution of the appropriate indole and pyridine in toluene, heated at 55° C., was added dropwise .alpha.-chlorophenylacetyl chloride. The reaction mixture was heated at 55° C. for 2 hours. After cooling to room temperature, water and methanol were added. After 1 hour at room temperature, the precipitate was filtered, washed with water and dried to give the desired compound. If there was no precipitate, the reaction mixture was diluted with ethyl acetate and washed with water. The phases were separated. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography or precipitation to give the desired compound.

General procedure B.

A mixture of 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone, amine and triethylamine in DMF was heated at 100° C. overnight in a sealed tube. The solvent was evaporated under vacuum. The residue was partitioned between ethyl acetate and 5% hydrochloric acid solution. The phases were separated. The organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography followed by recrystallization.

General procedure C.

A mixture of α-haloketone, amine and base (DIPEA or triethylamine) in a solvent (e.g. DMF, ethanol, acetonitrile, dioxane or THF) was irradiated in a microwave oven at 100-200°C (more specifically at 120-200°C) in within 5-180 minutes (more specifically within 15-120 minutes). The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography.

General Procedure D.

A mixture of α-haloketone, amine and PS-DIPEA in acetonitrile was irradiated in a microwave oven at 200°C for 30 min. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography. Further purification by preparative HPLC gave the product.

General procedure E.

A mixture of α-haloketone and aniline in acetonitrile was irradiated in a microwave oven at 100-200°C (more specifically at 130-150°C) for 5-120 minutes (more specifically for 15-30 minutes). Then the reaction mixture was concentrated. The residue was divided between ethyl acetate and 1N. hydrochloric acid solution. The phases were separated. The organic phase was washed with saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel.

General Procedure F.

DMAP (0.1-0.5 eq ., more specifically, 0.1 eq). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate solution. The phases were separated. The aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with saturated ammonium chloride solution, water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The BOC-protected compound was used in the next step without further purification.

General procedure G.

To a mixture of aldehyde (1.0 eq.) and magnesium sulfate (1.3 eq.) in ethanol was added an amine (1.0 eq.). The reaction mixture was stirred overnight at room temperature and filtered. The filtrate was concentrated under reduced pressure to give quantitative imine, which was used without further purification in the next step.

General procedure N.

To a mixture of aldehyde (1.0 eq.) and magnesium sulfate (1.3 eq.) in ethanol was added an amine (1.0 eq.). The mixture was heated overnight at 80°C and filtered. The filtrate was concentrated under reduced pressure to give quantitative imine, which was used without further purification in the next step.

General procedure I.

A mixture of aldehyde (1.0 eq.) and amine (1.0 eq.) was heated in a sealed tube at 60° C. for 6 h. used in the next step without further purification.

J general procedure.

A mixture of aldehyde (1.0 eq.), magnesium sulfate (100 mg) and amine (1.0 eq.) in ethanol was heated at 80° C. overnight. The reaction mixture was filtered. Imine formation was quantitative and the imine-containing filtrate was used in the next step without purification.

General procedure K.

Triethylamine was added to a solution of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-yl chloride in ethanol, and the mixture was stirred at 70° C. for 5 minutes. Aldehyde and a solution of imine in ethanol were added to the resulting yellow solution. The reaction mixture was stirred in a sealed tube

- 59 040588 at 50-70°C for 18-170 h, after which the reaction mixture was irradiated in a microwave oven at

160°C for 4 min. The reaction mixture was concentrated under reduced pressure, and the crude material was purified by silica gel flash chromatography or precipitation.

General procedure L.

Triethylamine was added to a solution of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride in ethanol, and the mixture was stirred at 70°C for 5 minutes. Aldehyde and a solution of imine in ethanol were added to the resulting yellow solution. The reaction mixture was stirred in a sealed tube at 50-70° C. for 18-120 hours. The reaction mixture was concentrated under reduced pressure and the crude material was purified by silica gel flash chromatography or precipitation.

General procedure M.

To a solution of the appropriate indole in DMF was added the alkyl halide and potassium carbonate. The reaction mixture was stirred at room temperature for 1-20 hours. Water was added. The resulting precipitate was filtered, dried and recrystallized to give the desired compound. If there was no precipitate, the reaction mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, evaporated under reduced pressure and purified by flash chromatography.

General procedure N.

To a solution of alcohol (1.0 eq.) in THF (e.g. 3.5 ml/mmol) was added DBU (1-2 eq., more specifically 1.0 eq.) and TBDMSCl (1-2 eq., more specifically , 2.0 eq.). After 4 hours at room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel.

General procedure O.

To a solution of indole in dichloromethane, cooled to 0°C, was added dropwise a 1M solution of diethylaluminum chloride in hexane. After 30 minutes at 0° C., a solution of the acyl chloride in dichloromethane was added. The reaction mixture was stirred at 0°C for 2-3 h and poured into a mixture of ice/buffer solution (pH 7). Alternatively, saturated sodium bicarbonate solution or 1M Rochelle's salt solution was added to the reaction mixture. The phases were separated. The organic phase was washed with saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography or precipitation.

General procedure R.

To a solution of α-methyl ketone in THF, cooled to 0°C, was added a solution of phenyltrimethylammonium tribromide in THF. The reaction mixture was stirred at 0° C. for 1 hour and at room temperature for 2-20 hours. The reaction mixture was filtered and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography or precipitation.

General procedure Q.

DMAP and acetic anhydride were added to a solution of alcohol in dichloromethane. The reaction mixture was stirred at room temperature for 15-60 minutes. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel.

General procedure R.

DMF was added to a solution of oxalyl chloride in anhydrous dichloromethane cooled to 0°C. After 30 minutes at 0° C., indole was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was taken up in THF and 20% ammonium acetate solution. The mixture was refluxed for 30 minutes. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate. The phases were separated and the organic phase was washed with sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel.

General procedure S.

Potassium carbonate was added to a solution of the ester in a mixture of THF and methanol. The reaction mixture was stirred at 20-45° C. for 3-5 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel.

Example 1 Preparation of 2-((3,4-dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone.

Step 1 2-Chloro-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure A from indole (1.000 g, 8.536 mmol), pyridine (0.690 ml, 8.531 mmol) and α-chlorophenylacetyl chloride ( 1.610 g, 8.565 mmol) in toluene (22 ml). Purification by precipitation gave 1.294 g (56%) of the desired compound as a white solid. ESI/APCI(+): 270, 272 (M+H); 292, 294 (M+Na). ESI/APCI(-): 268, 270 (M-H).

Step 2 2-((3,4-Dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure B from 2-chloro-1-(III-indol-3- yl)-2-phenylethanone (0.125 g, 0.463 mmol), 4-aminoveratrol (0.142 g, 0.927 mmol) and triethylamine (0.200 ml, 1.443 mmol) in DMF (2 ml). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-100%) in heptane followed by recrystallization from ethanol gave 0.014 g (8%) of the desired compound as a beige solid. ESI/APCI(+): 387 (M+H); 409 (M + Na). ESI/APCI(-): 385 (M-H). ¹ H NMR (DMSO-d6) δ 8.87 (1H, br s); 8.15 (1H, m); 7.61-7.64 (2H, m); 7.45 (1H, d); 7.13-7.30 (4H, m); 6.60-6.65 (2H, m); 6.24 (1H, m); 5.97-6.07 (2H, m); 3.65 (3H, s); 3.57 (3H, s).

Example 2 Preparation of 2-((3,5-dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone.

2-((3,5-Dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure B from 2-chloro-1-(1H-indol-3-yl)- 2-phenylethanone (0.054 g, 0.200 mmol), 3,5-dimethoxyaniline (0.068 g, 0.444 mmol) and triethylamine (0.100 ml, 0.717 mmol) in DMF (2 ml). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-100%) in heptane followed by recrystallization from ethanol gave 0.005 g (6%) of the desired compound as a beige solid. ESI/APCI(+): 387 (M+H). ESI/APCI(-): 385 (M-H). 1H NMR (DMSO-d6) δ 12.12 (1H, br s); 8.88 (1H, s); 8.16 (1H, m); 7.61-7.64 (2H, m); 7.45 (1H, m); 7.14-7.31 (5H, m); 6.35 (1H, m); 6.03-6.08 (3H, m); 5.70 (1H, s); 3.61 (6H, s).

Example 3 Preparation of 2-((3-ethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone.

2-((3-Ethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure C from 2-chloro-1-(1H-indol-3-yl)-2- phenylethanone (0.050 g, 0.185 mmol), 3-ethoxyaniline (0.100 ml, 0.751 mmol) and DIPEA (0.100 ml, 0.574 mmol) in DMF (2 ml) irradiated in a microwave oven at 180°C for 15 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-40%) in heptane gave 0.010 g (15%) of the desired compound as a beige solid. ESI/APCI(+): 371 (M+H); 393 (M + Na). ESI/APCI(-): 369 (M-H). ¹ H NMR (CDCL3) δ 8.56 (1H, br s); 8.41 (1H, m); 8.01 (1H, d); 7.53-7.55 (2H, m); 7.40 (1H, m); 7.20-7.32 (5H, m); 7.01 (1H, m); 6.29 (1H, d); 6.20-6.24 (2H, m); 5.72 (1H, m); 5.52 (1H, m); 3.94 (2H, q); 1.35 (3H, t).

Example 4 Preparation of 2-((4-chloro-3-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone.

2-((4-Chloro-3-methoxyphenyl)amino)-1-(III-indol-3-yl)-2-phenylethanone was prepared according to general procedure C from 2-chloro-1-(1H-indol-3-yl )-2-phenylethanone (0.104 g, 0.386 mmol), 3-methoxy-4-chloroaniline (0.105 g, 0.666 mmol) and DIPEA (0.200 ml, 1.148 mmol) in DMF (2 ml) irradiated in a microwave oven at 180° C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-40%) in heptane gave 0.027 g (18%) of the desired compound as a white solid. ESI/APCI(+): 391, 393 (M+H); 413, 415 (M+Na). ESI/APCI(-): 389, 391 (M-H). 1H NMR (CDCl ₃ ) δ 8.65 (1H, br s); 8.40 (1H, m); 7.95-8.11 (2H, m); 7.50-7.53 (2H, m); 7.24-7.53 (5H, m); 7.05 (1H, d); 6.18-6.28 (2H, m); 5.70 (1H, s); 3.79 (3H, s).

Example 5 Preparation of 1-(1H-indol-3-yl)-2-phenyl-2-((3-(trifluoromethoxy)phenyl)amino)ethanone.

1-(1H-Indol-3-yl)-2-phenyl-2-((3-(trifluoromethoxy)phenyl)amino)ethanone was prepared according to General Procedure C from 2-chloro-1-(1H-indol-3-yl )-2-phenylethanone (0.050 g, 0.185 mmol), 3-(trifluoromethoxy)aniline (0.100 ml, 0.751 mmol) and DIPEA (0.100 ml, 0.574 mmol) in DMF (2 ml) irradiated in a microwave oven at 180°C within 15 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-40%) in heptane gave 0.009 g (12%) of the desired compound as a beige solid. ESI/APCI(+): 371 (M+H); 393 (M + Na).

ESI/APCI(-): 369 (MH). 1H NMR (CDCl ₃ ) δ 8.56 (1H, br s); 8.41 (1H, m); 8.01 (1H, d); 7.53-7.55 (2H, m); 7.40 (1H, m); 7.20-7.32 (5H, m); 7.01 (1H, m); 6.29 (1H, d); 6.20-6.24 (2H, m); 5.72 (1H, m); 5.52 (1H, m); 3.94 (2H,q); 1.35 (3H, t).

Example 6 Preparation of 2-((3-chlorophenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone.

2-((3-Chlorophenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure C from 2-chloro-1-(1H-indol-3-yl)-2- phenylethanone (0.105 g, 0.389 mmol), 3-chloroaniline (0.200 ml, 1.890 mmol) and DIPEA (0.200 ml, 1.148 mmol) in DMF (2 ml) irradiated in a microwave oven at 180°C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-40%) in heptane followed by recrystallization from methanol gave 0.005 g (4%) of the desired compound as a white solid. ESI/APCI(+): 361, 363 (M+H); 383, 385 (M+Na). ESI/APCI(-): 359, 361 (M-H). 1H NMR (CDCl ₃ ) δ 8.59 (1H, br s); 8.40 (1H, m); 8.02 (1H, d); 7.51-7.53 (2H, m); 7.21-7.38 (6H, m); 7.02 (1H, m); 6.54-6.65 (3H, m); 5.70 (1H, s).

Example 7 Preparation of 2-((3,4-difluorophenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone.

2-((3,4-Difluorophenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure C from 2-chloro-1-(1H-indol-3-yl)- 2-phenylethanone (0.105 g, 0.389 mmol), 3,4-difluoroaniline (0.200 ml, 2.017 mmol) and DIPEA (0.200 ml, 1.148 mmol) in DMF (2 ml), irradiated in a microwave oven at 180°C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-40%) in heptane followed by preparative HPLC purification (XBridge column, method 1)

- 61 040588 received 0.025 g (18%) of the desired compound in the form of an amorphous salt. ESI/APCI(+): 363 (M+H); 385 (M + Na). ESI/APCI(-): 361 (M-H). ¹ H NMR (CDCl ₃ ) δ 8.59 (1H, br s); 8.40 (1H, m); 8.00 (1H, d); 7.49-7.52 (2H, m); 7.23-7.41 (6H, m); 6.71 (1H, m); 6.32-6.46 (2H, m); 5.30-5.64 (2H, m).

Example 8 Preparation of 2-((3-fluorophenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone

2-((3-Fluorophenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure C from 2-chloro-1-(1H-indol-3-yl)-2- phenylethanone (0.103 g, 0.382 mmol), 3-fluoroaniline (0.200 ml, 2.081 mmol) and DIPEA (0.200 ml, 1.148 mmol) in ethanol (2 ml) irradiated in a microwave oven at 180°C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10%-40%) in heptane gave 0.030 g (23%) of the desired compound as a beige solid. ESI/APCI(+): 345 (M+H); 367 (M+Na). ESI/APCI(-): 343 (M-H). ¹ H NMR (CDCb) δ 8.59 (1H, br s); 8.40 (1H, m); 8.01 (1H, d); 7.51-7.54 (2H, m); 7.22-7.41 (6H, m); 7.04 (1H, m); 6.46 (1H, d); 6.31-6.37 (2H, m); 5.69 (1H, s); 5.30 (1H, s).

Example 9 Preparation of 1-(1H-indol-3-yl)-2-phenyl-2-((3-(trifluoromethyl)phenyl)amino)ethanone.

1-(1H-Indol-3-yl)-2-phenyl-2-((3-(trifluoromethyl)phenyl)amino)ethanone was prepared according to General Procedure C from 2-chloro-1-(1H-indol-3-yl )-2-phenylethanone (0.104 g, 0.386 mmol), 3-(trifluoromethyl)aniline (0.100 ml, 0.801 mmol) and DIPEA (0.200 ml, 1.148 mmol) in ethanol (2 ml) irradiated in a microwave oven at 180°C within 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-40%) in heptane gave 0.028 g (18%) of the desired compound as a beige solid. ESI/APCI(+): 395 (M+H). ESI/APCI(-): 393 (M-H). ¹ H NMR (CDCb) δ 8.59 (1H, br s); 8.41 (1H, m); 8.01 (1H, d); 7.51-7.54 (2H, m); 7.17-7.41 (7H, m); 6.80-6.90 (3H, m); 5.83 (1H, brs); 5.73 (1H, s).

Example 10 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone

1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to the 2 different procedures described herein as Method A and Method B.

Method A 1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to General Procedure C from 2-chloro-1-(1H-indol-3-yl) -2-phenylethanone (0.103 g, 0.382 mmol), 3-methoxyaniline (0.100 ml, 0.894 mmol) and DIPEA (0.100 ml, 0.574 mmol) in ethanol (2 ml) irradiated in a microwave oven at 180°C for 30 min . Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-40%) in heptane gave 0.050 g (37%) of the desired compound as a white solid. ESI/APCI(+): 357 (M+H); 379 (M + Na). ESI/APCI(-): 355 (M-H). ¹ H NMR (CDCl ₃ ) δ 8.67 (1H, br s); 8.41 (1H, m); 7.98 (1H, d); 7.50-7.53 (2H, m); 7.20-7.39 (6H, m); 7.01 (1H, m); 6.23-6.25 (2H, m); 5.70 (1H, s); 5.52 (1H, brs); 3.72 (3H, s).

Method B.

Step 1. 1-(1H-Indol-3-yl)-2-phenylethanone was prepared according to the general procedure O from a solution of 1Hindole (2.500 g, 21.34 mmol) in dichloromethane (80 ml), a 1M solution of diethylaluminum chloride in hexane (32 .00 ml, 32.00 mmol) and a solution of phenylacetyl chloride (4.300 ml, 32.27 mmol) in dichloromethane (80 ml). Purification by precipitation from ethyl acetate gave 3.240 g (65%) of the desired compound as a white solid. ESI/APCI(+): 236 (M+H). ESI/APCI(-): 234 (M-H).

Step 2 2-Bromo-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure P from a solution of 1-(1H-indol-3-yl)-2-phenylethanone (3.240 g, 13. 77 mmol) in THF (140 ml) and a solution of phenyltrimethylammonium tribromide (5.700 g, 15.16 mmol) in THF (70 ml). The reaction mixture was stirred at 0° C. for 1 hour and at room temperature for 4 hours. Purification by precipitation from ethyl acetate gave 3.690 g (85%) of the desired product as a white solid. ESI/APCI(+): 314, 316 (M+H); 336, 338 (M+Na). ESI/APCI(-): 312, 314 (M-H). ¹ H NMR (DMSO-d6) δ 12.21 (1H, br s); 8.67 (1H, s); 8.20 (1H, m); 7.68 (1H, d); 7.0-7.4 (7H, m); 6.84 (1H, s).

Step 3 1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to General Procedure E from 2-bromo-1-(1H-indol-3-yl) -2-phenylethanone (0.032 g, 0.102 mmol) and meta-anisidine (0.063 ml, 0.563 mmol) in acetonitrile (0.5 ml) irradiated in a microwave oven at 100°C for 15 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-60%) in heptane gave 0.030 g (83%) of the desired product as a white powder.

Example 11 Preparation of 2-((3,5-difluorophenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone

2-((3,5-Difluorophenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure C from 2-chloro-1-(1H-indol-3-yl)- 2-phenylethanone (0.103 g, 0.382 mmol), 3,5-difluoroaniline (0.117 g, 0.906 mmol) and DIPEA (0.100 ml, 0.574 mmol) in ethanol (2 ml), irradiated in a microwave oven at 180°C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-40%) in heptane gave 0.008 g (6%) of the desired compound as a beige solid. ESI/APCI(+): 363 (M+H); 385 (M + Na). ESI/APCI(-): 361 (M-H). ¹ H NMR (CDCl ₃ ) δ 8.63 (1H, br s); 8.38 (1H, m); 7.99 (1H, d); 7.51-7.54 (2H, m); 7.23-7.41 (7H, m); 6.08-6.18 (2H, m); 5.88 (1H, brs); 5.65 (1H, m).

Example 12 Preparation of 2-((3,5-dimethoxyphenyl)amino)-1-(2-methyl-1H-indol-3-yl)-2-phenylethanone

Step 1 To a solution of 2-methylindole (0.098 g, 0.747 mmol) and pyridine (0.070 ml, 0.865 mmol) in toluene (2 ml) heated at 55°C was added α-chlorophenylacetyl chloride (0.120 ml, 0.762

- 62040588 mmol). Brownish oil was separated after addition. The mixture was heated for 4 hours at 55° C. and then water was added. The phases were separated. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography using a gradient of ethyl acetate (10-40%) in heptane to give 0.068 g (32%) of 2-chloro-1-(2-methyl-1H-indol-3-yl)-2-phenylethanone as beige foam. ESI/APCI(+) 284 (M+H); 306 (M + Na). ESI/APCI(-): 282 (M-H).

Step 2 2-((3,5-Dimethoxyphenyl)amino)-1-(2-methyl-1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure C from 2-chloro-1-(2- methyl-1H-indol-3-yl)-2-phenylethanone (0.068 g, 0.240 mmol), 3,5-dimethoxyaniline (0.173 g, 1.129 mmol) and DIPEA (0.250 ml, 1.435 mmol) in ethanol (2 ml), irradiated in a microwave oven at 180°C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-40%) in heptane gave 0.029 g (30%) of the desired compound as a beige solid. ESI/APCI(+): 401 (M+H); 423 (M + Na). ESI/APCI(-): 399 (M-H). 1H NMR (CDCl ₃ ) δ 8.40 (1H, br s); 8.10 (1H, d); 7.46-7.47 (2H, m); 7.20-7.32 (6H, m); 6.04 (1H, d); 5.85-5.89 (3H, m); 5.43 (1H, brs); 3.73 (6H, s); 2.68 (3H, s).

Example 13 Preparation of 1-(6-chloro-1H-indol-3-yl)-2-((3,5-dimethoxyphenyl)amino)-2-phenylethanone

Step 1 To a solution of 6-chloroindole (0.103 g, 0.679 mmol) and pyridine (0.060 ml, 0.742 mmol) in toluene (2 ml) heated at 55°C, α-chlorophenylacetyl chloride (0.100 ml, 0.635 mmol) was added dropwise . Brownish oil was separated after addition. The mixture was stirred for 18 hours at 55° C. and then water was added. The phases were separated. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (20-60%) in heptane to give 0.073 g (35%) of 2-chloro-1-(6-chloro-1H-indol-3-yl)-2-phenylethanone as a brown solid. ESI/APCI(+): 304, 306 (M+H); 326, 328 (M+Na). ESI/APCI(-): 302, 304 (M-H).

Step 2 1-(6-Chloro-1H-indol-3-yl)-2-((3,5-dimethoxyphenyl)amino)-2-phenylethanone was prepared according to General Procedure C from 2-chloro-1-(6- chloro-1H-indol-3-yl)-2-phenylethanone (0.073 g, 0.240 mmol), 3,5-dimethoxyaniline (0.100 g, 0.653 mmol) and DIPEA (0.200 ml, 1.148 mmol) in ethanol (2 ml), irradiated in a microwave oven at 180°C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-40%) in heptane followed by purification by preparative HPLC (XBridge column; method 2) gave 0.010 g (10%) of the desired compound as a white solid. ESI/APCI(+): 421, 423 (M+H). ESI/APCI(-): 419, 421 (M-H). 1H NMR (CDCl ₃ ) δ 8.63 (1H, br s); 8.30 (1H, d); 7.95 (1H, d); 7.48-7.51 (2H, m); 7.21-7.37 (6H, m); 5.84-5.87 (3H, m); 5.66 (1H, s); 5.49 (1H, brs); 3.70 (6H, s).

Example 14 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxy-5-(trifluoromethyl)phenyl)amino)-2-phenylethanone

1-(1H-Indol-3-yl)-2-((3-methoxy-5-(trifluoromethyl)phenyl)amino)-2-phenylethanone was prepared according to General Procedure C from 2-chloro-1-(1H-indol- 3-yl)-2-phenylethanone (0.109 g, 0.404 mmol), 3-methoxy-5(trifluoromethyl)aniline (0.108 g, 0.565 mmol) and DIPEA (0.100 ml, 0.574 mmol) in ethanol (2 ml), irradiated in microwave oven at 180°C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-40%) in heptane followed by purification by preparative HPLC (XBridge column; method 1) gave 0.024 g (14%) of the desired compound as a white solid. ESI/APCI(+): 425 (M+H); 447 (M + Na). ESI/APCI(-): 423 (M-H). 1H NMR (CDCl ₃ ) δ 8.63 (1H, br s); 8.41 (1H, m); 7.99 (1H, d); 7.50-7.52 (2H, m); 7.21-7.38 (6H, m); 6.54 (1H, s); 6.42 (1H, s); 6.33 (1H, s); 5.84 (1H, brs); 5.70 (1H, m); 3.74 (3H, s).

Example 15 Preparation of 2-((3-fluoro-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone

2-((3-Fluoro-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure C from 2-chloro-1-(1H-indol-3-yl )-2-phenylethanone (0.105 g, 0.389 mmol), 3-methoxy-5-fluoroaniline (0.100 ml, 0.849 mmol) and DIPEA (0.100 ml, 0.574 mmol) in ethanol (2 ml) irradiated in a microwave at 180° C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-40%) in heptane followed by purification by preparative HPLC (XBridge column; method 1) gave 0.047 g (32%) of the desired compound as a white solid. ESI/APCI(+): 375 (M+H); 397 (M+Na). ESI/APCI(-): 373 (M-H). 1H NMR (CDCl ₃ ) δ 8.61 (1H, br s); 8.41 (1H, m); 8.00 (1H, d); 7.50-7.52 (2H, m); 7.25-7.33 (6H, m); 5.95-6.02 (3H, m); 5.68 (2H, m); 3.70 (3H, s).

Example 16 Preparation of 1-(1H-indol-3-yl)-2-phenyl-2-(pyridin-3-ylamino)ethanone

1-(1H-Indol-3-yl)-2-phenyl-2-(pyridin-3-ylamino)ethanone was prepared according to General Procedure D from 2-chloro-1-(1H-indol-3-yl)-2- phenylethanone (0.107 g, 0.397 mmol), 3-aminopyridine (0.099 g, 1.052 mmol) and PS-DIPEA (solid phase support 3.56 mmol/g; 0.300 g, 1.068 mmol) in acetonitrile (2 mL). Purification by flash chromatography on silica gel using a gradient of methanol (0-20%) in dichloromethane followed by purification by preparative HPLC (XBridge column; method 2) gave 0.004 g (3%) of the desired compound as a beige amorphous solid. ESI/APCI(+): 328 (M+H). ESI/APCI(-): 326 (M-H). 1H NMR (CDCl ,) δ 8.70 (1H, br s); 8.37 (1H, m); 8.11 (1H, d); 7.99 (1H, d); 7.89 (1H, d); 7.48-7.51 (2H, m); 7.35 (1H, m); 7.19-7.29 (5H, m); 6.93-6.99 (2H, m); 5.67-5.72 (2H, m).

- 63 040588

Example 17 Preparation of 1-(1H-indol-3-yl)-2-phenyl-2-(pyridin-4-ylamino)ethanone

1-(1H-Indol-3-yl)-2-phenyl-2-(pyridin-4-ylamino)ethanone was obtained according to general procedure D from 2-chloro-1-(III-indol-3-yl)-2- phenylethanone (0.103 g, 0.382 mmol), 4-aminopyridine (0.098 g, 1.041 mmol) and PS-DIPEA (solid phase support 3.56 mmol/g; 0.295 g, 1.050 mmol) in acetonitrile (2 mL). Purification by flash chromatography on silica gel using a gradient of methanol (0-20%) in dichloromethane followed by purification by preparative HPLC (XBridge column; method 5) gave 0.022 g (18%) of the desired compound as a beige solid. ESI/APCI(+): 328 (M+H). ESI/APCI(-): 326 (M-H). ¹ H NMR (CDCl ₃ ) δ 8.32 (1H, m); 8.22 (1H, m); 8.05 (1H, d); 7.3-7.55 (11H, m); 6.80 (1H, d).

Example 18 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)(methyl)amino)-2-phenylethanone

1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)(methyl)amino)-2-phenylethanone was prepared according to General Procedure D from 2-chloro-1-(1H-indol-3-yl) -2-phenylethanone (0.101 g, 0.374 mmol), N-methyl-3-methoxyaniline (0.100 ml, 0.752 mmol) and PS-DIPEA (solid phase support 3.56 mmol/g; 0.292 g, 1.040 mmol) in acetonitrile (2 ml) . Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10%-40%) in heptane followed by purification by preparative HPLC (XBridge column; method 1) gave 0.011 g (8%) of the desired compound as a beige solid. ESI/APCI(+): 371 (M+H); 393 (M + Na). ESI/APCI(-): 369 (M-H). ¹ H NMR (CDCl ₃ ) δ 8.41 (1H, m); 7.73 (1H, s); 7.13-7.41 (7H, m); 6.26-6.50 (4H, m); 3.77 (3H, s); 2.93 (3H, s).

Example 19 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyridin-3-yl)ethanone

Step 1. tert-Butyl-3-formyl-1H-indole-1-carboxylate was prepared according to General Procedure F from 1H-indole-3-carbaldehyde (3.770 g, 25.97 mmol), di-tert-butyl dicarbonate (6.800 g, 31.16 mmol) and DMAP (0.317 g, 2.595 mmol) in acetonitrile (70 ml) to give 6.100 g (96%) of the desired compound as a yellow solid. 1H NMR (DMSO-d ₆ ) δ 10.09 (1H, s); 8.66 (1H, s); 8.15 (2H, dd); 7.327.53 (2H, m); 1.68 (9H, s).

Step 2 3-Methoxy-N-(pyridin-3-ylmethylene)aniline was quantified according to General Procedure G from 3-pyridinylcarboxaldehyde (0.179 ml, 1.867 mmol), magnesium sulfate (0.300 g, 2.492 mmol) and 3-methoxyaniline (0.230 g, 1.867 mmol) in ethanol (1 ml).

Step 3 1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyridin-3-yl)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5-( 2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.101 g, 0.373 mmol) and triethylamine (0.052 ml, 0.373 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1H-indole-1-carboxylate ( 0.549 g, 2.239 mmol) and a solution of 3-methoxy-N-(pyridin-3-ylmethylene)aniline (1.867 mmol) in ethanol (1 ml) heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-100%) in heptane followed by precipitation from acetonitrile gave 0.050 g (8%) of the desired compound as a white solid. ESI/APCI(+): 358 (M+H). ESI/APCI(-): 356 (M-H).

Example 20 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyridin-4-yl)ethanone

Step 1 3-Methoxy-N-(pyridin-4-ylmethylene)aniline was quantified according to General Procedure G from 4-pyridinylcarboxaldehyde (0.179 ml, 1.867 mmol), magnesium sulfate (0.300 g, 2.492 mmol) and 3-methoxyaniline (0.230 g, 1.867 mmol) in ethanol (1 ml).

Step 2 1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyridin-4-yl)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5-( 2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.101 g, 0.373 mmol) and triethylamine (0.052 ml, 0.373 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1H-indole-1-carboxylate ( 0.549 g, 2.239 mmol) and a solution of 3-methoxy-N-(pyridin-4-ylmethylene)aniline (1.867 mmol) in ethanol (1 ml) heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-100%) in heptane followed by precipitation from dichloromethane gave 0.074 g (11%) of the desired compound as a white solid. ESI/APCI(+): 358 (M+H). ESI/APCI(-): 356 (M-H).

Example 21 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(4-(methylsulfonyl)phenyl)ethanone.

Step 1 3-Methoxy-N-(4-(methylsulfonyl)benzylidene)aniline was quantified according to General Procedure G from 4-(methylsulfonyl)benzaldehyde (0.748 g, 4.061 mmol), magnesium sulfate (0.600 g, 4.985 mmol) and 3 -methoxyaniline (0.500 g, 4.060 mmol) in ethanol (5 ml). ESI/APCI(+): 290 (M+H).

Step 2. 1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(4-(methylsulfonyl)phenyl)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5- (2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.056 g, 0.207 mmol) and triethylamine (0.029 ml, 0.207 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1Hindole-1-carboxylate (0.305 g, 1.244 mmol) and a solution of 3-methoxy-N-(4-(methylsulfonyl)benzylidene)aniline (1.037 mmol) in ethanol (1 ml), heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-100%) in heptane followed by precipitation from dichloromethane gave 0.048 g (10%) of the desired compound as a white solid. ESI/APCI(+): 435 (M+H). ESI/APCI(-): 433 (M-H).

Example 22 Preparation of 1-(1H-indol-3-yl)-2-((5-methylisoxazol-3-yl)amino)-2-phenylethanone

Step 1 N-Benzylidene-5-methylisoxazol-3-amine was prepared according to General Procedure G from ben- 64 040588 zaldehyde (0.193 ml, 2.039 mmol), magnesium sulfate (0.300 g, 2.492 mmol) and 3-amino-5-methylisoxazole (0.200 g, 2.039 mmol) in ethanol (2 ml).

Step 2. 1-(1H-Indol-3-yl)-2-((5-methylisoxazol-3-yl)amino)-2-phenylethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl )-4-methylthiazol-3-ium chloride (0.056 g, 0.207 mmol) and triethylamine (0.029 ml, 0.207 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1H-indole-1-carboxylate (0.308 g, 1.257 mmol) and a solution of K-benzylidene-5-methylisoxazol-3-amine (1.047 mmol) in ethanol (1 ml), heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-100%) in heptane followed by purification by preparative HPLC (XBridge column, method 2) gave 0.060 g (16%) of the desired compound as a white powder. ESI/APCI(+): 332 (M+H). ESI/APCI(-): 330 (M-H).

Example 23 Preparation of 2-(furan-2-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone

Step 1. N-(Furan-2-ylmethylene)-3-methoxyaniline was quantified according to General Procedure G from 2-furaldehyde (0.390 g, 4.059 mmol), magnesium sulfate (0.733 g, 6.090 mmol) and 3-methoxyaniline (0.500 g , 4.060 mmol) in ethanol (5 ml). 1H NMR (DMSO-d ₆ ) δ 8.45 (1H, s); 7.95 (1H, s); 7.24-7.41 (1H, m); 7.16 (1H, d); 6.77-6.87 (3H, m); 6.72 (1H, dd); 3.79 (3H, s).

Step 2 2-(Furan-2-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5-( 2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.046 g, 0.170 mmol) and triethylamine (0.024 ml, 0.170 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1H-indole-1-carboxylate ( 0.250 g, 1.019 mmol) and a solution of K-(furan-2-ylmethylene)-3-methoxyaniline (0.849 mmol) in ethanol (1 ml), heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-100%) in heptane followed by purification by preparative HPLC (XBridge column; method 1) gave 0.058 g (19%) of the desired compound as a white solid. ESI/APCI(+): 347 (M+H). ESI/APCI(-): 345 (M-H).

Example 24 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(thiophen-2-yl)ethanone

Step 1 3-Methoxy-N-(thiophen-2-ylmethylene)aniline was quantified according to General Procedure G from 2-thiophenecarboxaldehyde (0.455 g, 4.057 mmol), magnesium sulfate (0.733 g, 6.090 mmol) and 3-methoxyaniline (0.500 g, 4.060 mmol) in ethanol (5 ml).

Step 2. 1-(III-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(thiophen-2-yl)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5-( 2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.046 g, 0.170 mmol) and triethylamine (0.024 ml, 0.170 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1H-indole-1-carboxylate ( 0.250 g, 1.019 mmol) and a solution of 3-methoxy-N-(thiophen-2-ylmethylene)aniline (0.185 g, 0.849 mmol) in ethanol (1 ml), heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by purification by preparative HPLC (XBridge column; method 2) gave 0.058 g (7%) of the desired compound as an oil. ESI/APCI(+): 363 (M+H).

ESI/APCI(-): 361(M-H).

Example 25 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(5-methylisoxazol-3yl)ethanone

Step 1. 3-Methoxy-N-((5-methylisoxazol-3-yl)methylene)aniline was quantitatively obtained according to General Procedure I from 5-methylisoxazole-3-carbaldehyde (0.151 g, 1.359 mmol) and 3-methoxyaniline (0.152 ml , 1.353 mmol). 1H NMR (DMSO-d6) δ 8.69 (1H, s); 7.35 (1H, t); 6.85-6.97 (3H, m); 6.69 (1H, s); 3.81 (3H, s); 2.50 (3H, s).

Step 2. 1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(5-methylisoxazol-3-yl)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazolium chloride (0.180 g, 0.667 mmol) and triethylamine (0.095 ml, 0.676 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1H-indole-1-carboxylate (0.400 g , 1.631 mmol) and a solution of 3-methoxy-N-((5-methylisoxazol-3-yl)methylene)aniline (1.353 mmol) in ethanol (1 ml) heated at 70°C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by precipitation from diethyl ether, 0.142 g (29%) of the desired compound was obtained as a white powder. ESI/APCI(+): 362 (M+H). ESI/APCI(-): 360 (M-H).

Example 26 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(1-methyl-1H-imidazol-2yl)ethanone

Step 1. 3-Methoxy-N-((1-methyl-1H-imidazol-2-yl)methylene)aniline was quantified according to General Procedure I from 1-methyl-1H-imidazole-2-carbaldehyde (0.098 g, 0.890 mmol ) and 3-methoxyaniline (0.100 ml, 0.890 mmol).

Step 2. 1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(1-methyl-1H-imidazol-2-yl)ethanone was prepared according to general procedure K from mixture 3 -benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.120 g, 0.445 mmol) and triethylamine (0.065 ml, 0.462 mmol) in ethanol (1 ml), tert-butyl-3-formyl- 1Hindole-1-carboxylate (0.265 g, 1.080 mmol) and a solution of 3-methoxy-N-((1-methyl-1H-imidazol-2-yl)methylene)aniline (0.890 mmol) in ethanol (0.5 ml), heated at 70°C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (50-100%) in heptane followed by precipitation from diethyl ether gave 0.065 g (22%) of the desired compound as a white powder. ESI/APCI(+): 361 (M+H). ESI/APCI(-): 359 (M-H).

Example 27 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(thiophen-3-yl)ethanone

Step 1 3-Methoxy-N-(thiophen-3-ylmethylene)aniline was quantified according to General Procedure I from thiophene-3-carbaldehyde (0.120 mL, 1.370 mmol) and 3-methoxyaniline (0.152 mL, 1.353 mmol).

Step 2. 1-(III-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(thiophen-3-yl)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5-( 2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.180 g, 0.667 mmol) and triethylamine (0.095 ml, 0.676 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1H-indole-1- carboxylate (0.400 g, 1.631 mmol) and 3-methoxy-N-(thiophen-3-ylmethylene)aniline (1.353 mmol) in ethanol (1 ml) heated at 70°C for 24 h. Purification by silica gel flash chromatography using a gradient of ethyl acetate (0-50%) in heptane followed by precipitation from diethyl ether, 0.076 g (15%) of the desired compound was obtained as a pale yellow powder. ESI/APCI(+): 363 (M+H). ESI/APCI(-): 361 (M-H).

Example 28 Preparation of 2-(1H-imidazol-2-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone

Step 1 N-((1H-Imidazol-2-yl)methylene)-3-methoxyaniline was quantitatively obtained according to General Procedure I from 1H-imidazole-2-carbaldehyde (0.086 g, 0.895 mmol) and 3-methoxyaniline (0.100 ml, 0.890 mmol).

Step 2. 2-(1H-Imidazol-2-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.120 g, 0.445 mmol) and triethylamine (0.065 ml, 0.462 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1H-indol- 1-carboxylate (0.265 g, 1.080 mmol) and N-((1H-imidazol-2-yl)methylene)-3-methoxyaniline (0.890 mmol) in ethanol (0.5 ml) heated at 70°C for 3 days. Purification by precipitation from methanol gave 0.046 g (15%) of the desired compound as a pale brown solid. ESI/APCI(+): 347 (M+H). ESI/APCI(-): 345 (M-H).

Example 29 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyrimidin-5-yl)ethanone

Step 1 3-Methoxy-N-(pyrimidin-5-ylmethylene)aniline was quantified according to General Procedure I from pyrimidine-5-carboxaldehyde (0.115 g, 1.064 mmol) and 3-methoxyaniline (0.120 ml, 1.068 mmol).

Step 2. 1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyrimidin-5-yl)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5-( 2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.144 g, 0.534 mmol) and triethylamine (0.100 ml, 0.712 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1H-indole-1-carboxylate ( 0.295 g, 1.203 mmol) and a solution of 3-methoxy-N-(pyrimidin-5-ylmethylene)aniline (1.064 mmol) in ethanol (0.5 ml) heated at 70°C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (50-100%) in heptane followed by precipitation from diethyl ether gave 0.065 g (17%) of the desired compound as a beige powder. ESI/APCI(+): 359 (M+H). ESI/APCI(-): 357 (M-H).

Example 30 Preparation of 2-(imidazo[1,2-a]pyridin-2-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone

Step 1 N-(Imidazo[1,2-a]pyridin-2-ylmethylene)-3-methoxyaniline was quantified according to General Procedure I from imidazo[1,2-a]pyridine-2-carbaldehyde (0.156 g, 1.067 mmol ) and 3-methoxyaniline (0.120 ml, 1.068 mmol).

Step 2. 2-(Imidazo[1,2-a]pyridin-2-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to the general procedure K from mixtures of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.144 g, 0.534 mmol) and triethylamine (0.100 ml, 0.712 mmol) in ethanol (1 ml), tert-butyl-3- formyl 1Hindole-1-carboxylate (0.295 g, 1.03 mmol) and a solution of N-(imidaαzo[1,2-α]niridin-2-ylmethylene)-3-methoxyaniline (1.067 mmol) in ethanol (0.5 ml ) heated at 70° C. for 24 hours. Purification by silica gel flash chromatography using a gradient of ethyl acetate (50-100%) in heptane followed by precipitation from diethyl ether gave 0.111 g (28%) of the desired compound as a beige powder. ESI/APCI(+): 397 (M+H). ESI/APCI(-): 395 (M-H).

Example 31 Preparation of 2-((2-hydroxypyridin-4-yl)amino)-1-(1H-indol-3-yl)-2-phenylethanone

A mixture of 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.104 g, 0.386 mmol), 2-methoxypyridine-4-amine (0.100 g, 0.806 mmol) and DIPEA (0.100 ml, 0.574 mmol ) in acetonitrile (2 ml) was irradiated in a microwave oven at 120°C for 60 min. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography using a gradient of methanol (2-20%) in dichloromethane. Further purification by recrystallization from dichloromethane gave 0.017 g (13%) of 2-((2-hydroxypyridin-4-yl)amino)-1-(1H-indol-3-yl)-2-phenylethanone as a white solid. ESI/APCI(+): 344 (M+H); 366 (M+Na). ESI/APCI(-): 342 (M-H). ¹ H NMR (DMSO-d ₆ ) δ 11.99 (1H, s); 8.27 (1H, s); 8.18 (1H, m); 7.2-7.5 (7H, m); 6.89 (1H, d); 6.09 (2H, s); 5.64 (1H, d); 5.29 (1H, s).

Example 32 Preparation of 1-(1H-indol-3-yl)-2-phenyl-2-((pyridin-2-ylmethyl)amino)ethanone

1-(1H-Indol-3-yl)-2-phenyl-2-((pyridin-2-ylmethyl)amino)ethanone was prepared according to General Procedure C from 2-chloro-1-(1H-indol-3-yl) -2-phenylethanone (0.108 g, 0.400 mmol), pyridin-2-ylmethanamine

- 66 040588 (0.100 ml, 0.970 mmol) and DIPEA (0.100 ml, 0.574 mmol) in acetonitrile (2 ml) irradiated in a microwave oven at 200°C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-100%) in heptane followed by recrystallization from dichloromethane gave 0.003 g (2%) of the desired compound as a solid. ESI/APCI(+): 342 (M+H). ESI/APCI(-): 340 (M-H). 1H NMR (MeOD) δ 8.46 (1H, m); 8.37 (1H, m); 7.91 (1H, s); 7.69 (1H, m); 7.20-7.46 (10H, m); 5.16 (1H, s); 3.90 (2H, m).

Example 33 Preparation of 1-(1H-indol-3-yl)-2-phenyl-2-((thiophen-2-ylmethyl)amino)ethanone

1-(1H-Indol-3-yl)-2-phenyl-2-((thiophen-2-ylmethyl)amino)ethanone was prepared according to General Procedure C from 2-chloro-1-(1H-indol-3-yl) -2-phenylethanone (0.111 g, 0.412 mmol), thiophen-2-ylmethanamine (0.100 ml, 0.972 mmol) and DIPEA (0.200 ml, 1.148 mmol) in acetonitrile (2 ml), irradiated in a microwave oven at 200°C for 30 min. Purification by flash chromatography on silica gel using a gradient of methanol (2-20%) in dichloromethane followed by recrystallization from dichloromethane gave 0.021 g (15%) of the desired compound as a solid. ESI/APCI(+): 347 (M+H); 369 (M + Na). ESI/APCI(-): 345 (M-H). ¹ H NMR (DMSO-d ₆ ) δ 12.01 (1H, br s); 8.50 (1H, s); 8.18 (1H, m); 7.14-7.58 (9H, m); 6.38 (1H, s); 6.24 (1H, s); 5.25 (1H, s); 3.67 (2H, s).

Example 34 Preparation of 2-((furan-2-ylmethyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone

2-((Furan-2-ylmethyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure C from 2-chloro-1-(1H-indol-3-yl)- 2-phenylethanone (0.103 g, 0.382 mmol), furan-2-ylmethanamine (0.100 ml, 0.382 mmol) and DIPEA (0.200 ml, 1.148 mmol) in acetonitrile (2 ml), irradiated in a microwave oven at 200°C for 30 min. Purification by flash chromatography on silica gel using a gradient of methanol (2-20%) in dichloromethane followed by recrystallization from dichloromethane gave 0.040 g (32%) of the desired compound as a solid. ESI/APCI(+): 331 (M+H); 353 (M+Na). ESI/APCI(-): 329 (M-H). 1H NMR (DMSO-d6) δ 12.01 (1H, br s); 8.49 (1H, s); 8.20 (1H, m); 7.16-7.53 (9H, m); 6.89-6.93 (2H, m); 5.27 (1H, s); 3.80 (2H, s).

Example 35 Preparation of 3-((2-(1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)benzonitrile

3-((2-(1H-Indol-3-yl)-2-oxo-1-phenylethyl)amino)benzonitrile was prepared according to General Procedure C from 2-chloro-1-(1H-indol-3-yl)-2 -phenylethanone (0.100 g, 0.371 mmol), 3-aminobenzonitrile (0.098 g, 0.830 mmol) and DIPEA (0.200 ml, 1.148 mmol) in acetonitrile (2 ml) irradiated in a microwave oven at 200°C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane followed by recrystallization from dichloromethane gave 0.007 g (5%) of the desired compound as a solid. ESI/APCI(+): 352 (M+H). ESI/APCI(-): 350 (M-H). 1H NMR (CDCl3) δ 8.59 (1H, br s); 8.40 (1H, m); 8.01 (1H, s); 7.51 (2H, d); 7.17-7.41 (7H, m); 6.84-6.91 (3H, m); 5.70 (1H, s).

Example 36 Preparation of 4-(2-(1H-indol-3-yl)-1-((3-methoxyphenyl)amino)-2-oxoethyl)benzonitrile

Step 1 4-(((3-Methoxyphenyl)imino)methyl)benzonitrile was quantified according to General Procedure I from 4-formylbenzonitrile (0.135 g, 1.030 mmol) and 3-methoxyaniline (0.116 mL, 1.030 mmol).

Step 2 4-(2-(1H-Indol-3-yl)-1-((3-methoxyphenyl)amino)-2-oxoethyl)benzonitrile was prepared according to General Procedure K from a mixture of 3-benzyl-5-(2- hydroxyethyl)-4-methylthiazolium chloride (0.144 g, 0.534 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1H-indole-1-carboxylate (0.252 g, 1.028 mmol) and a solution of 4-(((3-methoxyphenyl)imino)methyl)benzonitrile (1.030 mmol) in ethanol (0.5 ml) heated at 70°C for 24 h. Purification by silica gel flash chromatography using an ethyl acetate gradient ( 5-60%) in heptane followed by precipitation from diethyl ether gave 0.203 g (52%) of the desired compound as a pale yellow solid. ESI/APCI(+): 382 (M+H). ESI/APCI(-): 380 (M-H).

Example 37 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(quinoxalin-6-yl)ethanone

Step 1 3-Methoxy-M-(quinoxalin-6-ylmethylene)aniline was quantitatively obtained according to General Procedure I from quinoxaline-6-carbaldehyde (0.100 g, 0.632 mmol) and 3-methoxyaniline (0.071 ml, 0.632 mmol).

Step 2 1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(quinoxalin-6-yl)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5-( 2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g, 0.491 mmol) and triethylamine (0.055 ml, 0.397 mmol) in ethanol (0.7 ml), tert-butyl-3-formyl-1H-indole 1- carboxylate (0.155 g, 0.630 mmol) and a solution of 3-methoxy-M-(quinoxalin-6-ylmethylene)aniline (0.632 mmol) in ethanol (0.7 ml), heated at 70°C for 18 hours. silica gel chromatography using a gradient of ethyl acetate (50-100%) in heptane followed by precipitation from methanol gave 0.069 g (27%) of the desired compound as a yellow solid. ESI/APCI(+): 409 (M+H). ESI/APCI(-): 408 (M-H).

Example 38 Preparation of 1-(1H-indol-3-yl)-2-((2-methoxyphenyl)amino)-2-phenylethanone

1-(1H-Indol-3-yl)-2-((2-methoxyphenyl)amino)-2-phenylethanone was prepared according to General Procedure C from 2-chloro-1-(1H-indol-3-yl)-2- phenylethanone (0.109 g, 0.404 mmol), 2-methoxyaniline (0.100 ml, 0.893 mmol) and DIPEA (0.200 ml, 1.148 mmol) in acetonitrile (2 ml) irradiated in a microwave oven at

- 67 040588

200°C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-40%) in heptane followed by recrystallization from dichloromethane gave 0.013 g (9%) of the desired compound as white crystals. ESI/APCI(+): 357 (M+H); 379 (M + Na). ESI/APCI(-): 355 (M-H). ¹ H NMR (CDCl ₃ ) δ 8.55 (1H, br s); 8.42 (1H, m); 8.05 (1H, s); 7.54 (2H, d); 7.20-7.38 (6H, m); 6.576.78 (4H, m); 5.72 (1H, s); 3.88 (3H, s).

Example 39 Preparation of 2-((2,5-dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone

2-((2,5-Dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure C from 2-chloro-1-(1H-indol-3-yl)- 2-phenylethanone (0.110 g, 0.408 mmol), 2,5-dimethoxyaniline (0.102 g, 0.666 mmol) and DIPEA (0.200 ml, 1.148 mmol) in acetonitrile (2 ml), irradiated in a microwave oven at 200°C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-40%) in heptane followed by recrystallization from dichloromethane gave 0.009 g (6%) of the desired compound as a white solid. ESI/APCI(+): 387 (M+H); 409 (M + Na). ESI/APCI(-): 385 (M-H). ¹ H NMR (CDCl ₃ ) δ 8.62 (1H, br s); 8.41 (1H, m); 7.98 (1H, s); 7.52 (2H, d); 7.19-7.37 (5H, m); 6.66 (1H, d); 6.10-6.18 (2H, m); 5.67 (1H, s); 5.30 (1H, s); 3.84 (3H, s); 3.66 (3H, s).

Example 40 Preparation of 2-((2,3-dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone

2-((2,3-Dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure C from 2-chloro-1-(1H-indol-3-yl)- 2-phenylethanone (0.044 g, 0.163 mmol), 2,3-dimethoxyaniline (0.050 ml, 0.326 mmol) and DIPEA (0.100 ml, 0.574 mmol) in acetonitrile (2 ml), irradiated in a microwave oven at 200°C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-40%) in heptane followed by recrystallization from dichloromethane gave 0.008 g (13%) of the desired compound as white crystals. ESI/APCI(+): 387 (M+H); 409 (M + Na). ESI/APCI(-): 385 (M-H). ¹ H NMR (CDCl ₃ ) δ 8.54 (1H, br s); 8.42 (1H, m); 8.03 (1H, s); 7.52 (2H, d); 7.20-7.38 (6H, m); 6.81 (1H, m); 6.29 (2H, m); 5.75 (1H, s); 3.89 (3H, s); 3.82 (3H, s).

Example 41 Preparation of 3-(2-(1H-indol-3-yl)-1-((3-methoxyphenyl)amino)-2-oxoethyl)benzonitrile

Step 1 3-(((3-Methoxyphenyl)imino)methyl)benzonitrile was quantified according to General Procedure I from 3-formylbenzonitrile (0.135 g, 1.030 mmol) and 3-methoxyaniline (0.116 mL, 1.032 mmol).

Step 2 3-(2-(1H-Indol-3-yl)-1-((3-methoxyphenyl)amino)-2-oxoethyl)benzonitrile was prepared according to General Procedure L from a mixture of 3-benzyl-5-(2- hydroxyethyl)-4-methylthiazol-3-ium chloride (0.144 g, 0.534 mmol) and triethylamine (0.100 ml, 0.712 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1H-indole-1-carboxylate (0.252 g , 1.028 mmol) and a solution of 3-(((3-methoxyphenyl)imino)methyl)benzonitrile (1.030 mmol) in ethanol (0.5 ml) heated at 70°C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-50%) in heptane followed by precipitation from diethyl ether gave 0.077 g (20%) of the desired compound as a solid. ESI/APCI(+): 382 (M+H). ESI/APCI(-): 380 (M-H).

Example 42 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(1-methyl-1H-pyrazol-4yl)ethanone

Step 1 3-Methoxy-N-((1-methyl-1H-pyrazol-4-yl)methylene)aniline was quantified according to General Procedure I from 1-methyl-1H-pyrazole-4-carbaldehyde (0.110 g, 0.999 mmol ) and 3-methoxyaniline (0.112 ml, 0.999 mmol).

Step 2 3-(2-(1H-Indol-3-yl)-1-((3-methoxyphenyl)amino)-2-oxoethyl)benzonitrile was prepared according to General Procedure K from a mixture of 3-benzyl-5-(2- hydroxyethyl)-4-methylthiazol-3-yl chloride (0.135 g, 0.500 mmol) and triethylamine (0.100 ml, 0.712 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1H-indole-1-carboxylate (0.245 g , 0.999 mmol) and a solution of 3-methoxy-N-((1-methyl-1H-pyrazol-4-yl)methylene)aniline (0.999 mmol) in ethanol (0.5 ml), heated at 70°C for 24 h. After concentrating the reaction mixture under reduced pressure, purification by precipitation from dichloromethane gave 0.219 g (61%) of the desired compound as a white solid. ESI/APCI(+): 361 (M+H). ESI/APCI(-): 359 (M-H).

Example 43 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyrazolo[1,5-a]pyridin-7yl)ethanone.

Step 1. 3-Methoxy-M-(pyrazolo[1,5-a]pyridin-7-ylmethylene)aniline was quantified according to General Procedure I from pyrazolo[1,5-a]pyridine-7-carbaldehyde (0.100 g, 0.684 mmol) and 3-methoxyaniline (0.077 ml, 0.685 mmol). ESI/APCI (+): 252 (M+H).

Step 2. 1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyrazolo[1,5-a]pyridin-7-yl)ethanone was prepared according to the general procedure K from mixtures of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.095 g, 0.352 mmol) and triethylamine (0.070 ml, 0.502 mmol) in ethanol (1 ml), tert-butyl-3- formyl1H-indole-1-carboxylate (0.168 g, 0.684 mmol) and a solution of 3-methoxy-N-(pyrazolo[1,5-a]pyridin-7ylmethylene)aniline (0.684 mmol) in ethanol (0.5 ml), heated at 50°C for 3 days. After concentrating the reaction mixture under reduced pressure, methanol was added. The resulting precipitate was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (0-50%) in heptane, followed by precipitation from diethyl ether to give 0.095 g (35%) of the desired compound as a yellow solid. ESI/APCI(+): 397 (M+H). ESI/APCI(-): 395 (M-H).

Example 44 Preparation of 1-(1H-indol-3-yl)-2-((3-(methylsulfonyl)phenyl)amino)-2-phenylethanone

1-(1H-Indol-3-yl)-2-((3-(methylsulfonyl)phenyl)amino)-2-phenylethanone was obtained according to general procedure C from 2-chloro-1-(III-indol-3-yl) -2-phenylethanone (0.100 g, 0.371 mmol), 3-(methylsulfonyl)aniline hydrochloride (0.112 g, 0.539 mmol) and DIPEA (0.300 ml, 1.722 mmol) in acetonitrile (2 ml), irradiated in a microwave oven at 200°C in within 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30-100%) in heptane gave 0.017 g (11%) of the desired compound as amorphous crystals. ESI/APCI(+): 405 (M+H); 427 (M+Na); ESI/APCI(-): 403 (M-H).

Example 45 Preparation of 1-(1H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-phenylethanone

Step 1 N-Benzylidene-2-methoxypyridine-4-amine was quantified according to General Procedure I from benzaldehyde (2.027 ml, 20.01 mmol) and 2-methoxypyridine-4-amine (2.483 g, 20.01 mmol).

Step 2. 1-(III-Indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-phenylethanone was prepared according to General Procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl )-4-methylthiazol-3-ium chloride (0.125 g, 0.463 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1H-indole-1-carboxylate (0.197 g, 0.803 mmol) and a solution of N-benzylidene-2-methoxypyridine-4-amine (0.803 mmol) in ethanol (2 ml) heated at 70°C for 65 h. Purification by flash chromatography on silica gel using an ethyl acetate gradient (30- 100%) in heptane followed by recrystallization from dichloromethane gave 0.015 g (5%) of the desired compound as a solid. ESI/APCI(+): 358 (M+H); 380 (M + Na). ESI/APCI(-): 356 (M-H). ¹ H NMR (CDCl ₃ ) δ 9.39 (1H, br s); 8.42 (1H, d); 7.87 (2H, s); 7.48 (2H, d); 7.20-7.35 (4H, m); 6.40 (1H, d); 6.20 (1H, m); 6.01 (1H, s); 5.87 (1H, d); 5.29 (1H, s); 3.76 (3H, s).

Example 46 Preparation of 2-((3-ethylphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone

2-((3-Ethylphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure C from 2-chloro-1-(1H-indol-3-yl)-2- phenylethanone (0.106 g, 0.393 mmol), 3-ethylaniline (0.100 ml, 0.805 mmol) and DIPEA (0.200 ml, 1.148 mmol) in acetonitrile (2 ml) irradiated in a microwave oven at 200°C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane followed by recrystallization from dichloromethane gave 0.028 g (20%) of the desired compound as a solid. ESI/APCI(+): 355 (M+H); 377 (M + Na). ESI/APCI(-): 353 (M-H). 1H NMR (CDCl ₃ ) δ 8.55 (1H, br s); 8.40 (1H, m); 8.02 (1H, s); 7.54 (2H, d); 7.20-7.40 (6H, m); 7.04 (1H, m); 6.51-6.55 (3H, m); 5.72 (1H, s); 5.46 (1H, brs); 2.57 (2H, q); 1.17 (3H, t).

Example 47 Preparation of 1-(1H-indol-3-yl)-2-(isoquinolin-5-yl)-2-((3-methoxyphenyl)amino)ethanone

Step 1 N-(Isoquinolin-5-ylmethylene)-3-methoxyaniline was quantitatively prepared according to General Procedure I from isoquinoline-5-carbaldehyde (0.119 g, 0.757 mmol) and 3-methoxyaniline (0.087 ml, 0.774 mmol).

Step 2. 1-(III-Indol-3-yl)-2-(isoquinolin-5-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-( 2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.100 g, 0.371 mmol) and triethylamine (0.080 ml, 0.574 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1H-indole-1-carboxylate ( 0.186 g, 0.759 mmol) and a solution of N-(isoquinolin-5-ylmethylene)-3-methoxyaniline (0.757 mmol) in ethanol (0.5 ml) heated at 60°C for 2 days. After concentrating the reaction mixture under reduced pressure, purification by precipitation from methanol gave 0.093 g (30%) of the desired compound as a white powder. ESI/APCI (+): 408 (M+H). ESI/APCI (-): 406 (M-H).

Example 48 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(4-(pyrimidin-5-yl)phenyl)ethanone

Step 1. 3-Methoxy-N-(4-(pyrimidin-5-yl)benzylidene)aniline was quantitatively obtained according to General Procedure I from 5-(4-formylphenyl)pyrimidine (0.125 g, 0.679 mmol) and 3-methoxyaniline (0.076 ml, 0.679 mmol). ESI/APCI (+): 290 (M+H).

Step 2 1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(4-(pyrimidin-5-yl)phenyl)ethanone was prepared according to General Procedure L from a mixture of 3- benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.090 g, 0.334 mmol) and triethylamine (0.070 ml, 0.502 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1Hindole -1-carboxylate (0.166 g, 0.677 mmol) and a solution of 3-methoxy-N- (4- (pyrimidin-5-yl) benzylidene) aniline (0.679 mmol) in ethanol (0.5 ml), heated at 75 ° C within 3.5 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by precipitation from diethyl ether and dichloromethane gave 0.061 g (21%) of the desired compound as a pale yellow solid. ESI/APCI (+): 435 (M+H). ESI/APCI (-): 433 (M-H).

Example 49 Preparation of 2-((3-methoxyphenyl)amino)-1-(1-methyl-1H-indol-3-yl)-2-phenylethanone

The present compound was prepared according to the 2 different procedures described herein as Method A and Method B.

Method A.

Step 1 N-Benzylidene-3-methoxyaniline was quantified according to General Procedure G from benzaldehyde (3.030 ml, 29.98 mmol), 3-methoxyaniline (3.690 ml, 32.84 mmol) and magnesium sulfate (3.610 g, 29.99 mmol) in ethanol (15 ml). 1H NMR (DMSO-d ₆ ) δ 8.63 (1H, s); 7.95 (2H, dd); 7.47-7.63 (3H, m); 7.32 (1H, t); 6.75-6.93 (3H, m); 3.80 (3H, s).

- 69 040588

Step 2 2-((3-Methoxyphenyl)amino)-1-(1-methyl-1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl )-4-methylthiazol-3-yl chloride (0.169 g, 0.628 mmol) and triethylamine (0.088 ml, 0.628 mmol) in ethanol (2 ml), 1-methyl-1H-indole-3-carbaldehyde (0.200 g, 1.256 mmol ) and a solution of N-benzylidene-3-methoxyaniline (1.256 mmol) in ethanol (1 ml), heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by purification by preparative HPLC (XBridge column; method 1) gave 0.028 g (6%) of the desired compound as a white foam. ESI/APCI(+): 371 (M+H).

Method B.

Step 1 2-Chloro-1-(1-methyl-1H-indol-3-yl)-2-phenylethanone was prepared according to General Method M from 2-chloro-1-(1H-indol-3-yl)-2- phenylethanone (0.200 g, 0.741 mmol), methyl iodide (0.166 ml, 2.573 mmol) and potassium carbonate (0.205 g, 1.476 mmol) in DMF (5 ml) The reaction mixture was stirred at room temperature for 3 hours. Purification by silica gel flash chromatography using a gradient of ethyl acetate (2-40%) in heptane, 0.140 g (66%) of the desired compound was obtained as a beige solid. ESI/APCI(+): 284, 286 (M+H); 306, 308 (M+Na).

Step 2 2-((3-Methoxyphenyl)amino)-1-(1-methyl-1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure C from 2-chloro-1-(1-methyl- 1H-indol-3-yl)-2-phenylethanone (0.140 g, 0.493 mmol), 3-methoxyaniline (0.110 ml, 0.987 mmol) and DIPEA (0.169 ml, 0.987 mmol) in acetonitrile (1.5 ml) irradiated in a microwave at 200°C for 1.5 hours After settling at room temperature for 24 hours, the precipitate formed was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography using dichloromethane as eluent. Further purification by preparative TLC using dichloromethane as eluent gave 0.011 g (6%) of the desired compound as a beige solid. ESI/APCI(+): 371 (M+H).

Example 50 Preparation of 1-(1H-indol-3-yl)-2-phenyl-2-(quinoxalin-6-ylamino)ethanone

1-(1H-Indol-3-yl)-2-phenyl-2-(quinoxalin-6-ylamino)ethanone was prepared according to general procedure C from 2-chloro-1-(1H-indol-3-yl)-2- phenylethanone (0.101 g, 0.374 mmol), quinoxaline-6-amine (0.094 g, 0.648 mmol) and DIPEA (0.200 ml, 1.148 mmol) in acetonitrile (2 ml) irradiated in a microwave oven at 200°C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30-100%) in heptane followed by purification by preparative HPLC (XBridge column; method 2) gave 0.008 g (6%) of the desired compound as an orange solid. ESI/APCI(+): 379 (M+H). ESI/APCI(-): 377 (M-H).

Example 51 Preparation of 3-((2-(1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)-N,N-dimethylbenzamide.

3-((2-(1H-Indol-3-yl)-2-oxo-1-phenylethyl)amino)-N,N-dimethylbenzamide was prepared according to General Procedure C from 2-chloro-1-(1H-indole-3 -yl)-2-phenylethanone (0.099 g, 0.367 mmol), 3-amino-N,N-dimethylbenzamide (0.095 g, 0.579 mmol) and DIPEA (0.200 ml, 1.148 mmol) in acetonitrile (2 ml) irradiated in microwave oven at 200°C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30-100%) in heptane followed by purification by preparative HPLC (XBridge column; method 2) gave 0.028 g (19%) of the desired compound as a pink solid. ESI/APCI(+): 398 (M+H). ESI/APCI(-): 396 (M-H).

Example 52 Preparation of 3-((2-(1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)-N-methylbenzenesulfonamide.

-((2-(1H-Indol-3-yl)-2-oxo-1-phenylethyl)amino)-N-methylbenzenesulfonamide was prepared according to General Procedure C from 2-chloro-1-(1H-indol-3-yl )-2-phenylethanone (0.096 g, 0.356 mmol), 3-amino-N-methylbenzenesulfonamide hydrochloride (0.101 g, 0.454 mmol) and DIPEA (0.300 ml, 1.722 mmol) in acetonitrile (2 ml), irradiated in a microwave oven at 200°C in within 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30-100%) in heptane followed by purification by preparative HPLC (XBridge column; method 2) gave 0.006 g (4%) of the desired compound as an orange solid. ESI/APCI(+): 420 (M+H). ESI/APCI(-): 418 (M-H).

Example 53 Preparation of 1-(4-chloro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone

Step 1. tert-Butyl-4-chloro-3-formyl-1H-indole-1-carboxylate was prepared according to General Procedure F from 4-chloro-1H-indole-3-carbaldehyde (0.310 g, 1.726 mmol), di-tert -butyl dicarbonate (0.451 g, 2.066 mmol) and DMAP (0.021 g, 0.172 mmol) in acetonitrile (4 ml) to give 0.431 g (89%) of the desired compound.

Step 2 1-(4-Chloro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to General Procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl )-4-methylthiazol-3-ium chloride (0.232 g, 0.860 mmol) and triethylamine (0.120 ml, 0.860 mmol) in ethanol (3 ml), tert-butyl-4-chloro-3-formyl-1H-indole 1-carboxylate (0.481 g, 1.720 mmol) and a solution of N-benzylidene-3-methoxyaniline (1.718 mmol) in ethanol (1 ml), heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by purification by preparative HPLC (XBridge column; method 1) gave 0.009 g (1%) of the desired compound as a white powder. ESI/APCI(+): 391, 393 (M+H). ESI/APCI(-): 389, 391 (M-H).

- 70 040588

Example 54 Preparation of 1-(III-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(3-(pyrimidin-5-yl)phenyl)ethanone

Step 1. 3-Methoxy-N-(3-(pyrimidin-5-yl)benzylidene)aniline was quantitatively obtained according to General Procedure I from 3-pyrimidin-5-ylbenzaldehyde (0.125 g, 0.679 mmol) and 3-methoxyaniline (0.076 ml , 0.679 mmol). ESI/APCI (+): 290 (M+H).

Step 2 1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(3-(pyrimidin-5-yl)phenyl)ethanone was prepared according to General Procedure L from a mixture of 3- benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.091 g, 0.337 mmol) and triethylamine (0.070 ml, 0.502 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1Hindole -1-carboxylate (0.166 g, 0.677 mmol) and a solution of 3-methoxy-N- (3- (pyrimidin-5-yl) benzylidene) aniline (0.679 mmol) in ethanol (0.5 ml), heated at 65 ° C within 5 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (50-100%) in heptane followed by precipitation from diethyl ether gave 0.066 g (22%) of the desired compound as a yellow solid. ESI/APCI (+): 435 (M+H). ESI/APCI (-): 433 (M-H).

Example 55 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6-methoxypyridin-3yl)ethanone

Step 1. 3-Methoxy-M-((6-methoxypyridin-3-yl)methylene)aniline was quantified according to General Procedure I from 6-methoxynicotinaldehyde (0.140 g, 1.021 mmol) and 3-methoxyaniline (0.115 mL, 1.021 mmol) . ESI/APCI (+): 243 (M+H).

Step 2. 1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6-methoxypyridin-3-yl)ethanone was prepared according to General Procedure L from a mixture of 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.143 g, 0.530 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1Hindole-1- carboxylate (0.251 g, 1.020 mmol) and a solution of 3-methoxy-M-((6-methoxypyridin-3-yl)methylene)aniline (1.021 mmol) in ethanol (0.5 ml), heated at 65°C for 5 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-50%) in heptane followed by precipitation from diethyl ether gave 0.097 g (25%) of the desired compound as a pale yellow solid. ESI/APCI (+): 388 (M+H). ESI/APCI (-): 386 (M-H).

Example 56 Preparation of 6-((2-(1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)benzo[d]oxazol-2(3H)one.

6-((2-(1H-Indol-3-yl)-2-oxo-1-phenylethyl)amino)benzo[d]oxazol-2(3H)-one was prepared according to General Procedure C from 2-chloro-1- (1H-indol-3-yl)-2-phenylethanone (0.102 g, 0.378 mmol), 6-aminobenzo[d]oxazol-2(3H)-one (0.104 g, 0.693 mmol) and DIPEA (0.200 ml, 1.148 mmol ) in acetonitrile (2 ml), irradiated in a microwave oven at 200°C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-100%) in heptane followed by purification by preparative HPLC (XBridge column; method 2) gave 0.023 g (16%) of the desired compound as an amorphous salt. ESI/APCI(+): 384 (M+H); 406 (M + Na). ESI/APCI(-): 382 (M-H).

Example 57 Preparation of 2-((3-(1H-1,2,4-triazol-1-yl)phenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone

2-((3-(1H-1,2,4-Triazol-1-yl)phenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure C from 2 -chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.104 g, 0.386 mmol), 3-(1H-1,2,4triazol-1-yl)aniline (0.093 g, 0.581 mmol) and DIPEA (0.200 ml, 1.148 mmol) in acetonitrile (2 ml) microwaved at 200°C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-100%) in heptane followed by purification by preparative HPLC (XBridge column; method 2) gave 0.009 g (6%) of the desired compound as an amorphous salt. ESI/APCI(+): 394 (M+H); 416 (M+Na). ESI/APCI(-): 392 (M-H).

Example 58 Preparation of 1-(1H-indol-3-yl)-2-((3-(oxazol-5-yl)phenyl)amino)-2-phenylethanone

1-(1H-Indol-3-yl)-2-((3-(oxazol-5-yl)phenyl)amino)-2-phenylethanone was prepared according to General Procedure C from 2-chloro-1-(1H-indol- 3-yl)-2-phenylethanone (0.101 g, 0.374 mmol), 3-(oxazol-5-yl)aniline (0.086 g, 0.537 mmol) and DIPEA (0.200 ml, 1.148 mmol) in acetonitrile (2 ml), irradiated in a microwave oven at 200°C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-100%) in heptane followed by purification by preparative HPLC (XBridge column; Method 1) gave 0.008 g (5%) of the desired compound as an amorphous salt. ESI/APCI(+): 394 (M+H); 416 (M+Na). ESI/APCI(-): 392 (M-H).

Example 59 Preparation of 5-(2-(1H-indol-3-yl)-1-((3-methoxyphenyl)amino)-2-oxoethyl)-1,3-dimethyl1H-benzo[d]imidazole-2(3H )-she.

Step 1. 5-(((3-Methoxyphenyl)imino)methyl)-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one was quantified according to General Procedure I from 1,3-dimethyl- 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5carbaldehyde (0.109 g, 0.573 mmol) and 3-methoxyaniline (0.065 ml, 0.578 mmol). ESI/APCI (+): 296 (M+H).

Stage 2. 5-(2-(1 H-Indol-3-yl)-1 -((3-methoxyphenyl)amino)-2-oxoethyl)-1,3-dimethyl-1 H-benzo[d]imidazole- 2(3H)-one was prepared according to the general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (0.077 g, 0.285 mmol) and triethylamine (0.060 ml, 0.430 mmol) in ethanol (1 ml), tert-Butyl-3-formyl-1H-indole-1-carboxylate (0.140 g, 0.572 mmol) and a solution of 5-(((3-methoxyphenyl- 71 040588 nyl)imino)methyl)-1,3-dimethyl-1H- benzo[d]imidazol-2(3H)-one (0.573 mmol) in ethanol (0.5 ml) heated at 65° C. for 3 days. Concentration of the reaction mixture under reduced pressure by precipitation from acetone and diethyl ether gave 0.049 g (19%) of the desired compound as a pale yellow solid. ESI/APCI (+): 441 (M+H). ESI/APCI (-): 439 (M-H).

Example 60 Preparation of 4-(2-(1H-indol-3-yl)-1-((2-methoxypyridin-4-yl)amino)-2-oxoethyl)benzonitrile.

Step 1 4-(((2-Methoxypyridin-4-yl)imino)methyl)benzonitrile was quantified according to General Procedure J from 4-formylbenzonitrile (0.131 g, 0.998 mmol), 2-methoxypyridin-4-amine (0.124 g, 0.999 mmol) and magnesium sulfate (0.100 g, 0.831 mmol) in ethanol (1 ml).

Step 2. 4-(2-(III-Indol-3-yl)-1-((2-methoxypyridin-4-yl)amino)-2-oxoethyl)benzonitrile was prepared according to general procedure K from a mixture of 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1Hindole-1- carboxylate (0.245 g, 0.999 mmol) and a solution of 4-(((2-methoxypyridin-4-yl)imino)methyl)benzonitrile (0.999 mmol) in ethanol (1 ml) heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane gave 0.125 g (31%) of the desired compound as a white powder. ESI/APCI(+): 383 (M+H). ESI/APCI(-): 381 (M-H).

Example 61 Preparation of 1-(1H-indol-3-yl)-2-((4-methoxy-6-methylpyrimidin-2-yl)amino)-2-phenylethanone

Step 1 N-Benzylidene-4-methoxy-6-methylpyrimidin-2-amine was quantified according to General Procedure J from benzaldehyde (0.100 mL, 0.987 mmol), 4-methoxy-6-methylpyrimidin-2-amine (0.132 g, 0.949 mmol) and magnesium sulfate (0.100 g, 0.831 mmol) in ethanol (1 ml). ESI/APCI(+): 228 (M+H).

Step 2 1-(1H-Indol-3-yl)-2-((4-methoxy-6-methylpyrimidin-2-yl)amino)-2-phenylethanone was prepared according to General Procedure L from a mixture of 3-benzyl-5- (2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.124 g, 0.460 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1Hindole-1-carboxylate (0.204 g, 0.832 mmol) and a solution of N-benzylidene-4-methoxy-6-methylpyrimidin-2-amine (0.949 mmol) in ethanol (2 ml) heated at 70°C for 65 h. Purification by silica gel flash chromatography using an ethyl acetate gradient (30-100%) in heptane followed by recrystallization from dichloromethane gave 0.001 g (1%) of the desired compound as a powder. ESI/APCI(+): 373 (M+H); 395 (M + Na). ESI/APCI(-): 371 (M-H).

Example 62 Preparation of 2-(6-hydroxypyridin-3-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone

Step 1 5-(((3-Methoxyphenyl)imino)methyl)pyridin-2-ol was quantitatively obtained according to General Procedure I from 6-hydroxynicotinaldehyde (0.125 g, 1.015 mmol) and 3-methoxyaniline (0.115 ml, 1.023 mmol). ESI/APCI (+): 229 (M+H). ESI/APCI (-): 227 (M-H).

Step 2 2-(6-Hydroxypyridin-3-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to General Procedure L from a mixture of 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.140 g, 0.519 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1Hindole-1- carboxylate (0.249 g, 1.016 mmol) and a solution of 5-(((3-methoxyphenyl)imino)methyl)pyridin-2ol (1.015 mmol) in ethanol (1 ml) heated at 65°C for 4 days. The residue was purified by silica gel flash chromatography using a gradient of ethyl acetate (50-100%) in heptane. Further purification by flash chromatography on silica gel using a gradient of methanol (0-5%) in dichloromethane followed by purification by preparative HPLC (XBridge column; method 2) gave 0.078 g (21%) of the desired compound as a yellow solid. ESI/APCI (+): 374 (M+H). ESI/APCI (): 372 (M-H).

Example 63 Preparation of 2-(imidazo[1,2-a]pyridin-2-yl)-1-(1H-indol-3-yl)-2-((2-methoxypyridin-4yl)amino)ethanone.

Step 1 N-(Imidazo[1,2-a]pyridin-2-ylmethylene)-2-methoxypyridin-4-amine was prepared according to the 2 different procedures described herein as Method A and Method B.

Method A: N-(Imidazo[1,2-a]pyridin-2-ylmethylene)-2-methoxypyridine-4-amine was quantified according to General Procedure H from imidazo[1,2-a]pyridine-2-carbaldehyde (0.150 g, 1.026 mmol), magnesium sulfate (0.200 g, 1.662 mmol) and 4-amino-2-methoxypyridine (0.29 g, 1.039 mmol) in ethanol (1 ml). ESI/APCI (+): 253 (M+H).

Method B: A mixture of imidazo[1,2-a]pyridine-2-carbaldehyde (0.250 g, 1.711 mmol) and 4-amino-2-methoxypyridine (0.215 g, 1.732 mmol) in 2-methyltetrahydrofuran (5 mL) was refluxed at help from the Dean-Stark apparatus. The solvent was evaporated under reduced pressure to give quantitatively N-(imidazo[1,2-a]pyridin-2-ylmethylene)-2-methoxypyridin-4-amine, which was used in the next step without further purification. ESI/APCI (+): 253 (M+H).

Step 2. 2-(Imidazo[1,2-a]pyridin-2-yl)-1-(1H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (0.140 g, 0.519 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (1 ml), tert-butyl-3formyl- 1H-indole-1-carboxylate (0.252 g, 1.027 mmol) and a solution of N-(umudαzo[1,2-α]nirudin-2-ylmethu- 72 040588 len)-2-methoxypyridine-4-amine (1.026 mmol) in ethanol (1 ml), heated at 65°C for 4 days.

Purification by flash chromatography on silica gel using a gradient of methanol (0-5%) in dichloromethane followed by purification by preparative HPLC (XBridge column; method 3) gave 0.031 g (7%) of the desired compound as a yellow solid. ESI/APCI (+): 398 (M+H). ESI/APCI (-): 396 (M-H).

Example 64 Preparation of 3-((2-(1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)benzamide.

3-((2-(1H-Indol-3-yl)-2-oxo-1-phenylethyl)amino)benzamide was prepared according to General Procedure C from 2-chloro-1-(1H-indol-3-yl)-2 -phenylethanone (0.105 g, 0.389 mmol), 3-aminobenzamide (0.099 g, 0.727 mmol) and DIPEA (0.200 ml, 1.148 mmol) in acetonitrile (2 ml) irradiated in a microwave oven at 200°C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-100%) in heptane followed by purification by preparative HPLC (XBridge column; method 2) gave 0.003 g (2%) of the desired compound as a solid. ESI/APCI(+): 370 (M+H); 392 (M + Na). ESI/APCI(-): 368 (M-H).

Example 65 Preparation of 1-(1H-indol-3-yl)-2-((4-methoxypyridin-2-yl)amino)-2-phenylethanone

Step 1 N-Benzylidene-4-methoxypyridine-2-amine was quantified according to General Procedure J from benzaldehyde (0.100 ml, 0.987 mmol), 4-methoxypyridine-2-amine (0.124 g, 0.999 mmol) and magnesium sulfate (0.100 g , 0.831 mmol) in ethanol (1 ml). ESI/APCI(+): 213 (M+H).

Step 2. 1-(III-Indol-3-yl)-2-((4-methoxypyridin-2-yl)amino)-2-phenylethanone was prepared according to General Procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl )-4-methylthiazol-3-ium chloride (0.128 g, 0.474 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1H-indole-1-carboxylate (0.202 g, 0.824 mmol) and a solution of N-benzylidene-4-methoxypyridin-2-amine (0.999 mmol) in ethanol (2 ml) heated at 70°C for 65 hours. Purification by flash chromatography on silica gel using an ethyl acetate gradient (30- 100%) in heptane followed by purification by preparative HPLC (SunFire column; Method 2) gave 0.032 g (11%) of the desired compound as an amorphous salt. ESI/APCI(+): 358 (M+H). ESI/APCI(-): 356 (M-H).

Example 66 Preparation of 1-(1H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2-phenylethanone

Step 1 N-Benzylidene-5-methoxypyridine-3-amine was quantified according to General Procedure J from benzaldehyde (0.100 ml, 0.987 mmol), 5-methoxypyridine-3-amine (0.130 g, 1.047 mmol) and magnesium sulfate (0.100 g , 0.831 mmol) in ethanol (1 ml). ESI/APCI(+): 213 (M+H).

Step 2. 1-(III-Indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2-phenylethanone was prepared according to General Procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl )-4-methylthiazol-3-ium chloride (0.124 g, 0.460 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1H-indole-1-carboxylate (0.203 g, 0.828 mmol) and a solution of N-benzylidene-5-methoxypyridin-3-amine (0.987 mmol) in ethanol (2 ml) heated at 70°C for 65 hours. Purification by flash chromatography on silica gel using an ethyl acetate gradient (30- 100%) in heptane followed by precipitation from diethyl ether gave 0.033 g (11%) of the desired compound as a solid. ESI/APCI(+): 358 (M+H); 380 (M + Na). ESI/APCI(-): 356 (M-H). 1H NMR (DMSO-d ₆ ): δ 12.19 (1H, br s); 8.91 (1H, m); 8.15 (1H, m); 7.83 (1H, m); 7.65 (2H, m); 7.48 (2H, m); 7.19-7.32 (4H, m); 6.68-6.81 (2H, m); 6.16 (1H, m); 3.70 (3H, s).

Example 67 Preparation of ethyl 3-((2-(1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)benzoate.

Ethyl 3-((2-(1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)benzoate was prepared according to General Procedure C from 2-chloro-1-(1H-indol-3-yl) -2-phenylethanone (0.292 g, 1.083 mmol), ethyl 3-aminobenzoate (0.322 g, 1.949 mmol) and DIPEA (0.400 ml, 2.296 mmol) in acetonitrile (2 ml), irradiated in a microwave oven at 200°C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-40%) in heptane followed by precipitation from diethyl ether gave 0.123 g (29%) of the desired compound as a solid. ESI/APCI(+): 399 (M+H); 421 (M+Na). ESI/APCI(): 397 (M-H). ¹ H NMR (CDCl ₃ ) δ 8.58 (1H, br s); 8.40 (1H, m); 8.02 (1H, m); 7.54 (2H, m); 7.18-7.38 (9H, m); 6.87 (1H, m); 5.77 (1H, s); 4.32 (2H, q); 1.36 (3H, t).

Example 68 Preparation of 1-(6-chloro-1H-indol-3-yl)-2-(imidazo[1,2-a]pyridin-2-yl)-2-((2-methoxypyridin-4-yl) amino)ethanone.

Step 1. tert-Butyl-6-chloro-3-formyl-1H-indole-1-carboxylate was prepared according to General Procedure F from 6-chloro-1H-indole-3-carbaldehyde (0.500 g, 2.784 mmol), di-tert -butyl dicarbonate (0.740 g, 3.391 mmol) and DMAP (0.050 g, 0.409 mmol) in acetonitrile (9 mL) to give 0.760 g (98%) of the desired compound as a brown solid. 1H NMR (DMSO-d ₆ ) δ 10.07 (1H, s); 8.70 (1H, s); 8.13 (2H, m); 7.45 (1H, d); 1.67 (9H, s).

Step 2. 1-(6-Chloro-1H-indol-3-yl)-2-(imidazo[1,2-a]pyridin-2-yl)-2-((2-methoxypyridin-4yl)amino)ethanone was obtained according to the general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.141 g, 0.476 mmol) and triethylamine (0.085 ml, 0.611 mmol) in ethanol (1 ml), t- butyl 6-chloro-3-formyl-1H-indol-1-carboxylate (0.240 g, 0.856 mmol) and a solution of N-(umudazo[1,2-a]pyridin-2-ylmethylene)-2-methoxypyridine-4- amine (0.856 mmol) in ethanol (2 ml) heated at 65°C for 5 days. The residue was purified by silica gel flash chromatography using a gradient of ethyl acetate (25-100%) in heptane. Additional purification by preparative HPLC (column

- 73 040588

XBridge; method 3) followed by precipitation from acetone and heptane gave 0.015 g (4%) of the desired compound as a beige solid. ESI/APCI (+): 432, 434 (M+H).

Example 69 Preparation of 1-(1H-indol-3-yl)-2-((5-methoxy-1,2,4-thiadiazol-3-yl)amino)-2-phenylethanone

Step 1 N-Benzylidene-5-methoxy-1,2,4-thiadiazol-3-amine was quantified according to General Procedure J from benzaldehyde (0.100 ml, 0.987 mmol), 5-methoxy-1,2,4-thiadiazol- 3-amine (0.157 g, 1.197 mmol) and magnesium sulfate (0.100 g, 0.831 mmol) in ethanol (1 ml). ESI/APCI(+): 220 (M+H).

Step 2 1-(1H-Indol-3-yl)-2-((5-methoxy-1,2,4-thiadiazol-3-yl)amino)-2-phenylethanone was prepared according to General Procedure L from a mixture of 3- benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.130 g, 0.482 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1H -indole-1-carboxylate (0.210 g, 0.856 mmol) and a solution of N-benzylidene-5-methoxy-1,2,4-thiadiazol-3-amine (0.987 mmol) in ethanol (2 ml), heated at 70°C for 24 hours Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-80%) in heptane followed by recrystallization from diethyl ether gave 0.002 g (1%) of the desired compound as a solid. ESI/APCI(+): 365 (M+H); 387 (M + Na). ESI/APCI(-): 363 (M-H).

Example 70 Preparation of 3-((2-(1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)benzoic acid.

A mixture of ethyl 3-((2-(1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)benzoate (0.067 g, 0.168 mmol) and lithium hydroxide (0.065 g, 2.714 mmol) in ethanol ( 2.5 ml) and water (2.5 ml) were stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The phases were separated. The aqueous phase was acidified with 1N. hydrochloric acid solution and extracted with ethyl acetate. The phases were separated. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by recrystallization from diethyl ether gave 0.010 g (16%) of the desired compound as a white solid. ESI/APCI(+): 371 (M+H). ESI/APCI(-): 369 (M-H).

Example 71 Preparation of 1-(1H-indol-3-yl)-2-((6-methoxypyrimidin-4-yl)amino)-2-phenylethanone

Step 1. A solution of N-benzylidene-6-methoxypyrimidin-4-amine in methanol was prepared by heating a solution of benzaldehyde (0.100 ml, 0.987 mmol) and 6-methoxypyrimidine-4-amine (0.165 g, 1.319 mmol) in methanol (1 ml) at 70° C. for 18 hours. Imine formation was quantitative and the solution was used without further purification. ESI/APCI(+): 214 (M+H).

Step 2 To a solution of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.147 g, 0.545 mmol) in ethanol (1 ml) was added triethylamine (0.100 ml, 0.717 mmol) and the mixture was stirred at 70°C for 5 min. To the resulting yellow solution was added tert-butyl-3-formyl-1H-indole-1-carboxylate (0.208 g, 0.848 mmol) and a solution of N-benzylidene-6-methoxypyrimidine-4-amine (0.987 mmol) in methanol (1 ml) . The reaction mixture was stirred in a sealed tube at 70° C. for 65 hours. The reaction mixture was concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30-100%) in heptane gave 0.015 g (5%) of 1-(1H-indol-3-yl)-2-((6-methoxypyrimidin-4-yl)amino )-2-phenylethanone as a white solid. ESI/APCI(+): 359 (M+H); 381 (M + Na). ESI/APCI(-): 357 (M-H).

Example 72 Preparation of 1-(6-chloro-1H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-phenylethanone

-(6-Chloro-1 H-indol-3 -yl)-2-((2-methoxypyridin-4-yl)amino)-2-phenylethanone was obtained according to the general procedure K from a mixture of 3-benzyl-5-(2- hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.498 mmol) in ethanol (1 ml), tert-butyl-6-chloro-3-formyl-1H-indole 1- carboxylate (0.280 g, 1.001 mmol) and a solution of N-benzylidene-2-methoxypyridine-4-amine (1.000 mmol) in ethanol (1 ml) heated at 70°C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-100%) in heptane followed by precipitation from diethyl ether gave 0.094 g (23%) of the desired compound as a solid. ESI/APCI(+): 392, 394 (M+H). ESI/APCI(-): 390, 392 (M-H).

Example 73 Preparation of 1-(1H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-(pyridin-3-yl)ethanone

Step 1. 2-Methoxy-N-(pyridin-3-ylmethylene)pyridin-4-amine was quantified according to General Procedure H from nicotinaldehyde (0.094 mL, 0.999 mmol), 2-methoxypyridin-4-amine (0.124 g, 0.999 mmol ) and magnesium sulfate (0.100 g, 0.831 mmol) in ethanol (1 mL).

Step 2. 1-(1H-Indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-(pyridin-3-yl)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl -5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g, 0.555 mmol) and triethylamine (0.070 ml, 0.498 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1H- indole-1-carboxylate (0.245 g, 0.999 mmol) and a solution of 2-methoxy-N-(pyridin-3-ylmethylene)pyridine-4-amine (0.999 mmol) in ethanol (1 ml), heated at 70°C for 3 days . Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-100%) in heptane gave 0.069 g (19%) of the desired compound. ESI/APCI(+): 359 (M+H). ESI/APCI(-): 357 (M-H).

Example 74 Preparation of 1-(6-fluoro-1H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-phenylethanone

- 74 040588

Step 1. tert-Butyl-6-fluoro-3-formyl-1H-indole-1-carboxylate was prepared according to General Procedure F from 6-fluoro-1H-indole-3-carbaldehyde (0.653 g, 4.003 mmol), di-tert -butyl dicarbonate (1.048 g,

4.802 mmol) and DMAP (0.049 g, 0.401 mmol) in acetonitrile (10 mL) to give 0.924 g (88%) of the desired compound as a white solid. ESI/APCI(+): 264 (M+H). 1H NMR (DMSO-d ₆ ) δ 10.06 (1H, s); 8.67 (1H, s); 8.14 (1H, t); 7.83 (1H, d); 7.28 (1H, t); 1.67 (9H, s).

Step 2. 1-(6-Fluoro-1H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5- (2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.498 mmol) in ethanol (1 ml), tert-butyl-6-fluoro-3-formyl-1Hindole -1-carboxylate (0.263 g, 0.999 mmol) and a solution of K-benzylidene-2-methoxypyridine-4-amine (0.999 mmol) in ethanol (1 ml), heated at 70°C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane gave 0.107 g (28%) of 1-(6-fluoro-Shindol-3-yl)-2-((2-methoxypyridin-4-yl )amino)-2-phenylethanone. ESI/APCI(+): 376 (M+H). ESI/APCI(-): 374 (M-H).

Example 75 Preparation of 1-(6-methoxy-1H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-phenylethanone

Step 1. tert-Butyl-3-formyl-6-methoxy-1H-indole-1-carboxylate was prepared according to General Procedure F from 6-methoxy-1H-indole-3-carbaldehyde (0.466 g, 2.660 mmol), di-tert -butyl dicarbonate (0.697 g, 3.134 mmol) and DMAP (0.032 g, 0.266 mmol) in acetonitrile (4 mL) to give 0.648 g (88%) of the desired compound as a white solid.

Step 2. 1-(6-Methoxy-1H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5- (2-hydroxyethyl)-4-methylthiazol-3-yl chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.498 mmol) in ethanol (1 ml), tert-butyl-3-formyl-6methoxy-1H-indole -1-carboxylate (0.275 g, 0.999 mmol) and a solution of K-benzylidene-2-methoxypyridine-4amine (0.999 mmol) in ethanol (1 ml), heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by precipitation from diethyl ether gave 0.070 g (18%) of the desired compound as a solid. ESI/APCI(+): 388 (M+H). ESI/APCI(-): 386 (M-H).

Example 76 Preparation of 1-(6-methoxy-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone

1-(6-Methoxy-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was obtained according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4 -methylthiazol-3-yl chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.498 mmol) in ethanol (1 ml), tert-butyl-3-formyl-6-methoxy-1H-indole-1-carboxylate (0.275 g , 0.999 mmol) and a solution of K-benzylidene-3-methoxyaniline (0.999 mmol) in ethanol (1 ml), heated at 70°C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by precipitation from diethyl ether gave 0.053 g (13%) of the desired compound as a solid. ESI/APCI(+): 387 (M+H). ESI/APCI(-): 385 (M-H).

Example 77 Preparation of 1-(5-methoxy-1H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-phenylethanone

Step 1. tert-Butyl-3-formyl-5-methoxy-1H-indole-1-carboxylate was prepared according to General Procedure F from 5-methoxy-1H-indole-3-carbaldehyde (0.701 g, 4.001 mmol), di-tert -butyl dicarbonate (1.048 g, 4.712 mmol) and DMAP (0.049 g, 0.4007 mmol) in acetonitrile (10 mL) to give 0.934 g (85%) of the desired compound as a white solid. ESI/APCI(+): 276 (M+H).

Step 2. 1-(5-Methoxy-1H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5- (2-hydroxyethyl)-4-methylthiazol-3-yl chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.498 mmol) in ethanol (1 ml), tert-butyl-3-formyl-5methoxy-1H-indole -1-carboxylate (0.275 g, 0.999 mmol) and a solution of K-benzylidene-2-methoxypyridine-4amine (0.999 mmol) in ethanol (1 ml), heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by precipitation from diethyl ether gave 0.085 g (21%) of the desired compound as a solid. ESI/APCI(+): 388 (M+H). ESI/APCI(-): 386 (M-H).

Example 78 Preparation of methyl 3-(2-((2-methoxypyridin-4-yl)amino)-2-phenylacetyl)-1H-indole-6carboxylate.

Step 1. 1-tert-Butyl-6-methyl-3-formyl-1H-indole-1,6-dicarboxylate was prepared according to General Procedure F from methyl 3-formyl-1H-indole-6-carboxylate (0.813 g, 4.001 mmol), di-tert-butyl dicarbonate (1.048 g, 4.712 mmol) and DMAP (0.049 g, 0.4007 mmol) in acetonitrile (10 mL) to give 1.139 g (94%) of the desired compound as a white solid.

Step 2 Methyl 3-(2-((2-methoxypyridin-4-yl)amino)-2-phenylacetyl)-1H-indole-6-carboxylate was prepared according to General Procedure K from a mixture of 3-benzyl-5-(2 -hydroxyethyl)-4-methylthiazol-3-yl chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.498 mmol) in ethanol (1 ml), 1-tert-butyl-6-methyl3-formyl-1H-indole -1,6-dicarboxylate (0.303 g, 0.999 mmol) and a solution of K-benzylidene-2-methoxypyridine-4-amine (0.999 mmol) in ethanol (1 ml), heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by precipitation from diethyl ether gave 0.055 g (13%) of the desired compound as a solid. ESI/APCI(+): 416 (M+H). ESI/APCI(-): 414 (M-H).

Example 79 Preparation of 2-(6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazin-2-yl)-1-(1H-indol-3-yl)-2-( (3methoxyphenyl)amino)ethanone.

Step 1 N-((6,8-Dihydro-5H-imidazo[2,1-c]oxazin-2-yl)methylene)-3-methoxyaniline was quantitatively obtained according to General Procedure I from 6,8-dihydro-5H- imidazo[2,1-c][1,4]oxazine-2-carbaldehyde (0.125 g, 0.999 mmol) and 3-methoxyaniline (0.115 ml, 1.023 mmol).

Step 2. 2-(6,8-Dihydro-5H-imidazo[2,1-c][1,4]oxazin-2-yl)-1-(1H-indol-3-yl)-2-(( 3-Methoxyphenyl)amino)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.140 g, 0.519 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1H-indole-1-carboxylate (0.245 g, 0.999 mmol) and a solution of N-((6,8-dihydro5H-imidazo[2,1-c]oxazine-2 -yl)methylene)-3-methoxyaniline (0.999 mmol) in ethanol (1 ml) heated at 65°C for 3 days and at 80°C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (50-100%) in heptane followed by precipitation from dichloromethane and diethyl ether gave 0.036 g (9%) of the desired compound as a white solid. ESI/APCI(+): 403 (M+H). ESI/APCI(-): 401 (M-H).

Example 80 Preparation of 2-(5-fluoroimidazo[1,2-a]pyridin-2-yl)-1-(1H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino) ethanone.

Step 1. A solution of N-((5-fluoroimidazo[1,2-a]pyridin-2-yl)methylene)-2-methoxypyridin-4-amine in ethanol was prepared by heating a solution of 5-fluoroimidazo[1,2-a] pyridine-2-carbaldehyde (0.100 g, 0.609 mmol) and 6-methoxypyrimidine-4-amine (0.076 g, 0.609 mmol) in ethanol (1 ml) at 65°C for 18 h. Imine formation was quantitative and the solution was used without additional cleaning. ESI/APCI(+): 271 (M+H).

Step 2. 2-(5-Fluorimidazo[1,2-a]pyridin-2-yl)-1-(1H-indol-3-yl)-2-((2-methoxypyridin-4yl)amino)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.080 g, 0.297 mmol) and triethylamine (0.065 ml, 0.466 mmol) in ethanol (1 ml), tert-butyl- 3-formyl-1H-indol-1-carboxylate (0.215 g, 0.611 mmol) and a solution of N-((5fluoroimidazo[1,2-a]pyridin-2-yl)methylene)-2-methoxypyridin-4-amine (0.609 mmol) in ethanol (1 ml) heated at 65°C for 4 days. The residue was purified by silica gel flash chromatography using a gradient of ethyl acetate (30-100%) in heptane and then methanol (25%) in dichloromethane as eluent. Further purification by preparative HPLC (XBridge column; method 3) gave 0.063 g (25%) of the desired compound as a white solid. ESI/APCI(+): 416 (M+H). ESI/APCI(-): 414 (M-H).

Example 81 Preparation of 1-(1H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-(thiazol-4-yl)ethanone

Step 1 A mixture of thiazole-4-carbaldehyde (0.115 g, 1.016 mmol) and 4-amino-2-methoxypyridine (0.126 g, 1.016 mmol) in ethanol (1 ml) was stirred at 65° C. for 16 h. The solvent was evaporated and the residue was dried under reduced pressure to give quantitatively 2-methoxy-N(thiazol-4-ylmethylene)pyridin-4-amine, which was used without further purification. ESI/APCI (+): 220 (M+H).

Step 2. 1-(1H-Indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-(thiazol-4-yl)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl -5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.140 g, 0.519 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1H- indole-1-carboxylate (0.249 g, 1.017 mmol) and a solution of 2-methoxy-N-(thiazol-4-ylmethylene)pyridine-4-amine (1.016 mmol) in ethanol (1 ml), heated at 65°C for 6 days . Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by precipitation from diethyl ether gave 0.044 g (12%) of the desired compound as a white solid. ESI/APCI(+): 365 (M+H). ESI/APCI(-): 363 (M-H).

Example 82 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyrazolo[1,5-a]pyridin-2yl)ethanone

Step 1 To a solution of pyrazolo[1,5-a]pyridine-2-carboxylic acid (0.202 g, 1.246 mmol) in dichloromethane (2 ml) were added HATU (0.472 g, 1.241 mmol) and DIPEA (0.450 ml, 2.577 mmol) . After stirring for 5 minutes at room temperature, N,O-dimethylhydroxylamine hydrochloride (0.128 g, 1.312 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed with water. The phases were separated. The organic phase was washed with 1N. hydrochloric acid solution, 1N. sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give N-methoxy-N-methylpyrazolo[1,5-a]pyridine-2-carboxamide, which was used in the next step without further purification. ESI/APCI (+): 206 (M+H).

Step 2 To a solution of N-methoxy-N-methylpyrazolo[1,5-a]pyridine-2-carboxamide (1.246 mmol) in dry THF (3 ml) cooled at -15°C (acetone/cold) was added aluminum hydride lithium (0.048 g, 1.257 mmol) and the solution was stirred for 3 hours. 1N was added. Rochelle's salt solution and the reaction mixture were stirred at room temperature for 10 min. The phases were separated. The aqueous phase was extracted with ether. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica using a gradient of ethyl acetate (0-30%) in heptane gave 0.088 g (48% over 2 steps) of pyrazolo[1,5a]pyridine-2-carbaldehyde as a white solid. ESI/APCI (+): 147 (M+H).

Step 3. 3-Methoxy-N-(pyrazolo[1,5-a]pyridin-2-ylmethylene)aniline was quantified according to General Procedure I from pyrazolo[1,5-a]pyridine-2-carbaldehyde (0.087 g, 0.595 mmol) and 3-methoxyaniline (0.070 ml, 0.623 mmol).

Step 4 1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyrazolo[1,5-a]pyridin-2-yl)ethanone was prepared according to the general procedure K from mixtures of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.082 g, 0.304 mmol) and triethylamine (0.060 ml, 0.430 mmol) in ethanol (0.7 ml), tert-butyl- 3formyl-1H-indole-1-carboxylate (0.151 g, 0.616 mmol) and a solution of 3-methoxy-N-(nyrαzolo[1,5a]pyridin-2-ylmethylene)aniline (0.623 mmol) in ethanol (0.7 ml) heated at 65°C all night. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-60%) in heptane followed by precipitation from dichloromethane gave 0.055 g (23%) of the desired compound as a yellow solid. ESI/APCI(+): 397 (M+H). ESI/APCI(-): 395 (M-H).

Example 83 Preparation of 1-(7-chloro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone

Step 1. tert-Butyl-7-chloro-3-formyl-III-indole-1-carboxylate was prepared according to General Procedure F from 7-chloro-1H-indole-3-carbaldehyde (0.718 g, 3.998 mmol), di-tert -butyl dicarbonate (1.048 g, 4.712 mmol) and DMAP (0.049 g, 0.401 mmol) in acetonitrile (10 mL) to give 0.687 g (61%) of the desired compound as a white solid.

Step 2. 1-(7-Chloro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl )-4-methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.498 mmol) in ethanol (1 ml), tert-butyl-7-chloro-3-formyl-1H-indole-1-carboxylate (0.280 g, 1.001 mmol) and a solution of K-benzylidene-3-methoxyaniline (0.999 mmol) in ethanol (1 ml), heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by precipitation from acetonitrile gave 0.058 g (14%) of the desired compound as a solid. ESI/APCI(+): 391 (M+H). ESI/APCI(-): 389 (M-H).

Example 84 Preparation of methyl 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1H-indole-6carboxylate

Methyl 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1H-indole-6-carboxylate was obtained according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazole -3-chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.498 mmol) in ethanol (1 ml), 1-tert-butyl-6-methyl-3-formyl-1Hindole-1,6-dicarboxylate ( 0.303 g, 0.999 mmol) and a solution of K-benzylidene-3-methoxyaniline (0.999 mmol) in ethanol (1 ml), heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by precipitation from diethyl ether gave 0.038 g (9%) of the desired compound as a solid. ESI/APCI(+): 415 (M+H). ESI/APCI(-): 413 (M-H).

Example 85 Preparation of 1-(5-chloro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone

Step 1. tert-Butyl-5-chloro-3-formyl-III-indole-1-carboxylate was prepared according to General Procedure F from 5-chloro-1H-indole-3-carbaldehyde (0.718 g, 3.998 mmol), di-tert -butyl dicarbonate (1.048 g, 4.712 mmol) and DMAP (0.049 g, 0.401 mmol) in acetonitrile (10 mL) to give 1.001 g (89%) of the desired compound as a white solid.

Step 2. 1-(5-Chloro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl )-4-methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.498 mmol) in ethanol (1 ml), tert-butyl-5-chloro-3-formyl-1H-indole-1-carboxylate (0.280 g, 1.001 mmol) and a solution of K-benzylidene-3-methoxyaniline (0.999 mmol) in ethanol (1 ml), heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by precipitation from diethyl ether gave 0.011 g (3%) of the desired compound as a solid. ESI/APCI(+): 391 (M+H). ESI/APCI(-): 389 (M-H).

Example 86 Preparation of 2-((2,6-dimethoxypyrimidin-4-yl)amino)-1-(III-indol-3-yl)-2-phenylethanone

Step 1. A solution of N-benzylidene-2,6-dimethoxypyrimidin-4-amine in methanol was prepared by heating a solution of benzaldehyde (0.100 ml, 0.987 mmol) and 2,6-dimethoxypyrimidine-4-amine (0.136 g, 0.877 mmol) in methanol (1 ml) at 70° C. for 18 hours. Imine formation was quantitative and the solution was used without further purification. ESI/APCI(+): 244 (M+H).

Step 2 To a solution of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.132 g, 0.489 mmol) in ethanol (1 ml) was added triethylamine (0.100 ml, 0.717 mmol) and the mixture was stirred at 70°C for 5 min. To the resulting yellow solution was added a solution of K-benzylidene-2,6-dimethoxypyrimidine-4-amine (0.877 mmol) in methanol (1 ml) and tert-butyl-3-formyl-1H-indole-1-carboxylate

- 77 040588 (0.208 g, 0.848 mmol). The reaction mixture was stirred in a sealed tube at 70° C. for 24 hours. The reaction mixture was concentrated. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (30-100%) in heptane. Additional purification of the preparative

HPLC (XBridge column; method 2) gave 0.005 g (2%) of the desired compound as a white solid. ESI/APCI(+): 389 (M+H); 411 (M+Na). ESI/APCI(-): 387 (M-H).

Example 87 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(8-methylimidazo[1,2a]pyridin-2-yl)ethanone

Stage 1. A solution of 3-methoxy-N-((8-methylimidazo[1,2-a]pyridin-2-yl)methylene)aniline in ethanol was obtained by heating a solution of 8-methylimidazo[1,2-a]pyridine-2 α-carbaldehyde (0.162 g, 1.011 mmol) and 3-methoxyaniline (0.115 ml, 1.023 mmol) in ethanol (0.5 ml) at 65° C. for 24 h. Imine formation was quantitative and the solution was used without further purification. ESI/APCI(+): 266 (M+H); 288 (M+Na); 531 (2M+H); 553 (2M+Na).

Step 2. 1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(8-methylimidazo[1,2-a]pyridin-2yl)ethanone was prepared according to the general procedure K from mixtures of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3ium chloride (0.140 g, 0.519 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (1 ml), tert-butyl-3formyl-1H- indole-1-carboxylate (0.270 g, 1.101 mmol) and a solution of 3-methoxy-N-((8-methylimidazo[1,2a]pyridin-2-yl)methylene)aniline (1.011 mmol) in ethanol (1 ml), heated at 65°C all night. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-70%) in heptane followed by precipitation from diethyl ether and dichloromethane gave 0.022 g (5%) of the desired compound as a pale yellow solid. ESI/APCI(+): 411 (M+H). ESI/APCI(-): 409 (M-H).

Example 88 Preparation of 1-(1H-indol-3-yl)-2-((4-methoxypyrimidin-2-yl)amino)-2-phenylethanone

Step 1 A solution of N-benzylidene-4-methoxypyrimidin-4-amine in methanol was prepared by heating a solution of benzaldehyde (0.100 ml, 0.987 mmol) and 4-methoxypyrimidine-2-amine (0.163 g, 1.303 mmol) in methanol (1 ml) at 70° C. for 18 hours. Imine formation was quantitative and the solution was used without further purification. ESI/APCI(+): 214 (M+H).

Step 2. 1-(1H-Indol-3-yl)-2-((4-methoxypyrimidin-2-yl)amino)-2-phenylethanone was prepared according to General Procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl )-4-methylthiazol-3-ium chloride (0.163 g, 0.604 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1H-indole-1-carboxylate (0.195 g, 0.795 mmol) and a solution of N-benzylidene-4-methoxypyrimidin-4-amine (0.987 mmol) in methanol (1 ml) heated at 70°C for 24 hours. Purification by flash chromatography on silica gel using a methanol gradient (0- 20%) in ethyl acetate followed by recrystallization from methanol gave 0.020 g (7%) of the desired compound as a white solid. ESI/APCI(+): 359 (M+H); 381 (M + Na). ESI/APCI(-): 357 (M+H).

Example 89 Preparation of 2-(4-fluorophenyl)-1-(1H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)ethanone

Step 1 N-(4-Fluorobenzylidene)-2-methoxypyridine-4-amine was quantitatively obtained according to the general procedure H from 4-fluorobenzaldehyde (0.106 ml, 1.004 mmol), magnesium sulfate (0.100 g, 0.831 mmol) and 2-methoxypyridine- 4-amine (0.124 g, 0.999 mmol) in ethanol (1 ml).

Step 2. 2-(4-Fluorophenyl)-1-(1H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.498 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1H-indol- 1 carboxylate (0.245 g, 0.999 mmol) and a solution of N-(4-fluorobenzylidene)-2-methoxypyridine-4-amine (0.999 mmol) in ethanol (1 ml) heated at 70°C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by purification by preparative HPLC (XBridge column; method 2) gave 0.068 g (17%) of the desired compound. ESI/APCI(+): 376 (M+H). ESI/APCI(-): 374 (M-H).

Example 90 Preparation of 2-(3-fluorophenyl)-1-(1H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)ethanone

Step 1 N-(3-Fluorobenzylidene)-2-methoxypyridine-4-amine was quantitatively obtained according to the general procedure H from 3-fluorobenzaldehyde (0.106 ml, 1.003 mmol), magnesium sulfate (0.100 g, 0.831 mmol) and 2-methoxypyridine- 4-amine (0.124 g, 0.999 mmol) in ethanol (1 ml).

Step 2. 2-(3-Fluorophenyl)-1-(1H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.498 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1H-indol- 1 carboxylate (0.245 g, 0.999 mmol) and a solution of N-(3-fluorobenzylidene)-2-methoxypyridine-4-amine (0.999 mmol) in ethanol (1 ml) heated at 70°C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by purification by preparative HPLC (XBridge column; method 5) gave 0.093 g (24%) of the desired compound. ESI/APCI(+): 376 (M+H). ESI/APCI(-): 374 (M-H).

Example 91 Preparation of 1-(5-methoxy-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone

1-(5-Methoxy-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was obtained according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4 -methylthiazol-3-th chloride (0.135 g, 0.500 mmol) and

- 78 040588 triethylamine (0.070 ml, 0.498 mmol) in ethanol (1 ml), tert-butyl-3-formyl-5-methoxy-1H-indole-1-carboxylate (0.275 g, 0.999 mmol) and a solution of K-benzylidene-3- methoxyaniline (0.999 mmol) in ethanol (1 ml) heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane gave 0.085 g (22%) of the desired compound.

ESI/APCI(+): 387 (M+H). ESI/APCI(-): 385 (M-H).

Example 92 Preparation of 3-(2-((2-methoxypyridin-4-yl)amino)-2-phenylacetyl)-1H-indole-6-carbonitrile

Step 1. tert-Butyl-6-cyano-3-formyl-1H-indole-1-carboxylate was prepared according to General Procedure F from 3-formyl-1H-indole-6-carbonitrile (0.511 g, 3.003 mmol), di-tert -butyl dicarbonate (0.786 g, 3.601 mmol) and DMAP (0.037 g, 0.303 mmol) in acetonitrile (7 mL) to give 0.697 g (76%) of the desired compound as a white solid.

Step 2. 3-(2-((2-Methoxypyridin-4-yl)amino)-2-phenylacetyl)-1H-indole-6-carbonitrile was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl )-4-methylthiazol-3-yl chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.498 mmol) in ethanol (1 ml), tert-butyl-6-cyano-3-formyl-III-indole-1-carboxylate (0.270 g, 0.999 mmol) and a solution of N-benzylidene-2-methoxypyridine-4amine (0.999 mmol) in ethanol (1 ml) heated at 70°C for 24 h. Purification by flash chromatography on silica gel using an ethyl acetate gradient (0- 100%) in heptane gave 0.058 g (15%) of the desired compound. ESI/APCI(+): 383 (M+H). ESI/APCI(-): 381 (M-H).

Example 93 Preparation of 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1H-indole-6-carbonitrile

3-(2-((3-Methoxyphenyl)amino)-2-phenylacetyl)-1H-indole-6-carbonitrile was obtained according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazole-3 chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.498 mmol) in ethanol (1 ml), tert-butyl-6-cyano-3-formyl-1H-indole-1-carboxylate (0.270 g, 0.999 mmol) and a solution of K-benzylidene-3-methoxyaniline (0.999 mmol) in ethanol (1 ml) heated at 70°C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane gave 0.038 g (9%) of the desired compound. ESI/APCI(+): 382 (M+H). ESI/APCI(-): 380 (M-H).

Example 94 Preparation of 2-(6,8-dihydro-5H-umidαzo[2,1-c][1,4]oxazin-2-yl)-1-(1H-indol-3-yl)-2-( (2methoxypyridin-4-yl)amino)ethanone.

Step 1: A mixture of 6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde (0.156 g, 1.025 mmol) and 4-amino-2-methoxypyridine (0.130 g, 1.047 mmol) in ethanol (1 ml) was stirred at 65°C for 2.5 days. The solvent was evaporated and the residue was dried under reduced pressure to give quantitatively N-((6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazin-2-yl)methylene)-2-methoxypyridine -4-amine, which was used without further purification.

Step 2. 2-(6,8-Dihydro-5H-imidazo[2,1-c][1,4]oxazin-2-yl)-1-(1H-indol-3-yl)-2-(( 2-Methoxypyridin-4-yl)amino)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5-(2hydroxyethyl)-4-methylthiazol-3-ium chloride (0.133 g, 0.493 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (1 mL), tert-butyl-3-formyl-1H-indole-1-carboxylate (0.252 g, 1.026 mmol) and N-((6,8-dihydro-5H-imidazo[2.1 -c][1,4]oxazin-2-yl)methylene)-2-methoxypyridin-4-amine (1.025 mmol) in ethanol (1 ml) heated at 65°C for 7 days. The residue was purified by flash chromatography on silica gel eluting first with ethyl acetate and then with methanol (30%) in dichloromethane. Further purification by preparative HPLC (XBridge column; method 2) gave 0.131 g (32%) of the desired compound as a yellow oil. ESI/APCI(+): 404 (M+H). ESI/APCI(-): 402 (M-H).

Example 95 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(7-methylimidazo[1,2a]pyridin-2-yl)ethanone

Stage 1. A solution of 3-methoxy-N-((7-methylimidazo[1,2-a]pyridin-2-yl)methylene)aniline in ethanol was obtained by heating a solution of 7-methylimidazo[1,2-a]pyridine-2 α-carbaldehyde (0.160 g, 0.999 mmol) and 3-methoxyaniline (0.113 ml, 1.009 mmol) in ethanol (0.5 ml) at 65° C. for 24 h. Imine formation was quantitative and the solution was used without further purification. ESI/APCI (+): 266 (M+H).

Step 2. 1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(7-methylimidazo[1,2-a]pyridin-2yl)ethanone was prepared according to the general procedure K from mixtures of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3ium chloride (0.140 g, 0.519 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (0.7 ml), tert-butyl 3-formyl- 1H-indole-1-carboxylate (0.270 g, 1.102 mmol) and a solution of 3-methoxy-N-((7-methylimudαzo[1,2a]pyridin-2-yl)methylene)aniline (0.999 mmol) in ethanol (1 ml ), heated at 65°C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30-100%) in heptane followed by precipitation from acetone gave 0.050 g (12%) of the desired compound as a pale yellow solid. ESI/APCI(+): 411 (M+H). ESI/APCI(-): 409 (M-H).

Example 96 Preparation of 1-(1H-indol-3-yl)-2-(1H-indol-5-yl)-2-((2-methoxypyridin-4-yl)amino)ethanone

Step 1. A solution of N-((1H-indol-5-yl)methylene)-2-methoxypyridine-4-amine in ethanol was prepared by heating a solution of 1H-indole-5-carbaldehyde (0.098 g, 0.675 mmol) and 2-methoxypyridine -4-amine (0.144 g, 1.160 mmol) in ethanol (1 mL) at 70°C for 65 hours. Imine formation was quantitative and the solution was used without further purification. ESI/APCI(+): 252 (M+H). ESI/APCI(-): 250 (M-H).

Step 2. 1-(III-Indol-3-yl)-2-(III-indol-5-yl)-2-((2-methoxypyridin-4-yl)amino)ethanone was prepared according to general procedure L from a mixture of 3 -benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.156 g, 0.578 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (1 ml), tert-butyl-3-formyl- 1H-indole-1-carboxylate (0.214 g, 0.872 mmol) and a solution of N-((1H-indol-5-yl)methylene)-2-methoxypyridine-4-amine (0.675 mmol) in ethanol (1 ml), heated at 70 °C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30-100%) in heptane, followed by purification by preparative HPLC (XBridge column; method 2) gave 0.011 g (3%) of the desired compound as a white solid substances. ESI/APCI(+): 397 (M+H). ESI/APCI(-): 395 (M-H).

Example 97 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6-methylimidazo[1,2a]pyridin-2-yl)ethanone

Stage 1. A solution of 3-methoxy-N-((6-methylimidazo[1,2-a]pyridin-2-yl)methylene)aniline in ethanol was obtained by heating a solution of 6-methylimidazo[1,2-a]pyridine-2 α-carbaldehyde (0.160 g, 0.999 mmol) and 3-methoxyaniline (0.113 ml, 1.009 mmol) in ethanol (0.5 ml) at 65° C. for 24 h. Imine formation was quantitative and the solution was used without further purification. ESI/APCI (+): 266 (M+H).

Step 2. 1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6-methylimidazo[1,2-a]pyridin-2yl)ethanone was prepared according to the general procedure K from mixtures of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3ium chloride (0.140 g, 0.519 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (0.7 ml), tert-butyl 3-formyl- 1H-indole-1-carboxylate (0.270 g, 1.102 mmol) and a solution of 3-methoxy-N-((6-methylimidaαzo[1,2a]pyridin-2-yl)methylene)aniline (0.999 mmol) in ethanol (1 ml ), heated overnight at 65°C. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30-100%) in heptane followed by precipitation from acetone gave 0.084 g (21%) of the desired compound as a white solid. ESI/APCI(+): 411 (M+H). ESI/APCI(-): 409 (M-H).

Example 98 Preparation of 1-(5-chloro-1H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-phenylethanone

-(5-Chloro-1 H-indol-3 -yl)-2-((2-methoxypyridin-4-yl)amino)-2-phenylethanone was obtained according to the general procedure K from a mixture of 3-benzyl-5-(2- hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.498 mmol) in ethanol (1 ml), tert-butyl-5-chloro-3-formyl-1H-indole 1- carboxylate (0.280 g, 1.001 mmol) and a solution of K-benzylidene-2-methoxypyridine-4-amine (0.999 mmol) in ethanol (1 ml), heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by precipitation from diethyl ether gave 0.089 g (22%) of the desired compound. ESI/APCI(+): 392, 394 (M+H). ESI/APCI(-): 390, 392 (M-H).

Example 99 Preparation of 2-((2-methoxypyridin-4-yl)amino)-1-(1-methyl-1H-indol-3-yl)-2-phenylethanone

2-((2-Methoxypyridin-4-yl)amino)-1-(1-methyl-1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2 -hydroxyethyl)-4-methylthiazol-3-yl chloride (0.169 g, 0.628 mmol) and triethylamine (0.088 ml, 0.628 mmol) in ethanol (2 ml), 1-methyl-1H-indole-3-carbaldehyde (0.200 g, 1.256 mmol) and a solution of K-benzylidene-2-methoxypyridine-4-amine (1.256 mmol) in ethanol (1 ml), heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by preparative HPLC (XBridge column; method 5) gave 0.034 g (7%) of the desired compound. ESI/APCI(+): 372 (M+H). ESI/APCI(-): 370 (M-H).

Example 100 Preparation of 1-(7-chloro-1H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-phenylethanone

-(7-Chloro-1 H-indol-3 -yl)-2-((2-methoxypyridin-4-yl)amino)-2-phenylethanone was obtained according to the general procedure K from a mixture of 3-benzyl-5-(2- hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.498 mmol) in ethanol (1 ml), tert-butyl-7-chloro-3-formyl-1H-indole 1- carboxylate (0.280 g, 1.001 mmol) and a solution of K-benzylidene-2-methoxypyridine-4-amine (0.212 g, 0.999 mmol) in ethanol (1 ml), heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by purification by preparative HPLC (XBridge column; method 5) gave 0.083 g (21%) of the desired compound. ESI/APCI(+): 392, 394 (M+H). ESI/APCI(-): 390, 392 (M-H).

Example 101 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(3-methylisoxazol-5yl)ethanone

Step 1. 3-Methoxy-N-((3-methylisoxazol-5-yl)methylene)aniline was quantitatively obtained according to General Procedure I from 3-methylisoxazole-5-carbaldehyde (0.111 g, 1.000 mmol) and 3-methoxyaniline (0.113 ml , 1,000 mmol). ESI/APCI(+): 217 (M+H).

Step 2. 1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(3-methylisoxazol-5-yl)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.069 ml, 0.497 mmol) in ethanol (0.7 ml), tert-butyl-3-formyl-1H-indole 1-carboxylate ( 0.294 g, 1.199 mmol) and a solution of 3-methoxy-N-((3-methylisoxazol-5-yl)methylene)aniline

- 80 040588 (1.000 mmol) in ethanol (0.7 ml) heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by recrystallization from ethyl acetate gave 0.051 g (14%) of the desired compound as a white solid. ESI/APCI(+): 362 (M+H); 384 (M+Na); 745 (2M+Na). ESI/APCI(-): 360 (M-H).

Example 102 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(1-methyl-1H-imidazol-4yl)ethanone

Step 1. 3-Methoxy-N-((1-methyl-1H-imidazol-4-yl)methylene)aniline was quantified according to General Procedure I from 1-methyl-1H-imidazole-4-carbaldehyde (0.110 g, 0.999 mmol ) and 3-methoxyaniline (0.113 ml, 1.000 mmol). ESI/APCI(+): 216 (M+H).

Stage 2. 1-(III-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(1-methyl-III-imidazol-4-yl)ethanone was obtained according to the general procedure K from a mixture of 3 -benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.069 ml, 0.497 mmol) in ethanol (0.7 ml), tert-butyl-3-formyl III-indole- 1-carboxylate (0.294 g, 1.199 mmol) and a solution of 3-methoxy-N- ((1-methyl-1H-imidazol-4yl) methylene) aniline (0.999 mmol) in ethanol (0.7 ml), heated at 70 ° C within 2 days. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane. Further purification by flash chromatography on silica gel using a gradient of methanol (0-10%) in dichloromethane followed by precipitation from dichloromethane gave 0.045 g (12%) of the desired compound as a beige powder. ESI/APCI(+): 361 (M+H); 383 (M+Na); 743 (2M+Na). ESI/APCI(-): 359 (M-H).

Example 103 Preparation of 1-(1-(2-hydroxyethyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone

Step 1 2-Chloro-1-(1-(2-hydroxyethyl)-1H-indol-3-yl)-2-phenylethanone was prepared according to General Method M from 2-chloro-1-(1H-indol-3-yl )-2-phenylethanone (0.150 g, 0.556 mmol), 2-bromoethanol (0.079 ml, 1.113 mmol) and potassium carbonate (0.115 g, 0.834 mmol) in DMF (3 ml). The reaction mixture was stirred at room temperature overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane gave 0.020 g (11%) of the desired compound as a white solid. ESI/APCI(+): 314 (M+H); 336 (M+Na). ESI/APCI(-): 312 (M-H).

Step 2 1-(1-(2-Hydroxyethyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to General Procedure C from 2-chloro-1-( 1-(2-hydroxyethyl)-1H-indol-3-yl)-2-phenylethanone (0.020 g, 0.064 mmol), 3-methoxyaniline (0.014 ml, 0.127 mmol) and DIPEA (0.021 ml, 0.127 mmol) in acetonitrile ( 0.5 ml), irradiated in a microwave oven at 200°C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-20%) in dichloromethane gave 0.006 g (25%) of the desired compound as a beige solid. ESI/APCI(+): 401 (M+H).

Example 104 Preparation of 1-(1-(2-aminoethyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone and tert-butyl-(2-(3-(2- ((3-methoxyphenyl)amino)-2-phenylacetyl)-1H-indol-1yl)ethyl)carbamate.

Step 1 tert-Butyl-(2-(3-(2-chloro-2-phenylacetyl)-1H-indol-1-yl)ethyl)carbamate was prepared according to General Method M from 2-chloro-1-(1H-indole -3-yl)-2-phenylethanone (0.150 g, 0.556 mmol), tert-butyl-(2-bromoethyl) carbamate (0.249 g, 1.111 mmol) and potassium carbonate (0.154 g, 1.114 mmol) in DMF (3 mL). The reaction mixture was stirred at room temperature overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane gave 0.120 g (52%) of the desired compound as a pink solid. ESI/APCI(+): 413 (M+H); 435 (M + Na).

Step 2. tert-Butyl-(2-(3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1H-indol-1-yl)ethyl)carbamate was prepared according to General Procedure C from tert-butyl -(2-(3-(2-chloro-2-phenylacetyl)-1H-indol-1yl)ethyl)carbamate (0.120 g, 0.291 mmol), 3-methoxyaniline (0.065 ml, 0.581 mmol) and DIPEA (0.099 ml, 0.581 mmol) in acetonitrile (3 ml) irradiated in a microwave oven at 200°C for 1.5 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (1-10%) in dichloromethane gave 0.066 g (45%) the desired compound as an orange solid. ESI/APCI(+): 500 (M+H), 522 (M+Na).

Step 3 To a solution of tert-butyl-(2-(3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1H-indol-1yl)ethyl)carbamate (0.066 g, 0.132 mmol) in dichloromethane (6 ml) was added triperoxonane acid (3 ml) and the mixture was stirred at room temperature for 2 hours, the Reaction mixture was concentrated under reduced pressure. The residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The phases were separated. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography using a gradient of methanol (1-15%) in dichloromethane. Further purification by preparative TLC using 10% methanol in dichloromethane as eluent gave 0.033 g (62%) 1-(1-(2aminoethyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)- 2-phenylethanone as a beige solid. ESI/APCI(+): 400 (M+H); 422 (M + Na).

Example 105 Preparation of ethyl 2-(3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1H-indol-1yl)acetate

Step 1. Ethyl 2-(3-(2-chloro-2-phenylacetyl)-1H-indol-1-yl)acetate was prepared according to general procedure M from 2-chloro-1-(1H-indol- 3-yl)-2-phenylethanone (0.400 g, 1.483 mmol), ethyl bromoacetate (0.329 ml, 2.974 mmol) and potassium carbonate (0.410 g, 2.967 mmol) in DMF (10 ml). The reaction mixture was stirred at room temperature for 1 hour. Purification by precipitation followed by recrystallization from ethanol gave 0.475 g (90%) of the desired compound as a beige solid.

ESI/APCI(+): 356, 358 (M+H). ESI/APCI(-): 354, 356 (M-H).

Step 2 Ethyl 2-(3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1H-indol-1-yl)acetate was prepared according to General Procedure C from ethyl 2-(3-( 2-chloro-2-phenylacetyl)-1H-indol-1-yl)acetate (0.250 g, 0.703 mmol), 3-methoxyaniline (0.157 ml, 1.402 mmol) and DIPEA (0.240 ml, 1.402 mmol) in acetonitrile (3 ml ) irradiated in a microwave oven at 200° C. for 1.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography using a gradient of ethyl acetate (2-40%) in heptane. Further purification by flash chromatography on silica gel eluting with dichloromethane followed by purification by preparative HPLC (XBridge column; method 1) gave 0.058 g (19%) of the desired compound as a beige solid. ESI/APCI(+): 443 (M+H). ESI/APCI(-): 441 (M-H).

Example 106 Preparation of 2-(3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1H-indol-1-yl)acetic acid.

1N . sodium hydroxide solution (0.108 ml, 0.108 mmol) and the reaction mixture was stirred at room temperature for 3 hours. Ethanol was evaporated under reduced pressure. The residue was diluted with water and extracted with dichloromethane. The phases were separated. The aqueous phase was acidified with 1N. hydrochloric acid solution to pH 2-3 and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and evaporated under reduced pressure to give 0.021 g (55%) 2-(3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1H-indol-1-yl)acetic acid as a white solid. ESI/APCI(+): 415 (M+H). ESI/APCI(-): 413 (M-H).

Example 107 Preparation of 2-(1-ethyl-1H-pyrazol-5-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone

Step 1 N-((1-Ethyl-1H-pyrazol-5-yl)methylene)-3-methoxyaniline was quantitatively obtained according to General Procedure I from 1-ethyl-1H-pyrazole-5-carbaldehyde (0.254 g, 2.046 mmol) and 3-methoxyaniline (0.229 ml, 2.045 mmol). ESI/APCI(+): 230 (M+H).

Step 2 To a solution of 1H-indole-3-carbaldehyde (5.000 g, 34.45 mmol) in DMSO (35 ml) was added sodium hydride (60% dispersion in mineral oil; 1.520 g, 37.89 mmol) and the mixture was stirred at room temperature for 30 min. Ethyl chloroformate (3.520 ml, 37.89 mmol) was added and the reaction mixture was stirred for 30 minutes. The reaction mixture was poured into ice-water. The resulting precipitate was filtered and taken up in ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane gave 6.79 g (91%) of ethyl 3-formyl-III-indole-1-carboxylate as a beige solid. ESI/APCI(+): 218 (M+H).

Step 3 2-(1-Ethyl-1H-pyrazol-5-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to General Procedure L from mixture 3 -benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (0.124 g, 0.460 mmol) and triethylamine (0.064 ml, 0.462 mmol) in ethanol (2 ml), ethyl 3-formyl-III-indole-1-carboxylate ( 0.200 g, 0.921 mmol) and a solution of N-((1-ethyl-1H-pyrazol-5-yl)methylene)-3-methoxyaniline (0.921 mmol) in ethanol (1 ml), heated overnight at 70°C. The residue was purified by silica gel flash chromatography using a gradient of ethyl acetate (5-50%) in dichloromethane followed by precipitation from dichloromethane and diethyl ether to give 0.008 g (2%) of the desired compound as a beige solid. ESI/APCI(+): 375 (M+H). ESI/APCI(-): 373 (M-H).

Example 108 Preparation of 1-(1H-indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-(5-methylisoxazol-3-yl)ethanone

Step 1. 2-Methoxy-N-((5-methylisoxazol-3-yl)methylene)pyridine-4-amine was quantitatively obtained according to General Procedure H from 5-methylisoxazole-3-carbaldehyde (0.111 g, 0.999 mmol), magnesium sulfate (0.100 g, 0.831 mmol) and 2-methoxypyridine-4-amine (0.124 g, 0.999 mmol) in ethanol (1 ml).

Step 2. 1-(1H-Indol-3-yl)-2-((2-methoxypyridin-4-yl)amino)-2-(5-methylisoxazol-3-yl)ethanone was prepared according to general procedure K from mixture 3 -benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.498 mmol) in ethanol (1 ml), tert-butyl-3-formyl 1H- indole-1-carboxylate (0.245 g, 0.999 mmol) and a solution of 2-methoxy-H-((5-methylisoxazol-3yl)methylene)pyridine-4-amine (0.999 mmol) in ethanol (1 ml), heated at 70 ° C within 2 days. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane. Further purification by preparative HPLC (XBridge column; method 5) followed by purification by preparative TLC using 65% ethyl acetate in heptane as eluent gave 0.021 g (6%) of the desired compound. ESI/APCI(+): 363 (M+H). ESI/APCI(-): 361 (M-H).

Example 109 Preparation of 2-(5-fluoroimidazo[1,2-a]pyridin-2-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone

Step 1. A solution of 5-fluoroimidazo[1,2-a]pyridine-2-carbaldehyde (0.151 g, 0.920 mmol) and 3-82 040588 methoxyaniline (0.105 ml, 0.934 mmol) in ethanol (1 ml) was stirred overnight at 60 °C. The reaction mixture was evaporated and dried under reduced pressure to give quantitatively

Pure ((5-fluoroimidazo[1,2-a]pyridin-2-yl)methylene)-3-methoxyaniline, which was used without further purification. ESI/APCI (+): 270 (M+H).

Step 2. 2-(5-Fluorimidazo[1,2-a]pyridin-2-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to the general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.125 g, 0.463 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (0.7 ml), t- butyl 3formyl-1H-indole-1-carboxylate (0.270 g, 1.102 mmol) and a solution of N-((5-fluoroimidazo[1,2-a]pyridin-2yl)methylene)-3-methoxyaniline (0.920 mmol) in ethanol (1 ml), heated at 60°C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-70%) in heptane followed by purification by preparative HPLC (XBridge column; method 5) gave 0.072 g (19%) of the desired compound. ESI/APCI(+): 415 (M+H). ESI/APCI(-): 413 (M-H).

Example 110 Preparation of 2-(6-fluoroimidazo[1,2-a]pyridin-2-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone

Step 1. A solution of N-((6-fluoroimidazo[1,2-a]pyridin-2-yl)methylene)-3-methoxyaniline in ethanol was obtained by heating a solution of 6-fluoroimidazo[1,2-a]pyridine-2- carbaldehyde (0.150 g, 0.914 mmol) and 3-methoxyaniline (0.113 ml, 1.009 mmol) in ethanol (0.5 ml) at 65° C. for 18 h. Imine formation was quantitative and the solution was used without further purification. ESI/APCI (+): 270 (M+H); 292 (M + Na).

Step 2. 2-(6-Fluorimidazo[1,2-a]pyridin-2-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to the general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.130 g, 0.482 mmol) and triethylamine (0.090 ml, 0.646 mmol) in ethanol (0.7 ml), tert butyl 3formyl-1H-indole-1-carboxylate (0.275 g, 1.121 mmol) and a solution of N-((6-fluoroimidazo[1,2-a]pyridin-2yl)methylene)-3-methoxyaniline (0.914 mmol) in ethanol (1 ml) heated at 65°C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-70%) in heptane gave 0.078 g (21%) of the desired compound as a brown solid. ESI/APCI(+): 415 (M+H). ESI/APCI(-): 413 (M-H).

Example 111 Preparation of 2-((3-methoxyphenyl)amino)-1-(1-(methylsulfonyl)-1H-indol-3-yl)-2phenylethanone

Step 1 To a suspension of 1H-indole-3-carbaldehyde (0.214 g, 1.447 mmol) in dichloromethane (3 ml) were added methanesulfonyl chloride (0.200 ml, 2.578 mmol) and DIPEA (0.300 ml, 1.722 mmol). The reaction mixture was stirred at room temperature for 18 hours. Water was added and the solution stirred for 1 hour. The phases were separated. The organic phase was washed with saturated bicarbonate and water, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-40%) in heptane gave 0.189 g (57%) of 1-(methylsulfonyl)-1H-indole-3-carbaldehyde as a beige solid. ESI/APCI(+): 224 (M+H).

Step 2 2-((3-Methoxyphenyl)amino)-1-(1-(methylsulfonyl)-1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure L from a mixture of 3-benzyl-5-(2 -hydroxyethyl)-4-methylthiazol-3-yl chloride (0.157 g, 0.582 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (1 ml), 1-(methylsulfonyl)-1Hindole-3-carbaldehyde (0.144 g, 0.645 mmol) and a solution of N-benzylidene-3-methoxyaniline (0.914 mmol) in ethanol (2 ml) heated at 70°C for 24 h. Purification by flash chromatography on silica gel using an ethyl acetate gradient (10-60%) in heptane followed by purification by preparative HPLC (XBridge column; method 2) gave 0.041 g (15%) of the desired compound. ESI/APCI(+): 435 (M+H); 457 (M + Na). ESI/APCI(-): 433 (M-H).

Example 112 Preparation of 2-(4-(2-(dimethylamino)ethoxy)phenyl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone

Step 1 N-(4-(2-(Dimethylamino)ethoxy)benzylidene)-3-methoxyaniline was prepared according to General Procedure I from 4-(2-(dimethylamino)ethoxy)benzaldehyde (0.185 g, 0.943 mmol) and 3-methoxyaniline (0.108 ml, 0.965 mmol). ESI/APCI(+): 299 (M+H).

Step 2. 2-(4-(2-(Dimethylamino)ethoxy)phenyl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to the general procedure K from a mixture of 3 -benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3ium chloride (0.129 g, 0.478 mmol) and triethylamine (0.066 ml, 0.496 mmol) in ethanol (0.7 ml), tert-butyl 3-formyl-1H- indole-1-carboxylate (0.281 g, 1.146 mmol) and a solution of N- (4- (2- (dimethylamino) ethoxy) benzylidene) -3-methoxyaniline (0.943 mmol) in ethanol (0.7 ml), heated at 70 ° C within 2 days. Purification by flash chromatography on silica gel using a gradient of methanol (0-30%) in dichloromethane followed by purification by preparative HPLC (XBridge column; method 5) gave 0.087 g (20%) of the desired compound as a yellow solid. ESI/APCI(+): 444 (M+H). ESI/APCI(-): 442 (M-H).

Example 113 Preparation of 1-(1-(2-(dimethylamino)ethyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)2-phenylethanone

To a solution of 1-(1-(2-aminoethyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone (0.020 g,

- 83 040588

0.056 mmol) in a mixture of THF (1 ml) and acetonitrile (1 ml) was added a 37% solution of formaldehyde in water (0.020 ml, 0.250 mmol) and sodium cyanoborohydride (0.004 g, 0.080 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The phases were separated. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by preparative TLC using 5% methanol in dichloromethane as eluent gave 0.006 g (30%) of 1(1-(2-(dimethylamino)ethyl)-1H-indol-3-yl)-2-((3-methoxyphenyl) amino)-2-phenylethanone as a beige solid. ESI/APCI(+): 428 (M+H). ESI/APCI(-): 426 (M-H).

Example 114 Preparation of N-(2-(1H-indol-3-yl)-2-oxo-1-phenylethyl)-2-(dimethylamino)-N-(3methoxyphenyl)acetamide.

Step 1 To a solution of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone (0.050 g, 0.140 mmol) in dichloromethane (3 ml) cooled at 0°C , triethylamine (0.059 ml, 0.421 mmol) and chloroacetyl chloride (0.034 ml, 0.421 mmol) were added. The reaction mixture was allowed to warm to room temperature over 15 minutes. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The phases were separated. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane gave 0.027 g (44%) N-(2-(1H-indol-3-yl)-2-oxo-1phenylethyl)-2-chloro -K-(3-methoxyphenyl)acetamide as a beige solid. ESI/APCI(+): 433, 435 (M+H). ESI/APCI(-): 431, 433 (M-H).

Step 2 To a solution of N-(2-(1H-indol-3-yl)-2-oxo-1-phenylethyl)-2-chloro-N-(3methoxyphenyl)acetamide (0.027 g, 0.062 mmol) in dry THF ( 2 ml), cooled at 0°C, was added a 2 M solution of dimethylamine in THF (0.156 ml, 0.312 mmol). The reaction mixture was stirred at room temperature for 2 hours and then heated at 55° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. Purification by preparative TLC using 10% methanol in dichloromethane as eluent gave 0.015 g (57%) N-(2-(1H-indol-3-yl)-2-oxo-1-phenylethyl)-2(dimethylamino)-K -(3-methoxyphenyl)acetamide as a beige solid. ESI/APCI(+): 442 (M+H). ESI/APCI(-): 440 (M-H).

Example 115 Preparation of 1-(6-chloro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(5-methylisoxazol3-yl)ethanone

1-(6-Chloro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(5-methylisoxazol-3-yl)ethanone was prepared according to general procedure L from a mixture of 3-benzyl- 5-(2-hydroxyethyl)-4-methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.498 mmol) in ethanol (1 ml), tert-butyl-6-chloro-3-formyl-1Nindole-1 -carboxylate (0.280 g, 1.001 mmol) and a solution of 3-methoxy-K-((5-methylisoxazol-3-yl)methylene)aniline (0.999 mmol) in ethanol (1 ml), heated at 70°C for 3 days . Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by purification by preparative HPLC (XBridge column; method 1) gave 0.060 g (14%) of the desired compound. ESI/APCI (+): 396, 398 (M+H). ESI/APCI (-): 394, 396 (M-H).

Example 116 Preparation of 2-((3-methoxyphenyl)amino)-1-(1-methyl-1H-indol-3-yl)-2-(5-methylisoxazol-3-yl)ethanone

2-((3-Methoxyphenyl)amino)-1-(1-methyl-1 H-indol-3-yl)-2-(5-methylisoxazol-3-yl)ethanone was prepared according to general procedure L from a mixture of 3-benzyl -5-(2-hydroxyethyl)-4-methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.498 mmol) in ethanol (1 ml), 1-methyl-1H-indole-3-carbaldehyde (0.159 g, 0.999 mmol) and a solution of 3-methoxy-N-((5-methylisoxazol-3-yl)methylene)aniline (0.999 mmol) in ethanol (1 ml), heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by purification by preparative HPLC (XBridge column; method 1) gave 0.005 g (1%) of the desired compound. ESI/APCI (+): 376 (M+H).

Example 117 Preparation of 1-(6-chloro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone

1-(6-Chloro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was obtained according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4 -methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.498 mmol) in ethanol (1 ml), tert-butyl-6-chloro-3-formyl-1H-indole-1-carboxylate (0.280 g, 0.999 mmol) and a solution of K-benzylidene-3-methoxyaniline (0.999 mmol) in ethanol (1 ml), heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by recrystallization from ethyl acetate gave 0.047 g (12%) of the desired compound as a solid. ESI/APCI (+): 391, 393 (M+H). ESI/APCI (-): 389, 391 (M-H).

Example 118 Preparation of 1-(5-fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone

Step 1 tert-Butyl 5-fluoro-3-formyl-1H-indole-1-carboxylate was prepared according to General Procedure F from 5-fluoro-1H-indole-3-carbaldehyde (0.454 g, 2.783 mmol), di-tert -butyl dicarbonate (0.728 g, 3.336 mmol) and DMAP (0.034 g, 0.278 mmol) in acetonitrile (7 mL) to give 0.473 g (65%) of the desired compound as a solid. 1H NMR (DMSO-d ₆ ) δ 10.07 (1H, s); 8.74 (1H, s); 8.12 (1H, dd); 7.82 (1H, dd); 7.33 (1H, dt); 1.66 (9H, s).

- 84 040588

Step 2. 1-(5-Fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl )-4-methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.498 mmol) in ethanol (1 ml), tert-butyl-5-fluoro-3-formyl-1H-indole 1-carboxylate (0.263 g, 0.999 mmol) and a solution of K-benzylidene-3-methoxyaniline (0.999 mmol) in ethanol (1 ml), heated at 70°C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by precipitation from diethyl ether gave 0.043 g (11%) of the desired compound as a solid. ESI/APCI(+): 375 (M+H). ESI/APCI(-): 373 (M-H).

Example 119 Preparation of 4-(2-(7-chloro-1H-indol-3-yl)-1-((3-methoxyphenyl)amino)-2-oxoethyl)benzonitrile

4-(2-(7-Chloro-1H-indol-3-yl)-1-((3-methoxyphenyl)amino)-2-oxoethyl)benzonitrile was obtained according to general procedure K from a mixture of 3-benzyl-5-( 2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.498 mmol) in ethanol (1 ml), tert-butyl-7-chloro-3-formyl-1H- indole 1-carboxylate (0.280 g, 1.001 mmol) and a solution of 4-(((3-methoxyphenyl)imino)methyl)benzonitrile (0.999 mmol) in ethanol (1 ml) heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by recrystallization from ethyl acetate gave 0.050 g (12%) of the desired compound as a solid. ESI/APCI(+): 416 (M+H). ESI/APCI(-): 414 (M-H).

Example 120 Preparation of 2-((2-methoxypyridin-4-yl)amino)-1-(1-(methylsulfonyl)-1H-indol-3-yl)2-phenylethanone

2-((2-Methoxypyridin-4-yl)amino)-1 -(1 -(methylsulfonyl)-1 H-indol-3-yl)-2-phenylethanone was obtained according to the general procedure L from a mixture of 3-benzyl-5- (2-hydroxyethyl)-4-methylthiazol-3-yl chloride (0.166 g, 0.615 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (1 ml), 1-(methylsulfonyl)-1Hindole-3-carbaldehyde (0.189 g, 0.847 mmol) and a solution of N-benzylidene-2-methoxypyridine-4-amine (0.909 mmol) in ethanol (2 ml) heated at 70° C. for 24 h. The reaction mixture was concentrated. The residue was purified by silica gel flash chromatography using a gradient of methanol (0-10%) in ethyl acetate, followed by purification by preparative HPLC (XBridge column; method 2) to give 0.008 g (2%) of the desired compound. ESI/APCI(+): 436 (M+H). ESI/APCI(-): 434 (M-H).

Example 121 Preparation of 2-((3-methoxyphenyl)amino)-1-(6-methyl-1H-indol-3-yl)-2-phenylethanone

Step 1 2-Chloro-1-(6-methyl-1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure A from 6-methyl-1H-indole (0.200 g, 1.525 mmol), pyridine (0.100 ml, 1.270 mmol) and α-chlorophenylacetyl chloride (0.240 ml, 1.530 mmol) in toluene (2.5 ml). Purification by precipitation gave 0.200 g (46%) of the desired compound as a beige solid. ESI/APCI(+): 284, 286. ESI/APCI(-): 282, 284 (M-H).

Step 2 2-((3-Methoxyphenyl)amino)-1-(6-methyl-N-indol-3-yl)-2-phenylethanone was prepared according to General Procedure C from 2-chloro-1-(6-methyl- 1H-indol-3-yl)-2-phenylethanone (0.110 g, 0.388 mmol), 3-methoxypyridine (0.087 ml, 0.388 mmol), DIPEA (0.133 g, 0.775 mmol) and a catalytic amount of sodium iodide in acetonitrile (1.5 ml) irradiated in a microwave oven at 200°C for 30 min. Purification by flash chromatography on silica gel eluting with dichloromethane followed by purification by preparative HPLC (XBridge column, method 5) gave 0.006 g (4%) of the desired compound as a white solid. ESI/APCI(+): 371 (M+H). ESI/APCI(-): 369 (M-H).

Example 122 Preparation of 1-(6-fluoro-III-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone

Step 1 2-Chloro-1-(6-fluoro-1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure A from 6-fluoro-1H-indole (0.250 g, 1.850 mmol), pyridine (0.120 ml, 1.518 mmol) and α-chlorophenylacetyl chloride (0.292 ml, 1.861 mmol) in toluene (3 ml). Purification by precipitation gave 0.150 g (28%) of the desired compound as a beige solid. ESI/APCI(+): 288, 290 (M+H). ESI/APCI(-): 286, 288 (M-H).

Step 2 1-(6-Fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to General Procedure C from 2-chloro-1-(6-fluoro- 1H-indol-3-yl)-2-phenylethanone (0.100 g, 0.348 mmol), 3-methoxyaniline (0.078 ml, 0.695 mmol), DIPEA (0.119 ml, 0.695 mmol) and a catalytic amount of sodium iodide in a mixture of dioxane (1 ml) and DMF (0.5 ml) irradiated in a microwave oven at 160°C for 30 min. Purification by flash chromatography on silica gel eluting with dichloromethane followed by purification by preparative HPLC (XBridge column; method 5) gave 0.012 g (9%) of the desired compound as a beige solid. ESI/APCI(+): 375 (M+H). ESI/APCI(-): 373 (M-H).

Example 123 Preparation of 2-(4-((dimethylamino)methyl)phenyl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone

Step 1. A solution of N-(4-((dimethylamino)methyl)benzylidene)-3-methoxyaniline in ethanol was prepared by heating a solution of para-dimethylaminomethylbenzaldehyde (0.161 g, 0.986 mmol) and 3-methoxyaniline (0.113 ml, 1.000 mmol) in ethanol (0.5 ml) at 65° C. for 18 hours. Imine formation was quantitative and the solution was used without further purification. ESI/APCI (+): 269 (M+H).

Stage 2. 2-(4-((Dimethylamino)methyl)phenyl)-1 -(1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone

- 85 040588 was prepared according to the general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-y chloride (0.135 g, 0.500 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (0 .7 ml), tert-butyl-3-formyl-III-indole-1-carboxylate (0.270 g, 1.101 mmol) and a solution of N-(4-((dimethylαmino)methyl)benzylidene)-3-methoxyaniline (0.986 mmol) in ethanol (1.5 ml), heated overnight at 65°C. Purification by preparative HPLC (XBridge column; method 2) gave 0.135 g (33%) of the desired compound as a brown solid. ESI/APCI(+): 414 (M+H). ESI/APCI(-): 412 (M-H).

Example 124 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(4-methyl-1H-imidazol-5yl)ethanone

Step 1 A solution of 3-methoxy-N-((4-methyl-1H-imidazol-5-yl)methylene)aniline in ethanol was prepared by heating a solution of 4-methyl-1H-imidazole-5-carbaldehyde (0.110 g, 0.999 mmol ) and 3-methoxyaniline (0.115 ml, 1.023 mmol) in ethanol (0.7 ml) at 65° C. for 24 hours. Imine formation was quantitative and the solution was used without further purification. ESI/APCI (+): 216 (M+H). ESI/APCI (-): 214 (M-H).

Stage 2. 1-(III-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(4-methyl-III-imidazol-5-yl)ethanone was obtained according to the general procedure K from a mixture of 3 -benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.134 g, 0.496 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (0.7 ml), tert-butyl-3- formylIII-indole-1-carboxylate (0.270 g, 1.101 mmol) and a solution of 3-methoxy-Ni((4-methyl-III-imidazol-5yl)methylene)aniline (0.999 mmol) in ethanol (1.5 ml), heated overnight at 65°C. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (XBridge column, method 3). Further purification by preparative HPLC (SunFire column; method 3) gave 0.043 g (12%) of the desired compound. ESI/APCI(+): 361 (M+H).

Example 125 Preparation of 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1H-indole-5-carbonitrile

Step 1. tert-Butyl-5-cyano-3-formyl-1H-indole-1-carboxylate was prepared according to General Procedure F from 3-formyl-1H-indole-5-carbonitrile (0.340 g, 1.999 mmol), di-tert -butyl dicarbonate (0.524 g, 2.401 mmol) and DMAP (0.024 g, 0.197 mmol) in acetonitrile (7 mL) to give 0.379 g (73%) of the desired compound as a solid. 1H NMR (DMSO-d ₆ ) δ 10.11 (1H, s); 8.85 (1H, s); 8.50 (1H, s); 8.27 (lH, d); 7.87 (lH,dd); 1.68 (9H, s).

Step 2 3-(2-((3-Methoxyphenyl)amino)-2-phenylacetyl)-1H-indole-5-carbonitrile was prepared according to General Procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4- methylthiazol-3-chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.498 mmol) in ethanol (1 ml), tert-butyl-5-cyano-3-formyl-1Hindole-1-carboxylate (0.270 g, 1.000 mmol) and a solution of N-benzylidene-3-methoxyaniline (0.999 mmol) in ethanol (1 ml) heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by recrystallization from ethyl acetate gave 0.034 g (9%) of the desired compound as a white solid. ESI/APCI(+): 382 (M+H). ESI/APCI(-): 380 (M-H).

Example 126 Preparation of 2-(4-(hydroxymethyl)phenyl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone

Step 1. ((4-Bromobenzyl)oxy)(tert-butyl)dimethylsilane was prepared according to the general procedure N from 4-bromobenzyl alcohol (0.500 g, 2.673 mmol), DBU (0.408 ml, 2.734 mmol) and TBdMsCI (0.816 g, 5.414 mmol) in THF (10 ml). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-50%) in heptane gave 0.749 g (93%) of the desired compound as a colorless liquid.

Step 2 To a solution of ((4-bromobenzyl)oxy)(tert-butyl)dimethylsilane (0.500 g, 1.660 mmol) in THF (6 ml) cooled at -70° C., a 2.5 M solution of n- butylium in hexane (0.800 ml, 2.000 mmol). After 30 minutes at -70° C., DMF (0.300 ml, 3.875 mmol) was added and the reaction mixture was allowed to warm to -5° C. over 4 hours. The reaction was quenched by adding saturated ammonium chloride solution. After warming to room temperature, the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of dichloromethane (10-80%) in heptane to give 0.382 g (92%) of 4-(((tert-butyldimethylsilyl)oxy)methyl)benzaldehyde as a colorless liquid. 1H NMR (DMSO-d ₆ ) δ 9.89 (1H, s); 7.79 (2H, d); 7.44 (2H, d); 4.72 (2H, s); 0.82 (9H, s); 0.00 (6H, s).

Step 3 N-(4-(((tert-Butyldimethylsilyl)oxy)methyl)benzylidene)-3-methoxyaniline was quantitatively obtained according to General Procedure I from 4-(((tert-butyldimethylsilyl)oxy)methyl)benzaldehyde (0.250 g, 0.998 mmol) and meta-anisidine (0.113 ml, 1.000 mmol). ESI/APCI(+): 356 (M+H).

Step 4 2-(4-(((tert-Butyldimethylsilyl)oxy)methyl)phenyl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to the general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.069 ml, 0.498 mmol) in ethanol (0.7 ml), tert-butyl-3 -formyl-1H-indole-1-carboxylate (0.294 g, 1.199 mmol) and a solution of N-(4-(((tert-butyldimethylsilyl)oxy)methyl)benzylidene)-3-methoxyaniline (0.998 mmol) in ethanol (0.7 ml ), heated at 70°C for 2 days. The residue was purified by silica gel flash chromatography using a gradient of ethyl acetate (20-50%) in heptane. Further purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-50%) in heptane gave 0.148 g (30%) of the desired compound as a yellow oil. ESI/APCI(+): 501 (M+H); 523 (M + Na). ESI/APCI(-): 499 (M-H).

Step 5. To a solution of 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-1-(1H-indol-3-yl)-2-((3methoxyphenyl)amino)ethanone (0.148 g, 0.296 mmol) in DMF (2.5 ml) was added cesium fluoride (0.221 g, 1.455 mmol). After 3 hours at room temperature, the reaction mixture was concentrated. The residue was divided between ethyl acetate and 1N. hydrochloric acid solution. The phases were separated.

The organic phase was washed with saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel flash chromatography using a gradient of methanol (0-8%) in dichloromethane followed by recrystallization from ethyl acetate to give 0.027 g (24%) of 2-(4-(hydroxymethyl)phenyl)-1-(1Hindol-3-yl) -2-((3-methoxyphenyl)amino)ethanone as a white powder. ESI/APCI(+): 387 (M+H); 409 (M + Na). ESI/APCI(-): 385 (M-H).

Example 127 Preparation of 1-(1-(3-hydroxypropyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone

Step 1. 2-Chloro-1-(1-(3-hydroxypropyl)-1H-indol-3-yl)-2-phenylethanone was prepared according to General Method M from 2-chloro-1-(1H-indol-3-yl )-2-phenylethanone (0.200 g, 0.741 mmol), 3-bromopropan-1ol (0.206 g, 1.482 mmol) and potassium carbonate (0.205 g, 1.483 mmol) in DMF (3 mL). The reaction mixture was stirred at room temperature overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15-70%) in heptane gave 0.215 g (84%) of the desired compound as a red oil. ESI/APCI(+): 328, 330 (M+H). ESI/APCI(-): 326, 328 (M-H).

Step 2 1-(1-(3-Hydroxypropyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to General Procedure E from 2-chloro-1-( 1-(3-hydroxypropyl)-1H-indol-3-yl)-2-phenylethanone (0.070 g, 0.213 mmol), 3-methoxyaniline (0.478 ml, 4.270 mmol) in acetonitrile (1 ml), irradiated in a microwave oven at 150°C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15-70%) in heptane followed by preparative TLC purification using 10% ethyl acetate in dichloromethane as eluent gave 0.027 g (30%) of the desired compound as a beige solid. ESI/APCI(+): 415 (M+H).

Example 128 Preparation of 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-N,N-dimethyl-1H-indole-5sulfonamide.

Step 1. tert-Butyl-5-(N,N-dimethylsulfamoyl)-3-formyl-1H-indole-1-carboxylate was prepared according to General Procedure F from 3-formyl-N,N-dimethyl-1H-indole-5- sulfonamide (0.505 g, 2.003 mmol), di-tert-butyl dicarbonate (0.524 g, 2.401 mmol) and DMAP (0.024 g, 0.197 mmol) in acetonitrile (5 mL) to give 0.602 g (85%) of the desired compound as a solid . 1H NMR (DMSO-d ₆ ) δ 10.13 (1H, s); 8.87 (1H, s); 8.50 (1H, s); 8.36 (1H, d); 7.84 (1H, d); 2.62 (6H, s); 1.68 (9H, s).

Step 2 3-(2-((3-Methoxyphenyl)amino)-2-phenylacetyl)-N,N-dimethyl-1H-indole-5-sulfonamide was prepared according to General Procedure L from a mixture of 3-benzyl-5-(2 -hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.498 mmol) in ethanol (1 ml), tert-butyl-5-(N,Ndimethylsulfamoyl)-3-formyl -1H-indole-1-carboxylate (0.352 g, 0.999 mmol) and a solution of N-benzylidene-3-methoxyaniline (0.999 mmol) in ethanol (1 ml), heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by precipitation from diethyl ether gave 0.047 g (9%) of the desired compound as a solid. ESI/APCI(+): 464 (M+H). ESI/APCI(-): 462 (M-H).

Example 129 Preparation of 2-((3-methoxyphenyl)amino)-1-(5-methyl-1H-indol-3-yl)-2-phenylethanone

Step 1. tert-Butyl-3-formyl-5-methyl-1H-indole-1-carboxylate was prepared according to General Procedure F from 5-methyl-1H-indole-3-carbaldehyde (0.478 g, 3.003 mmol), di-tert -butyl dicarbonate (0.524 g, 3.602 mmol) and DMAP (0.036 g, 0.295 mmol) in acetonitrile (8 mL) to give 0.710 g (91%) of the desired compound as a solid. 1H NMR (DMSO-d ₆ ) δ 10.06 (1H, s); 8.61 (1H, s); 7.91-8.03 (2H, m); 7.27 (1H, d); 2.43 (3H, s); 1.66 (9H, s).

Step 2 2-((3-Methoxyphenyl)amino)-1-(5-methyl-1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl )-4-methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.498 mmol) in ethanol (1 ml), tert-butyl-3-formyl-5-methyl-1Hindole-1-carboxylate (0.259 g, 0.999 mmol) and a solution of N-benzylidene-3-methoxyaniline (0.999 mmol) in ethanol (1 ml), heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of 0-100% ethyl acetate in heptane followed by precipitation from methyl t-butyl ether gave 0.053 g (14%) of the desired compound as a solid. ESI/APCI(+): 371 (M+H). ESI/APCI(-): 369 (M-H).

Example 130 Preparation of 2-((3,5-dimethoxyphenyl)amino)-1-(5-fluoro-1H-indol-3-yl)-2-phenylethanone

Step 1 2-Chloro-1-(5-fluoro-1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure A from 5-fluoro-1H-indole (1.000 g, 7.400 mmol), pyridine (0.120 ml, 7.419 mmol) and α-chlorophenylacetyl chloride (1.100 ml, 7.390 mmol) in toluene (19 ml). Purification by precipitation gave 0.978 g (46%)

- 87 040588 the desired compound in the form of a light yellow solid. ESI/APCI(+): 288, 290 (M+H); 310, 312 (M+Na). ESI/APCI(-): 286, 288 (M-H).

Step 2 2-((3,5-Dimethoxyphenyl)amino)-1-(5-fluoro-III-indol-3-yl)-2-phenylethanone was prepared according to General Method E from 2-chloro-1-(5- fluoro-1H-indol-3-yl)-2-phenylethanone (0.100 g, 0.348 mmol) and 3,5-dimethoxyaniline (0.484 g, 3.160 mmol) in acetonitrile (1 ml), irradiated in a microwave oven at 150°C in within 15 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane gave 0.045 g (32%) of the desired compound as a beige solid. ESI/APCI(+): 405 (M+H). ESI/APCI(-): 403 (M-H).

Example 131 Preparation of 4-(2-(1H-indol-3-yl)-1-((3-methoxyphenyl)amino)-2-oxoethyl)-2-fluorobenzonitrile

Step 1 A solution of 2-fluoro-4-(((3-methoxyphenyl)imino)methyl)benzonitrile in ethanol was prepared by heating a solution of 2-fluoro-4-formylbenzonitrile (0.137 g, 0.919 mmol) and 3-methoxyaniline (0.107 ml, 0.952 mmol) in ethanol (1 ml) at 60° C. for 18 hours. Imine formation was quantitative and the solution was used without further purification. ESI/APCI (+): 255 (M+H).

Step 2 4-(2-(1H-Indolol-3-yl)-1-((3-methoxyphenyl)amino)-2-oxoethyl)-2-fluorobenzonitrile was prepared according to general procedure K from a mixture of 3-benzyl-5- (2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.124 g, 0.460 mmol) and triethylamine (0.090 ml, 0.646 mmol) in ethanol (0.5 ml), tert-butyl-3-formyl 1H-indole-1 -carboxylate (0.260 g, 1.060 mmol) and a solution of 2-fluoro-4-(((3-methoxyphenyl)imino)methyl)benzonitrile (0.919 mmol) in ethanol (1.5 ml), heated at 60°C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-40%) in heptane gave 0.154 g (42%) of the desired compound as a yellow foam. ESI/APCI(+): 400 (M+H). ESI/APCI(-): 398 (M-H).

Example 132 Preparation of 4-(2-(1H-indol-3-yl)-1-((3-methoxyphenyl)amino)-2-oxoethyl)-3,5-difluorobenzonitrile

Step 1 A solution of 3,5-difluoro-4-(((3-methoxyphenyl)imino)methyl)benzonitrile in ethanol was prepared by heating a solution of 3,5-difluoro-4-formylbenzonitrile (0.151 g, 0.904 mmol) and 3-methoxyaniline (0.105 ml, 0.934 mmol) in ethanol (1 ml) at 60° C. for 24 hours. Imine formation was quantitative and the solution was used without further purification. ESI/APCI (+): 273 (M+H).

Step 2 4-(2-(1H-Indol-3-yl)-1-((3-methoxyphenyl)amino)-2-oxoethyl)-3,5-difluorobenzonitrile was prepared according to general procedure K from a mixture of 3-benzyl -5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.124 g, 0.460 mmol) and triethylamine (0.090 ml, 0.646 mmol) in ethanol (0.5 ml), tert-butyl-3formyl-1H- indole-1-carboxylate (0.260 g, 1.060 mmol) and a solution of 3,5-difluoro-4-(((3-methoxyphenyl)imino)methyl)benzonitrile (0.904 mmol) in ethanol (1.5 ml), heated at 60 °C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-50%) in heptane gave 0.214 g (58%) of the desired compound as a yellow oil. ESI/APCI(+): 418 (M+H).

Example 133 Preparation of 1-(6-hydroxy-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone

Step 1. 6-((tert-Butyldimethylsilyl)oxy)-1H-indole was prepared according to the general procedure N from 6hydroxyindole (0.500 g, 3.755 mmol), DBU (0.573 ml, 3.839 mmol) and TBDMSC1 (1.150 g, 7.630 mmol) in THF (13 ml). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2050%) in heptane gave 0.888 g (96%) of the desired compound as a white solid. ESI/APCI(+): 248 (M+H). ESI/APCI(-): 246 (M-H).

Step 2 1-(6-((tert-Butyldimethylsilyl)oxy)-1H-indol-3-yl)-2-chloro-2-phenylethanone was prepared according to General Procedure A from 6-((tert-butyldimethylsilyl)oxy)- 1H-indole (0.785 g, 3.173 mmol), pyridine (0.275 ml, 3.276 mmol) and α-chlorophenylacetyl chloride (0.547 ml, 3.461 mmol) in toluene (8 ml). The residue obtained after extraction was purified by precipitation from ethyl acetate to give 0.669 g (53%) of the desired compound as a white solid. ESI/APCI(+): 400, 402 (M+H); 422, 424 (M+Na). ESI/APCI(-): 398, 400 (M-H).

Step 3 1-(6-((tert-Butyldimethylsilyl)oxy)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone was prepared according to General Procedure E from 1-(6-( (tert-Butyldimethylsilyl)oxy)-1H-indol3-yl)-2-chloro-2-phenylethanone (0.300 g, 0.750 mmol) and 3-methoxyaniline (1.680 ml, 15.02 mmol) in acetonitrile (3 ml), irradiated in a microwave oven at 150°C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-50%) in heptane gave 0.200 g (55%) of the desired compound as a beige powder. ESI/APCI(+): 487 (M+H); 509 (M+Na). ESI/APCI(-): 485 (M-H).

Step 4 To a solution of 1-(6-((tert-butyldimethylsilyl)oxy)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone (0.200 g, 0.411 mmol) in DMF (3.5 ml) was added cesium fluoride (0.312 g, 2.054 mmol). After 2.5 hours at room temperature, the reaction mixture was concentrated. The residue was divided between ethyl acetate and 1N. hydrochloric acid solution. The phases were separated. The organic phase was washed with saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel using a gradient of methanol (0-10%) in dichloromethane followed by recrystallization from ethyl acetate and heptane gave 0.020 g (13%) of 1-(6-hydroxy-1H-indol-3-yl)-2- ((3-methoxyphenyl)amino)-2-phenylethanone as a gray powder. ESI/APCI(+): 373 (M+H); 395 (M + Na).

- 88 040588

ESI/APCI(-): 371 (M-H).

Example 134 Preparation of 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-III-indole-6-carboxylic acid

To a solution of methyl 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1H-indole-6-carboxylate (0.100 g, 0.241 mmol) in a mixture of THF (3 ml) and methanol (3 ml) added 6n. sodium hydroxide solution (1.500 ml, 9.000 mmol) and the mixture was refluxed for 3 hours. The reaction mixture was partially concentrated under reduced pressure. The remaining aqueous solution was acidified with 1N. hydrochloric acid solution to pH 2-3. The precipitate was filtered, washed with water and dried. Further purification of the precipitate by preparative HPLC (XBridge column; method 2) gave 0.020 g (21%) of 3(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1H-indole-6-carboxylic acid as a white solid . ESI/APCI(+): 401 (M+H). ESI/APCI(-): 399 (M-H).

Example 135 Preparation of 1-(1-(2-methoxyethyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone

Step 1. 2-Chloro-1-(1-(2-methoxyethyl)-1H-indol-3-yl)-2-phenylethanone was prepared according to General Method M from 2-chloro-1-(1H-indol-3-yl )-2-phenylethanone (0.200 g, 0.741 mmol), 1-bromo-2-methoxyethane (0.206 g, 1.482 mmol) and potassium carbonate (0.205 g, 0.183 mmol) in DMF (3 ml). The reaction mixture was stirred at room temperature overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane gave 0.115 g (47%) of the desired compound as a beige solid. ESI/APCI(+): 350, 352 (M+Na). ESI/APCI(-): 326, 328 (M-H).

Step 2 1-(1-(2-Methoxyethyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to General Procedure E from 2-chloro-1-( 1-(3-hydroxypropyl)-1H-indol-3-yl)-2-phenylethanone (0.050 g, 0.153 mmol), 3-methoxyaniline (0.354 ml, 3.150 mmol) in acetonitrile (1 ml), irradiated in a microwave oven at 150°C for 15 min. Purification by flash chromatography on silica gel using 5% ethyl acetate in dichloromethane as eluent followed by purification by preparative HPLC (XBridge column; method 1) gave 0.025 g (39%) of the desired compound as a white solid. ESI/APCI(+): 415 (M+H). ESI/APCI(-): 413 (M-H). 1H NMR (DMSO-d6) δ 8.95 (1H, s); 8.17 (1H, d); 7.57-7.68 (3H, m); 7.11-7.33 (5H, m); 6.92 (1H, t); 6.34-6.46 (3H, m); 6.11 (1H, d); 6.05 (1H, d); 4.45 (2H, br s); 3.73 (2H, m); 3.62 (3H, s); 3.23 (3H, s).

Example 136 Preparation of 1-(5-fluoro-1-methyl-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone

Step 1 2-Chloro-1-(5-fluoro-1-methyl-1H-indol-3-yl)-2-phenylethanone was prepared according to General Method M from 2-chloro-1-(5-fluoro-1H-indole -3-yl)-2-phenylethanone (0.200 g, 0.695 mmol), iodomethane (0.216 ml, 3.470 mmol) and potassium carbonate (0.192 g, 1.389 mmol) in DMF (3 ml). The reaction mixture was stirred at room temperature overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15-50%) in heptane gave 0.076 g (36%) of the desired compound as a beige solid. ESI/APCI(+): 302, 304 (M+H); 324, 326 (M+Na). ESI/APCI(-): 300, 302 (M-H).

Step 2 1-(5-Fluoro-1-methyl-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to General Procedure E from 2-chloro-1-( 5-fluoro-1-methyl-1H-indol-3-yl)-2-phenylethanone (0.070 g, 0.232 mmol), 3-methoxyaniline (0.519 ml, 4.619 mmol) in acetonitrile (1 ml), irradiated at 150°C within 30 min. Purification by flash chromatography twice on silica gel using a first gradient of ethyl acetate (5-50%) in heptane and then a gradient of dichloromethane (15-70%) in heptane, followed by precipitation from t-butyl methyl ether gave 0.020 g (22%) of the desired compound in as a beige solid. ESI/APCI(+): 389 (M+H). ESI/APCI(-): 387 (M-H). 1H NMR (DMSO-d6) δ 8.99 (1H, s); 7.79-7.88 (1H, dd); 7.63 (2H, d); 7.54-7.61 (1H, m); 7.25-7.35 (2H, m); 7.10-7.24 (2H, m); 6.92 (1H, t); 6.336.44 (3H, m); 6.11 (1H, d); 5.99 (1H, d); 3.91 (3H, s); 3.62 (3H, s).

Example 137 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(m-tolyl)ethanone

Step 1 A solution of 3-methoxy-N-(3-methylbenzylidene)aniline in ethanol was prepared by heating a solution of 3-methylbenzaldehyde (0.120 ml, 1.019 mmol) and 3-methoxyaniline (0.120 ml, 1.068 mmol) in ethanol (1 ml) at 60° C. for 18 hours. Imine formation was quantitative and the solution was used without further purification. ESI/APCI (+): 226 (M+H).

Step 2. 1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(m-tolyl)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5-(2- hydroxyethyl)-4-methylthiazol-3-ium chloride (0.140 g, 0.519 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (0.5 ml), tert-butyl-3-formyl-1H-indole-1-carboxylate ( 0.270 g, 1.101 mmol) and a solution of 3-methoxy-N-(3-methylbenzylidene)aniline (1.019 mmol) in ethanol (1.5 ml) heated at 60°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-30%) in heptane followed by preparative HPLC (XBridge column; method 1) gave 0.085 g (23%) of the desired compound. ESI/APCI(+): 371 (M+H). ESI/APCI(-): 369 (M-H).

Example 138 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(para-tolyl)ethanone

Step 1 A solution of 3-methoxy-N-(4-methylbenzylidene)aniline in ethanol was prepared by heating a solution of 4-methylbenzaldehyde (0.120 ml, 1.014 mmol) and 3-methoxyaniline (0.120 ml, 1.068 mmol) in

- 89 040588 ethanol (1 ml) at 60°C for 18 hours. Imine formation was quantitative and the solution was used without further purification. ESI/APCI (+): 226 (M+H).

Step 2. 1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(para-tolyl)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5-(2- hydroxyethyl)-4-methylthiazol-3-ium chloride (0.138 g, 0.512 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (0.5 ml), tert-butyl-3-formyl-1H-indole-1-carboxylate ( 0.274 g, 1.117 mmol) and a solution of 3-methoxy-M-(4-methylbenzylidene)aniline (1.014 mmol) in ethanol (1.5 ml) heated at 60°C for 24 h. Purification by flash chromatography on silica gel with using a gradient of ethyl acetate (0-40%) in heptane followed by precipitation from acetone and heptane gave 0.085 g (23%) of the desired compound as a beige solid. ESI/APCI(+): 371 (M+H). ESI/APCI(-): 369 (M-H).

Example 139 Preparation of 1-(6-(hydroxymethyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone

Step 1 To a suspension of lithium aluminum hydride (0.866 g, 22.82 mmol) in dry THF (30 ml) cooled at 0°C was added a solution of methyl 1H-indole-6-carboxylate (2.000 g, 11.42 mmol ) in THF (30 ml) under nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight. The reaction was quenched by the careful addition of 1N. Rochelle salt solution. The reaction mixture was stirred at room temperature for 2 hours and then extracted with dichloromethane. The phases were separated. The organic phase was dried over magnesium sulfate and evaporated under reduced pressure to give 2.050 g of (1H-indolyl-6-yl)methanol as a yellow oil which was used in the next step without further purification. ESI/APCI(-): 146 (M-H).

Step 2 To a solution of (1H-indol-6-yl)methanol (0.500 g, 3.397 mmol) in dry THF (20 ml) cooled at 0°C was added sodium hydride (60% in mineral oil; 0.271 g, 6.775 mmol). After stirring for 5 minutes, TBDMSCl (0.512 g, 3.397 mmol) was added. The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The phases were separated. The aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane gave 0.482 g (46% over 2 steps) of 6-(((tert-butyldimethylsilyl)oxy)methyl)-1H-indole as a white solid. ESI/APCI(+): 262 (M+H). ESI/APCI(-): 260 (M-H).

Step 3 2-Chloro-1-(6-(hydroxymethyl)-1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure A from 6-(((tert-butyldimethylsilyl)oxy)methyl)-1H- indole (0.265 g, 1.014 mmol), pyridine (0.082 ml, 1.014 mmol) and α-chlorophenylacetyl chloride (0.151 ml, 1.014 mmol) in toluene (2.6 ml). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-100%) in heptane gave 0.064 g (21%) of the desired compound. ESI/APCI(+): 300, 302 (M+H); 322, 324 (M+Na). ESI/APCI(-): 298, 300 (M-H). ¹ H NMR (DMSO-d6) δ 12.15 (1H, br s); 8.61 (1H, d); 8.09 (1H, d); 7.63 (2H, d); 7.25-7.48 (5H, m); 7.16 (1H, d); 6.73 (1H, s); 5.20 (1H, t); 4.58 (2H, d).

Step 4 1-(6-(Hydroxymethyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to General Procedure E from 2-chloro-1-(6- (hydroxymethyl)-1H-indol-3-yl)-2-phenylethanone (0.060 g, 0.200 mmol) and 3-methoxyaniline (0.448 ml, 3.987 mmol) in acetonitrile (1 ml), irradiated in a microwave oven at 130°C in within 15 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in dichloromethane followed by another purification by flash chromatography on silica gel using a gradient of ethyl acetate (30-100%) in heptane gave 0.021 g (27%) of the desired compound as a beige solid. ESI/APCI(+): 387 (M+H). ESI/APCI(-): 385 (M-H).

Example 140 Preparation of 1-(6-(2-hydroxyethoxy)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone

Step 1 To a solution of 6-hydroxyindole (0.645 g, 4.844 mmol) in acetone (25 ml) was added potassium carbonate (1.350 g, 9.768 mmol) and ethyl bromoacetate (1.000 ml, 9.018 mmol). The reaction mixture was refluxed overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-50%) in heptane gave the dialkylated product contaminated ethyl 2-((1H-indol-6-yl)oxy)acetate as a pink oil. This mixture was used in the next step without further purification. ESI/APCI(+): 220 (M+H); 242 (M + Na). ESI/APCI(-): 218 (M-H).

Step 2 To a suspension of lithium aluminum hydride (0.406 g, 10.97 mmol) in THF cooled at 0°C was added dropwise a solution of ethyl 2-((1H-indol-6-yl)oxy)acetate (crude, 4.844 mmol) in THF (15 ml) over 25 min. After one night at room temperature, the reaction mixture was diluted with diethyl ether and cooled to 0°C. A 1M solution of Rochelle's salt was added and the reaction mixture was stirred at room temperature for 2 hours. The phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (50-90%) in heptane gave 0.586 g (68% over 2 steps) of 2-((1H-indol-6-yl)oxy)ethanol as a pink powder.

ESI/APCI(+): 178 (M+H); 200 (M + Na). ESI/APCI(-): 176 (M-H). 1H NMR (DMSO-d6) δ 10.84 (1H, s); 7.39 (1H, d); 7.18 (1H, s); 6.89 (1H, s); 6.66 (1H, d); 6.32 (1H, s), 4.85 (1H, m), 3.98 (2H, m); 3.73 (2H, m).

Step 3 6-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)-1H-indole was prepared according to General Procedure N from 2-((1H-indol-6-yl)oxy)ethanol (0.581 g, 3.279 mmol) , DBU (0.500 ml, 3.350 mmol) and TBDMSCl (1.000 g, 6.635 mmol) in THF (12 ml).

Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-50%) in heptane gave 0.757 g (79%) of the desired compound as a pink solid. ESI/APCI(+): 292 (M+H); 314 (M+Na). ESI/APCI(-): 290 (M-H).

Step 4 1-(6-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)-1H-indol-3-yl)-2-chloro-2-phenylethanone was prepared according to General Procedure A from 6-(2-( (tert-Butyldimethylsilyl)oxy)ethoxy)-1H-indole (0.400 g, 1.372 mmol), pyridine (0.115 ml, 1.422 mmol) and α-chlorophenylacetyl chloride (0.240 ml, 1.536 mmol) in toluene (3.5 ml). The residue obtained after extraction was purified by precipitation from ethyl acetate and heptane. Further purification by recrystallization from ethyl acetate gave 0.060 g (10%) of the desired compound as a beige powder. The recrystallization filtrate was purified by silica gel flash chromatography using a gradient of ethyl acetate (20-80%) in heptane to give 0.066 g of the desired compound (11%) as a pink powder. ESI/APCI(+): 444, 446 (M+H); 466, 468 (M+Na). ESI/APCI(-): 442, 444 (M-H).

Step 5 1-(6-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to General Procedure E from 1-(6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-1H-indol-3-yl)-2-chloro-2-phenylethanone (0.242 g, 0.545 mmol) and 3-methoxyaniline (1.157 ml , 10.344 mmol) in acetonitrile (2.6 ml) irradiated in a microwave oven at 150°C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2050%) in heptane gave 0.099 g (34%) of the desired compound as a beige powder. ESI/APCI(+): 487 (M+H); 509 (M+Na). ESI/APCI(-): 485 (M-H).

Step 6 To a solution of 1-(6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone (0.099 g , 0.186 mmol) in dichloromethane (2.75 ml) cooled to 0° C. was added 4N. a solution of hydrogen chloride in dioxane (0.645 ml, 2.580 mmol). After 2.5 h at room temperature, the reaction mixture was diluted with dichloromethane and converted to the base with 2N. sodium hydroxide solution. The phases were separated. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (50-95%) in heptane gave 0.043 g (55%)-1-(6-(2hydroxyethoxy)-1H-indol-3-yl)-2-((3- methoxyphenyl)amino)-2-phenylethanone as a yellow oil. ESI/APCI(+): 417 (M+H); 439 (M+Na); 855 (2M+Na). ESI/APCI(-): 415 (M-H). ¹ H NMR (DMSO-d ₆ ) δ 11.92 (1H, s); 8.75 (1H, s); 8.00 (1H, d); 7.63 (1H, d); 7.28 (2H, m); 7.19 (1H, m); 6.92 (3H, m); 6.08 (2H, m); 4.86 (1H, t); 3.98 (2H, t); 3.72 (2H,q); 3.62 (3H, s).

Example 141 Preparation of methyl 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1H-indole-5-carboxylate

Step 1 Methyl 3-(2-chloro-2-phenylacetyl)-1H-indole-5-carboxylate was prepared according to General Procedure A from methyl 1H-indole-5-carboxylate (2.000 g, 11.42 mmol), pyridine (0.923 ml, 11.42 mmol) and α-chlorophenylacetyl chloride (1.676 ml, 11.42 mmol) in toluene (30 ml). Precipitation of the precipitate gave 0.324 g (9%) of the desired compound as a pink solid. ESI/APCI(+): 328, 330 (M+H). ESI/APCI(-): 326, 328 (M-H). 1H NMR (DMSO-d6) δ 12.53 (1H, br. s); 8.87 (1H, s); 8.76 (1H, d); 7.87 (1H, dd); 7.54-7.69 (3H, m); 7.29-7.45 (3H, m); 6.79 (1H, s); 3.88 (3H, s).

Step 2 Methyl 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1H-indole-5-carboxylate was prepared according to General Procedure E from methyl 3-(2-chloro-2-phenylacetyl) -1H-indole-5-carboxylate (0.100 g, 0.305 mmol) and 3-methoxyaniline (0.683 ml, 6.101 mmol) in acetonitrile (1 ml) irradiated in a microwave oven at 150°C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by precipitation from ethyl acetate gave 0.040 g (32%) of the desired compound as a white solid. ESI/APCI(+): 415 (M+H). ESI/APCI(-): 413 (M-H).

Example 142 Preparation of methyl 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1H-indole-5carboxylate

To a solution of methyl 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1H-indole-5-carboxylate (0.028 g, 0.068 mmol) in a mixture of methanol (0.5 ml) and THF (0 .5 ml) was added 6n. sodium hydroxide solution (0.250 ml, 1.500 mmol). The mixture was refluxed for 3 hours and concentrated under reduced pressure. The residue was dissolved in water and acidified with 1N. hydrochloric acid solution. The resulting precipitate was filtered and washed with water. Further purification by preparative HPLC (XBridge column; method 2) gave 0.007 g (22%) of 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1Hindole-5-carboxylic acid. ESI/APCI(+): 401 (M+H). ESI/APCI(-): 399 (M-H).

- 91 040588

Example 143 Preparation of 2-(2-fluorophenyl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone

Step 1 A solution of N-(2-fluorobenzylidene)-3-methoxyaniline was prepared by heating a solution of 2-fluorobenzaldehyde (0.105 ml, 0.998 mmol) and 3-methoxyaniline (0.120 ml, 1.068 mmol) in ethanol (1 ml) at 60°C for 18 hours Imine formation was quantitative and the solution was used without further purification. ESI/APCI (+): 230 (M+H).

Step 2 2-(2-Fluorophenyl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to General Procedure L from a mixture of 3-benzyl-5-(2- hydroxyethyl)-4-methylthiazolium chloride (0.139 g, 0.515 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (0.5 ml), tert-butyl-3-formyl-1H-indole-1-carboxylate (0.272 g, 1.109 mmol) and a solution of N-(2-fluorobenzylidene)-3-methoxyaniline (0.998 mmol) in ethanol (1.5 ml), heated at 60°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-35%) in heptane followed by purification by preparative HPLC (XBridge column; method 1) gave 0.037 g (10%) of the desired compound as a beige solid. ESI/APCI (+): 375 (M+H). ESI/APCI (-): 373 (M-H).

Example 144 Preparation of 1-(5-fluoro-1-(2-(methoxymethoxy)ethyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone

Step 1 2-Chloro-1-(5-fluoro-1-(2-(methoxymethoxy)ethyl)-1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure M from 2-chloro-1-( 5-fluoro-1H-indol-3-yl)-2-phenylethanone (0.200 g, 0.695 mmol), 1-bromo-2-(methoxymethoxy)ethane (0.235 g, 1.390 mmol) and potassium carbonate (0.288 g, 2.084 mmol ) in DMF (5 ml). The reaction mixture was stirred at room temperature for 4 hours and heated at 60° C. for 2 hours. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane gave 0.070 g (27%) of the desired compound as oils. ESI/APCI(+): 376, 378 (M+H); 398, 400 (M+Na). ESI/APCI(-): 374, 376 (M-H).

Step 2 1-(5-Fluoro-1-(2-(methoxymethoxy)ethyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone was prepared according to General Procedure E from 2- chloro-1-(5-fluoro-1-(2-(methoxymethoxy)ethyl)-1Hindol-3-yl)-2-phenylethanone (0.070 g, 0.186 mmol), 3-methoxyaniline (0.417 ml, 3.711 mmol) in acetonitrile (1 ml), irradiated in a microwave oven at 150°C for 15 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane gave 0.036 g (42%) of the desired compound as a red solid. ESI/APCI(+): 463 (M+H); 485 (M+H). ESI/APCI(-): 461 (M-H).

Example 145 Preparation of 1-(5-fluoro-1-(2-hydroxyethyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)2-phenylethanone

-(5-Fluoro-1-(2-(methoxymethoxy)ethyl)-1 H-indol-3 -yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone (0.036 g, 0.078 mmol) was dissolved in 4N solution of hydrogen chloride in dioxane (3 ml, 12.00 mmol). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was neutralized with potassium carbonate, diluted with ethyl acetate and washed with water. The phases were separated. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in dichloromethane followed by purification by preparative HPLC (XBridge column; method 1) gave 0.015 g (45%) of 1(5-fluoro-1-(2-hydroxyethyl) -1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone as a white solid. ESI/APCI(+): 419 (M+H); 441 (M + Na). ESI/APCI(-): 417 (M-H).

Example 146 Preparation of 2-((3,5-dimethoxyphenyl)amino)-1-(1-(2-(methoxymethoxy)ethyl)-1H-indol3-yl)-2-phenylethanone

Step 1. 2-Chloro-1-(1-(2-(methoxymethoxy)ethyl)-1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure M from 2-chloro-1-(1H-indol- 3-yl)-2-phenylethanone (0.300 g, 1.112 mmol), 1-bromo-2(methoxymethoxy)ethane (0.375 g, 2.218 mmol) and potassium carbonate (0.461 g, 3.336 mmol) in DMF (5 ml). The reaction mixture was stirred at room temperature for 4 hours and heated at 60°C for 3 hours. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15-70%) in heptane gave 0.144 g (36%) of the desired compound as oils. ESI/APCI(+): 358, 360 (M+H); 380, 382 (M+Na). ESI/APCI(-): 356, 358 (M-H).

Step 2 2-((3,5-Dimethoxyphenyl)amino)-1-(1-(2-(methoxymethoxy)ethyl)-1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure E from 2- chloro-1-(1-(2-(methoxymethoxy)ethyl)-1H-indol-3yl)-2-phenylethanone (0.070 g, 0.196 mmol), 3,5-dimethoxyaniline (0.300 g, 1.958 mmol) in acetonitrile (1 ml), irradiated in a microwave oven at 130°C for 15 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane gave 0.038 g (41%) of the desired compound as a beige solid. ESI/APCI(+): 463 (M+H); 485 (M+H). ESI/APCI(-): 461 (M-H).

Example 147 Preparation of 2-((3,5-dimethoxyphenyl)amino)-1-(1-(2-hydroxyethyl)-1H-indol-3-yl)-2phenylethanone

2-((3,5-Dimethoxyphenyl)amino)-1-(1-(2-(methoxymethoxy)ethyl)-1H-indol-3-yl)-2-phenylethanone (0.036 g, 0.079 mmol) was dissolved in 4 N a solution of hydrogen chloride in dioxane (3 ml, 12.00 mmol). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was neutralized with potassium carbonate, diluted with ethyl acetate and washed with water. The phases were separated. Organic

- 92 040588 the layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-40%) in dichloromethane followed by purification by preparative HPLC (XBridge column; method 1) gave 0.005 g (15%) 2((3,5-dimethoxyphenyl)amino)-1 -(1-(2-hydroxyethyl)-1H-indol-3-yl)-2-phenylethanone as a white solid. ESI/APCI(+): 431 (M+H).

Example 148 Preparation of 2-(4-fluorophenyl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone

Step 1 A solution of N-(4-fluorobenzylidene)-3-methoxyaniline in ethanol was prepared by heating a solution of 4-fluorobenzaldehyde (0.156 g, 1.257 mmol) and 3-methoxyaniline (0.140 ml, 1.253 mmol) in ethanol (0.5 ml) at 60° C. for 18 hours. Imine formation was quantitative and the solution was used without further purification. ESI/APCI (+): 230 (M+H).

Step 2 2-(4-Fluorophenyl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5-(2- hydroxyethyl)-4-methylthiazol-3-ium chloride (0.170 g, 0.630 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (0.5 ml), tert-butyl-3-formyl-1H-indole-1-carboxylate ( 0.350 g, 1.136 mmol) and a solution of N-(4-fluorobenzylidene)-3-methoxyaniline (1.253 mmol) in ethanol (1.5 ml) heated at 60°C for 4 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-50%) in heptane gave 0.120 g (26%) of the desired compound as a yellow solid. ESI/APCI(+): 375 (M+H).

Example 149 Preparation of 1-(6-chloro-1H-indol-3-yl)-2-(imidazo[1,2-a]pyridin-2-yl)-2-((3-methoxyphenyl)amino)ethanone

1-(6-Chloro-1H-indol-3-yl)-2-(imidazo[1,2-a]pyridin-2-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to the general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.156 g, 0.542 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (0.5 ml), tert-butyl -6-chloro-3formyl-1H-indole-1-carboxylate (0.319 g, 1.140 mmol) and a solution of N-(imidaαzo[1,2-α]n-pyridin-2ylmethylene)-3-methoxyaniline (1.068 mmol) in ethanol (1 .5 ml) heated at 60° C. for 18 hours. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-70%) in heptane followed by precipitation from ethyl acetate and heptane gave 0.052 g (11%) of the desired compound in form of a white solid. ESI/APCI(+): 431, 433 (M+H). ESI/APCI(-): 429, 431 (M-H).

Example 150 Preparation of 1-(5-fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyridin-3-yl)ethanone

-(5-Fluoro-III-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyridin-3-yl)ethanone was obtained according to the general procedure K from a mixture of 3-benzyl-5-( 2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.067 g, 0.248 mmol) and triethylamine (0.035 ml, 0.252 mmol) in ethanol (0.37 ml), tert-butyl-5-fluoro-3-formyl- 1Hindole-1-carboxylate (0.158 g, 0.600 mmol) and a solution of 3-methoxy-N-(pyridin-3-ylmethylene)aniline (0.499 mmol) in ethanol (0.75 ml) heated at 70°C for 20 h Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by recrystallization from ethyl acetate and heptane gave 0.036 g (19%) of the desired compound as a white solid. ESI/APCI(+): 376 (M+H); 398 (M + Na). ESI/APCI(-): 374 (M-H).

Example 151 Preparation of 1-(6-fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyridin-3yl)ethanone

-(6-Fluoro-III-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyridin-3-yl)ethanone was obtained according to the general procedure K from a mixture of 3-benzyl-5-( 2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.067 g, 0.248 mmol) and triethylamine (0.035 ml, 0.252 mmol) in ethanol (0.37 ml), tert-butyl-6-fluoro-3-formyl- 1Hindole-1-carboxylate (0.158 g, 0.600 mmol) and a solution of 3-methoxy-N-(pyridin-3-ylmethylene)aniline (0.499 mmol) in ethanol (0.75 ml) heated at 70°C for 20 h Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by recrystallization from ethyl acetate and heptane gave 0.045 g (24%) of the desired compound as a yellow solid. ESI/APCI(+): 376 (M+H); 398 (M + Na). ESI/APCI(-): 374 (M-H).

Example 152 Preparation of 1-(7-fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyridin-3-yl)ethanone

Stage 1. The synthesis was carried out as described in WO 2009/015067. Phosphorus oxychloride (0.350 ml, 3.748 mmol) was added dropwise to a solution of DMF (0.600 ml, 7.749 mmol) in dichloromethane (2 ml) cooled at -15°C. After 15 minutes at -15° C., 7-fluoroindole (0.497 g, 3.678 mmol) was added in portions. The reaction mixture was then allowed to warm to room temperature and stirred at room temperature overnight. The reaction mixture was turned into a base with 1N. sodium hydroxide solution to pH 8 and extracted with ethyl acetate. The aqueous phase was extracted with ethyl acetate and a mixture of methanol in dichloromethane. The organic phases were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 0.078 g of a yellow solid. After 24 hours the precipitate in the aqueous phase was filtered to give 0.264 g of a white solid. The filtrate was converted to the base with 1N. sodium hydroxide solution to pH 12 and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 0.290 g of a yellow solid. The three solids were mixed, taken up on

- 93 040588 silica gel and purified by flash chromatography on silica gel using 40% ethyl acetate in heptane as eluent to obtain 0.485 g (81%) of 7-fluoro-1H-indole-3-carbaldehyde as a pink solid. ESI/APCI(+): 164 (M+H). ESI/APCI(-): 162 (M-H).

Step 2 tert-Butyl 7-fluoro-3-formyl-1H-indole-1-carboxylate was prepared according to General Procedure F from 7-fluoro-1H-indole-3-carbaldehyde (0.485 g, 2.973 mmol), di-tert -butyl dicarbonate (0.780 g, 3.574 mmol) and DMAP (0.046 g, 0.377 mmol) in acetonitrile (9 mL) to give 0.687 g (88%) of the desired compound as a beige solid. 1H NMR (DMSO-d ₆ ) δ 10.08 (1H, s); 8.77 (1H, s); 8.01 (1H, d); 7.25-7.43 (2H, m); 1.64 (9H, s).

Step 3. 1-(7-Fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyridin-3-yl)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl -5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.067 g, 0.248 mmol) and triethylamine (0.035 ml, 0.252 mmol) in ethanol (0.37 ml), tert-butyl-7-fluoro- 3-formyl1H-indole-1-carboxylate (0.158 g, 0.600 mmol) and a solution of 3-methoxy-M-(pyridin-3-ylmethylene)aniline (0.499 mmol) in ethanol (0.75 ml) heated at 70°C for 20 hours Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by recrystallization from ethyl acetate and heptane gave 0.033 g (18%) of the desired compound as a white powder. ESI/APCI(+): 376 (M+H); 398 (M + Na). ESI/APCI(-): 374 (M-H).

Example 153 Preparation of 1-(5-fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6-methoxypyridin-3-yl)ethanone

-(5-Fluoro-III-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6-methoxypyridin-3-yl)ethanone was obtained according to the general procedure K from a mixture of 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.034 g, 0.125 mmol) and triethylamine (0.013 ml, 0.093 mmol) in ethanol (0.25 ml), tert-butyl-5-fluoro-3- formyl1H-indole-1-carboxylate (0.066 g, 0.251 mmol) and a solution of 3-methoxy-N-((6-methoxypyridin-3yl)methylene)aniline (0.248 mmol) in ethanol (0.25 ml), heated at 70° C for 24 hours. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by recrystallization from ethyl acetate and heptane gave 0.004 g (4%) of the desired compound as a beige solid. ESI/APCI(+): 406 (M+H). ESI/APCI(-): 404 (M-H).

Example 154 Preparation of 1-(7-fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6-methoxypyridin-3-yl)ethanone

-(7-Fluoro-III-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6-methoxypyridin-3-yl)ethanone was obtained according to the general procedure K from a mixture of 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.034 g, 0.125 mmol) and triethylamine (0.013 ml, 0.093 mmol) in ethanol (0.25 ml), tert-butyl-7-fluoro-3- formyl1H-indole-1-carboxylate (0.066 g, 0.251 mmol) and a solution of 3-methoxy-N-((6-methoxypyridin-3yl)methylene)aniline (0.248 mmol) in ethanol (0.25 ml), heated at 70° C for 24 hours. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by recrystallization from ethyl acetate and heptane gave 0.005 g (5%) of the desired compound as a beige solid. ESI/APCI(+): 406 (M+H). ESI/APCI(-): 404 (M-H).

Example 155 Preparation of 2-((3,5-dimethoxyphenyl)amino)-1-(5-fluoro-1-(3-hydroxypropyl)-1H-indol3-yl)-2-phenylethanone

Step 1 2-Chloro-1-(5-fluoro-1-(3-hydroxypropyl)-1H-indol-3-yl)-2-phenylethanone was prepared according to General Method M from 2-chloro-1-(5-fluoro -1H-indol-3-yl)-2-phenylethanone (0.200 g, 0.695 mmol), 3-bromopropan-1-ol (0.193 g, 1.389 mmol) and potassium carbonate (0.192 g, 1.389 mmol) in DMF (5 ml). The reaction mixture was stirred at room temperature overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-40%) in dichloromethane gave 0.219 g (91%) of the desired compound as a brown oil. ESI/APCI(+): 346, 348 (M+H); 368, 370 (M+Na).

Step 2 2-((3,5-Dimethoxyphenyl)amino)-1-(5-fluoro-1-(3-hydroxypropyl)-1H-indol-3-yl)-2phenylethanone was prepared according to General Procedure E from 2-chloro -1-(5-fluoro-1-(3-hydroxypropyl)-Shindol-3-yl)-2-phenylethanone (0.125 g, 0.361 mmol), 3,5-dimethoxyaniline (0.554 g, 3.617 mmol) in acetonitrile (1 ml), irradiated in a microwave oven at 130°C for 15 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-40%) in dichloromethane followed by a second purification by flash chromatography on silica gel using a gradient of ethyl acetate (30-100%) in heptane gave 0.032 g (19%) of the desired product as a white solid. substances. ESI/APCI(+): 463 (M+H).

Example 156 Preparation of 1-(6-fluoro-1H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2-phenylethanone

1-(6-Fluoro-1H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2-phenylethanone was obtained according to general procedure K from a mixture of 3-benzyl-5-(2- hydroxyethyl)-4-methylthiazol-3-ium chloride (0.067 g, 250 mmol) and triethylamine (0.035 ml, 0.250 mmol) in ethanol (1 ml), tert-butyl-6-fluoro-3-formyl-1H-indole 1- carboxylate (0.132 g, 0.500 mmol) and a solution of N-benzylidene-5-methoxypyridine-3-amine (0.500 mmol) in ethanol (1 ml) heated at 70°C for 18 h. Purification by silica gel flash chromatography using a gradient of methanol (1-10%) in dichloromethane followed by precipitation from dichloromethane gave 0.017 g (9%) of the desired compound as a beige solid. ESI/APCI(+): 376 (M+H). ESI/APCI(-): 374 (M-H).

- 94 040588

Example 157 Preparation of 1-(III-indol-3-yl)-2-(6-methoxypyridin-3-yl)-2-((5-methoxypyridin-3yl)amino)ethanone

Step 1 A mixture of 6-methoxynicotinaldehyde (0.137 g, 0.999 mmol) and 5-methoxypyridine-3-amine (0.124 mg; 0.999 mmol) in ethanol (1.5 ml) was heated at 60°C for 6 h. The reaction mixture was concentrated under reduced pressure and dried under vacuum over phosphorus(V) oxide to obtain quantitatively 5-methoxy-N-((6-methoxypyridin-3-yl)methylene)pyridine-3-amine, which was used without further purification in the next step . ESI/APCI (+): 244 (M+H).

Step 2. 1-(1H-Indol-3-yl)-2-(6-methoxypyridin-3-yl)-2-((5-methoxypyridin-3-yl)amino)ethanone was prepared according to general procedure K from mixture 3 -benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.134 g, 0.500 mmol) and triethylamine (0.069 ml, 0.496 mmol) in ethanol (2 ml), tert-butyl-3-formyl 1H- indole-1-carboxylate (0.245 g, 0.999 mmol) and a solution of 5-methoxy ^-((6-methoxypyridin-3yl)methylene)pyridine-3-amine (0.999 mmol) in ethanol (1 ml) heated at 70°C for 18 hours Purification by flash chromatography on silica gel using a gradient of methanol (1-15%) in dichloromethane followed by precipitation from diethyl ether and dichloromethane gave 0.025 g (6%) of the desired compound as a beige solid. ESI/APCI(+): 389 (M+H). ESI/APCI(-): 387 (M-H).

Example 158 Preparation of 4-(2-(1H-indol-3-yl)-1-((5-methoxypyridin-3-yl)amino)-2-oxoethyl)benzonitrile

Step 1 A mixture of 4-formylbenzonitrile (0.131 g, 0.999 mmol) and 5-methoxypyridine-3-amine (0.124 mg; 0.999 mmol) in ethanol (1.5 ml) was heated at 60°C for 6 h. The reaction mixture was concentrated under reduced pressure and dried under vacuum over phosphorus(V) oxide to give quantitatively 4-(((5-methoxypyridin-3-yl)imino)methyl)benzonitrile, which was used without further purification in the next step. ESI/APCI (+): 238 (M+H).

Step 2. 4-(2-(III-Indol-3-yl)-1-((5-methoxypyridin-3-yl)amino)-2-oxoethyl)benzonitrile was prepared according to general procedure K from a mixture of 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.134 g, 0.500 mmol) and triethylamine (0.069 ml, 0.496 mmol) in ethanol (2 ml), tert-butyl-3-formyl-1Hindole-1- carboxylate (0.245 g, 0.999 mmol) and a solution of 4-(((5-methoxypyridin-3-yl)imino)methyl)benzonitrile (0.999 mmol) in ethanol (1 ml), heated at 70°C for 18 hours. flash chromatography on silica gel using a gradient of methanol (1-7%) in dichloromethane followed by precipitation from diethyl ether gave 0.132 g (34%) of the desired compound as a white solid. ESI/APCI(+): 383 (M+H). ESI/APCI(-): 381 (M-H).

Example 159 Preparation of 1-(benzo[b]thiophen-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone

Stage 1. To a solution of thianaphthene (0.300 g, 2.235 mmol) and phenylacetyl chloride (0.300 ml, 2.266 mmol) in dichloroethane (5 ml), cooled at 0 ° C, aluminum trichloride (0.894 g, 6.705 mmol) was added portionwise over 2 hours . The reaction mixture was then stirred at room temperature overnight. A 1M solution of Rochelle's salt was added and the reaction mixture was stirred at room temperature for 1 hour. The phases were separated. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of dichloromethane (30-90%) in heptane gave 0.239 g (42%) of 1-(benzo[b]thiophen-3-yl)-2-phenylethanone as a white solid. ESI/APCI(+): 253 (M+H); 275 (M + Na). ESI/APCI(-): 251 (M-H). ¹ H NMR (CDCl ₃ ) δ 8.78 (1H, d); 8.37 (1H, s); 7.85 (1H, d); 7.5-7.2 (7H, m); 4.30 (2H, s).

Step 2 1-(Benzo[b]thiophen-3-yl)-2-bromo-2-phenylethanone was prepared according to the 2 different procedures described herein as Method A and Method B.

Method A.

A solution of phenyltrimethylammonium tribromide (0.171 g, 0.455 mmol) in THF (5 ml). The reaction mixture was stirred at 0° C. for 15 minutes and at room temperature for 1 hour. The reaction mixture was filtered and the solid was washed with diethyl ether. The filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with water. The phases were separated. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of dichloromethane (20-80%) in heptane gave 0.114 g of a mixture containing 1-(benzo[b]thiophen-3-yl)-2-bromo-2-phenylethanone as a brown oil. ESI/APCI(+): 331.333 (M+H). 1H NMR (DMSO-d6) δ 9.27 (1H, s); 8.61 (1H, d); 8.11 (1H, d); 7.7-7.1 (7H, m); 7.17 (1H, s) (80% pure).

Method B.

To a solution of 1-(benzo[b]thiophen-3-yl)-2-phenylethanone (0.108 g, 0.428 mmol) in ethyl acetate (2 ml) was added copper(II) bromide (0.162 g, 0.725 mmol). The reaction mixture was refluxed for 2.5 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. cleaning

- 95 040588 flash chromatography on silica gel using a gradient of dichloromethane (30-80%) in heptane gave 0.102 g of a mixture containing 1-(benzo[b]thiophen-3-yl)-2-bromo-2-phenylethanone (with this the same purity as in method A) as a brown oil.

Step 3 1-(Benzo[b]thiophen-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to General Procedure C from 1-(benzo[b]thiophen-3-yl) -2-bromo-2-phenylethanone (0.050 g, 0.151 mmol), DIPEA (0.052 ml, 0.298 mmol) and 3-methoxyaniline (0.034 ml, 0.303 mmol) in acetonitrile (2 ml) irradiated in a microwave oven at 200°C within 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-50%) in heptane followed by a second purification by flash chromatography on silica gel using a gradient of dichloromethane (20-90%) in heptane gave 0.029 g (44% over two steps) of the desired product in yellow oil. ESI/APCI(+): 374 (M+H); 396 (M+Na). ESI/APCI(-): 372 (M-H). ¹ H NMR (DMSO-d ₆ ) δ 9.51 (1H, s); 8.53 (1H, d); 8.07 (1H, d); 7.6-7.2 (7H, m); 6.94 (1H, t); 6.42 (4H, m); 6.14 (1H, dd); 3.63 (3H, s).

Example 160 Preparation of 2-((3-methoxyphenyl)amino)-2-phenyl-1-(1H-pyrrolo[2,3-b]pyridin-3yl)ethanone

Step 1. tert-Butyl-3-formyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate was prepared according to General Procedure F from 7-azaindole-3-carboxaldehyde (0.500 g, 3.421 mmol), di-tert -butyl dicarbonate (0.896 g, 4.105 mmol) and DMAP (0.042 g, 0.342 mmol) in acetonitrile (8 mL) to give 0.779 g (92%) of the desired compound as a white solid. ESI/APCI(+): 269 (M+Na).

Step 2 2-((3-Methoxyphenyl)amino)-2-phenyl-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethanone was prepared according to General Procedure L from a mixture of 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazolium chloride (0.114 g, 0.423 mmol) and triethylamine (0.059 ml, 0.423 mmol) in ethanol (0.5 ml), tert-butyl-3-formyl-Spirrolo[2,3- b]pyridine-1-carboxylate (0.250 g, 1.015 mmol) and a solution of N-benzylidene-3-methoxyaniline (0.846 mmol) in ethanol (0.5 ml) heated at 70°C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by a second purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-100%) in heptane gave 0.028 g (9%) of the desired compound as solid. ESI/APCI(+): 358 (M+H). ESI/APCI(-): 356 (M-H).

Example 161 Preparation of 2-((3-methoxyphenyl)amino)-2-phenyl-1-(1H-pyrrolo[3,2-b]pyridin-3yl)ethanone

Step 1 A mixture of 4-azaindole (0.500 g, 4.223 mmol), hexamethylenetetramine (0.890 g, 6.348 mmol) and acetic acid (3.630 ml, 63.45 mmol) in water (9 ml) was refluxed for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (2-4%) in dichloromethane gave 0.550 g (89%) 1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde. ESI/APCI(+): 147 (M+H). ESI/APCI(-): 145 (M-H).

Step 2: tert-Butyl 3-formyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate was prepared according to General Procedure F from 1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde (0.550 g , 3.763 mmol), di-tert-butyl dicarbonate (0.986 g, 4.518 mmol) and DMAP (0.048 g, 0.376 mmol) in acetonitrile (8 mL) to give 0.802 g (87%) of the desired compound as a white solid. ESI/APCI(+): 269 (M+Na).

Step 3 2-((3-Methoxyphenyl)amino)-2-phenyl-1-(1H-pyrrolo[3,2-b]pyridin-3-yl)ethanone was prepared according to General Procedure L from a mixture of 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazolium chloride (0.137 g, 0.508 mmol) and triethylamine (0.071 ml, 0.508 mmol) in ethanol (0.5 ml), tert-butyl-3-formyl-Spirrolo[3,2- b]pyridine-1-carboxylate (0.300 g, 1.218 mmol) and a solution of N-benzylidene-3-methoxyaniline (1.015 mmol) in ethanol (0.5 ml) heated at 70° C. for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-100%) in heptane followed by precipitation from dichloromethane gave 0.019 g (5%) of the desired compound as a solid. ESI/APCI(+): 358 (M+H). ESI/APCI(-): 356 (M-H).

Example 162 Preparation of 1-(imidazo[1,2-a]pyridin-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone

1-(Imidazo[1,2-a]pyridin-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to General Procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl) -4-methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1 ml), imidazo[1,2-a]pyridine-3-carbaldehyde (0.146 g, 0.999 mmol) and solution N-benzylidene-3-methoxyaniline (0.999 mmol) in ethanol (1 ml) heated at 70°C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by precipitation from diethyl ether gave 0.112 g (31%) of the desired compound as a solid. ESI/APCI(+): 358 (M+H). ESI/APCI(-): 356 (M-H).

Example 163 Preparation of 2-((3-methoxyphenyl)amino)-2-phenyl-1-(pyrazolo[1,5-a]pyridin-3-yl)ethanone

Step 1 To a solution of ethylpyrazolo[1,5-a]pyridine-3-carboxylate (0.400 g, 2.103 mmol) in dry dichloromethane (8 ml) cooled at -78° C. under nitrogen, a 1M solution of diisobutylaluminum hydride was added dropwise in dichloromethane (4.630 ml, 4.630 mmol). The reaction mixture was stirred for 1.5 h at -78°C after which it was allowed to warm to -15°C for 30 min. The reaction was quenched

- 96 040588 by adding 1n. Rochelle's salt solution and the reaction mixture were vigorously stirred for 1 h. The phases were separated and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-100%) in heptane gave 0.128 g (41%) pyrazolo[1,5-a]pyridin-3-ylmethanol as a colorless oil. ESI/APCI(+): 149 (M+H).

Step 2 To a solution of pyrazolo[1,5-a]pyridin-3-ylmethanol (0.128 g, 0.864 mmol) in dichloromethane (10 mL) were added molecular sieves (4A) and pyridinium dichromate (0.488 g, 1.296 mmol). The reaction mixture was stirred at room temperature overnight. Celite® was added and the reaction mixture was stirred for 30 minutes. The red suspension was filtered. The filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane gave 0.064 g (51%) of pyrazolo[1,5-a]pyridine-3-carbaldehyde as a white solid. ESI/APCI(+): 147 (M+H).

Step 3 2-((3-Methoxyphenyl)amino)-2-phenyl-1-(pyrazolo[1,5-a]pyridin-3-yl)ethanone was prepared according to General Procedure L from a mixture of 3-benzyl-5-( 2-hydroxyethyl)-4-methylthiazolium chloride (0.059 g, 0.219 mmol) and triethylamine (0.031 ml, 0.219 mmol) in ethanol (0.5 ml), pyrazolo[1,5-a]pyridine-3-carbaldehyde (0.093 g, 0.438 mmol) and a solution of N-benzylidene-3-methoxyaniline (0.438 mmol) in ethanol (0.5 ml) heated at 70°C for 24 h. Purification by flash chromatography on silica gel using an ethyl acetate gradient (0-100%) in heptane followed by purification by preparative HPLC (XBridge column; method 2) gave 0.020 g (13%) of the desired compound. ESI/APCI(+): 358 (M+H).

Example 164 Preparation of 1-(1H-indazol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone

Step 1. tert-Butyl-3-formyl-1H-indazole-1-carboxylate was prepared according to General Procedure F from 1H-indazole-3-carboxaldehyde (0.500 g, 3.421 mmol), di-tert-butyl dicarbonate (0.896 g, 4.105 mmol ) and DMAP (0.042 g, 0.342 mmol) in acetonitrile (8 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane gave 0.318 g (38%) of the desired compound. ESI/APCI(+): 269 (M+Na).

Step 2 1-(1H-Indazol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to General Procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4- methylthiazolium chloride (0.174 g, 0.646 mmol) and triethylamine (0.091 ml, 0.646 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1H-indazole-1-carboxylate (0.318 g, 1.291 mmol) and N-benzylidene solution -3-methoxyaniline (1.291 mmol) in ethanol (1 ml) heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by purification by preparative HPLC (XBridge column; method 1) gave 0.004 g (1%) of the desired compound. ESI/APCI(+): 358 (M+H). ESI/APCI(-): 356 (M-H).

Example 165 Preparation of 1-(benzo[b]thiophen-3-yl)-2-(imidazo[1,2-a]pyridin-2-yl)-2-((2-methoxypyridin-4-yl)amino) ethanone.

1-(Benzo[b]thiophen-3-yl)-2-(imidazo[1,2-a]pyridin-2-yl)-2-((2-methoxypyridin-4-yl)amino)ethanone was obtained according to the general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (0.110 g, 0.408 mmol) and triethylamine (0.080 ml, 0.574 mmol) in ethanol (0.5 ml), benzo[b]thiophene -3-carbaldehyde (0.140 g, 0.863 mmol) and a mixture of N-(imidazo[1,2-a]pyridin-2-ylmethylene)-2-methoxypyridin-4-amine (0.856 mmol) in ethanol (1 ml) heated at 65 °C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (50-100%) in heptane followed by precipitation from ethanol and heptane gave 0.022 g (6%) of the desired compound as a pink solid. ESI/APCI(+): 415 (M+H).

Example 166 Preparation of 2-((3-methoxyphenyl)amino)-2-phenyl-1-(1H-pyrrolo[2,3-c]pyridin-3yl)ethanone

Step 1 To a solution of 1H-pyrrolo[2,3-c]pyridine (0.400 g, 3.386 mmol) in a mixture of 1,2-dichloroethane (10 ml) and nitromethane (10 ml) cooled at 0°C under argon, dichloro(methoxy)methane (1.544 ml, 16.92 mmol) and aluminum trichloride (1.500 g, 11.25 mmol) were added over 1 hour. After the addition, the reaction was quenched by adding water and saturated sodium bicarbonate solution. The reaction mixture was extracted with a solution of dichloromethane and ethanol (9/1, 6x100 ml). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 0.295 g (60%) 1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde which was used without further purification. ESI/APCI(+): 147 (M+H). ESI/APCI(-): 145 (M-H). 1H NMR (DMSO-d6) δ 10.01 (1H, s); 8.88 (1H, s); 8.50 (1H, s); 8.33 (1H, d); 8.00 (1H, d).

Step 2. tert-Butyl-3-formyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate was prepared according to General Procedure F from 1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde (0.295 g , 2.019 mmol), di-t-butyl dicarbonate (0.529 g, 2.019 mmol) and DMAP (0.025 g, 0.202 mmol) in acetonitrile (5 mL) to give 0.411 g (83%) of the desired compound as a solid. 1H NMR (DMSO-d ₆ ) δ 10.13 (1H, s); 9.32 (1H, s); 8.86 (1H, s); 8.51 (1H, d); 8.07 (1H, d), 1.69 (9H, s).

Step 3 2-((3-Methoxyphenyl)amino)-2-phenyl-1-(1H-pyrrolo[2,3-c]pyridin-3-yl)ethanone was prepared

- 97 040588 according to the general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1 ml), t- butyl 3-formyl-1Hpyrrolo[2,3-c]pyridine-1-carboxylate (0.246 g, 0.999 mmol) and a solution of K-benzylidene-3-methoxyaniline (0.999 mmol) in ethanol (1 ml), heated at 70 ° C within 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by a second purification by flash chromatography on silica gel using a gradient of methanol (0-10%) in dichloromethane and precipitation from diethyl ether gave 0.055 g (14%) of the desired compounds in the form of a solid. ESI/APCI(+): 358 (M+H). ESI/APCI(-): 356 (M-H).

Example 167 Preparation of 2-((3-methoxyphenyl)amino)-2-phenyl-1-(1H-pyrrolo[3,2-c]pyridin-3yl)ethanone

Stage 1. To a solution of 1H-pyrrolo[3,2-c]pyridine (0.400 g, 3.386 mmol) in a mixture of 1,2-dichloroethane (10 ml) and nitromethane (10 ml), cooled at 0°C, under argon atmosphere dichloro(methoxy)methane (1.544 ml, 16.92 mmol) and aluminum trichloride (1.500 g, 11.25 mmol) were added over 1 hour. After the addition, the reaction was quenched by adding water and saturated sodium bicarbonate solution. The reaction mixture was extracted with a solution of dichloromethane and ethanol (9/1, 6x100 ml). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 0.333 g (67%) of 1H-pyrrolo[3,2-c]pyridine-3-carbaldehyde which was used without further purification. ESI/APCI(+): 147 (M+H). ESI/APCI(-): 145 (M-H). 1H NMR (DMSO-d6) δ 10.00 (1H, s); 9.29 (1H, s); 8.42 (1H, s); 8.35 (1H, d); 7.53 (1H, d).

Step 2 tert-Butyl 3-formyl-1H-pyrrolo[3,2-c]pyridine-1-carboxylate was prepared according to General Procedure F from 1H-pyrrolo[3,2-c]pyridine-3-carbaldehyde (0.330 g , 2.258 mmol), di-t-butyl dicarbonate (0.591 g, 2.708 mmol) and DMAP (0.027 g, 0.226 mmol) in acetonitrile (5 mL) to give 0.374 g (67%) of the desired compound as a brown solid. 1H NMR (DMSO-d ₆ ) δ 10.12 (1H, s); 9.33 (1H, s); 8.77 (1H, s); 8.57 (1H, d); 8.02 (1H, d); 1.63-1.74 (9H, m).

Step 3 2-((3-Methoxyphenyl)amino)-2-phenyl-1-(1H-pyrrolo[3,2-c]pyridin-3-yl)ethanone was prepared according to General Procedure L from a mixture of 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1 ml), tert-butyl-3-formyl-Spyrrolo[3,2-c] pyridine-1-carboxylate (0.246 g, 0.999 mmol) and a solution of K-benzylidene-3-methoxyaniline (0.999 mmol) in ethanol (1 ml), heated at 70°C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by a second purification by flash chromatography on silica gel using a gradient of methanol (0-10%) in dichloromethane and precipitation from diethyl ether gave 0.056 g (14%) of the desired compounds in the form of a solid. ESI/APCI(+): 358 (M+H). ESI/APCI(-): 356 (M-H).

Example 168 Preparation of 2-((3-methoxyphenyl)amino)-1-(6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)-2-phenylethanone

Step 1 To a suspension of ethyl 2-amino-6-methyl-4,5,6,7-tetrahydrothieno-[2,3-c]pyridine-3-carboxylate (1.000 g, 4.161 mmol) in dioxane (5 ml) concentrated hydrochloric acid solution (3.200 mL, 38.40 mmol) was added. After cooling to -5°C, a solution of sodium nitrite (0.316 g, 4.580 mmol) in water (0.5 ml) was added. The resulting black reaction mixture was stirred at -5°C for 40 min and then added in portions to a mixture of 50% orthophosphoric acid solution (9 ml) and diethyl ether (9 ml) cooled at 0°C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight. The reaction mixture was carefully poured into ice/1N. sodium hydroxide solution and extracted with dichloromethane. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (5-10%) in dichloromethane gave 0.431 g (46%) of ethyl 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3 -carboxylate as a brown oil. ESI/APCI(+): 226 (M+H). 1H NMR (DMSO-d6) δ 8.12 (1H, s); 4.23 (2H, q); 3.53 (2H, s); 2.85 (2H, t); 2.61 (2H, t); 2.35 (3H, s); 1.28 (3H, s).

Step 2: A suspension of lithium aluminum hydride (0.110 g, 2.899 mmol) in diethyl ether (20 ml) was refluxed for 30 minutes. After cooling to room temperature, a solution of ethyl 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (0.580 g, 2.574 mmol) in diethyl ether (6 ml) was added. The reaction mixture was refluxed for 5.5 hours After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with 1N. sodium hydroxide solution. The phases were separated. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 0.415 g (6-methyl4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl) methanol, which was used in the next step without further purification. ESI/APCI(+): 184 (M+H).

To a solution of (6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)methanol (crude; 2.264 mmol) in dichloromethane (18 mL) was added a 15% solution of Dess-Martin reagent in dichloromethane (5.700 ml, 2.750 mmol). After 5 h at room temperature, a 15% Dess reagent solution was added again.

- 98 040588

Martin in dichloromethane (1.000 ml, 0.480 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with diethyl ether and added 1N. sodium hydroxide solution. After 15 min at room temperature, the phases were separated. The organic phase was washed with 1N. sodium hydroxide solution, water and brine, dried over Na2SO ₄ , filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (5-10%) in dichloromethane gave 0.235 g (50% over two steps) of 6-methyl-4,5,6,7tetrahydrothieno[2,3-c]pyridine-3- carbaldehyde as a brown solid. ESI/APCI(+): 182 (M+H). ¹ H NMR (DMSO-d6) δ 9.87 (1H, s); 8.41 (1H, s); 3.55 (2H, s); 2.86 (2H, m); 2.51 (2H, t); 2.36 (3H, s).

Step 3 2-((3-Methoxyphenyl)amino)-1-(6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)-2-phenylethanone was prepared according to General Procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (0.117 g, 0.554 mmol) and triethylamine (0.039 ml, 0.281 mmol) in ethanol (1 ml), 6-methyl-4,5,6,7 -tetrahydrothieno[2,3-c]pyridine-3-carbaldehyde (0.100 g, 0.552 mmol) and a mixture of N-benzylidene-3-methoxyaniline (0.117 g, 0.554 mmol) in ethanol (1 ml) heated at 70°C for 24 h. The residue was purified by silica gel flash chromatography using a gradient of methanol (0-10%) in methanol and preparative TLC using 10% methanol in dichloromethane as eluent and preparative HPLC (XBridge column; method 4) gave 0.023 g (11% ) of the desired compound as a yellow solid. ESI/APCI(+): 393 (M+H); 415 (M + Na). ESI/APCI(-): 391 (M-H).

Example 169 Preparation of 2-((3-methoxyphenyl)amino)-1-(1-methyl-1H-indazol-3-yl)-2-phenylethanone

2-((3-Methoxyphenyl)amino)-1-(1-methyl-1H-indazol-3-yl)-2-phenylethanone was prepared according to General Procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4 -methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1 ml), 1-methyl-1H-indazole-3-carbaldehyde (0.160 g, 0.999 mmol) and a solution of N-benzylidene- 3-methoxyaniline (1.000 mmol) in ethanol (1 ml) heated at 70°C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by precipitation from diethyl ether gave 0.139 g (37%) of the desired compound as a white solid. ESI/APCI(+): 372 (M+H).

Example 170 Preparation of 1-(indolin-1-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone

Step 1 To a solution of indoline (0.050 ml, 0.444 mmol) in dichloromethane (5 ml) were added potassium carbonate (0.262 g, 1.896 mmol) and α-chlorophenylacetyl chloride (0.150 ml, 0.952 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give 2-chloro-1-(indolin-1-yl)-2-phenylethanone, which was used in the next step without further purification. ESI/APCI(+): 272 (M+H); 294 (M + Na).

Step 2: Mixture of 2-chloro-1-(indolin-1-yl)-2-phenylethanone (crude; 0.444 mmol), 3-methoxyaniline (0.100 ml, 0.893 mmol) and DIPEA (0.100 ml, 0.514 mmol) in acetonitrile (2 ml ) were irradiated in a microwave oven at 120°C for 30 min. The reaction mixture was concentrated under reduced pressure. Purification by flash chromatography using a gradient of ethyl acetate (10-40%) in heptane followed by purification by preparative HPLC (XBridge column; method 1) gave 0.043 g (27% over two steps) of the desired product as a white solid. ESI/APCI(+): 359 (M+H); 381 (M + Na). ¹ H NMR (CDCl ₃ ): δ 8.26 (1H, m); 7.50 (1H, m); 7.17-7.36 (8H, m); 7.03 (1H, m); 6.21-6.27 (2H, m); 5.21 (1H, s); 4.26 (1H, m); 3.92 (1H, m); 3.73 (3H, s); 3.08-3.30 (2H, m).

Example 171 Preparation of 1-(7-fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone

1-(7-Fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was obtained according to the general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4 -methylthiazol-3-ium chloride (0.163 g, 0.604 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol, tert-butyl-7-fluoro-3-formyl-1H-indole-1-carboxylate (0.277 g, 1.052 mmol) and a solution of N-benzylidene-3-methoxyaniline (1.046 mmol) in ethanol (1.5 ml) heated at 60°C for 48 h. The residue was purified by flash chromatography on silica gel using an ethyl acetate gradient (0-40% ) in heptane. Further purification by precipitation from diisopropyl ether and ethyl acetate gave 0.042 g (11%) of the desired compound as a yellow solid. ESI/APCI(+): 375 (M+H). ESI/APCI(-): 373 (M-H).

Example 172 Preparation of 2-((3,5-dimethoxyphenyl)amino)-1-(5-fluoro-1H-indol-3-yl)-2-(6-methoxypyridin-3-yl)ethanone

Step 1 A solution of 3,5-dimethoxy-N-((6-methoxypyridin-3-yl)methylene)aniline in ethanol was prepared by heating a solution of 6-methoxynicotinaldehyde (0.139 g, 1.014 mmol) and 3,5-dimethoxyaniline (0.158 g , 1.031 mmol) in ethanol (0.5 ml) at 60° C. for 18 hours. Imine formation was quantitative and the solution was used without further purification. ESI/APCI(+): 273 (M+H).

Step 2 2-((3,5-Dimethoxyphenyl)amino)-1-(5-fluoro-1H-indol-3-yl)-2-(6-methoxypyridin-3yl)ethanone was prepared according to the general procedure K from a mixture of 3 -benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3ium chloride (0.160 g, 0.593 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (0.5 ml), tert-butyl 5-fluoro-3- formyl 1H-indole-1-carboxylate (0.290 g, 1.102 mmol) and a solution of 3,5-dimethoxy-N-((6methoxypyridin-3-yl)methylene)aniline (1.014 mmol) in ethanol (2 ml), heated at 60°C for 24 h. Purification by flash chromatography on silica gel using an ethyl acetate gradient (30-70%) in

- 99,040,588 heptane followed by precipitation from dichloromethane gave 0.043 g (9%) of the desired compound as a white solid. ESI/APCI(+): 436 (M+H). ESI/APCI(-): 434 (M-H).

Example 173 Preparation of 2-((2-fluoropyridin-4-yl)amino)-1-(1H-indol-3-yl)-2-phenylethanone

Step 1 A solution of N-benzylidene-2-fluoropyridine-4-amine in ethanol was prepared by heating a solution of benzaldehyde (0.115 ml, 1.138 mmol) and 4-amino-2-fluoropyridine (0.130 g, 1.160 mmol) in ethanol (0.5 ml) at 60°C for 18 hours. Imine formation was quantitative and the solution was used without further purification. ESI/APCI(+): 201 (M+H).

Step 2 2-((2-Fluoropyridin-4-yl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl )-4-methylthiazol-3-ium chloride (0.158 g, 0.586 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (0.5 ml), tert-butyl-3-formyl-1H-indole-1-carboxylate (0.311 g, 1.268 mmol) and a solution of N-benzylidene-2-fluoropyridine-4-amine (1.138 mmol) in ethanol (1.5 ml) heated at 60°C for 96 h. Purification by silica gel flash chromatography using an ethyl acetate gradient (0-50%) in heptane followed by purification by preparative HPLC (XBridge column; method 1) gave 0.035 g (9%) of the desired compound as a white solid. ESI/APCI(+): 346 (M+H). ESI/APCI(-): 344 (M-H).

Example 174 Preparation of 2-((3-methoxyphenyl)amino)-2-phenyl-1-(1-((tetrahydrofuran-3yl)sulfonyl)-1H-indol-3-yl)ethanone

Step 1 To a solution of 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.200 g, 0.741 mmol) in DMF (5 ml) cooled to 0°C was added sodium hydride (60% dispersion in mineral oil, 0.053 g, 1.333 mmol). The reaction mixture was stirred at room temperature for 0.5 h. Tetrahydrofuran-3-sulfonyl chloride (0.253 g, 1.483 mmol) and DMAP (0.005 g, 0.037 mmol) were added and the reaction mixture was stirred at room temperature for 3 h. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane gave 0.299 g (100%) of 2-chloro-2-phenyl-1-(1-((tetrahydrofuran-3-yl)sulfonyl)-1H-indole -3-yl)ethanone as a solid. ESI/APCI(+): 404 (M+H). ESI/APCI(-): 402 (M-H).

Step 2 2-((3-Methoxyphenyl)amino)-2-phenyl-1-(1-((tetrahydrofuran-3-yl)sulfonyl)-1H-indol3-yl)ethanone was prepared according to General Procedure E from 2-chloro -2-phenyl-1-(1-((tetrahydrofuran-3yl)sulfonyl)-1H-indol-3-yl)ethanone (0.100 g, 0.248 mmol) and meta-anisidine (0.277 ml, 2.474 mmol) in acetonitrile (1 ml), irradiated in a microwave oven at 100°C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane followed by purification by preparative HPLC (XBridge column; method 1) gave 0.058 g (48%) of the desired compound as a beige solid. ESI/APCI(+): 491 (M+H). ESI/APCI(-): 489 (M-H).

Example 175 Preparation of 2-((3-methoxyphenyl)amino)-1-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)1 H-indol-3-yl)-2-phenylethanone.

Step 1 To a solution of 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.200 g, 0.741 mmol) in DMF (5 ml) cooled to 0°C was added sodium hydride (60% dispersion in mineral oil, 0.053 g, 1.333 mmol). The reaction mixture was stirred at room temperature for 0.5 h. 1-methyl-1H-imidazole-4-sulfonyl chloride (0.268 g, 1.484 mmol) and DMAP (0.005 g, 0.037 mmol) were added and the reaction mixture was stirred at room temperature for 3 h Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30-100%) in heptane gave 0.301 g (98%) of 2-chloro-1-(1-((1-methyl-III-imidazol-4-yl)sulfonyl)-III -indol-3-yl)-2-phenylethanone as a solid. ESI/APCI(+): 414 (M+H); 436 (M + Na). ESI/APCI(-): 412 (M-H).

Step 2 2-((3-Methoxyphenyl)amino)-1-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-1H-indol-3yl)-2-phenylethanone was obtained according to general procedure E from 2-chloro-1-(1-((1-methyl-1H-imidazol-4yl)sulfonyl)-1H-indol-3-yl)-2-phenylethanone (0.166 g, 0.402 mmol) and meta -anisidine (0.449 ml, 4.011 mmol) in acetonitrile (1.5 ml) irradiated in a microwave oven at 100°C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30-100%) in heptane followed by purification by preparative HPLC (XBridge column; method 1) gave 0.058 g (29%) of the desired compound as a beige solid. ESI/APCI(+): 501 (M+H). ESI/APCI(-): 499 (MH).

Example 176 Preparation of 2-((3,5-dimethoxyphenyl)amino)-1-(1-(3-hydroxypropyl)-1H-indol-3-yl)2-phenylethanone

2-((3,5-Dimethoxyphenyl)amino)-1-(1-(3-hydroxypropyl)-1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure E from 2-chloro-1-(1 -(3-hydroxypropyl)-1H-indol-3-yl)-2-phenylethanone (0.125 g, 0.381 mmol) and 3,5-dimethoxyaniline (0.584 g, 3.813 mmol) in acetonitrile (1 ml) irradiated in a microwave oven at 130°C for 15 min. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (2-20%) in dichloromethane. Further purification by flash chromatography on silica gel using a gradient of ethyl acetate (30-100%) in heptane followed by purification by preparative HPLC (XBridge column; method 1) gave 0.022 g (13%) of the desired compound as a white solid. ESI/APCI(+): 445 (M+H).

Example 177 Preparation of 1-(1-(ethylsulfonyl)-III-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone.

Step 1 To a solution of 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.200 g, 0.741 mmol) in DMF (5 ml) cooled to 0°C was added sodium hydride (60% dispersion in mineral oil, 0.053 g, 1.333 mmol). The reaction mixture was stirred at room temperature for 0.5 h. Ethanesulfonyl chloride (0.141 ml, 1.480 mmol) and DMAP (0.005 g, 0.037 mmol) were added and the reaction mixture was stirred at room temperature for 3 h. Water was added and the reaction mixture was extracted with ethyl acetate . The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane gave 0.247 g (92%) of 2-chloro-1-(1(ethylsulfonyl)-1H-indol-3-yl)-2-phenylethanone in as a beige solid. ESI/APCI(+): 362 (M+H). ESI/APCI(-): 360 (M-H).

Step 2 1-(1-(Ethylsulfonyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to General Procedure E from 2-chloro-1-(1- (ethylsulfonyl)-1H-indol-3-yl)-2-phenylethanone (0.130 g, 0.359 mmol) and meta-anisidine (0.402 ml, 3.591 mmol) in acetonitrile (1.5 ml) irradiated in a microwave at 100° C for 45 min. Purification by flash chromatography on silica gel using a gradient of dichloromethane (15-70%) in heptane gave 0.039 g (25%) of the desired compound as a beige solid. ESI/APCI(+): 449 (M+H). ESI/APCI(-): 447 (M-H). 1H NMR (DMSO-d ₆ ) δ 9.15 (1H, s); 8.23 (1H, d); 7.87 (1H, d); 7.62 (2H, d); 7.43 (2H, m); 7.25-7.35 (2H, m); 7.14-7.24 (1H, m); 6.896.98 (1H, m); 6.39-6.53 (3H, m); 6.28-6.38 (1H, m); 6.12 (1H, d); 3.68-3.87 (2H, m); 3.63 (3H, s); 1.03 (3H, t).

Example 178 Preparation of 1-(5-fluoro-1-(methylsulfonyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)2-phenylethanone

Step 1. To a solution of 2-chloro-1-(5-fluoro-1H-indol-3-yl)-2-phenylethanone (0.200 g, 0.695 mmol) in DMF (5 ml), cooled to 0°C, was added the hydride sodium (60% dispersion in mineral oil; 0.053 g, 1.333 mmol). The reaction mixture was stirred at room temperature for 0.5 h. Mesyl chloride (0.108 ml, 1.395 mmol) and DMAP (0.005 g, 0.037 mmol) were added and the reaction mixture was stirred at room temperature for 3 h. Water was added and the reaction mixture was extracted with ethyl acetate . The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane gave 0.219 g (86%) of 2-chloro-1-(5fluoro-1-(methylsulfonyl)-1H-indol-3-yl)-2 -phenylethanone as a solid. ESI/APCI(+): 366 (M+H). ESI/APCI(-): 364 (M-H).

Step 2 1-(5-Fluoro-1-(methylsulfonyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to General Procedure E from 2-chloro-1 -(5-fluoro-1-(methylsulfonyl)-1H-indol-3-yl)-2-phenylethanone (0.130 g, 0.355 mmol) and meta-anisidine (0.398 ml, 3.555 mmol) in acetonitrile (1 ml) irradiated in microwave oven at 100°C for 45 min. The residue was purified by flash chromatography on silica gel using a gradient of dichloromethane (15-70%) in heptane. Further purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane gave 0.030 g (18%) of the desired compound as a beige solid. ESI/APCI(+): 453 (M+H). ESI/APCI(-): 451 (M-H). ¹ H NMR (DMSO-d6) δ 9.22 (1H, s); 7.85-7.96 (2H, m); 7.62 (2H, d); 7.32 (3H, m); 7.15-7.26 (1H, m); 6.93 (1H, t); 6.39-6.50 (3H, m); 6.27-6.35 (1H, m); 6.13 (1H, d); 3.69 (3H, s); 3.63 (3H, s).

Example 179 Preparation of 1-(6-fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6-methoxypyridin-3-yl)ethanone

-(6-Fluoro-III-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6-methoxypyridin-3-yl)ethanone was obtained according to general procedure L from a mixture of 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.067 g, 0.248 mmol) and triethylamine (0.035 ml, 0.248 mmol) in ethanol (0.4 ml), tert-butyl-6-fluoro-3- formyl1H-indole-1-carboxylate (0.158 g, 0.600 mmol) and a solution of 3-methoxyA-((6-methoxypyridin-3yl)methylene)aniline (0.503 mmol) in ethanol (0.735 ml), heated at 70°C for 113 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by preparative TLC using methanol (5%) in dichloromethane as eluent gave 0.032 g (16%) of the desired compound as a yellow solid connections. ESI/APCI(+): 406 (M+H); 428 (M+Na). ESI/APCI(-): 404 (M-H).

Example 180 Preparation of 2-(6-fluoropyridin-3-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone

Step 1 A solution of N-((6-fluoropyridin-3-yl)methylene)-3-methoxyaniline in ethanol was prepared by heating a solution of 6-fluoronicotinaldehyde (0.131 g, 1.047 mmol) and 3-methoxyaniline (0.120 ml, 1.074 mmol) in ethanol (0.5 ml) at 60° C. for 4 hours. Imine formation was quantitative and the solution was used without further purification. ESI/APCI(+): 231 (M+H).

Step 2 2-(6-Fluoropyridin-3-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was obtained

- 101 040588 according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-yl chloride (0.160 g, 0.593 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (0. 5 ml), tert-butyl-3-formyl-III-indole-1-carboxylate (0.281 g, 1.146 mmol) and a solution of N-((6-fluoropyridin-3-yl)methylene)-3-methoxyaniline (1.047 mmol) in ethanol (1.5 ml) heated at 60° C. for 16 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-50%) in heptane, followed by purification by preparative HPLC (XBridge column; method 1) gave 0.123 g (31%) of the desired compound as a yellow solid. ESI/APCI(+): 376 (M+H). ESI/APCI(-): 374 (M-H).

Example 181 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(2-methoxypyridin-3yl)ethanone

Step 1 A solution of 3-methoxy-N-((2-methoxypyridin-3-yl)methylene)aniline in ethanol was prepared by heating a solution of 2-methoxynicotinaldehyde (0.141 g, 1.028 mmol) and 3-methoxyaniline (0.122 g, 1.088 mmol) in ethanol (0.5 ml) at 60° C. for 18 hours. Imine formation was quantitative and the solution was used without further purification. ESI/APCI(+): 243 (M+H).

Step 2. 1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(2-methoxypyridin-3-yl)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.156 g, 0.578 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (0.5 ml), tert-butyl-3-formyl 1H-indol- 1-carboxylate (0.294 g, 1.199 mmol) and a solution of 3-methoxy-Na((2-methoxypyridin-3yl)methylene)aniline (1.028 mmol) in ethanol (1.5 ml) heated at 60°C for 16 h Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-50%) in heptane, followed by purification by solid phase extraction on a C18 reverse phase column using a gradient of acetonitrile (30-100%) in water gave 0.105 g (26 %) of the desired compound as a yellow foam. ESI/APCI(+): 388 (M+H). ESI/APCI(-): 386 (M-H).

Example 182 Preparation of 2-((3-methoxyphenyl)amino)-1-(1-(2-morpholinoethyl)-1H-indol-3-yl)-2phenylethanone

Step 1 To a solution of 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.200 g, 0.741 mmol) in DMF (5 ml) cooled to 0°C was added sodium hydride (60% dispersion in mineral oil, 0.053 g, 1.333 mmol). The reaction mixture was stirred at room temperature for 0.5 h. 4-(2Bromoethyl)morpholine (0.287 g, 1.479 mmol) and DMAP (0.005 g, 0.037 mmol) were added and the reaction mixture was stirred at room temperature overnight. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (1-5%) in dichloromethane gave 0.198 g (70%) of 2-chloro-1-(1-(2morpholinoethyl)-1H-indol-3-yl)-2-phenylethanone in the form of oil. ESI/APCI(+): 383 (M+H); 405 (M + Na). ESI/APCI(-): 381 (M-H).

Step 2 2-((3-Methoxyphenyl)amino)-1-(1-(2-morpholinoethyl)-1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure E from 2-chloro-1-( 1-(2-morpholinoethyl)-1H-indol-3-yl)-2-phenylethanone (0.130 g, 0.261 mmol) and meta-anisidine (0.402 ml, 3.591 mmol) in acetonitrile (1 ml) irradiated in a microwave oven at 150°C for 15 min. The residue was purified by silica gel flash chromatography using a gradient of methanol (1-10%) in dichloromethane. Further purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in dichloromethane followed by purification by preparative HPLC (XBridge column; method 4) gave 0.019 g (15%) of the desired product as a beige solid. ESI/APCI(+): 470 (M+H). ESI/APCI(-): 468 (M-H). 1H NMR (DMSO-d ₆ ) δ 8.95 (1H, s); 8.17 (1H, d); 7.57 (3H, m); 7.15-7.35 (5H, m); 6.92 (1H, t); 6.32 (3H, m); 6.11 (1H, d); 6.02 (1H, d); 4.40 (2H, m); 3.62 (3H, s); 3.52 (4H, m); 3.37 (2H, m); 2.74 (2H, m); 2.40 (3H, m).

Example 183 Preparation of 2-((3-methoxyphenyl)amino)-2-phenyl-1-(1-(piperidin-4-ylsulfonyl)-1Hindol-3-yl)ethanone

Step 1 To a solution of 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.200 g, 0.741 mmol) in DMF (5 ml) cooled to 0°C was added sodium hydride (60% dispersion in mineral oil, 0.053 g, 1.333 mmol). The reaction mixture was stirred at room temperature for 0.5 h. Benzyl-4-(chlorosulfonyl)piperidine-1-carboxylate (0.471 g, 1.482 mmol) and DMAP (0.005 g, 0.037 mmol) were added and the reaction mixture was stirred at room temperature in over 3 hours. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane gave 0.320 g (78%) benzyl-4-((3-(2-chloro-2-phenylacetyl)-1H-indole-1- yl)sulfonyl)piperidine-1-carboxylate as a white solid. ESI/APCI(+): 551 (M+H); 573 (M + Na). ESI/APCI(-): 549 (M-H).

Step 2. Benzyl 4-((3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1H-indol-1-yl)sulfonyl)piperidine-1-carboxylate was prepared according to General Procedure E from benzyl 4-((3-(2-chloro-2-phenylacetyl)1H-indol-1-yl)sulfonyl)piperidine-1-carboxylate (0.150 g, 0.272 mmol) and meta-anisidine (0.304 ml, 2.724 mmol) in acetonitrile (1 ml), irradiated in a microwave oven at 150°C for 15 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane gave 0.068 g (39%) of the desired compound as a beige solid. ESI/APCI(+): 638

- 102 040588 (M+H); 660 (M+Na). ESI/APCI(-): 636 (M-H).

Step 3: Benzyl 4-((3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-N-indol-1-yl)sulfonyl)piperidine-1-carboxylate mixture (0.135 g, 0.212 mmol ), ammonium formate (0.047 g, 0.741 mmol) and palladium hydroxide (0.003 g, 0.021 mmol) in a mixture of methanol (1 ml) and THF (0.5 ml) were irradiated in a microwave at 100°C for 10 min. The mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (1-10%) in dichloromethane followed by purification by preparative HPLC (XBridge column; method 4) gave 0.009 g (8%) 2-((3-methoxyphenyl)amino)-2- phenyl-1-(1-(piperidin-4ylsulfonyl)-1H-indol-3-yl)ethanone as a beige solid. ESI/APCI(+): 504 (M+H). ESI/APCI(-): 502 (M-H).

Example 184 Preparation of 4-((2-(1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)-2-methoxybenzonitrile

Step 1 4-(Benzylideneamino)-2-methoxybenzonitrile was quantified according to General Procedure I from benzaldehyde (0.102 mL, 1.004 mmol) and 4-amino-2-methoxybenzonitrile (0.148 g, 0.999 mmol).

Step 2. 4-((2-(III-Indol-3-yl)-2-oxo-1-phenylethyl)amino)-2-methoxybenzonitrile was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl )-4-methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (2 ml), tert-butyl-3-formyl-1H-indole-1-carboxylate (0.245 g, 1.000 mmol) and a solution of 4-(benzylideneamino)-2-methoxybenzonitrile (0.999 mmol) in ethanol (1 ml) heated at 70° C. overnight. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (15-70%) in heptane. Further purification by flash chromatography on silica gel using a gradient of dichloromethane (30-100%) in heptane followed by flash chromatography on silica gel using a gradient of ethyl acetate (1-10%) in dichloromethane gave 0.100 g (26%) of the desired compound as a beige solid. substances. ESI/APCI(+): 382 (M+H). ESI/APCI(-): 380 (M-H). 1H NMR (DMSO-d6) δ 12.25 (1H, br s); 8.89 (1H, s); 8.17 (1H, d); 7.65 (2H, d); 7.46 (2H, t); 7.12-7.38 (6H, m); 6.63 (1H, brs); 6.49 (1H, d); 6.24 (1H, d); 3.76 (3H, s).

Example 185 Preparation of 1-(5-(hydroxymethyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone

Step 1 To a solution of (1H-indol-5-yl)methanol (0.253 g, 1.719 mmol), triethylamine (0.479 ml, 3.437 mmol) and DMAP (0.021 g, 0.172 mmol) in dichloromethane (4 ml) was added TBDMSCl (0.285 g, 1.891 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic phases were combined, washed with 0.5N. hydrochloric acid solution and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 0.370 g (82%) of 5-(((tert-butyldimethylsilyl)oxy)methyl)-1H-indole. 1H NMR (DMSO-d ₆ ) δ 10.95 (1H, br s); 7.39 (1H, s); 7.20-7.31 (2H, m); 6.96 (1H, d); 6.32 (1H, s); 4.67 (2H, s); 3.27 (6H, s); 0.83 (9H, s).

Step 2 1-(5-(((tert-Butyldimethylsilyl)oxy)methyl)-1H-indol-3-yl)-2-chloro-2-phenylethanone was prepared according to General Procedure A from α-chlorophenylacetyl chloride (0.208 ml, 1.415 mmol), 5-(((tert-butyldimethylsilyl)oxy)methyl)-1H-indole (0.370 g, 1.415 mmol) and pyridine (0.114 ml, 1.415 mmol) in toluene (4 ml) at 55°C. The solid obtained after precipitation was recrystallized from acetonitrile to give 0.183 g (31%) of the desired compound as a pink solid. ESI/APCI(-): 412, 414 (M-H).

Step 3 1-(5-(Hydroxymethyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to General Procedure E from 1-(5-(((tert -butyldimethylsilyl)oxy)methyl)-1H-indol-3-yl)-2chloro-2-phenylethanone (0.100 g, 0.242 mmol) and 3-methoxyaniline (0.541 ml, 4.832 mmol) in acetonitrile (1 ml) irradiated in microwave oven at 150°C for 30 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by purification by preparative HPLC (XBridge column; method 5) gave 0.002 g (2%) of the desired product. ESI/APCI(+): 387 (M+H). ESI/APCI(-): 385 (M-H).

Example 186 Preparation of tert-butyl-3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1-methyl-6,7dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H )-carboxylate.

tert-Butyl-3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1-methyl-6,7-dihydro-1H-pyrazolo[4,3c]pyridine-5(4H)-carboxylate was obtained according to the general procedure L from a mixture of 3-benzyl-5-(2hydroxyethyl)-4-methylthiazol-3-ium chloride (0.117 g, 0.433 mmol) and triethylamine (0.061 ml, 0.433 mmol) in ethanol (1 ml), t- butyl 3-formyl-1-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)carboxylate (0.230 g, 0.867 mmol) and a solution of N-benzylidene-3-methoxyaniline ( 0.867 mmol) in ethanol (1 ml) heated at 70° C. for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-80%) in heptane gave 0.235 g (57%) of the desired compound. ESI/APCI(+): 477 (M+H).

Example 187 Preparation of 2-((3-methoxyphenyl)amino)-1-(1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3c]pyridin-3-yl)-2-phenylethanone hydrochloride.

- 103 040588

To a solution of tert-butyl-3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1-methyl-6,7-dihydro-1Hpyrazolo[4,3-c]pyridine-5(4H)- carboxylate (0.235 g, 0.493 mmol) in dioxane (2 ml) cooled to 0°C was added dropwise 4n. a solution of hydrogen chloride in dioxane (5.000 ml, 20.00 mmol). The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was triturated with diethyl ether and the resulting solid was filtered and dried under reduced pressure over phosphorus(V) oxide to give 0.104 g (48%) 2-((3-methoxyphenyl)amino)-1(1-methyl-4, 5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-phenylethanone hydrochloride as a green solid. ESI/APCI(+): 377 (M+H). ESI/APCI(-): 375 (M-H).

Example 188 Preparation of 1-(7-methoxy-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone

Step 1 To a solution of DMF (0.600 ml, 7.749 mmol) in dichloromethane (2 ml) cooled to -15° C., phosphorus oxychloride (0.350 ml, 3.755 mmol) was added dropwise. After 15 min at -15°C, a solution of 7-methoxy-1H-indole (0.498 g, 3.384 mmol) in dichloromethane (1.5 ml) was added. The reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight. The reaction mixture was basified with 1M sodium hydroxide solution and extracted with dichloromethane. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using ethyl acetate (50%) in heptane as eluent gave 0.346 g (58%) of 7-methoxy-1H-indole-3-carbaldehyde as a green solid. 1H NMR (DMSO-d ₆ ) δ 12.31 (1H, br s); 9.92 (1H, s); 8.17 (1H, s); 7.65 (1H, d); 7.14 (1H, t); 6.84 (1H, d); 3.94 (3H, s).

tert-Butyl-3-formyl-7-methoxy-1H-indole-1-carboxylate was prepared according to General Procedure F from 7-methoxy-1H-indole-3-carbaldehyde (0.346 g, 1.975 mmol), di-tert-butyl- dicarboxylate (0.552 g, 2.529 mmol) and DMAP (0.032 g, 0.262 mmol) in acetonitrile (6 mL) to give 0.505 g (93%) of the desired product as an orange solid. ESI/APCI(+): 276 (M+H). 1H NMR (DMSO-d ₆ ) δ 10.03 (1H, s); 8.59 (1H, s); 7.74 (1H, d); 7.73 (1H, t); 7.05 (1H, d); 3.92 (3H, s); 1.61 (9H, s).

Step 3. 1-(7-Methoxy-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl )-4-methylthiazol-3-ium chloride (0.161 g, 0.597 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol, tert-butyl-3-formyl-7-methoxy-1Hindole-1-carboxylate (0.297 g, 1.079 mmol) and a solution of K-benzylidene-3-methoxyaniline (1.037 mmol) in ethanol (1.5 ml) heated at 60°C for 16 hours. Purification by flash chromatography on silica gel using an ethyl acetate gradient (0-40% ) in heptane followed by purification by preparative HPLC (XBridge column; method 2) gave 0.018 g (4%) of the desired compound as a yellow solid. ESI/APCI(+): 387 (M+H). ESI/APCI(-): 385 (M-H).

Example 189 Preparation of 1-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-((3methoxyphenyl)amino)-2 -phenylethanone.

To a stirred solution of 2-((3-methoxyphenyl)amino)-1-(1-methyl-4,5,6,7-tetrahydro-1Hpyrazolo[4,3-c]pyridin-3-yl)-2-phenylethanone hydrochloride (0.086 g, 0.208 mmol) in THF (2 ml) was added triethylamine (0.087 ml, 0.625 mmol), formaldehyde (0.047 ml, 0.625 mmol), sodium triacetoxyborohydride (0.132 g, 0.625 mmol) and a drop of acetic acid. The reaction mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. The residue was dissolved in dichloromethane and a mixture of methanol and 25% ammonium hydroxide solution (9/1) was added. The precipitate was filtered and washed with dichloromethane. The filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol/25% ammonium hydroxide (9/1) (0-10%) in dichloromethane gave 0.030 g (35%) of 1-(1,5-dimethyl-4,5,6, 7-tetrahydro-1H-pyrazolo[4,3c]pyridin-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone. ESI/APCI(+): 391 (M+H). 1H NMR (DMSOd6) δ 7.51 (2H, d); 7.27-7.36 (2H, m); 7.18-7.26 (1H, m); 6.92 (1H, t); 6.33-6.44 (1H, m); 6.18-6.32 (3H, m); 6.12 (1H, d); 3.84 (3H, s); 3.61 (3H, s); 3.37-3.51 (2H, m); 2.53-2.75 (4H, m); 2.32 (3H, s).

Example 190 Preparation of 2-((3-methoxyphenyl)amino)-1-(7-methyl-1H-indol-3-yl)-2-phenylethanone

Step 1. tert-Butyl-3-formyl-7-methyl-1H-indole-1-carboxylate was prepared according to General Procedure F from 7-methyl-1H-indole-3-carbaldehyde (0.500 g, 3.141 mmol), di-tert -butyl dicarboxylate (0.910 g, 4.170 mmol) and DMAP (0.057 g, 0.467 mmol) in acetonitrile (10 mL) to give 0.790 g (97%) of the desired product as a beige solid. ESI/APCI(+): 260 (M+H). 1H NMR (DMSO-d ₆ ) δ 10.05 (1H, s); 8.65 (1H, s); 8.03 (1H, d); 7.28 (2H, m); 2.54 (3H, s); 1.64 (9H, s).

Step 2 2-((3-Methoxyphenyl)amino)-1-(7-methyl-1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl )-4-methylthiazol-3-ium chloride (0.145 g, 0.537 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (0.5 ml), tert-butyl-3-formyl-7-methyl-1Hindole-1 -carboxylate (0.280 g, 1.080 mmol) and a solution of N-benzylidene-3-methoxyaniline (0.989 mmol) in ethanol (1.5 ml) heated at 60°C for 16 h. Purification by flash chromatography on silica gel using a gradient ethyl acetate (20-50%) in heptane followed by precipitation from diethyl ether gave 0.019 g (5%) of the desired compound as a yellow solid. ESI/APCI(+): 371 (M+H). ESI/APCI(-): 369 (M-H).

- 104 040588

Example 191 Preparation of 2-((3-methoxyphenyl)amino)-1-(6-methyl-III-pyrrolo[2,3-b]pyridin-3-yl)-2phenylethanone

Step 1: tert-Butyl 3-formyl-6-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate was prepared according to General Procedure F from 6-methyl-1H-pyrrolo[2,3-b] pyridine-3-carbaldehyde (0.481 g, 3.003 mmol), di-tert-butyl dicarbonate (0.786 g, 3.601 mmol) and DMAP (0.037 g, 0.300 mmol) in acetonitrile (7.5 ml) to give 0.753 g (96%) desired connection.

Step 2 2-((3-Methoxyphenyl)amino)-1-(6-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenylethanone was prepared according to General Procedure L from a mixture of 3- benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g, 0.556 mmol) and triethylamine (0.075 ml, 0.541 mmol) in ethanol (1 ml), tert-butyl-3-formyl-6-methyl -1H-pyrrolo[2,3-b]pyridine-1-carboxylate (0.260 g, 0.999 mmol) and a solution of K-benzylidene-3methoxyaniline (0.999 mmol) in ethanol (1 ml), heated at 70°C for 2 days . The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane. Further purification by flash chromatography on silica gel using ethyl acetate (55%) in heptane as eluent gave 0.058 g (15%) of the desired compound as a white solid. ESI/APCI(+): 372 (M+H). ESI/APCI(-): 370 (M-H).

Example 192 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6-methylpyridin-3yl)ethanone

Stage 1. A solution of 3-methoxy-N-((6-methylpyridin-3-yl)methylene)aniline in ethanol was obtained by heating a solution of 6-methylnicotinaldehyde (0.126 g, 1.023 mmol) and 3-methoxyaniline (0.125 g, 1.131 mmol) in ethanol (0.5 ml) at 60° C. for 18 hours. Imine formation was quantitative and the solution was used without further purification. ESI/APCI(+): 227 (M+H). ESI/APCI(-): 225 (M-H).

Step 2. 1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6-methylpyridin-3-yl)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.400 ml, 2.886 mmol) in ethanol (0.5 ml), tert-butyl-3-formyl-1H- indole 1-carboxylate (0.270 g, 1.101 mmol) and a solution of 3-methoxy-N-((6-methylpyridin-3-yl)methylene)aniline (1.023 mmol) in ethanol (1.5 ml), heated at 60°C in Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-70%) in heptane followed by precipitation from methanol gave 0.021 g (6%) of the desired compound as a beige solid. ESI/APCI(+): 372 (M+H). ESI/APCI(-): 370 (M-H).

Example 193 Preparation of 1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone

Step 1 To a solution of 5-fluoro-1H-pyrrolo[2,3-b]pyridine (0.545 g, 4.004 mmol) in a mixture of 1,2-dichloroethane (10 ml) and nitromethane (10 ml), cooled to 0°C, was added dichloro(methoxy)methane (1.825 ml, 20.00 mmol) and aluminum trichloride (1.600 g, 12.00 mmol) under argon. The reaction mixture was stirred for 1 hour. The reaction was quenched by adding water and saturated sodium bicarbonate solution. The reaction mixture was extracted with a mixture of dichloromethane and ethanol (9/1). The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 0.503 g (77%) of 5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde as a brown solid. ESI/APCI(-): 163 (M-H). 1H NMR (DMSO-d ₆ ) δ 12.88 (1H, br s); 9.94 (1H, s); 8.57 (1H, d); 8.37-8.42 (1H, m); 8.40 (1H, brs); 8.18 (1H, dd).

Step 2: tert-Butyl 5-fluoro-3-formyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate was prepared according to General Procedure F from 5-fluoro-1H-pyrrolo[2,3-b] pyridine-3-carbaldehyde (0.497 g, 3.028 mmol), ditert-butyl dicarbonate (0.793 g, 3.633 mmol) and DMAP (0.037 g, 0.303 mmol) in acetonitrile (7.5 ml) to give 0.687 g (86%) of the desired compound as a brown solid. 1H NMR (DMSO-d6) δ 10.06 (1H, s); 8.89 (1H, s); 8.54 (1H, d); 8.25 (1H, dd); 1.66 (9 H, s).

Step 3. 1-(5-Fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure L from a mixture of 3 -benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g, 0.556 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1 ml), tert-butyl-5-fluoro- 3formyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (0.264 g, 0.999 mmol) and a solution of N-benzylidene-3-methoxyaniline (0.998 mmol) in ethanol (1 ml), heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-80%) in heptane followed by precipitation from diethyl ether gave 0.034 g (9%) of the desired compound as a white solid. ESI/APCI(+): 376 (M+H). ESI/APCI(-): 374 (M+H).

Example 194 Preparation of 1-(5-((dimethylamino)methyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone

Step 1. A solution of 1H-indole-5-carbaldehyde (1.000 g, 6.889 mmol), 2 M dimethylamine in THF (5.170 ml, 10.34 mmol), acetic acid (2.370 ml, 41.40 mmol) and sodium triacetoxyborohydride ( 3.650 g, 17.22 mmol) in THF (20 mL) was heated to 75° C. for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol/25% ammonium hydroxide (9/1) (0-12%) in dichloromethane gave 0.657 g (55%) of 1-(1H-indol-5-yl)-N,N -dimethylmethanamine. ESI/APCI(+): 175 (M+H).

- 105 040588

Step 2 Phosphorus oxychloride (0.520 ml, 5.579 mmol) was added dropwise to DMF (2 ml) cooled to 0°C and the reaction mixture was stirred at 0°C for 30 min. A solution of 1-(1N-indol-5yl)-N,N-dimethylmethanamine (0.486 g, 2.789 mmol) in DMF (5 ml) was added dropwise to the cold Vilsmeier reagent and the reaction mixture was stirred at room temperature for 3 h. The suspension was poured into a mixture of ice/water and neutralized with 1N. sodium hydroxide solution. The aqueous layer was extracted with a mixture of dichloromethane and ethanol (9/1) and ethyl acetate. The organic phases were combined and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (0-10%) in dichloromethane gave 0.365 g (65%) of 5-((dimethylamino)methyl)-1Hindole-3-carbaldehyde. ESI/APCI(+): 203 (M+H).

Step 3 tert-Butyl 5-((dimethylamino)methyl)-3-formyl-1H-indole-1-carboxylate was prepared according to General Procedure F from 5-((dimethylamino)methyl)-1H-indole-3-carbaldehyde ( 0.365 g, 1.805 mmol), di-tert-butyl dicarbonate (0.473 g, 2.166 mmol) and DMAP (0.022 g, 0.180 mmol) in acetonitrile (5 mL) to give 0.112 g (21%) of the desired compound. ESI/APCI(+): 303 (M+H).

Step 5 1-(5-((Dimethylamino)methyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to General Procedure L from a mixture of 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazol-3-yl chloride (0.050 g, 0.185 mmol) and triethylamine (0.026 ml, 0.188 mmol) in ethanol (0.5 ml), tert-butyl-5 ((dimethylamino) methyl )-3-formyl-1H-indole-1-carboxylate (0.112 g, 0.370 mmol) and a solution of N-benzylidene-3-methoxyaniline (0.369 mmol) in ethanol (0.5 ml), heated at 70°C for 2 days. The residue was purified by silica gel flash chromatography using a gradient of methanol/25% ammonium hydroxide (9/1) (0-10%) in dichloromethane followed by preparative TLC purification using methanol (10%) in dichloromethane as eluent. Further purification by preparative HPLC (XBridge column; method 5) followed by purification by preparative TLC using methanol/25% ammonium hydroxide (9/1) (10%) in dichloromethane as eluent gave 0.001 g (1%) of the desired compound. ESI/APCI(+): 414 (M+H). ESI/APCI(-): 412 (M-H).

Example 195 Preparation of 2-((3-methoxyphenyl)amino)-1-(5-(methylsulfonyl)-1H-indol-3-yl)-2phenylethanone

Step 1 To a solution of 5-(methylsulfonyl)indoline (0.450 g, 2.281 mmol) in dioxane (10 mL) was added 2,3-dichloro-5,6-dicyanobenzoquinone (0.777 g, 3.423 mmol). The reaction mixture was heated at 80° C. for 2 hours. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in dichloromethane. Further purification by flash chromatography on silica gel using a gradient of ethyl acetate (15-70%) in heptane gave 0.210 g (47%) of 5-methylsulfonyl-III-indole as a white solid. ESI/APCI(+): 196 (M+H); 218 (M + Na). ESI/APCI(-): 194 (M-H).

Step 2 5-(Methylsulfonyl)-1H-indole-3-carbaldehyde was prepared according to General Procedure R from a solution of oxalyl chloride (0.107 ml, 1.231 mmol) in dichloromethane (8 ml), DMF (0.095 ml, 1.228 mmol) and 5-( methylsulfonyl)-1H-indole (0.200 g, 1.024 mmol). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15-70%) in dichloromethane gave 0.155 g (84%) of the desired compound as a white solid. ESI/APCI(+): 224 (M+H); 246 (M + Na). ESI/APCI(-): 222 (M-H).

Step 3 To a solution of 5-(methylsulfonyl)-1H-indole-3-carbaldehyde (0.155 g, 0.694 mmol) in dichloromethane (10 ml) was added di-tert-butyl dicarbonate (0.182 g, 0.831 mmol), DMAP (0.017 g, 0.139 mmol) and triethylamine (0.116 ml, 0.833 mmol). After stirring for 15 minutes, the reaction mixture was diluted with saturated ammonium chloride solution and extracted with dichloromethane. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15-100%) in heptane gave 0.198 g (88%) tert-butyl-3formyl-5-(methylsulfonyl)-1H-indole-1-carboxylate as a white solid. ESI/APCI(+): 324 (M+H); 346 (M + Na).

Step 4 2-((3-Methoxyphenyl)amino)-1-(5-(methylsulfonyl)-1H-indol-3-yl)-2-phenylethanone was prepared according to General Method K from a mixture of 3-benzyl-5-(2 -hydroxyethyl)-4-methylthiazolium chloride (0.093 g, 0.345 mmol) and triethylamine (0.042 ml, 0.313 mmol) in ethanol (2 ml), tert-butyl-3-formyl-5(methylsulfonyl)-1H-indole-1- carboxylate (0.198 g, 0.612 mmol) and a solution of N-benzylidene-3-methoxyaniline (0.610 mmol) in ethanol (1 ml), heated at 70° C. overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in dichloromethane followed by precipitation from dichloromethane gave 0.070 g (26%) of the desired compound as a yellowish solid. ESI/APCI(+): 435 (M+H). ESI/APCI(-): 433 (M-H). ¹ H NMR (DMSO-d ₆ ) δ 9.11 (1H, s); 8.73 (1H, s); 7.70-7.81 (2H, m); 7.67 (2H, d); 7.27-7.38 (2H, m); 7.23 (1H, m); 6.95 (1H, t); 6.35-6.49 (3H, m); 6.16 (2H, m); 3.65 (3H, s); 3.17 (3H, s).

Example 196 Preparation of 1-(4-fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone

Step 1 To a solution of DMF (0.670 ml, 8.653 mmol) in dichloromethane (2.5 ml) cooled to -15° C., phosphorus oxychloride (0.400 ml, 4.291 mmol) was added dropwise. After 15 min at -15°C, a solution of 4-fluoro-1H-indole (0.500 g, 3.700 mmol) in dichloromethane (2 ml) was added. The reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight. Saturated sodium bicarbonate solution was added and the reaction mixture was extracted with dichloromethane.

The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using ethyl acetate (50%) in heptane as eluent gave 0.144 g (24%) of 4-fluoro-1H-indole-3-carbaldehyde as a beige solid. ESI/APCI(+): 164. ESI/APCI(-): 162 (M-H).

Step 2 tert-Butyl 4-fluoro-3-formyl-1H-indole-1-carboxylate was prepared according to General Procedure F from 4-fluoro-1H-indole-3-carbaldehyde (0.164 g, 1.005 mmol), di-tert -butyl dicarboxylate (0.301 g, 1.379 mmol) and DMAP (0.032 g, 0.261 mmol) in acetonitrile (3 mL) to give 0.230 g (87%) of the desired product as a beige solid. 1H NMR (DMSO-d ₆ ) δ 10.08 (1H, s); 8.59 (1H, s); 8.00 (1H, d); 7.46 (1H, dt); 7.22 (1H, t); 1.66 (9H, s).

Step 3 1-(4-Fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to General Procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl )-4-methylthiazol-3-ium chloride (0.110 g, 0.408 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (0.5 ml), tert-butyl-4-fluoro-3-formyl-1Hindole-1 -carboxylate (0.230 g, 0.874 mmol) and a solution of N-benzylidene-3-methoxyaniline (0.809 mmol) in ethanol (1.5 ml) heated at 60°C for 72 hours. Purification by flash chromatography on silica gel using a gradient ethyl acetate (0-50%) in heptane followed by purification by preparative HPLC (XBridge column; method 2) gave 0.021 g (7%) of the desired compound as a beige solid. ESI/APCI(+): 375 (M+H). ESI/APCI(-): 373 (M-H).

Example 197 Preparation of 1-(4-methoxy-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone

Step 1. tert-Butyl-3-formyl-4-methoxy-1H-indole-1-carboxylate was prepared according to General Procedure F from 4-methoxy-1H-indole-3-carbaldehyde (0.400 g, 2.283 mmol), di-tert -butyl dicarboxylate (0.600 g, 2.749 mmol) and DMAP (0.030 g, 0.246 mmol) in acetonitrile (7 mL) to give 0.537 g (85%) of the desired product as a beige solid. APCI/ESCI(+): 276 (M+H). 1H NMR (DMSO-d ₆ ) δ 10.43 (1H, s); 8.19 (1H, s); 7.77 (1H, d); 7.40 (1H, t); 7.00 (1H, d); 3.98 (3H, s); 1.66 (9H, s).

Step 2. 1-(4-Methoxy-III-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl )-4-methylthiazol-3-ium chloride (0.115 g, 0.426 mmol) and triethylamine (0.085 ml, 0.610 mmol) in ethanol (0.5 ml), tert-butyl-3-formyl-4-methoxy1H-indole-1 -carboxylate (0.252 g, 0.915 mmol) and a solution of N-benzylidene-3-methoxyaniline (0.800 mmol) in ethanol (1.5 ml) heated at 60°C for 16 h. Purification by flash chromatography on silica gel using a gradient ethyl acetate (0-40%) in heptane followed by purification by preparative HPLC (XBridge column; method 2) gave 0.031 g (10%) of the desired compound as a yellow foam. ESI/APCI(+): 387 (M+H). ESI/APCI(-): 385 (M-H).

Example 198 Preparation of 2-((3,5-dimethoxyphenyl)amino)-1-(6-methyl-1H-pyrrolo[2,3-b]pyridin-3yl)-2-phenylethanone

Step 1 N-Benzylidene-3,5-dimethoxyaniline was quantified according to General Procedure I from benzaldehyde (0.101 ml, 0.999 mmol) and 3,5-dimethoxyaniline (0.153 g, 0.999 mmol).

Step 2 2-((3,5-Dimethoxyphenyl)amino)-1-(6-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenylethanone was prepared according to General Procedure L from a mixture 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.504 mmol) in ethanol (1 ml), tert-butyl-3formyl-6 -methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (0.260 g, 0.999 mmol) and a solution of N-benzylidene-3,5-dimethoxyaniline (0.999 mmol) in ethanol (1 ml) heated at 70°C within 4 days. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (080%) in heptane. Further purification by flash chromatography on silica gel using ethyl acetate (60%) in heptane as eluent followed by purification by preparative HPLC (XBridge column; method 5) gave 0.016 g (4%) of the desired compound as a white solid. ESI/APCI(+): 402 (M+H). ESI/APCI(-): 400 (M-H).

Example 199 Preparation of 4-(1-((3,5-dimethoxyphenyl)amino)-2-(1H-indol-3-yl)-2-oxoethyl)benzonitrile

Step 1 A solution of 4-(((3,5-dimethoxyphenyl)imino)methyl)benzonitrile in ethanol was prepared by heating a solution of 4-formylbenzonitrile (0.132 g, 1.007 mmol) and 3,5-dimethoxyaniline (0.166 g, 1.084 mmol) in ethanol (0.5 ml) at 60° C. for 18 hours. Imine formation was quantitative and the solution was used without further purification. ESI/APCI(+): 267 (M+H). ESI/APCI(-): 265 (M-H).

Step 2 4-(1-((3,5-Dimethoxyphenyl)amino)-2-(III-indol-3-yl)-2-oxoethyl)benzonitrile was prepared according to General Procedure K from a mixture of 3-benzyl-5-( 2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (0.5 ml), tert-butyl-3-formyl-1H-indole 1- carboxylate (0.270 g, 1.101 mmol) and a solution of 4-(((3,5-dimethoxyphenyl)imino)methyl)benzonitrile (1.007 mmol) in ethanol (1.5 ml) heated at 60°C for 16 hours. flash chromatography on silica gel using a gradient of ethyl acetate (10-60%) in heptane followed by precipitation from methanol and water gave 0.102 g (25%) of the desired compound as a yellow powder. ESI/APCI(+): 412 (M+H). ESI/APCI(-): 410 (M-H).

Example 200 Preparation of 2-((3,5-dimethoxyphenyl)amino)-1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-107040588yl)-2-phenylethanone.

2-((3,5-Dimethoxyphenyl)amino)-1-(5-fluoro-III-pyrrolo[2,3-b]pyridin-3-yl)-2-phenylethanone was obtained according to general procedure L from a mixture of 3-benzyl -5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1 ml), tert-butyl-5-fluoro-3formyl- 1H-pyrrolo[2,3-b]pyridine-1-carboxylate (0.264 g, 0.999 mmol) and a solution of K-benzylidene-3,5-dimethoxyaniline (0.999 mmol) in ethanol (1 ml), heated at 70°C for 2 days. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (0-80%) in heptane. Further purification by flash chromatography on silica gel using ethyl acetate (55%) in heptane as eluent followed by purification by preparative HPLC (XBridge column; method 5) gave 0.003 g (1%) of the desired compound as a white solid. ESI/APCI(+): 406 (M+H). ESI/APCI(-): 404 (M-H).

Example 201 Preparation of 2-((3,5-dimethoxyphenyl)amino)-2-(4-fluorophenyl)-1-(1H-indol-3-yl)ethanone

Step 1 A solution of 4-fluorobenzaldehyde (0.124 g, 0.999 mmol) and 3,5-dimethoxyaniline (0.153 g, 0.999 mmol) in ethanol (1 ml) was heated at 60° C. overnight. The reaction mixture was concentrated under reduced pressure to give N-(4-fluorobenzylidene)-3,5-dimethoxyaniline quantitatively, which was used in the next step without further purification.

Step 2 2-((3,5-Dimethoxyphenyl)amino)-2-(4-fluorophenyl)-1-(1H-indol-3-yl)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5-( 2-hydroxyethyl)-4-methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.069 ml, 0.498 mmol) in ethanol (2 ml), tert-butyl-3-formyl-1H-indole-1-carboxylate (0.245 g, 0.999 mmol) and a solution of K-(4-fluorobenzylidene)-3,5-dimethoxyaniline (0.999 mmol) in ethanol (1 ml), heated at 70°C overnight. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane. Further purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane followed by purification by preparative HPLC (XBridge column; method 1) gave 0.008 g (2%) of the desired compound as a beige solid. ESI/APCI(+): 405 (M+H). ESI/APCI(-): 403 (M-H).

Example 202 Preparation of 2-((3,5-dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(pyridin-3-yl)ethanone

2-((3,5-Dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(pyridin-3-yl)ethanone was prepared according to the 2 different procedures described herein as Method A and Method B .

Method A.

Step 1. A solution of 3,5-dimethoxy-N-(pyridin-3-ylmethylene)aniline in ethanol was prepared by heating a solution of nicotinaldehyde (0.107 g, 0.999 mmol) and 3,5-dimethoxyaniline (0.153 g, 0.999 mmol) in ethanol ( 1.5 ml) at 60° C. for 6 hours. Imine formation was quantitative and the solution was used without further purification.

Step 2 2-((3,5-Dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(pyridin-3-yl)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.069 ml, 0.498 mmol) in ethanol (1.5 ml), tert-butyl-3-formyl-1H-indole 1-carboxylate ( 0.245 g, 0.999 mmol) and a solution of 3,5-dimethoxy-N-(pyridin-3-ylmethylene)aniline (0.999 mmol) in a mixture of ethanol (1.5 ml) and dichloromethane (1.5 ml), heated at 70 ° C within 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30-100%) in dichloromethane followed by purification by preparative HPLC (XBridge column; method 5) gave 0.010 g (3%) of the desired compound as a white solid. ESI/APCI(+): 388 (M+H). ESI/APCI(-): 386 (MH). ¹ H NMR (DMSO-d6) δ 12.21 (1H, br s); 8.94 (1H, d); 8.88 (1H, s); 8.40 (1H, d); 8.16 (1H, d); 7.96 (1H, d); 7.48 (1H, d); 7.32 (1H, dd); 7.12-7.27 (2H, m); 6.48 (1H, d); 6.17 (1H, d); 6.06 (2H, s); 5.74 (1H, s); 3.62 (6H, s).

Method B.

Step 1 A mixture of (pyridin-3-yl)acetic acid (1.850 g, 10.67 mmol) in acetic anhydride (1 ml) was heated in a sealed tube at 85°C for 1 h and indole (1.250 g, 10 67 mmol). The reaction mixture was heated at 85°C for 20 min and at 105°C for 30 min. After cooling to room temperature, the reaction mixture was converted to base (pH 8) with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (1-10%) in dichloromethane gave 0.674 g (27%) of 1-(1H-indol-3-yl)-2-(pyridin-3-yl)ethanone as beige solid. ESI/APCI(+): 237 (M+H). ESI/APCI(-): 235 (M-H).

Step 2. 2-Bromo-1-(1H-indol-3-yl)-2-(pyridin-3-yl)ethanone was prepared according to general procedure P from a solution of 1-(1H-indol-3-yl)-2- (pyridin-3-yl)ethanone (0.570 g, 2.412 mmol) in THF (17 ml) and a solution of phenyltrimethylammonium tribromide (0.997 g, 2.652 mmol) in THF (22 ml). The reaction mixture was stirred at 0°C for 1 h and at room temperature overnight. Purification by flash chromatography on silica gel using a gradient of methanol (1-10%) in dichloromethane gave 0.275 g (36%) of the desired compound as a brown solid. ESI/APCI(+): 315, 317 (M+H).

Step 3: A mixture of 2-bromo-1-(1H-indol-3-yl)-2-(pyridin-3-yl)ethanone (0.050 g, 0.159 mmol) and 3.5-108 040588 dimethoxyaniline (0.121 g, 0.793 mmol) in acetonitrile (1 ml) was irradiated in a microwave oven at 100°C for 5 min. Saturated sodium bicarbonate solution was added and the reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography using a gradient of methanol (1-7%) in dichloromethane. Further purification by preparative HPLC (XBridge column; method 5) followed by precipitation from ethyl acetate gave 0.019 g (31%) of 2-((3,5-dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2- (pyridin-3yl)ethanone as a white solid. ESI/APCI(+): 388 (M+H). ESI/APCI(-): 386 (M-H).

Example 203 Preparation of 2-((3-methoxyphenyl)amino)-1-(6-Morpholin-1H-indol-3-yl)-2-phenylethanone

Step 1 To a solution of 6-nitroindole (0.800 g, 4.934 mmol) in pyridine (8 ml) cooled to 0°C was added acetic anhydride (2.000 ml, 21.16 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and brine. The phases were separated. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in a mixture of methanol (40 ml) and THF (40 ml). 10% palladium on carbon (0.080 g, 0.752 mmol) and ammonium formate (2.000 g, 31.72 mmol) were added. The reaction mixture was stirred at 60° C. for 2 hours. After cooling to room temperature, the reaction mixture was filtered through a pad of cellite and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and brine. The phases were separated. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15-70%) in dichloromethane gave 0.266 g (31%) of 1-(6-amino-1H-indol-1yl)ethanone as a brown solid.

Step 2: A mixture of 1-(6-amino-1H-indol-1-yl)ethanone (0.260 g, 1.493 mmol), 1-bromo-2-(2-bromoethoxy)ethane (0.415 g, 1.789 mmol) and DIPEA ( 0.766 ml, 4.475 mmol) in DMF (8 ml) was stirred at 90° C. overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15-70%) in heptane gave 0.242 g (80%) of 4-(1H-indol-6-yl)morpholine as a white solid. ESI/APCI(+): 203 (M+H). ESI/APCI(-): 201 (M-H).

Step 3 6-Morpholine-1H-indole-3-carbaldehyde was prepared according to General Procedure R from a solution of oxalyl chloride (0.125 ml, 1.438 mmol) in dichloromethane (8 ml), DMF (0.111 ml, 1.435 mmol) and 4-(1Hindole- 6-yl)morpholine (0.242 g, 1.197 mmol). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15-70%) in dichloromethane gave 0.228 g (83%) of the desired compound as a white solid. ESI/APCI(+): 231 (M+H). ESI/APCI(-): 229 (M-H).

Step 4 To a solution of 6-morpholine-1H-indole-3-carbaldehyde (0.228 g, 0.990 mmol) in dichloromethane (15 ml) was added di-tert-butyl dicarbonate (0.259 g, 1.188 mmol), DMAP (0.024 g, 0.198 mmol ) and triethylamine (0.165 ml, 1.190 mmol). After stirring for 30 minutes, the reaction mixture was washed with saturated bicarbonate solution. The organic phase was washed with saturated ammonium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 0.308 g (94%) tert-butyl-3-formyl-6-morpholine-1H-indole-1-carboxylate as a white solid substances. ESI/APCI(+): 331 (M+H).

Step 5 2-((3-Methoxyphenyl)amino)-1-(6-morpholin-1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl )-4-methylthiazolium chloride (0.082 g, 0.304 mmol) and triethylamine (0.042 ml, 0.303 mmol) in ethanol (2 ml), tert-butyl-3-formyl-6-morpholine 1H-indole-1-carboxylate (0.200 g, 0.605 mmol) and a solution of K-benzylidene-3-methoxyaniline (0.605 mmol) in ethanol (1 ml), heated at 70° C. overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in dichloromethane followed by precipitation from diethyl ether gave 0.059 g (22%) of the desired compound as a yellow solid. ESI/APCI(+): 442 (M+H). ESI/APCI(-): 440 (M-H). ¹ H NMR (DMSO-d6) δ 11.84 (1H, br s); 8.71 (1H, brs); 7.97 (1H, d); 7.62 (2H, d); 7.22 (2H, m); 7.19 (1H, d); 6.90 (2H, m); 6.86 (1H, brs); 6.35 (2H, m); 6.31 (1H, d); 6.10 (1H, d); 6.04 (1H, d); 3.75 (4H, brs); 3.62 (3H, s); 3.07 (4H, brs).

Example 204 Preparation of 2-(imidazo[1,2-b]pyridazin-2-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone

Step 1 To a solution of imidazo[1,2-b]pyridazine-2-carboxylic acid (0.390 g, 2.391 mmol) in dichloromethane (7 mL) was added DIPEA (1.500 mL, 8.589 mmol), 1-ethyl-3-(3 -dimethylaminopropyl)carbodiimide hydrochloride (0.505 g, 2.634 mmol) and hydroxybenzotriazole (0.406 g, 2.651 mmol). The solution was stirred at room temperature for 10 minutes and N,O-dimethylhydroxylamine hydrochloride (0.266 g, 2.727 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with dichloromethane and washed with water. The aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 0.360 g (73%) of N-methoxy-K-methylimidazo[1,2-n]pyridazine -2-carboxamide as a yellow oil. ESI/APCI(+): 207 (M+H).

- 109 040588

Step 2 To a solution of N-methoxy-N-methylimidazo[1,2-b]iridazine-2-carboxamide (0.360 g, 1.746 mmol) in THF (10 ml) cooled to 0°C was added lithium aluminum hydride (0.075 g, 1.976 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. Citric acid buffer solution (pH 5) was added and the reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was filtered through celite and the solid was washed with ethyl acetate. The phases were separated. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 0.190 g (74%) of imidazo[1,2-b]iridazine-2-carbaldehyde as a yellow solid. ESI/APCI(+): 148 (M+H). 1 H NMR (DMSO-d ₆ ) δ 10.09 (1H, s); 9.02 (1H, s); 8.69 (1H, s); 8.28 (1H, d); 7.39 (1H, d).

Step 3. A solution of N-(imidazo[1,2-b]pyridazin-2-ylmethylene)-3-methoxyaniline in ethanol was prepared by heating a solution of imidazo[1,2-b]iridazine-2-carbaldehyde (0.124 g, 0.843 mmol ) and 3-methoxyaniline (0.101 ml, 0.901 mmol) in ethanol (2 ml) at 60° C. for 20 h. Imine formation was quantitative and the solution was used without further purification. ESI/APCI(+): 253 (M+H).

Step 4 2-(Imidazo[1,2-b]pyridazin-2-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to the general procedure K from mixtures of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.120 g, 0.445 mmol) and triethylamine (0.080 ml, 0.574 mmol) in ethanol (0.5 ml), tert-butyl- 3formyl-1H-indole-1-carboxylate (0.250 g, 1.019 mmol) and a solution of N-(imidazo[1,2-b]iridazin-2ylmethylene)-3-methoxyaniline (0.843 mmol) in ethanol (2.5 ml), heated at 60° C. for 72 hours. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (50-100%) in heptane followed by crystallization from ethyl acetate gave 0.055 g (16%) of the desired compound as a white solid. ESI/APCI(+): 398 (M+H). ESI/APCI(-): 396 (M-H).

Example 205 Preparation of 2-(6-(dimethylamino)pyridin-3-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone

Step 1. 5-(((3-Methoxyphenyl)imino)methyl)-N,K-dimethylpyridin-2-amine was quantified according to General Procedure I from 6-(dimethylamino)nicotinaldehyde (0.150 g, 0.999 mmol) and 3-methoxyaniline (0.112 ml, 1.001 mmol).

Stage 2. 2-(6-(Dimethylamino)pyridin-3 -yl)-1 -(1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was obtained according to the general procedure K from a mixture of 3 -benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1 ml), tert-butyl-3-formyl 1H- indole-1-carboxylate (0.245 g, 0.999 mmol) and a solution of 5-(((3-methoxyphenyl)imino)methyl)-K,Kdimethylpyridine-2-amine (0.999 mmol) in ethanol (1 ml), heated at 70 ° C within 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-100%) in heptane followed by precipitation from ethyl acetate gave 0.026 g (6%) of the desired compound as a white solid. ESI/APCI(+): 401 (M+H). ESI/APCI(-): 399 (M+H).

Example 206 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(2-methoxypyrimidin-5yl)ethanone

Step 1. 3-Methoxy-N-((2-methoxypyrimidin-5-yl)methylene)aniline was quantitatively obtained according to General Procedure I from 2-methoxypyrimidine-5-carbaldehyde (0.138 g, 0.999 mmol) and 3-methoxyaniline (0.112 ml, 1.001 mmol).

Step 2. 1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(2-methoxypyrimidin-5-yl)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1Nindole-1- carboxylate (0.245 g, 0.999 mmol) and a solution of 3-methoxy-N-((2-methoxypyrimidin-5yl)methylene)aniline (0.999 mmol) in ethanol (1 ml), heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-100%) in heptane followed by precipitation from ethyl acetate gave 0.093 g (24%) of the desired compound as a white solid. ESI/APCI(+): 389 (M+H). ESI/APCI(-): 387 (M-H).

Example 207 Preparation of 1-(5-fluoro-1H-indol-3-yl)-2-(6-methoxypyridin-3-yl)-2-((5-methoxypyridin-3-yl)amino)ethanone

Stage 1. A solution of 5-methoxy-N-((6-methoxypyridin-3-yl)methylene)pyridine-3-amine in ethanol was obtained by heating a solution of 6-methoxynicotinaldehyde (0.137 g, 0.999 mmol) and 5methoxypyridine-3-amine ( 0.124 g, 0.999 mmol) in ethanol (0.25 ml) at 45° C. for 24 hours. Imine formation was quantitative and the solution was used without further purification. ESI/APCI(+): 244 (M+H); 487 (2M+H).

Step 2. 1-(5-Fluoro-1H-indol-3-yl)-2-(6-methoxypyridin-3-yl)-2-((5-methoxypyridin-3-yl)amino)ethanone was prepared according to the general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1 ml), tert-butyl-5fluoro- 3-formyl-1H-indole-1-carboxylate (0.263 g, 0.999 mmol) and a solution of 5-methoxy-N-((6methoxypyridin-3-yl)methylene)pyridin-3-amine (0.999 mmol) in ethanol (1 ml ), heated at 70°C for 4 days. Purification by flash chromatography on silica gel using a gradient of methanol (010%) in dichloromethane followed by precipitation from diethyl ether gave 0.095 g (23%) of the desired compound as a white solid. ESI/APCI(+): 407 (M+H). ESI/APCI(-): 405 (M-H).

Example 208 Preparation of 1-(6-fluoro-1H-indol-3-yl)-2-(6-methoxypyridin-3-yl)-2-((5methoxypyridin-3-yl)amino)ethanone

1-(6-Fluoro-1H-indol-3-yl)-2-(6-methoxypyridin-3-yl)-2-((5-methoxypyridin-3-yl)amino)ethanone was prepared according to General Procedure L from a mixture 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1 ml), tert-butyl-6-fluoro -3formyl-1H-indole-1-carboxylate (0.263 g, 0.999 mmol) and a solution of 5-methoxy-N-((6-methoxy-pyridin-3yl)methylene)pyridine-3-amine (0.999 mmol) in ethanol (1 ml) heated at 70°C for 4 days. Purification by flash chromatography on silica gel using a gradient of methanol (0-10%) in dichloromethane followed by precipitation from diethyl ether gave 0.053 g (13%) of the desired compound as a white solid. ESI/APCI(+): 407 (M+H). ESI/APCI(-): 405 (M+H).

Example 209 Preparation of 2-((3-(2-(dimethylamino)ethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3yl)-2-phenylethanone

Step 1 To a solution of N,N-dimethylethanolamine (2.000 g, 22.44 mmol) in diethyl ether (100 ml) cooled to 0° C., methanesulfonyl chloride (1.910 ml, 24.68 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 65 hours. The resulting white solid was filtered, washed with diethyl ether and dried under vacuum to give 4.460 g (97%) of 2(dimethylamino)ethyl methanesulfonate hydrochloride.

Step 2 To a solution of 3,5-dimethoxyaniline (2.500 g, 16.32 mmol) in NMP (12 ml) was added sodium methanethiolate (2.290 g, 32.64 mmol) and the reaction mixture was heated to 140° C. overnight. After cooling to room temperature, the reaction mixture was poured into a saturated sodium phosphate monobasic solution and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (1570%) in heptane gave 1.400 g (62%) of 3-amino-5-methoxyphenol as an orange oil. ESI/APCI(+): 140 (M+H).

Step 3 To a solution of 3-amino-5-methoxyphenol (0.500 g, 3.593 mmol) in DMF (25 ml) cooled to 0°C was added sodium hydride (60% dispersion in mineral oil; 0.316 g, 7.925 mmol) in portions and then 2-(dimethylamino)ethylmethanesulfonate hydrochloride (0.731 g, 3.593 mmol). The reaction mixture was stirred at room temperature for 60 hours. Saturated sodium bicarbonate solution was added and the reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol/25% ammonium hydroxide (9/1) (2-20%) in dichloromethane gave 0.264 g (35%) of 3-(2(dimethylamino)ethoxy)-5-methoxyaniline as brown oil.

ESI/APCI(+): 211 (M+H).

Step 4: Mixture of 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.150 g, 0.556 mmol) and 3-(2(dimethylamino)ethoxy)-5-methoxyaniline (0.117 g, 0.556 mmol ) in acetonitrile (1 ml) was irradiated in a microwave oven at 150°C for 30 min. The reaction mixture was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol/25% ammonium hydroxide (9/1) (2-20%) in dichloromethane followed by preparative TLC using methanol (10%) in dichloromethane as eluent gave 0.005 g (18 %) 2-((3-(2(dimethylamino)ethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone as a beige solid. ESI/APCI(+): 444 (M+H). ESI/APCI(-): 442 (M-H). ¹ H NMR (DMSO-d ₆ ) δ 12.14 (1H, br s); 8.90 (1H, brs); 8.16 (1H, d); 7.63 (2H, d); 7.46 (1H, d); 7.27 (2H, m); 7.19 (3H, m); 6.33 (1H, d); 5.97-6.17 (3H, m); 5.71 (1H, brs); 3.89 (2H, m); 3.61 (3H, s); 2.55 (2H, m); 2.18 (6H, s).

Example 210 Preparation of 1-(1-(2-(tert-butoxy)ethyl)-6-fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone

Step 1 To a solution of 2-(tert-butoxy)ethanol (2.220 ml, 16.92 mmol) in dichloromethane (50 ml) cooled to 0°C was added triethylamine (2.820 ml, 20.31 mmol), tosyl chloride (3.870 g, 20.31 mmol) and DMAP (0.413 g, 3.381 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with dichloromethane and washed with saturated ammonium chloride solution. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane gave 3.930 g (85%) of 2-(tert-butoxy)ethyl-4-methylbenzenesulfonate as a colorless oil. ESI/APCI(+): 295 (M+Na).

Step 2 To a solution of 2-chloro-1-(6-fluoro-1H-indol-3-yl)-2-phenylethanone (0.139 g, 0.483 mmol) in THF (4 ml) cooled to 0°C was added the hydride sodium (60% dispersion in mineral oil; 0.035 g, 0.870 mmol). The mixture was stirred at room temperature for 30 minutes. 2-(tert-Butoxy)ethyl-4-methylbenzenesulfonate (0.263 g, 0.966 mmol) was added and the reaction mixture was stirred at room temperature for 60 hours. The reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride solution. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane gave 0.085 g (45%) of 1-(1-(2-(tert-butoxy)ethyl)-6-fluoro-1H-indole-3 -yl)-2-chloro-2-phenylethanone as

- 111 040588 orange oil. ESI/APCI(+): 388 (M+H). ESI/APCI(-): 386 (M-H).

Step 3 1-(1-(2-(tert-Butoxy)ethyl)-6-fluoro-N-indol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone was prepared according to General Procedure E from 1-(1-(2-(t-butoxy)ethyl)-6-fluoro-1H-indol-3yl)-2-chloro-2-phenylethanone (0.085 g, 0.219 mmol) and meta-anisidine (0.245 ml, 2.188 mmol) in acetonitrile (1 ml), irradiated in a microwave oven at 150°C for 15 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane gave 0.066 g (64%) of 1-(1-(2-(tert-butoxy)ethyl)-6-fluoro-1H-indol-3-yl )-2-((3-methoxyphenyl)amino)-2-phenylethanone as an orange solid. ESI/APCI(+): 475 (M+H); 497 (M + Na). ESI/APCI(-): 473 (M-H).

Example 211 Preparation of 1-(6-fluoro-1-(2-hydroxyethyl)-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)2-phenylethanone

1-(1-(2-(tert-Butoxy)ethyl)-6-fluoro-1 H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone (0.066 g, 0.139 mmol ) was dissolved in 4n. a solution of hydrogen chloride in dioxane (3.000 ml, 12.00 mmol). The reaction mixture was stirred at room temperature overnight. The solution was neutralized with potassium carbonate and the reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15-70%) in heptane followed by purification by preparative HPLC (XBridge column; method 1) gave 0.007 g (11%) of 1-(6-fluoro-1-(2-hydroxyethyl )-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)2-phenylethanone as a white solid. ESI/APCI(+): 419 (M+H). ESI/APCI(-): 417 (M-H). 1H NMR (DMSO-d6) δ 8.95 (1H, br s); 8.14 (1H, m); 7.63 (2H, d); 7.51 (1H, d); 7.23-7.35 (2H, m); 7.19 (1H, m); 7.07 (1H, t); 6.91 (1H, t); 6.31-6.46 (3H, m); 6.11 (1H, d); 6.04 (1H, d); 4.99 (1H, brs); 4.30 (2H, m); 3.78 (2H, m); 3.62 (3H, s).

Example 212 Preparation of 2-((5-ethoxypyridin-3-yl)amino)-1-(1H-indol-3-yl)-2-phenylethanone

Step 1 Ethanol (2.460 ml, 42.21 mmol) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil; 1.690 g, 42.21 mmol) in DMF (15 ml) cooled to 0°C. The mixture was stirred at 0° C. for 30 minutes and 3,5-dibromopyridine (5.000 g, 21.11 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 60 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of dichloromethane (30-100%) in heptane gave 1.920 g (45%) of 3-bromo-5ethoxypyridine as an oil. ESI/APCI(+): 202, 204 (M+H).

Step 2 A mixture of 3-bromo-5-ethoxypyridine (1.000 g, 4.949 mmol), copper (II) sulfate pentahydride (0.238 g, 0.990 mmol) and 25% ammonium hydroxide solution (7.620 ml, 49.49 mmol) was placed in a sealed vessel and heated at 140° C. overnight. After cooling to room temperature was added 1N. sodium hydroxide solution and the mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30-100%) in dichloromethane gave 0.357 g (52%) of 5-ethoxypyridine-3-amine as an orange oil. ESI/APCI(+): 139 (M+H). ESI/APCI(-): 137 (M-H).

Step 3 N-Benzylidene-5-ethoxypyridine-3-amine was quantified according to General Procedure I from benzaldehyde (0.102 mL, 1.004 mmol) and 5-ethoxypyridine-3-amine (0.138 g, 0.999 mmol).

Step 4 2-((5-Ethoxypyridin-3-yl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl )-4-methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1.5 ml), tert-butyl-3-formyl-1H-indole-1-carboxylate (0.245 g, 0.999 mmol ) and a solution of N-benzylidene-5-ethoxypyridine-3-amine (0.999 mmol) in ethanol (1.5 ml), heated at 70° C. overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30-100%) in dichloromethane followed by precipitation from ethyl acetate gave 0.090 g (24%) of the desired compound as a green solid. ESI/APCI(+): 372 (M+H). ESI/APCI(-): 370 (M-H).

Example 213 Preparation of 1-(1H-indol-3-yl)-2-((5-isopropoxypyridin-3-yl)amino)-2-phenylethanone

Step 1 To a suspension of sodium hydride (60% dispersion in mineral oil; 1.690 g, 42.21 mmol) in DMF (15 ml) cooled to 0° C., isopropanol (3.230 ml, 42.21 mmol) was added dropwise. After 30 minutes at 0° C., 3,5-dibromopyridine (5.000 g, 21.11 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of dichloromethane (15-70%) in heptane gave 1.210 g (26%) of 3-bromo-5-isopropoxypyridine as an oil. ESI/APCI(+): 216, 218 (M+H).

Step 2 A mixture of 3-bromo-5-isopropoxypyridine (1.000 g, 4.628 mmol), copper (II) sulfate pentahydride (0.223 g, 0.926 mmol) and 25% ammonium hydroxide solution (7.130 ml, 46.28 mmol) was placed in a sealed vessel and heated at 140° C. overnight. After cooling to room temperature was added 1N. sodium hydroxide solution and the reaction mixture were extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30-100%) in dichloromethane gave 0.243 g (34%) of 5-112040588 isopropoxypyridine-3-amine as an orange oil. ESI/APCI(+): 153 (M+H).

Step 3 N-Benzylidene-5-isopropoxypyridine-3-amine was quantified according to General Procedure I from benzaldehyde (0.102 ml, 1.004 mmol) and 5-isopropoxypyridine-3-amine (0.152 g, 0.999 mmol).

Step 4 1-(1H-Indol-3-yl)-2-((5-isopropoxypyridin-3-yl)amino)-2-phenylethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl )-4-methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1.5 ml), tert-butyl-3-formyl-III-indole 1-carboxylate (0.245 g, 0.999 mmol ) and a solution of K-benzylidene-5-isopropoxypyridine-3-amine (0.999 mmol) in ethanol (1.5 ml), heated at 70° C. overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30-100%) in dichloromethane followed by precipitation from ethyl acetate and heptane gave 0.045 g (12%) of the desired compound as a beige solid. ESI/APCI(+): 386 (M+H). ESI/APCI(-): 384 (M-H).

Example 214 Preparation of 2-((5-ethylpyridin-3-yl)amino)-1-(1H-indol-3-yl)-2-phenylethanone

Step 1. A solution of N-benzylidene-5-ethylpyridine-3-amine in ethanol was prepared by heating a solution of benzaldehyde (0.102 ml, 1.008 mmol) and 3-amino-5-ethylpyridine (0.117 g, 0.958 mmol) in ethanol (0.5 ml) at 60°C for 16 hours. Imine formation was quantitative and the solution was used without further purification. ESI/APCI (+): 211 (M+H).

Step 2 2-((5-Ethylpyridin-3-yl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl )-4-methylthiazol-3-ium chloride (0.126 g, 0.467 mmol) and triethylamine (0.090 ml, 0.646 mmol) in ethanol (0.5 ml), tert-butyl-3-formyl-1H-indole-1-carboxylate (0.250 g, 1.019 mmol) and a solution of N-benzylidene-5-ethylpyridin-3-amine (0.958 mmol) in ethanol (1.5 ml) heated at 60°C for 16 h. α-phase chromatography using a gradient of acetonitrile (0-100%) in water gave 0.051 g (15%) of the desired compound as a yellow solid. ESI/APCI(+): 356 (M+H). ESI/APCI(-): 354 (M-H).

Example 215 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(5-methoxypyrazin-2yl)ethanone

Step 1. 3-Methoxy-N-((5-methoxypyrazin-2-yl)methylene)aniline was quantitatively obtained according to General Procedure I from 5-methoxypyrazin-2-carbaldehyde (0.138 g, 0.999 mmol) and 3-methoxyaniline (0.112 ml , 1.001 mmol).

Step 2 1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(5-methoxypyrazin-2-yl)ethanone was prepared according to General Procedure L from a mixture of 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1Hindole-1- carboxylate (0.245 g, 0.999 mmol) and a solution of 3-methoxy-N-((5-methoxypyrazin-2-yl)methylene)aniline (0.999 mmol) in ethanol (1 ml), heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by precipitation from dichloromethane gave 0.142 g (36%) of the desired compound as a white solid. ESI/APCI(+): 389 (M+H). ESI/APCI(-): 387 (M-H).

Example 216 Preparation of 2-(6-ethoxypyridin-3-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone

Step 1. A solution of N-((6-ethoxypyridin-3-yl)methylene)-3-methoxyaniline in ethanol was prepared by heating a solution of 6-ethoxynicotinaldehyde (0.153 g, 1.012 mmol) and 3-methoxyaniline (0.114 ml, 1.012 mmol) in ethanol (0.5 ml) at 60° C. for 16 hours. Imine formation was quantitative and the solution was used without further purification. ESI/APCI(+): 257 (M+H).

Step 2 2-(6-Ethoxypyridin-3-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.143 g, 0.530 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (0.5 ml), tert-butyl-3-formyl-1H- indole 1-carboxylate (0.273 g, 1.113 mmol) and a solution of K-((6-ethoxypyridin-3-yl)methylene)-3-methoxyaniline (1.012 mmol) in ethanol (1.5 ml), heated at 60°C for 72 hours Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-45%) in heptane followed by purification by preparative HPLC (XBridge column; method 2) gave 0.058 g (14%) of the desired compound as a white solid. ESI/APCI(+): 402 (M+H). ESI/APCI(-): 400 (M-H).

Example 217 Preparation of 2-((3-methoxyphenyl)amino)-1-(4-methyl-1H-indol-3-yl)-2-phenylethanone

Step 1. tert-Butyl-3-formyl-4-methyl-III-indole-1-carboxylate was prepared according to General Procedure F from 4-methyl-1H-indole-3-carbaldehyde (0.250 g, 1.571 mmol), di-tert -butyl dicarboxylate (0.445 g, 2.039 mmol) and DMAP (0.030 g, 0.246 mmol) in acetonitrile (4 mL) to give 0.392 g (96%) of the desired compound as a yellow solid. 1H NMR (DMSO-d ₆ ) δ 10.06 (1H, s); 8.59 (1H, s); 8.01 (1H, d); 7.33 (1H, t); 7.17 (1H, s); 2.76 (3H, s); 1.66 (9H, s).

Step 2 2-((3-Methoxyphenyl)amino)-1-(4-methyl-N-indol-3-yl)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl )-4-methylthiazol-3-ium chloride (0.137 g, 0.508 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (0.5 ml), tert-butyl-3-formyl-4-methyl-Shindol-1 -carboxylate (0.277 g, 1.068 mmol) and a solution of K-benzylidene-3-methoxyaniline (0.989 mmol) in

- 113 040588 ethanol (1.5 ml) heated at 60°C for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-50%) in heptane, followed by preparative HPLC purification (XBridge column; method 1 ) gave 0.046 g (13%) of the desired compound as a white solid. ESI/APCI(+): 371 (M+H). ESI/APCI(-): 369 (M-H).

Example 218 Preparation of 1-(1H-indol-3-yl)-2-((6-methoxypyrazin-2-yl)amino)-2-phenylethanone

Step 1. N-Benzylidene-6-methoxypyrazin-2-amine was quantified according to General Procedure I from benzaldehyde (0.102 mL, 1.004 mmol) and 6-methoxypyrazin-2-amine (0.125 g, 0.999 mmol).

Step 2. 1-(1H-Indol-3-yl)-2-((6-methoxypyrazin-2-yl)amino)-2-phenylethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl )-4-methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1.5 ml), tert-butyl-3-formyl-1H-indole-1-carboxylate (0.245 g, 0.999 mmol ) and a solution of Na-benzylidene-6-methoxypyrazin-2-amine (0.999 mmol) in ethanol (1 ml), heated at 70° C. overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in dichloromethane followed by precipitation from diethyl ether gave 0.048 g (13%) of the desired compound as a beige solid. ESI/APCI(+): 359 (M+H). ESI/APCI(-): 357 (M-H). 1H NMR (DMSO-d6) δ 12.02 (1H, br s); 8.72 (1H, s); 8.17 (1H, d); 7.78 (1H, d); 7.76 (1H, s); 7.67 (2H, d); 7.45 (1H, d); 7.31-7.38 (2H, m); 7.30 (1H, s); 7.13-7.28 (3H, m); 6.39 (1H, d); 3.60 (3H, s).

Example 219 Preparation of 2-((3-(2-(tert-butoxy)ethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)2-phenylethanone and 2-((3-ethoxy -5-methoxyphenyl)amino)-1-(1 H-indol-3-yl)-2-phenylethanone.

Step 1 To a solution of 3-amino-5-methoxyphenol (0.447 g, 3.214 mmol) in DMF (20 ml) cooled to 0°C was added sodium hydride (60% dispersion in mineral oil; 0.282 g, 7.050 mmol) in portions . After adding a solution of 2-(t-butoxy)ethyl-4-methylbenzenesulfonate (0.875 g, 3.213 mmol) in DMF (3 ml), the reaction mixture was stirred at room temperature for 20 hours. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane gave 0.241 g of 3-(2-(tert-butoxy)ethoxy)-5-methoxyaniline (contaminated with 3-ethoxy-5-methoxyaniline) as a brown oils. ESI/APCI(+): 240 (M+H).

Step 2 2-((3-(2-(tert-Butoxy)ethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure C from 2- chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.120 g, 0.445 mmol), 3-(2-(tert-butoxy)ethoxy)-5-methoxyaniline (0.106 g, 0.445 mmol) and triethylamine (0.124 ml, 0.890 mmol) in acetonitrile (0.5 ml) microwaved at 150°C for 30 min. Purification by flash chromatography on silica gel using dichloromethane as eluent gave 0.054 g (26%) of 2-((3-(2-(t-butoxy)ethoxy)-5-methoxyphenyl)amino)-1-(1H-indole- 3-yl)-2phenylethanone as a beige solid. ESI/APCI(+): 473 (M+H); 495 (M + Na). ESI/APCI(-): 471 (M-H).

2-((3-Ethoxy-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was also isolated after purification on the silica gel flash column described above. Further purification by preparative HPLC (XBridge column; method 5) gave 0.008 g of pure compound as a white solid. ESI/APCI(+): 401 (M+H). ESI/APCI(-): 399 (M-H). 1H NMR (DMSO-d6) δ 12.14 (1H, br s); 8.90 (1H, s); 8.16 (1H, d); 7.63 (2H, d); 7.46 (1H, d); 7.25-7.35 (2H, m); 7.11-7.24 (3H, m); 6.32 (1H, d); 5.97-6.13 (3H, m); 5.69 (1H, s); 3.87 (2H, q); 3.60 (3H, s); 1.24 (4H, t).

Example 220 Preparation of 2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2phenylethanone

2-((3-(2-(tert-Butoxy)ethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone (0.054 g, 0.114 mmol) was dissolved in 4N . a solution of hydrogen chloride in dioxane (3.000 ml, 12.00 mmol). The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into ice/water, neutralized with potassium carbonate and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in dichloromethane followed by precipitation from diethyl ether gave 0.009 g (19%) of 2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)- 1-(1H-indol-3-yl)-2-phenylethanone as a beige solid. ESI/APCI(+): 417 (M+H). ESI/APCI(-): 415 (M-H). 1H NMR (DMSO-d6) δ 12.13 (1H, br s); 8.89 (1H, s); 8.17 (1H, d); 7.63 (2H, d); 7.47 (1H, d); 7.25-7.33 (2H, m); 7.147.25 (3H, m); 6.32 (1H, d); 6.07 (1H, d); 6.05 (2H, br s); 5.72 (1H, s); 4.77 (1H, t); 3.78-3.90 (2H, m); 3.63-3.69 (2H, m); 3.62 (3H, s).

Example 221 Preparation of 2-((5,6-dimethoxypyridin-3-yl)amino)-1-(1H-indol-3-yl)-2-phenylethanone

Step 1 To a solution of sodium methoxide (0.215 g, 3.980 mmol) in methanol (13 ml) was added 2-chloro3-methoxy-5-nitropyridine (0.500 g, 2.652 mmol). After 5.5 hours at room temperature, sodium methoxide (0.215 g, 3.980 mmol) was added and the reaction mixture was stirred at room temperature overnight. Sodium methoxide (0.215 g, 3.980 mmol) was added again. After 4.5 hours at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The phases were separated. The organic phase was washed with brine, dried over

- 114 040588 sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-50%) in heptane gave 0.467 g (96%) of 2,3-dimethoxy-5-nitropyridine as a yellow powder. ESI/APCI(+): 185 (M+H). 1H NMR (DMSO-d6) δ 8.69 (1H, s); 7.94 (1H, s); 4.02 (3H, s); 3.93 (3H, s).

Step 2 To a suspension of 2,3-dimethoxy-5-nitropyridine (0.463 g, 2.514 mmol) in water (9 ml) was added acetic acid (0.500 ml, 8.734 mmol). After sodium dithionite (1.670 g, 9.562 mmol) was added portionwise, the suspension was stirred at room temperature for 4 hours. The reaction mixture was poured into ice/1N. sodium hydroxide solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (0-10%) in dichloromethane gave 0.111 g (29%) of 5,6-dimethoxypyridine-3-amine as a pink solid. ESI/APCI(+): 155 (M+H). ¹ H NMR (DMSO-d ₆ ) δ 7.03 (1H, s); 6.65 (1H, s); 4.72 (2H, br s); 3.70 (6H, m).

Step 3 A solution of N-benzylidene-5,6-dimethoxypyridine-3-amine in ethanol was prepared by heating a solution of benzaldehyde (0.067 ml, 0.661 mmol) and 5,6-dimethoxypyridine-3-amine (0.101 g, 0.655 mmol) in ethanol (1.3 ml) at 60° C. for 6 hours. Imine formation was quantitative and the solution was used without further purification. ESI/APCI(+): 243 (M+H).

Step 4 2-((5,6-Dimethoxypyridin-3-yl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5-(2 -hydroxyethyl)-4-methylthiazol-3-ium chloride (0.090 g, 0.334 mmol) and triethylamine (0.045 ml, 0.325 mmol) in ethanol (0.5 ml), tert-butyl-3-formyl-1H-indole-1-carboxylate (0.193 g, 0.787 mmol) and a solution of N-benzylidene-5,6-dimethoxypyridine-3-amine (0.655 mmol) in ethanol (1.3 ml) heated at 70°C for 65 h. The residue was purified by flash chromatography on silica gel using a gradient of methanol (0-10%) in dichloromethane. Further purification by preparative HPLC (XBridge column; method 5) followed by recrystallization from ethyl acetate and heptane gave 0.006 g (2%) of the desired product as a pink powder. ESI/APCI(+): 388 (M+H); 410 (M + Na). ESI/APCI(-): 386 (M-H). ¹ H NMR (DMSO-d6) δ 12.16 (1H, br s); 8.87 (1H, s); 8.16 (1H, d); 7.63 (2H, m); 7.30 (1H, d); 7.17-7.26 (6H, m); 7.05 (1H, s); 6.11 (2H, m); 3.67 (6H, d).

Example 222 Preparation of 2-((6-(dimethylamino)-5-methoxypyridin-3-yl)amino)-1-(1H-indol-3-yl)-2phenylethanone

Step 1 To a 2M solution of dimethylamine in THF (6.250 mL, 12.50 mmol) was added 2-chloro-3-methoxy5-nitropyridine (0.471 g, 2.500 mmol). The reaction mixture was stirred at 80°C for 16 h and concentrated under reduced pressure. The crude bright yellow residue was dissolved in methanol (20 ml). Palladium on charcoal (0.030 g, 0.282 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction mixture was filtered over diatomaceous earth and the filter cake was washed with ethanol. The filtrate was concentrated under reduced pressure.

Purification by flash chromatography on silica gel using a gradient of methanol (0-10%) in dichloromethane gave 0.337 g (81%) of 3-methoxy-N ² ,N ² -dimethylpyridine-2,5-diamine. ESI/APCI(+): 168 (M+H).

Stage 2. A mixture of benzaldehyde (0.102 ml, 1.004 mmol) and 3-methoxy-N ² ,N ² -dimethylpyridine-2,5diamine (0.167 g, 0.999 mmol) in methanol (0.25 ml) was stirred at 45°C for 24 hours The solvent was evaporated and the residue was dried under reduced pressure to obtain N ⁵ -benzylidene-3-methoxy-N ² ,N ² dimethylpyridine-2,5-diamine in quantitative terms, which was used without further purification. ESI/APCI (+): 256 (M+H).

Step 3 2-((6-(Dimethylamino)-5-methoxypyridin-3-yl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure K from a mixture of 3-benzyl- 5-(2-hydroxyethyl)-4-methylthiazol-3-yl chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1 ml), tert-butyl-3-formyl1H-indole-1 -carboxylate (0.245 g, 0.999 mmol) and a solution of N ⁵ -benzylidene-3-methoxy-N ² ,N ² dimethylpyridine-2,5-diamine (0.999 mmol) in ethanol (1 ml), heated at 70 ° C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by crystallization from acetonitrile gave 0.046 g (12%) of the desired compound as a light brown solid. ESI/APCI(+): 401 (M+H). ESI/APCI(-): 399 (M+H).

Example 223 Preparation of 2-((6-ethoxy-5-methoxypyridin-3-yl)amino)-1-(1H-indol-3-yl)-2-phenylethanone

Step 1 To a 21% solution of sodium ethoxide in ethanol (2.000 ml, 5.357 mmol) was added 2-chloro-3methoxy-5-nitropyridine (0.500 g, 2.652 mmol). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 0.476 g of 2-ethoxy3-methoxy-5-nitropyridine as a brown foam which was used in the next step without further purification. ESI/APCI(+): 199 (M+H).

Step 2 To a suspension of 2-ethoxy-3-methoxy-5-nitropyridine (0.250 g, 1.261 mmol) in ethanol (8.5

- 115 040588 ml), cooled to 0°C, was added 2n. hydrochloric acid solution (6.600 ml, 13.20 mmol). After zinc (1.800 g, 27.53 mmol) was added, the reaction mixture was stirred at room temperature for 3 h.

The reaction mixture was poured into ice/1N. sodium hydroxide solution and filtered through celite. The filtrate was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (0-10%) in dichloromethane gave 0.168 g (72% over two steps) of 6-ethoxy-5-methoxypyridine-3-amine as a brown solid. ESI/APCI(+): 169 (M+H); 191 (M + Na). ¹ H NMR (DMSO-d ₆ ) δ 7.02 (1H, s); 6.65 (1H, s); 4.68 (2H, br s); 4.15 (2H, q); 3.69 (3H, s); 1.25 (3H, t).

Step 3 A solution of N-benzylidene-6-ethoxy-5-methoxypyridine-3-amine in ethanol was prepared by heating a solution of benzaldehyde (0.100 ml, 0.942 mmol) and 6-ethoxy-5-methoxypyridine-3-amine (0.164 g, 0.975 mmol) in ethanol (2 ml) at 60°C for 6 h. Imine formation was quantitative and the solution was used without further purification. ESI/APCI(+): 257 (M+H).

Step 4 2-((6-Ethoxy-5-methoxypyridin-3-yl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5- (2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.134 g, 0.497 mmol) and triethylamine (0.067 ml, 0.483 mmol) in ethanol (0.7 ml), tert-butyl-3-formyl-1H-indole1 -carboxylate (0.287 g, 1.170 mmol) and a solution of N-benzylidene-6-ethoxy-5-methoxypyridine-3-amine (0.942 mmol) in ethanol (2 ml), heated at 70°C for 65 h. silica gel chromatography using a gradient of ethyl acetate (0-100%) in heptane followed by recrystallization from ethyl acetate and heptane gave 0.018 g (5%) of the desired product as a pink powder. ESI/APCI(+): 402 (M+H); 424 (M + Na). ESI/APCI(-): 400 (M-H). ¹ H NMR (DMSO-d6) δ 12.16 (1H, br s); 8.87 (1H, s); 8.15 (1H, d); 7.63 (2H, m); 7.46 (1H, d); 7.20-7.29 (6H, m); 7.04 (1H, s); 6.10 (2H, s); 4.09 (2H, q); 3.69 (3H, s); 1.22 (3H, t).

Example 224 Preparation of 2-((5-methoxypyridin-3-yl)amino)-1-(1-methyl-1H-indazol-3-yl)-2-phenylethanone

2-((5-Methoxypyridin-3-yl)amino)-1-(1-methyl-1H-indazol-3-yl)-2-phenylethanone was obtained according to the general procedure L from a mixture of 3-benzyl-5-(2 -hydroxyethyl)-4-methylthiazol-3-yl chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1 ml), 1-methyl-1H-indazole-3-carbaldehyde (0.160 g, 0.999 mmol) and a solution of N-benzylidene-5-methoxypyridin-3-amine (0.999 mmol) in ethanol (1 ml) heated at 70°C for 24 hours. Purification by flash chromatography on silica gel using an ethyl acetate gradient (0- 100%) in heptane followed by precipitation from ethanol and diethyl ether gave 0.092 g (24%) of the desired compound as a white solid. ESI/APCI(+): 373 (M+H). ESI/APCI(-): 371 (M-H).

Example 225 Preparation of 4-(1-((3-methoxyphenyl)amino)-2-(1-methyl-1H-indazol-3-yl)-2-oxoethyl)benzonitrile

4-(1-((3-Methoxyphenyl)amino)-2-(1-methyl-1H-indazol-3-yl)-2-oxoethyl)benzonitrile was prepared according to General Procedure L from a mixture of 3-benzyl-5-( 2-hydroxyethyl)-4-methylthiazol-3-yl chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1 ml), 1-methyl-1H-indazole-3-carbaldehyde (0.160 g, 0.999 mmol) and a solution of 4-(((3-methoxyphenyl)imino)methyl)benzonitrile (0.999 mmol) in ethanol (1 ml) heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by precipitation from ethanol gave 0.176 g (43%) of the desired compound as a white solid. ESI/APCI(+): 397 (M+H). ESI/APCI(-): 395 (M-H).

Example 226 Preparation of 1-(1H-indol-3-yl)-2-((5-methoxy-6-(methylamino)pyridin-3-yl)amino)-2phenylethanone

Step 1 To a 2M solution of methylamine in THF (6.250 mL, 12.500 mmol) was added 2-chloro-3-methoxy5-nitropyridine (0.471 g, 2.500 mmol). The reaction mixture was stirred at 80°C for 16 h and concentrated under reduced pressure. The crude bright yellow residue was dissolved in methanol (20 mL) and palladium on charcoal (0.030 g, 0.282 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction mixture was filtered through diatomaceous earth and the filter cake was washed with ethanol. The filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (1-10%) in dichloromethane gave 0.172 g (45%) of 3-methoxy-N ² -methylpyridine-2,5-diamine. ESI/APCI(+): 154 (M+H).

Step 2: A mixture of benzaldehyde (0.114 ml, 1.123 mmol) and 3-methoxy-M2-methylpyridine-2,5-diamine (0.172 g, 1.123 mmol) in methanol (0.25 ml) was stirred at 45°C for 24 h The reaction mixture was concentrated under reduced pressure to give quantitatively N-benzylidene 3-methoxy-M2-methylpyridine-2,5-diamine, which was used without further purification. ESI/APCI (+): 242 (M+H).

Step 3. 1-(1H-Indol-3-yl)-2-((5-methoxy-6-(methylamino)pyridin-3-yl)amino)-2-phenylethanone

- 116 040588 was prepared according to General Procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-yl chloride (0.151 g, 0.562 mmol) and triethylamine (0.079 ml, 0.562 mmol) in ethanol (1 ml), tert-butyl-3-formyl1H-indole-1-carboxylate (0.275 g, 1.121 mmol) and a solution of N-benzylidene-3-methoxy-K ² -methylpyridine 2,5-diamine (1.123 mmol) in ethanol (1 ml ), heated at 70°C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by crystallization from acetonitrile gave 0.008 g (2%) of the desired compound as a white solid. ESI/APCI(+): 387 (M+H). ESI/APCI(-): 385 (M-H).

Example 227 Preparation of 2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2phenylethanone

Step 1 To a solution of 3-amino-5-methoxybenzoic acid (2.500 g, 14.96 mmol) in ethanol (30 ml) cooled to 0° C., thionyl chloride (1.500 ml, 20.68 mmol) was added dropwise over 15 minutes. The resulting suspension was stirred at room temperature for 1 hour and refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The phases were separated. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give crude ethyl 5-amino-2-chlorobenzoate as a brown oil. To a suspension of lithium aluminum hydride (2.200 g, 57.99 mmol) in THF (15 ml) cooled to 0°C was slowly added a solution of ethyl 5-amino-2-chlorobenzoate (14.50 mmol) in THF (30 ml ). The reaction mixture was stirred at 0°C for 30 min and at room temperature for 2 h. After cooling to 0°C, the reaction was quenched by slow addition of 1N. Rochelle salt solution. The reaction mixture was stirred for 2 hours and extracted with dichloromethane. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15-70%) in dichloromethane gave 1.670 g (75%) of (3-amino-5-methoxyphenyl)methanol as a white solid. ESI/APCI(+): 154 (M+H).

Step 2 A solution of 3-(benzylideneamino)-5-methoxyphenyl)methanol in ethanol was prepared by heating a solution of benzaldehyde (0.102 ml, 1.004 mmol) and (3-amino-5-methoxyphenyl)methanol (0.153 g, 0.999 mmol) in ethanol ( 1 ml) at 60°C all night. Imine formation was quantitative and the solution was used without further purification. ESI/APCI(+): 342 (M+H).

Step 3 2-((3-(Hydroxymethyl)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5-(2 -hydroxyethyl)-4-methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1.5 ml), tert-butyl-3-formyl-1Hindole-1-carboxylate (0.245 g, 0.999 mmol) and a solution of (3-(benzylideneamino)-5-methoxyphenyl)methanol (0.999 mmol) in ethanol (1 ml) heated at 70° C. overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in dichloromethane followed by precipitation from dichloromethane gave 0.060 g (15%) of the desired compound as a white solid. ESI/APCI(+): 387 (M+H). ESI/APCI(-): 385 (M-H). 1H NMR (DMSO-d ₆ ) δ 12.10 (1H, br s); 8.87 (1H, s); 8.17 (1H, d); 7.64 (2H, d); 7.47 (1H, d); 7.29 (2H, t); 7.12-7.25 (3H, m); 6.41 (1H, s); 6.22-6.32 (2H, m); 6.12 (1H, s); 6.09 (1H, d); 4.97 (1H, brs); 4.30 (2H, d); 3.63 (3H, s).

Example 228 Preparation of 2-((3-((dimethylamino)methyl)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2phenylethanone

Step 1 To a solution of (3-amino-5-methoxyphenyl)methanol (0.500 g, 3.264 mmol) in dichloromethane (30 ml) was added triethylamine (0.635 ml, 4.581 mmol) followed by mesyl chloride (0.278 ml, 3.592 mmol). The mixture was stirred at room temperature for 2 hours. A 2M solution of dimethylamine in THF (2.000 ml, 4.000 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed with water. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol/25% ammonium hydroxide (9/1) (2-15%) in dichloromethane gave 0.192 g (32%) of 3((dimethylamino)methyl)-5-methoxyaniline as an oil. ESI/APCI(+): 180 (M+H).

Step 2: A mixture of 2-chloro-1-(1H-indol-3-yl)-2-phenylethanone (0.170 g, 0.630 mmol) and 3((dimethylamino)methyl)-5-methoxyaniline (0.102 g, 0.567 mmol) in acetonitrile (1 ml) was irradiated in a microwave oven at 150°C for 15 min. The reaction mixture was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol/25% ammonium hydroxide (9/1) (2-20%) in dichloromethane gave 0.032 g (13%) of 2-((3-((dimethylamino)methyl)-5methoxyphenyl) amino)-1-(1H-indol-3-yl)-2-phenylethanone as a white solid. ESI/APCI(+): 414 (M+H). ESI/APCI(-): 412 (M-H). 1H NMR (DMSO-d6) δ 12.14 (1H, br s); 8.89 (1H, d); 8.16 (1H, d); 7.64 (2H, d); 7.46 (1H, d); 7.24-7.24 (5H, m); 6.39 (1H, s); 6.24-6.34 (2H, m); 6.03-6.13 (2H, m); 3.61 (3H, s); 3.21 (2H, s); 2.09 (6H, s).

Example 229 Preparation of 2-((3-methoxyphenyl)amino)-2-(6-methoxypyridin-3-yl)-1-(1-methyl-1Hindazol-3-yl)ethanone

2-((3-Methoxyphenyl)amino)-2-(6-methoxypyridin-3-yl)-1-(1-methyl-1H-indazol-3-yl)ethanone was prepared according to general procedure L from a mixture of 3-benzyl -5-(2-hydroxyethyl)-4-methylthiazol-3-th chloride

- 117 040588 (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1 ml), 1-methyl-1H-indazole-3carbaldehyde (0.160 g, 0.999 mmol) and a solution of 3-methoxy-M- ((6-methoxypyridin-3-yl)methylene)aniline (0.999 mmol) in ethanol (1 ml) heated at 70°C for 24 hours. The precipitate was filtered, washed with ethanol and dried under reduced pressure to give 0.249 g (61 %) of the desired compound as a white solid. ESI/APCI(+): 403 (M+H). ESI/APCI(-): 401 (M-H).

Example 230 Preparation of 2-((3,5-dimethoxyphenyl)amino)-1-(1-methyl-1H-indazol-3-yl)-2-phenylethanone

2-((3,5-Dimethoxyphenyl)amino)-1-(1-methyl-1H-indazol-3-yl)-2-phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl) -4-methylthiazol-3-yl chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1 ml), 1-methyl-1H-indazole-3-carbaldehyde (0.160 g, 0.999 mmol) and a solution of N-benzylidene-3,5-dimethoxyaniline (0.999 mmol) in ethanol (1 ml) heated at 70°C for 2 days. The residue was purified by silica gel flash chromatography using a gradient of ethyl acetate (0-80%) in heptane followed by solid phase extraction on a C18 reverse phase column using a gradient of acetonitrile (30-100%) in water. Further purification by crystallization from acetonitrile gave 0.008 g (2%) of the desired compound as clear crystals. ESI/APCI(+): 402 (M+H).

Example 231 Preparation of 1-(6-methoxy-1-methyl-1H-indazol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone

Step 1 To a solution of 6-methoxy-1H-indazole-3-carbaldehyde (0.088 g, 0.500 mmol) and cesium carbonate (0.652 g, 2.000 mmol) in DMSO (2.5 ml) was added iodomethane (0.062 ml, 1.000 mmol) and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water until a precipitate formed. The solid was filtered, washed with water and dried under reduced pressure over phosphorus(V) oxide to give 0.063 g (66%) of 6-methoxy-1-methyl-1H-indazole-3-carbaldehyde as a gray solid. ESI/APCI(+): 191 (M+H).

1H NMR (DMSO-d ₆ ) δ 10.07 (1H, s); 7.97 (1H, d); 7.29 (1H, s); 7.01 (1H, d); 4.17 (3H, s); 3.89 (3H, s).

Step 2 1-(6-Methoxy-1-methyl-1H-indazol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to General Procedure L from a mixture of 3-benzyl-5- (2-hydroxyethyl)-4-methylthiazol-3-yl chloride (0.042 g, 0.158 mmol) and triethylamine (0.022 ml, 0.158 mmol) in ethanol (0.35 ml), 6-methoxy-1-methyl-1-Nindazole-3 -carbaldehyde (0.060 g, 0.315 mmol) and a solution of N-benzylidene-3-methoxyaniline (0.315 mmol) in ethanol (0.35 ml) heated at 70°C for 24 h. Purification by silica gel flash chromatography using a gradient ethyl acetate (0-80%) in heptane followed by precipitation from diethyl ether gave 0.042 g (32%) of the desired compound as a white solid. ESI/APCI(+): 402 (M+H).

Example 232 Preparation of 2-(1,5-dimethyl-1H-pyrazol-3-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone

Step 1 A solution of N-((1,5-dimethyl-1H-pyrazol-3-yl)methylene)-3-methoxyaniline in ethanol was prepared by heating a solution of 1,5-dimethyl-1H-pyrazole-3-carbaldehyde (0.127 g , 1.023 mmol) and 3-methoxyaniline (0.119 ml, 1.056 mmol) in ethanol (0.5 ml) at 60° C. for 18 hours. Imine formation was quantitative and the solution was used without further purification. ESI/APCI (+): 230 (M+H); 252 (M+Na); 481 (2M+Na).

Step 2 2-(1,5-Dimethyl-1H-pyrazol-3-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to the general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.141 g, 0.523 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (0.5 ml), tert butyl 3formyl-1H-indole-1-carboxylate (0.263 g, 1.072 mmol) and a solution of N-((1,5-dimethyl-1H-pyrazol-3yl)methylene)-3-methoxyaniline (1.023 mmol) in ethanol (1 .5 ml), heated at 60° C. for 24 hours. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (50-100%) in heptane. Further purification by precipitation from ethyl acetate followed by precipitation from a mixture of acetonitrile, water and DMF gave 0.085 g (22%) of the desired compound as a white solid. ESI/APCI(+): 375 (M+H). ESI/APCI(-): 373 (M-H).

Example 233 Preparation of 1-(1H-indol-3-yl)-2-(6-isopropoxypyridin-3-yl)-2-((3-methoxyphenyl)amino)ethanone

Step 1 A solution of N-((6-isopropoxypyridin-3-yl)methylene)-3-methoxyaniline in ethanol was prepared by heating a solution of 6-isopropoxynicotinaldehyde (0.156 g, 0.944 mmol) and 3-methoxyaniline (0.109 ml, 0.966 mmol) in ethanol (0.5 ml) at 60° C. for 18 hours. Imine formation was quantitative and the solution was used without further purification.

Step 2. 1-(1H-Indol-3-yl)-2-(6-isopropoxypyridin-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to General Protocol K from a mixture of 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.136 g, 0.504 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (0.5 ml), tert-butyl-3formyl-1H-indole- 1-carboxylate (0.267 g, 1.089 mmol) and a solution of N-((6-isopropoxypyridin-3yl)methylene)-3-methoxyaniline (0.944 mmol) in ethanol (1.5 ml), heated at 60°C for 120 h Purification by silica gel flash chromatography using a gradient of ethyl acetate (10-60%) in heptane followed by preparative HPLC purification (XBridge column; method 2) gave 0.084 g (21%) of the desired compound as a yellow solid. ESI/APCI(+): 416 (M+H). ESI/APCI(-): 414 (M-H).

Example 234 Preparation of 2-((5-(difluoromethoxy)pyridin-3-yl)amino)-1-(1H-indol-3-yl)-2-phenylethanone

Step 1. A mixture of 6-bromopyridinol (2.000 g, 11.49 mmol), sodium chlorodifluoroacetate (2.630 g, 17.24 mmol) and potassium carbonate (3.180 g, 22.99 mmol) in acetonitrile (50 ml) was placed in a sealed tube and heated at 110° C. overnight. After cooling to room temperature, the reaction mixture was diluted with diethyl ether and washed with saturated sodium bicarbonate solution. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using dichloromethane as eluent gave 0.393 g (15%) of 3-bromo-5(difluoromethoxy)pyridine as a yellow oil. ESI/APCI(+): 224.226 (M+H).

Step 2: A mixture of 3-bromo-5-(difluoromethoxy)pyridine (0.500 g, 2.232 mmol), copper (II) sulfate pentahydride (0.107 g, 0.446 mmol) and 25% ammonium hydroxide solution (3.440 ml, 22.32 mmol) placed in a sealed tube and heated at 150°C overnight. After cooling to room temperature was added 1N. sodium hydroxide solution and the reaction mixture were extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15-70%) in dichloromethane gave 0.291 g (81%) of 5(difluoromethoxy)pyridine-3-amine as a brown solid. ESI/APCI(+): 161 (M+H). ESI/APCI(-): 159 (M-H).

Step 3 A solution of N-benzylidene-5-(difluoromethoxy)pyridine-3-amine in ethanol was prepared by heating a solution of benzaldehyde (0.102 ml, 1.004 mmol) and 5-(difluoromethoxy)pyridine-3-amine (0.160 g, 0.999 mmol) in ethanol (1 ml) at 60°C for 6 hours. Imine formation was quantitative and the solution was used without further purification.

Step 4 2-((5-(Difluoromethoxy)pyridin-3-yl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5-( 2-hydroxyethyl)-4-methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1.5 ml), tert-butyl-3-formyl-1H-indole 1-carboxylate (0.245 g , 0.999 mmol) and a solution of K-benzylidene-5-(difluoromethoxy)pyridine-3-amine (0.999 mmol) in ethanol (1 ml), heated at 70° C. overnight. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (15-70%) in dichloromethane. Further purification by flash chromatography on silica gel using a gradient of methanol (1-7%) in dichloromethane followed by precipitation from dichloromethane gave 0.018 g (6%) of the desired compound as a white solid. ESI/APCI(+): 394 (M+H). ESI/APCI(-): 392 (M-H). ¹ H NMR (DMSO-d6) δ 12.20 (1H, br s); 8.89 (1H, s); 8.17 (1H, d); 8.11 (1H, d); 7.65 (3H, d); 7.48 (1H, d); 7.41 (1H, t); 7.26-7.37 (2H, m); 7.17-7.26 (3H, m); 7.08 (1H, d); 7.02 (1H, s); 6.21 (1H, d).

Example 235 Preparation of 1-(5-fluoro-1-methyl-1H-indazol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone

Step 1 A mixture of 5-fluoro-1H-indazole-3-carbaldehyde (0.050 g, 0.305 mmol), cesium carbonate (0.397 g, 1.218 mmol) and methyl iodide (0.038 ml, 0.609 mmol) in DMSO (2.5 ml) was stirred at room temperature for 2 hours. Water was added. The resulting precipitate was filtered, washed with water and dried to give 0.027 g (50%) of 5-fluoro-1-methyl-1H-indazole-3-carbaldehyde as a beige solid. ESI/APCI(+): 179 (M+H).

Step 2 1-(5-Fluoro-1-methyl-1H-indazol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to General Procedure L from a mixture of 3-benzyl-5- (2-hydroxyethyl)-4-methylthiazolium chloride (0.020 g, 0.076 mmol) and triethylamine (0.011 ml, 0.076 mmol) in ethanol (0.5 ml), 5-fluoro-1-methyl-1H-indazole-3-carbaldehyde (0.027 g, 0.152 mmol) and a solution of K-benzylidene-3-methoxyaniline (0.152 mmol) in ethanol (0.5 ml), heated at 70°C for 60 h. Purification by flash chromatography on silica gel using an ethyl acetate gradient (5- 50%) in heptane followed by precipitation from acetonitrile gave 0.010 g (17%) of the desired compound as a yellow solid. ESI/APCI(+): 390 (M+H). 1H NMR (DMSO-d6) δ 7.92 (1H, dd); 7.80 (1H, d); 7.61 (2H, d); 7.42-7.52 (1H, m); 7.29-7.39 (2H, m); 7.18-7.29 (1H, m); 6.95 (1H, t); 6.52-6.60 (1H, m); 6.39-6.48 (1H, m); 6.34 (2H, br s); 6.15 (1H, d); 4.29 (3H, s); 3.56 (3H, s).

Example 236 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6-(methylamino)pyridin3-yl)ethanone

Step 1. 5-(((3-Methoxyphenyl)imino)methyl)-N-methylpyridine-2-amine was quantitatively obtained according to General Procedure I from 6-(methylamino)nicotinaldehyde (0.136 g, 0.999 mmol) and 3-methoxyaniline (0.112 ml, 1.001 mmol).

Step 2 1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6-(methylamino)pyridin-3-yl)ethanone was prepared according to General Procedure L from a mixture of 3- benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1 ml), tert-butyl-3-formyl 1H-indole -1-carboxylate (0.245 g, 0.999 mmol) and a solution of 5-(((3-methoxyphenyl)imino)methyl)-Kmethylpyridine-2-amine (0.999 mmol) in ethanol (1 ml), heated at 70°C for 4 days. The residue was purified by silica gel flash chromatography using a gradient of methanol (0-12%) in dichloromethane. Further purification by flash chromatography on silica gel using a gradient of methanol (0-12%) in dichloromethane followed by precipitation from ethanol gave 0.006 g (2%) of the desired compound. ESI/APCI(+): 387 (M+H). ESI/APCI(-): 385 (M-H).

Example 237 Preparation of 2-((3-methoxyphenyl)amino)-2-(5-methoxypyrazin-2-yl)-1-(1-methyl-1H-indazol-3-yl)ethanone

2-((3-Methoxyphenyl)amino)-2-(5-methoxypyrazin-2-yl)-1-(1-methyl-1H-indazol-3-yl)ethanone was prepared according to general procedure L from a mixture of 3-benzyl -5-(2-hydroxyethyl)-4-methylthiazol-3-yl chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1 ml), 1-methyl-1H-indazole-3-carbaldehyde ( 0.160 g, 0.999 mmol) and a solution of 3-methoxy-N-((5-methoxypyrazin-2-yl)methylene)aniline (0.999 mmol) in ethanol (1 ml), heated at 70°C for 24 h. The precipitate was filtered , washed with ethanol and dried to give 0.312 g (76%) of the desired compound as a white solid. ESI/APCI(+): 404 (M+H). ¹ H NMR (DMSO-d ₆ ) δ 8.55 (1H, s); 8.21 (1H, s); 8.15 (1H, d); 7.81 (1H, d); 7.53 (1H, t); 7.33-7.43 (1H, m); 6.96 (1H, t); 6.62 (1H, d); 6.46 (1H, d); 6.33-6.42 (2H, m); 6.14-6.22 (1H, m); 4.22 (3H, s); 3.87 (3H, s); 3.63 (3 H, s).

Example 238 Preparation of 2-((3-methoxyphenyl)amino)-1-(1-methyl-III-indazol-3-yl)-2-(pyrazolo[1,5a]pyridin-2-yl)ethanone.

2-((3-Methoxyphenyl)amino)-1-(1-methyl-1H-indazol-3-yl)-2-(pyrazolo[1,5-a]pyridin-2-yl)ethanone was prepared according to the general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.118 g, 0.438 mmol) and triethylamine (0.062 ml, 0.438 mmol) in ethanol (1 ml), 1-methyl-1H -indazol-3-carbaldehyde (0.140 g, 0.874 mmol) and a solution of 3-methoxy-N-(pyrazolo[1,5-a]pyridin-2-ylmethylene)aniline (0.876 mmol) in ethanol (1 ml), heated at 70 ° C for 24 hours Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-80%) in heptane followed by precipitation from diethyl ether gave 0.209 g (56%) of the desired compound as a white solid. ESI/APCI(+): 412 (M+H).

Example 239 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyrazin-2-yl)ethanone

Step 1 3-Methoxy-N-(pyrazin-2-ylmethylene)aniline was quantified according to General Procedure I from pyrazin-2-carbaldehyde (0.108 g, 0.999 mmol) and 3-methoxyaniline (0.112 ml, 1.001 mmol). ESI/APCI(+): 214 (M+H).

Step 2 1-(III-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyrazin-2-yl)ethanone was prepared according to General Procedure L from a mixture of 3-benzyl-5-( 2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1H-indole-1-carboxylate ( 0.245 g, 0.999 mmol) and a solution of 3-methoxy-N-(pyrazin-2-ylmethylene)aniline (0.999 mmol) in ethanol (1 ml) heated at 70°C for 24 h. Purification by flash chromatography on silica gel with using a gradient of ethyl acetate (0-80%) in heptane followed by precipitation from diethyl ether, 0.046 g (13%) of the desired compound was obtained as a white solid. ESI/APCI(+): 359 (M+H). ESI/APCI(-): 357 (M-H).

Example 240 Preparation of 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1-methyl-1H-indazole-5carbonitrile

Step 1 To a solution of 3-formyl-1H-imidazole-5-carbonitrile (0.100 g, 0.584 mmol) in DMSO (3 ml) were added potassium carbonate (0.330 g, 2.388 mmol) and methyl iodide (0.073 ml, 1.167 mmol). The reaction mixture was stirred at room temperature for 18 hours. Water was added and the precipitate was filtered. The pink solid was dissolved in dichloromethane and washed with brine. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 0.083 g (77%) of 3-formyl-1-methyl-1H-indazole-5-carbonitrile as an orange solid. ESI/APCI(+): 186 (M+H).

Step 2 3-(2-((3-Methoxyphenyl)amino)-2-phenylacetyl)-1-methyl-1H-indazole-5-carbonitrile was prepared according to General Procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl )-4-methylthiazol-3-ium chloride (0.133 g, 0.493 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (0.7 ml), 3-formyl-1-methyl-1Hindazole-5-carbonitrile (0.179 g, 0.987 mmol) and a solution of N-benzylidene-3-methoxyaniline (0.985 mmol) in ethanol (1 ml) heated at 60° C. for 24 hours. The precipitate formed during the reaction was filtered. The solid was recrystallized from diethyl ether and washed with methanol to give 0.230 g (59%) of the desired compound as a bright yellow solid. ESI/APCI(+): 397 (M+H). ESI/APCI(-): 395 (M-H).

Example 241 Preparation of 2-((6-methoxypyrazin-2-yl)amino)-1-(1-methyl-1H-indazol-3-yl)-2-phenylethanone

2-((6-Methoxypyrazin-2-yl)amino)-1-(1-methyl-1H-indazol-3-yl)-2-phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5-(2 -hydroxyethyl)-4-methylthiazol-3-yl chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1 ml), 1-methyl-1H-indazole-3-carbaldehyde (0.160 g, 0.999 mmol) and a solution of N-benzylidene-6-methoxypyrazin-2-amine (0.999 mmol) in ethanol (1 ml) heated at 70°C for 24 h. Purification by flash chromatography on silica gel using an ethyl acetate gradient (0- 80%) in heptane followed by precipitation from diethyl ether gave 0.049 g (13%) of the desired compound as a white solid. ESI/APCI(+): 374 (M+H).

- 120 040588

Example 242 Preparation of 1-(III-indol-3-yl)-2-((6-methoxypyridin-2-yl)amino)-2-phenylethanone

1-(III-Indol-3-yl)-2-((6-methoxypyridin-2-yl)amino)-2-phenylethanone was prepared according to General Procedure E from 2-bromo-1-(1H-indol-3-yl )-2-phenylethanone (0.045 g, 0.143 mmol) and 2-amino-6-methoxypyridine (0.089 g, 0.717 mmol) in acetonitrile (0.6 ml) irradiated in a microwave oven at 120°C for 20 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-60%) in heptane followed by recrystallization from ethyl acetate and heptane gave 0.020 g (39%) of the desired product as a white powder. ESI/APCI(+): 358 (M+H); 380 (M + Na). ESI/APCI(-): 356 (M-H). ¹ H NMR (DMSO-d6) δ 11.99 (1H, br s); 8.71 (1H, s); 8.17 (1H, d); 7.65 (2H, m); 7.44 (1H, d); 7.1-7.35 (7H, m); 6.41 (1H, d); 6.30 (1H, d); 5.86 (1H, d); 3.54 (3H, s).

Example 243 Preparation of 2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(1-methyl-1H-indazol-3yl)-2-phenylethanone

2-((3-(Hydroxymethyl)-5-methoxyphenyl)amino)-1-(1-methyl-1H-indazol-3-yl)-2-phenylethanone was prepared according to general procedure L from a mixture of 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazol-3-yl chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1 ml), 1-methyl-1H-indazole-3-carbaldehyde (0.160 g , 0.999 mmol) and a solution of (3-(benzylideneamino)-5-methoxyphenyl)methanol (0.999 mmol) in ethanol (1 ml) heated at 70°C for 24 h. Purification by silica gel flash chromatography using an ethyl acetate gradient ( 10-100%) in heptane followed by precipitation from diethyl ether gave 0.187 g (45%) of the desired compound as a light yellow solid. ESI/APCI(+): 402 (M+H).

Example 244 Preparation of 2-((3,5-dimethoxyphenyl)amino)-1-(1-methyl-1H-indazol-3-yl)-2-(pyridin3-yl)ethanone

2-((3,5-Dimethoxyphenyl)amino)-1-(1-methyl-III-indazol-3-yl)-2-(pyridin-3-yl)ethanone was obtained according to general procedure L from a mixture of 3-benzyl- 5-(2-hydroxyethyl)-4-methylthiazol-3-yl chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1 ml), 1-methyl-1H-indazole-3-carbaldehyde (0.160 g, 0.999 mmol) and a solution of 3,5-dimethoxy-N-(pyridin-3-ylmethylene)aniline (0.999 mmol) in ethanol (1 ml) heated at 70°C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-100%) in heptane followed by precipitation from diethyl ether, 0.077 g (18%) of the desired compound was obtained as a white solid. ESI/APCI(+): 403 (M+H). ESI/APCI(-): 401 (M-H). L NMR (DMSO-d6) δ 8.83 (1H, d); 8.38-8.50 (1H, m); 8.14 (1H, d); 7.96 (1H, d); 7.82 (1H, d); 7.53 (1H, t); 7.30-7.44 (2H, m); 6.68 (1H, d); 6.49 (1H, d); 5.97 (2H, d); 5.77 (1H, s); 4.26 (3H, s); 3.60 (6H, s).

Example 245 Preparation of 1-(1H-indol-3-yl)-2-((6-methoxypyrazin-2-yl)amino)-2-(pyridin-3yl)ethanone

Step 1 A solution of 6-methoxy-N-(pyridin-3-ylmethylene)pyrazin-2-amine in ethanol was prepared by heating a solution of nicotinaldehyde (0.107 g, 0.999 mmol) and 6-methoxypyrazin-2-amine (0.125 g, 0.999 mmol ) in ethanol (1 ml) at 60°C for 6 hours. Imine formation was quantitative and the solution was used without further purification.

Step 2. 1-(1H-Indol-3-yl)-2-((6-methoxypyrazin-2-yl)amino)-2-(pyridin-3-yl)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl -5-(2-hydroxyethyl)-4-methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1.5 ml), tert-butyl-3-formyl-1H-indole 1- carboxylate (0.245 g, 0.999 mmol) and a solution of 6-methoxy-N-(pyridin-3-ylmethylene)pyrazin-2-amine (0.999 mmol) in ethanol (1 ml), heated at 70° C. overnight. Purification by flash chromatography on silica gel using a gradient of methanol (1-10%) in dichloromethane followed by purification by preparative HPLC (XBridge column; method 5) gave 0.005 g (1%) of the desired compound as a yellow solid. ESI/APCI(+): 360 (M+H). ESI/APCI(-): 358 (M-H).

Example 246 Preparation of 1-(6-fluoro-1-methyl-1H-indazol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone

Step 1 To a suspension of lithium aluminum hydride (0.210 g, 5.553 mmol) in THF (20 ml) cooled to 0°C, a solution of 6-fluoro-1H-indazole-3-carboxylic acid (0.500 g, 2.776 mmol) was added dropwise in THF (5 ml). The reaction mixture was stirred at room temperature for 2 hours. After cooling to 0° C., a saturated solution of Rochelle's salt was added. The reaction mixture was vigorously stirred and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give crude (6-fluoro-1H-indazol-3yl)methanol as a white solid. ESI/APCI(+): 167 (M+H).

To a solution of (6-fluoro-1H-indazol-3-yl)methanol (0.207 g, 1.25 mmol) in dichloromethane (15 ml) was added manganese(IV) oxide (1.080 g, 12.46 mmol). The resulting suspension was stirred at room temperature for 3 hours and filtered through a Celite pad. The solid was washed with dichloromethane. The filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15-70%) in heptane gave 0.153 g (34% over two steps) of 6-fluoro-1H-indazole-3-carbaldehyde as a white solid. ESI/APCI(+): 165 (M+H). ESI/APCI(-): 163 (M-H).

- 121 040588

Step 2 A mixture of 6-fluoro-1H-indazole-3-carbaldehyde (0.150 g, 0.914 mmol), cesium carbonate (1.190 g, 3.652 mmol) and methyl iodide (0.114 ml, 1.831 mmol) in DMSO (7.5 ml) was stirred at room temperature for 2 hours. Water was added and the precipitate was filtered, washed with water and dried to give 0.105 g (65%) of 6-fluoro-1-methyl-1H-indazole-3-carbaldehyde as a beige solid.

ESI/APCI(+): 179 (M+H).

Step 3 1-(6-Fluoro-1-methyl-1H-indazol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to General Procedure L from a mixture of 3-benzyl-5- (2-hydroxyethyl)-4-methylthiazolium chloride (0.079 g, 0.295 mmol) and triethylamine (0.041 ml, 0.295 mmol) in ethanol (1 ml), 6-fluoro-1-methyl-1H-indazole-3-carbaldehyde (0.105 g, 0.589 mmol) and a solution of K-benzylidene-3-methoxyaniline (0.589 mmol) in ethanol (1 ml), heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane followed by precipitation from acetonitrile gave 0.054 g (23%) of the desired compound as a yellow solid. ESI/APCI(+): 390 (M+H). ESI/APCI(-): 388 (M-H). ¹ H NMR (DMSO-d6) δ 8.13 (1H, dd); 7.74 (1H, d); 7.59 (2H, d); 7.18-7.40 (4H, m); 6.93 (1H, t); 6.49-6.60 (1H, m); 6.42 (1H, d); 6.26-6.37 (2H, m); 6.14 (1H, d); 4.22 (3H, s); 3.61 (3H, s).

Example 247 Preparation of 2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(pyridin-3-yl)ethanone.

Step 1. A solution of (3-methoxy-5-((pyridin-3-ylmethylene)amino)phenyl)methanol in ethanol was prepared by heating a solution of nicotinaldehyde (0.107 g, 0.999 mmol) and (3-amino-5-methoxyphenyl)methanol ( 0.153 g, 0.999 mmol) in ethanol (1 ml) at 60° C. for 6 h. Imine formation was quantitative and the solution was used without further purification.

Step 2 2-((3-(Hydroxymethyl)-5-methoxyphenyl)amino)-1-(1 H-indol-3-yl)-2-(pyridin-3-yl)ethanone was prepared according to the general procedure K from a mixture 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1.5 ml), tert-butyl-3formyl-1H-indole -1-carboxylate (0.245 g, 0.999 mmol) and a solution of (3-methoxy-5-((pyridin-3ylmethylene)amino)phenyl)methanol (0.999 mmol) in ethanol (1 ml), heated at 70° C. overnight. Purification by flash chromatography on silica gel using a gradient of methanol (1-10%) in dichloromethane followed by precipitation from diethyl ether and dichloromethane gave 0.150 g (39%) of the desired compound as a yellow solid. ESI/APCI(+): 388 (M+H). ESI/APCI(-): 386 (M-H). 1H NMR (DMSO-d6) δ 12.23 (1H, br s); 8.85-8.98 (2H, m); 8.41 (1H, d); 8.18 (1H, d); 7.98 (1H, d); 7.50 (1H, d); 7.34 (1H, dd); 7.15-7.29 (2H, m); 6.38-6.50 (2H, m); 6.31 (1H, brs); 6.20 (1H, d); 6.16 (1H, s); 5.02 (1H, t); 4.32 (2H, d); 3.65 (3H, s).

Example 248 Preparation of 2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(6methoxypyridin-3-yl)ethanone

Step 1 A solution of (3-methoxy-5-(((6-methoxypyridin-3-yl)methylene)amino)phenyl)-methanol in ethanol was prepared by heating a solution of 6-methoxynicotinaldehyde (0.137 g, 0.999 mmol) and (3- amino5-methoxyphenyl)methanol (0.153 g, 0.999 mmol) in ethanol (1 ml) at 60° C. for 6 hours. Imine formation was quantitative and the solution was used without further purification.

Step 2. 2-((3-(Hydroxymethyl)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(b-methoxypyridin3-yl)ethanone was obtained according to the general procedure K from mixtures of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1.5 ml), tert-butyl-3-formyl-1H- indole-1-carboxylate (0.245 g, 0.999 mmol) and a solution of (3-methoxy-5-(((6methoxypyridin-3-yl)methylene)amino)phenyl)methanol (0.999 mmol) in ethanol (1 ml), heated at 70°C all night. Purification by flash chromatography on silica gel using a gradient of methanol (17%) in dichloromethane followed by precipitation from diethyl ether gave 0.081 g (19%) of the desired compound as a yellow solid. ESI/APCI(+): 418 (M+H). ESI/APCI(-): 416 (M-H). 1H NMR (DMSO-d6) δ 12.17 (1H, br s); 8.88 (1H, s); 8.47 (1H, s); 8.16 (1H, d); 7.85 (1H, dd); 7.48 (1H, d); 7.20 (2H, m); 6.74 (1H, d); 6.41 (1H, s); 6.23-6.37 (2H, m); 6.05-6.18 (2H, m); 5.00 (1H, t); 4.31 (2H, d); 3.77 (3H, s); 3.63 (3H, s).

Example 249 Preparation of 1-(1H-indol-3-yl)-2-((6-methoxypyrazin-2-yl)amino)-2-(6-methoxypyridin-3-yl)ethanone

Step 1. A solution of 6-methoxy-N-((6-methoxypyridin-3-yl)methylene)pyrazin-2-amine in ethanol was prepared by heating a solution of 6-methoxynicotinaldehyde (0.137 g, 0.999 mmol) and 6-methoxypyrazine2-amine ( 0.125 g, 0.999 mmol) in ethanol (1 ml) at 60° C. for 6 h. Imine formation was quantitative and the solution was used without further purification. ESI/APCI(+): 245 (M+H).

Step 1. 1-(1H-Indol-3-yl)-2-((6-methoxypyrazin-2-yl)amino)-2-(6-methoxypyridin-3-yl)ethanone was prepared according to general procedure K from mixture 3 -benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1.5 ml), tert-butyl-3-formyl1H-indole- 1-carboxylate (0.245 g, 0.999 mmol) and a solution of 6-methoxy-N-((6-methoxypyridin-3-yl)methylene)pyrazin-2-amine (0.999 mmol) in ethanol (1 ml), heated at 70 ° From all night. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30-100%) in dichloromethane followed by precipitation from dichloromethane gave 0.137 g (30%) of the desired compound as a white

- 122 040588 solids. ESI/APCI(+): 390 (M+H). 1H NMR (|DMSO-d ₆ ) δ 12.08 (1H, br s); 8.76 (1H, s); 8.50 (1H,

d); 8.17 (1H, d); 7.80-7.94 (2H, m); 7.73 (1H, s); 7.46 (1H, d); 7.32 (1H, s); 7.12-7.26 (2H, m); 6.80 (1H, d);

6.39 (1H, d); 3.79 (3H, s); 3.60 (3H, s).

Example 250 Preparation of 1-(6-fluoro-1H-indol-3-yl)-2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)2-phenylethanone

1-(6-Fluoro-1H-indol-3-yl)-2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-2-phenylethanone was obtained according to the general procedure K from a mixture of 3-benzyl-5-( 2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.132 g, 0.489 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (1 ml), tert-butyl-6-fluoro-3-formyl-1Hindole- 1-carboxylate (0.262 g, 0.995 mmol) and a solution of (3-(benzylideneamino)-5-methoxyphenyl)methanol (0.974 mmol) in ethanol (1 ml) heated at 60° C. for 16 hours. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (20-70%) in heptane. Further purification by flash chromatography on silica gel using a gradient of ethyl acetate (40-80%) in heptane followed by solid phase extraction on a C18 reverse phase column using a gradient of acetonitrile (0-90%) in water gave 0.032 g (8%) desired compound as a yellow solid. ESI/APCI(+): 405 (M+H). ESI/APCI(-): 403 (M-H).

Example 251 Preparation of 3-(2-((3-methoxyphenyl)amino)-2-phenylacetyl)-1-methyl-1H-indazole-6carbonitrile

Step 1 To a solution of 3-formyl-1H-imidazole-6-carbonitrile (0.250 g, 1.461 mmol) in DMSO (7 ml) were added potassium carbonate (0.817 g, 5.911 mmol) and methyl iodide (0.185 ml, 2.958 mmol). The reaction mixture was stirred at room temperature for 18 hours. Water was added and the precipitate was filtered. The pink solid was dissolved in dichloromethane and washed with brine. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 0.247 g of crude 3-formyl-1-methyl-1H-indazole-6-carbonitrile (contaminated with 3-formyl2-methyl-2H-indazole-6-carbonitrile). ESI/APCI(+): 186 (M+H).

Step 2 3-(2-((3-Methoxyphenyl)amino)-2-phenylacetyl)-1-methyl-1H-indazole-6-carbonitrile was prepared according to General Procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl )-4-methylthiazol-3-ium chloride (0.070 g, 0.259 mmol) and triethylamine (0.050 ml, 0.359 mmol) in ethanol (0.3 ml), 3-formyl-1-methyl-1Hindazole-6-carbonitrile (0.095 g, crude) and a solution of N-benzylidene-3-methoxyaniline (0.488 mmol) in ethanol (0.5 ml) heated at 60°C for 16 hours. The precipitate formed during the reaction was filtered, washed with ethanol and water and dried. The solid was purified by preparative HPLC (XBridge column; method 2) to give 0.064 g (11% over two steps) of the desired compound as a yellow solid. ESI/APCI(+): 397 (M+H). ESI/APCI(-): 395 (M-H).

Example 252 Preparation of 1-(6-fluoro-1H-indol-3-yl)-2-((6-methoxypyrazin-2-yl)amino)-2-phenylethanone

-(6-Fluoro-III-indol-3-yl)-2-((6-methoxypyrazin-2-yl)amino)-2-phenylethanone was obtained according to the general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl )-4-methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (1 ml), tert-butyl-6-fluoro-3-formyl-1H-indole-1-carboxylate (0.268 g, 1.018 mmol) and a solution of N-benzylidene-6-methoxypyrazin-2-amine (0.999 mmol) in ethanol (1 ml) heated at 60°C for 72 h. Purification by silica gel flash chromatography using a gradient ethyl acetate (20-80%) in heptane followed by purification by preparative HPLC (XBridge column; method 2) gave 0.056 g (15%) of the desired compound as a pink solid. ESI/APCI(+): 377 (M+H). ESI/APCI(-): 375 (M-H).

Example 253 Preparation of 2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(5methoxypyrazin-2-yl)ethanone

Step 1 A solution of (3-methoxy-5-(((5-methoxypyrazin-2-yl)methylene)amino)phenyl)methanol in ethanol was prepared by heating a solution of 5-methoxypyrazin-2-carbaldehyde (0.138 g, 0.999 mmol) and (3amino-5-methoxyphenyl)methanol (0.153 g, 0.999 mmol) in ethanol (1 ml) at 60° C. for 6 hours. Imine formation was quantitative and the solution was used without further purification.

Step 2 2-((3-(Hydroxymethyl)-5-methoxyphenyl)amino)-1-(1 H-indol-3-yl)-2-(5-methoxypyrazin2-yl)ethanone was prepared according to the general procedure K from a mixture 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1.5 ml), tert-butyl-3-formyl-1H-indole -1-carboxylate (0.245 g, 0.999 mmol) and a solution of (3-methoxy-5-(((5methoxypyrazin-2-yl)methylene)amino)phenyl)methanol (0.999 mmol) in ethanol (1 ml), heated at 70 °C all night. The residue was purified by silica gel flash chromatography using a gradient of methanol (1-7%) in dichloromethane.

Further purification by flash chromatography on silica gel using a gradient of ethyl acetate (15-70%) in dichloromethane followed by purification by preparative HPLC (XBridge column; method 5) gave 0.089 g (21%) of the desired compound as a white solid. ESI/APCI(+): 419 (M+H). ESI/APCI(-): 417 (M-H). ¹ H NMR (DMSO-d ₆ ) δ 12.14 (1H, br s); 8.75 (1H, s); 8.49 (1H, s); 8.23 (1H, s); 8.15 (1H, d); 7.47 (1H, d); 7.12-7.28 (2H, m); 6.40 (1H, s); 6.26-6.36 (2H, m); 6.18-6.25 (1H, m); 6.15(1H,

- 123 040588

s); 5.01 (1H, t); 4.31 (2H, d); 3.84 (3H, s); 3.64 (3H, s).

Example 254 Preparation of 2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(III-indol-3-yl)-2-(pyrazolo[1,5-a]pyridin-2-yl) ethanone.

Step 1: A mixture of pyrazolo[1,5-a]pyridine-2-carbaldehyde (0.066g, 0.452mmol) and (3-amino-5methoxyphenyl)methanol (0.069g, 0.451mmol) in ethanol (0.4ml) was heated at 60°C all night. The reaction mixture was concentrated under reduced pressure, and the residue was dried under reduced pressure over phosphorus(V) oxide to give quantitatively 3-methoxy-5-((pyrazolo[1,5a]pyridin-2-ylmethylene)amino)phenyl)methanol, which used without further purification.

Step 2. 2-((3-(Hydroxymethyl)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(pyrazolo[1,5-a]pyridin-2-yl)ethanone prepared according to the general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.061 g, 0.226 mmol) and triethylamine (0.032 ml, 0.231 mmol) in ethanol (0.5 ml), tert-Butyl-3-formyl-1H-indole-1-carboxylate (0.111 g, 0.453 mmol) and (3-methoxy-5((pyrazolo[1,5-a]pyridin-2-ylmethylene)amino)phenyl) solution methanol (0.451 mmol) in ethanol (0.5 ml) heated at 70°C for 4 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-100%) in heptane followed by a gradient of methanol (0-10%) in dichloromethane gave 0.019 g (10%) of the desired compound as a white solid. ESI/APCI(+): 427 (M+H). ESI/APCI(-): 425 (M-H).

Example 255 Preparation of 1-(1H-indol-3-yl)-2-((6-methoxypyrazin-2-yl)amino)-2-(pyrazolo[1,5a]pyridin-2-yl)ethanone

Step 1 A mixture of pyrazolo[1,5-a]pyridine-2-carbaldehyde (0.066 g, 0.452 mmol) and 6-methoxypyrazine-2-amine (0.057 g, 0.456 mmol) in ethanol (0.4 ml) was heated at 60 °C all night. The reaction mixture was concentrated under reduced pressure, and the residue was dried under reduced pressure over phosphorus(V) oxide to give quantitatively 6-methoxy-N-(pyrazolo[1,5-a]pyridin-2ylmethylene)pyrazine-2-amine, which was used without additional cleaning.

Step 2. 1-(1H-Indol-3-yl)-2-((6-methoxypyrazin-2-yl)amino)-2-(pyrazolo[1,5-a]pyridin-2yl)ethanone was prepared according to the general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3ium chloride (0.061 g, 0.226 mmol) and triethylamine (0.032 ml, 0.231 mmol) in ethanol (1 ml), tert-butyl-3formyl- 1H-indole-1-carboxylate (0.111 g, 0.453 mmol) and a solution of 6-methoxy-N-(nipαzolo[1,5a]pyridin-2-ylmethylene)pyrazin-2-amine (0.452 mmol) in ethanol (1 ml) heated at 70°C for 4 days. The residue was purified by silica gel flash chromatography using a gradient of ethyl acetate (20-100%) in heptane followed by a gradient of methanol (0-12%) in dichloromethane. Further purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-100%) in heptane gave 0.004 g (2%) of the desired compound as a white solid. ESI/APCI(+): 399 (M+H). ESI/APCI(-): 397 (M-H).

Example 256 Preparation of 2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(6methoxypyridin-3-yl)ethanone

Step 1: Mixture of 3-amino-5-methoxyphenol (1.860 g, 13.37 mmol), cesium carbonate (8.710 g, 26.73 mmol) and 2-bromoethanol (1.040 ml, 14.70 mmol) in DMF (40 ml ) was stirred at 60°C for 3 days. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15-100%) in dichloromethane gave 0.749 g (30%) of 2-(3-amino-5-methoxyphenoxy)ethanol as a brown solid. ESI/APCI(+): 184 (M+H).

Step 2 2-(3-Methoxy-5-(((6-methoxypyridin-3-yl)methylene)amino)phenoxy)ethanol was quantitatively obtained according to General Procedure I from 6-methoxynicotinaldehyde (0.069 g, 0.503 mmol) and 2- (3amino-5-methoxyphenoxy)ethanol (0.092 g, 0.502 mmol).

Step 3. 2-((3-(2-Hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(6-methoxypyridin-3-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.067 g, 0.248 mmol) and triethylamine (0.035 ml, 0.252 mmol) in ethanol (1 ml), tert-butyl-3-formyl- 1H-indole-1-carboxylate (0.123 g, 0.501 mmol) and a solution of 2-(3-methoxy-5-(((6methoxypyridin-3-yl)methylene)amino)phenoxy)ethanol (0.502 mmol) in ethanol (1 ml ), heated at 70°C all night. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30-100%) in dichloromethane followed by purification by preparative HPLC (XBridge column; method 5) gave 0.011 g (5%) of the desired compound as a white solid. ESI/APCI(+): 448 (M+H). ESI/APCI(-): 446 (M-H). ¹ H NMR (DMSO-d6) δ 12.17 (1H, br s); 8.90 (1H, s); 8.46 (1H, s); 8.16 (1H, d); 7.84 (1H, d); 7.47 (1H, d); 7.13-7.28 (2H, m); 6.75 (1H, d); 6.37 (1H, d); 6.09 (1H, d); 6.05 (2H, br s); 5.73 (1H, s); 4.79 (1H, t); 3.84 (2H, br s); 3.77 (3H, s); 3.65 (2H, br s); 3.62 (3H, s).

Example 257 Preparation of 2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(5methoxypyrazin-2-yl)ethanone

Step 1. 2-(3-Methoxy-5-(((5-methoxypyrazin-2-yl)methylene)amino)phenoxy)ethanol was quantitatively obtained according to General Procedure I from 5-methoxypyrazine-2-carbaldehyde (0.069 g, 0.500 mmol ) and 2-(3-amino-5-methoxyphenoxy)ethanol (0.092 g, 0.502 mmol).

- 124 040588

Stage 2. 2-((3 - (2-Hidroxyethoxy) -5-methoxyphenyl) amino) -1 - (1 H-indol-3 -yl) -2- (5-methoxypyrazin-2-yl) ethanone was obtained according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.067 g, 0.248 mmol) and triethylamine (0.035 ml, 0.252 mmol) in ethanol (1 ml), tert-butyl-3-formyl- 1H-indole-1-carboxylate (0.123 g, 0.501 mmol) and a solution of 2-(3-methoxy-5-(((5methoxypyrazin-2-yl)methylene)amino)phenoxy)ethanol (0.500 mmol) in ethanol (1 ml ), heated at 70°C for 2 days. The residue was purified by silica gel flash chromatography using a gradient of methanol (1-7%) in dichloromethane. Further purification by flash chromatography on silica gel using a gradient of ethyl acetate (15-70%) in dichloromethane followed by purification by preparative HPLC (XBridge column; method 5) gave 0.008 g (3%) of the desired compound as a beige solid. ESI/APCI(+): 449 (M+H). ESI/APCI(-): 447 (M-H). ¹ H NMR (DMSO-d ₆ ) δ 12.14 (1H, br s); 8.76 (1H, s); 8.48 (1H, s); 8.23 (1H, s); 8.15 (1H, d); 7.47 (1H, d); 7.20 (2H, br s); 6.36 (1H, d); 6.21 (1H, d); 6.05 (2H, br s); 5.75 (1H, s); 4.79 (1H, t); 3.84 (5H, m); 3.55-3.71 (5H, m).

Example 258 Preparation of 2-((3,5-dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(pyrazolo[1,5-a]pyridin-2-yl)ethanone

Step 1: A mixture of pyrazolo[1,5-a]pyridine-2-carbaldehyde (0.066 g, 0.452 mmol) and 3,5-dimethoxyaniline (0.069 g, 0.450 mmol) in ethanol (0.4 ml) was heated at 60°C all night long. The reaction mixture was concentrated under reduced pressure and the residue was dried under reduced pressure over phosphorus(V) oxide to give quantitatively 3,5-dimethoxy-N-(pyrazolo[1,5a]pyridin-2-ylmethylene)aniline, which was used without additional cleaning.

Step 2. 2-((3,5-Dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(pyrazolo[1,5-a]pyridin-2-yl)ethanone was prepared according to the general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.061 g, 0.226 mmol) and triethylamine (0.032 ml, 0.231 mmol) in ethanol (1 ml), tert-butyl- 3formyl-1H-indole-1-carboxylate (0.111 g, 0.453 mmol) and a solution of 3,5-dimethoxy-N-(pyrazolo[1,5a]pyridin-2-ylmethylene)aniline (0.450 mmol) in ethanol (1 ml) heated at 70°C for 4 days. The residue was purified by silica gel flash chromatography using a gradient of ethyl acetate (20-100%) in heptane. Further purification by flash chromatography on silica gel using a gradient of methanol (0-10%) in dichloromethane followed by purification by preparative HPLC (XBridge column; method 4) gave 0.003 g (1%) of the desired compound. ESI/APCI(+): 427 (M+H). ESI/APCI(-): 425 (M-H).

Example 259 Preparation of 2-((3,5-dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(5-methoxypyrazin-2yl)ethanone

Step 1 A mixture of 5-methoxypyrazine-2-carbaldehyde (0.138 g, 0.999 mmol) and 3,5-dimethoxyaniline (0.153 g, 0.999 mmol) in ethanol (1 ml) was heated at 60° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue was dried under reduced pressure over phosphorus (V) oxide to give quantitatively 3,5-dimethoxy-N-((5-methoxypyrazin-2-yl)methylene)aniline, which was used without further purification. .

Step 2 2-((3,5-Dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(5-methoxypyrazin-2-yl)ethanone was prepared according to General Procedure L from a mixture of 3-benzyl -5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1Hindole- 1-carboxylate (0.245 g, 0.999 mmol) and a solution of 3,5-dimethoxy-N-((5-methoxypyrazin-2-yl)methylene)aniline (0.999 mmol) in ethanol (1 ml), heated at 70°C in within 4 days. The residue was purified by silica gel flash chromatography using a gradient of ethyl acetate (25-100%) in heptane. Further purification by flash chromatography on silica gel using ethyl acetate/dichloromethane/heptane (3/3/4) as eluent followed by purification by preparative HPLC (XBridge column; method 4) gave 0.009 g (2%) of the desired compound. ESI/APCI(+): 419 (M+H). ESI/APCI(-): 417 (M-H).

Example 260 Preparation of 1-(5-fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(5-methoxypyrazin-2-yl)ethanone

1-(5-Fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(5-methoxypyrazin-2-yl)ethanone was prepared according to General Procedure L from a mixture of 3-benzyl- 5-(2-hydroxyethyl)-4-methylthiazol-3-yl chloride (0.101 g, 0.374 mmol) and triethylamine (0.070 ml, 0.502 mmol) in ethanol (0.5 ml), tert-butyl-5-fluoro-3 -formyl1H-indole-1-carboxylate (0.194 g, 0.737 mmol) and a solution of 3-methoxy-N-((5-methoxypyrazin-2yl)methylene)aniline (0.724 mmol) in ethanol (1 ml), heated at 60°C Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-50%) in heptane followed by purification by preparative HPLC (XBridge column; method 2) gave 0.120 g (41%) of the desired compound as a yellow solid. ESI/APCI(+): 407 (M+H). ESI/APCI(-): 405 (M-H).

Example 261 Preparation of 1-(5-fluoro-1H-indol-3-yl)-2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)2-phenylethanone

1-(5-Fluoro-1H-indol-3-yl)-2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-2-phenylethanone was prepared according to General Procedure L from a mixture of 3-benzyl-5-( 2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.084 g, 0.311 mmol) and triethylamine (0.065 ml, 0.466 mmol) in ethanol (0.5 ml), tert-butyl-5-fluoro-3-formyl 1H- indole-1-carboxylate (0.177 g, 0.672 mmol) and a solution of (3-(benzylideneamino)-5-methoxyphenyl)methanol (0.655 mmol) in ethanol (1 ml) heated at 60°C for 96 h. silica gel using a gradient of ethyl acetate (0-50%) in heptane followed by

Purification by solid phase extraction on a C18 reverse phase column using a gradient of acetonitrile (20-80%) in water gave 0.053 g (20%) of the desired compound as a brown solid. ESI/APCI(+): 405 (M+H). ESI/APCI(-): 403 (M-H). 1H NMR (DMSOd6) δ 12.25 (1H, br s); 8.93 (1H, s); 7.82 (1H, dd); 7.63 (1H, d); 7.48 (1H, dd); 7.29 (1H, t); 7.16 (1H, t); 7.05 (1H, dt); 6.40 (1H, s); 6.29 (1H, d); 6.26 (1H, s); 6.11 (1H, s); 6.07 (1 H, d); 4.98 (1H, t); 4.29 (2H, d); 3.62 (3H, s).

Example 262 Preparation of 1-(6-fluoro-1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(5-methoxypyrazin-2-yl)ethanone

-(6-Fluoro-III-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(5-methoxypyrazin-2-yl)ethanone was obtained according to the general procedure L from a mixture of 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.133 g, 0.493 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (0.5 ml), tert-butyl-6-fluoro-3- formyl1H-indole-1-carboxylate (0.253 g, 0.961 mmol) and a solution of 3-methoxy-N-((5-methoxypyrazin-2-yl)methylene)aniline (0.933 mmol) in ethanol (1 ml), heated at 60° C for 96 hours Purification by silica gel flash chromatography using a gradient of ethyl acetate (0-40%) in heptane followed by precipitation from diethyl ether gave 0.146 g (39%) of the desired compound as a white solid. ESI/APCI(+): 407 (M+H). ESI/APCI(-): 405 (M-H).

Example 263 Preparation of 2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1-methyl-1H-indazol-3yl)-2-phenylethanone

Step 1 2-(3-(Benzylideneamino)-5-methoxyphenoxy)ethanol was quantified according to General Procedure I from benzaldehyde (0.102 mL, 1.004 mmol) and 2-(3-amino-5-methoxyphenoxy)ethanol (0.183 g, 0.999 mmol).

Step 2 2-((3-(2-Hidroxyethoxy)-5-methoxyphenyl)amino)-1-(1-methyl-1H-indazol-3-yl)-2-phenylethanone was prepared according to General Procedure L from a mixture 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1.5 ml), 1-methyl-1Hindazole-3-carbaldehyde (0.160 g, 0.999 mmol) and a solution of 2-(3-(benzylideneamino)-5-methoxyphenoxy)ethanol (0.999 mmol) in ethanol (1.5 ml) heated at 70° C. overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-40%) in dichloromethane followed by purification by preparative HPLC (XBridge column; method 1) gave 0.031 g (7%) of the desired compound as a beige solid. ESI/APCI(+): 432 (M+H). 1H NMR (DMSO-d ₆ ) δ 8.14 (1H, d); 7.82 (1H, d); 7.59 (2H, d); 7.46-7.56 (1H, m); 7.16-7.43 (5H, m); 6.54 (1H, d); 6.44 (1H, d); 5.95 (2H, brs); 5.74 (1H, s); 4.78 (1H, brs); 4.27 (3H, s); 3.81 (2H, m); 3.53-3.70 (5H, m).

Example 264 Enantiomeric separation of 1-(1H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2phenylethanone gave (-)-1-(1H-indol-3-yl)- 2-((5-methoxypyridin-3-yl)amino)-2-phenylethanone and (+)-1(1 H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)- 2-phenylethanone.

1-(1H-Indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2-phenylethanone (0.054 g) was separated into its enantiomers and purified by preparative HPLC (ChiralPak column; method 6). Under these conditions, 0.021 g of the faster eluting enantiomer (t _r = 6.7 min; ee >98%) and 0.020 g of the slower eluting enantiomer (t _r =12.1 min; ee = 96%) were obtained. ).

Example 265 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyridin-2-yl)ethanone

Step 1 3-Methoxy-N-(pyridin-2-ylmethylene)aniline was quantified according to General Procedure I from picolinaldehyde (0.107 g, 0.999 mmol) and 3-methoxyaniline (0.112 mL, 1.001 mmol).

Step 2 1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyridin-2-yl)ethanone was prepared according to General Procedure L from a mixture of 3-benzyl-5-( 2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1H-indole-1-carboxylate ( 0.245 g, 0.999 mmol) and a solution of 3-methoxy-N-(pyridin-2-ylmethylene)aniline (0.999 mmol) in ethanol (1 ml), heated at 70°C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by crystallization from acetonitrile gave 0.013 g (4%) of the desired compound as a white solid. ESI/APCI(+): 358 (M+H). ESI/APCI(-): 356 (M-H).

Example 266 Preparation of 1-(1H-indol-4-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone

Step 1. tert-Butyl-4-formyl-1H-indole-1-carboxylate was prepared according to General Procedure F from 1H-indole-4-carbaldehyde (0.435 g, 2.997 mmol), di-tert-butyl dicarbonate (0.786 g, 3.601 mmol ) and DMAP (0.037 g, 0.303 mmol) in acetonitrile (7.5 ml) to give 0.654 g (89%) of the desired compound as a brown oil. 1H NMR (DMSO-d ₆ ) 10.26 (1H, s); 8.41 (1H, d); 7.92 (1H, d); 7.88 (1H, d); 7.57 (1H, t); 7.34 (1H, d); 1.65 (9H, s).

Step 2. 1-(1H-Indol-4-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4- methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1 ml), tert-butyl-4-formyl-1H-indole-1-carboxylate (0.245 g, 0.999 mmol ) and a solution of K-benzylidene-3-methoxyaniline (0.999 mmol) in ethanol (1 ml), heated at 70°C for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by purification by preparative HPLC (XBridge column; method 4) gave 0.051 g (14%) of the desired compound. ESI/APCI(+): 357 (M+H). ESI/APCI(-):

- 126 040588

355 (M-N).

Example 267 Preparation of 1-(1-(2-hydroxyethyl)-III-indazol-3-yl)-2-((3-methoxyphenyl)amino)-2phenylethanone.

Step 1 To a solution of NMP-indazole-3-carbaldehyde (0.201 g, 1.375 mmol), potassium carbonate (0.218 g, 1.577 mmol) and lithium iodide (0.095 g, 0.710 mmol) in NMP (3 ml) was added 2-(2 -chloroethoxy)tetrahydro2H-pyran (0.210 ml, 1.422 mmol). The reaction mixture was stirred at 80° C. for 20 hours. After cooling to room temperature, water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-35%) in heptane gave 0.145 g (38%) of 1-(2-((tetrahydro-2H-pyran-2yl)oxy)ethyl)-1H-indazole-3 -carbaldehyde as a pale yellow oil.

Step 2. 2-((3-Methoxyphenyl)amino)-2-phenyl-1-(1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1Hindazol-3-yl)ethanone prepared according to the general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-yl chloride (0.067 g, 0.248 mmol) and triethylamine (0.050 ml, 0.359 mmol) in ethanol (0.7 ml), 1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-indazole-3-carbaldehyde (0.145 g, 0.529 mmol) and a solution of N-benzylidene-3-methoxyaniline (0.483 mmol) in ethanol (1.2 ml) heated at 60° C. for 16 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (030%) in heptane gave 0.138 g (59%) of the desired product as a yellow oil (80% purity). ESI/APCI(+): 486 (M+H).

Step 2. To a solution of 2-((3-methoxyphenyl)amino)-2-phenyl-1-(1-(2-((tetrahydro-2H-pyran-2yl)oxy)ethyl)-1H-indazol-3-yl )ethanone (0.138 g, 0.284 mmol) in acetonitrile (3 ml) was added 1N. hydrochloric acid solution (0.150 ml, 0.150 mmol). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure. Purification by preparative HPLC (XBridge column; method 2) gave 0.022 g (36%) of the desired compound as a yellow oil. ESI/APCI(+): 402 (M+H).

Example 268 Preparation of 2-((3-(2-(tert-butoxy)ethoxy)-5-methoxyphenyl)amino)-1-(1-methyl-1Hindol-3-yl)-2-phenylethanone

2-((3-(2-(tert-Butoxy)ethoxy)-5-methoxyphenyl)amino)-1-(1-methyl-1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure C from 2-chloro-1-(1-methyl-1H-indol-3-yl)-2-phenylethanone (0.100 g, 0.352 mmol), triethylamine (0.057 ml, 0.423 mmol) and 3-(2-(tert-butoxy) ethoxy)-5-methoxyaniline (0.107 g, 0.423 mmol) in acetonitrile (1 ml), irradiated in a microwave oven at 130°C for 15 min and at 150°C for 1 h. Purification by flash chromatography on silica gel using gradient of ethyl acetate (5-50%) in heptane gave 0.151 g (88%) of the desired compound as an oil. ESI/APCI(+): 487 (M+H), 509 (M+Na). ESEAPCI(-): 485 (M-H).

Example 269 Preparation of 2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1-methyl-1H-indol-3yl)-2-phenylethanone

2-((3-(2-(tert-Butoxy)ethoxy)-5-methoxyphenyl)amino)-1-(1-methyl-1H-indol-3-yl)-2-phenylethanone (0.150 g, 0.308 mmol ) was dissolved in 4n. a solution of hydrogen chloride in dioxane (10.00 ml, 40.00 mmol). The reaction mixture was stirred at room temperature for 6 hours and concentrated under reduced pressure. The residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The phases were separated. The organic phase was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (30-100%) in heptane. Further purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-40%) in dichloromethane gave 0.032 g (24%) of 2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1methyl- 1H-indol-3-yl)-2-phenylethanone as a white solid. ESI/APCI(+): 431 (M+H). 1H NMR (DMSO-d ₆ ) δ 8.94 (1H, br s); 8.17 (1H, d); 7.63 (2H, d); 7.55 (1H, d); 7.11-7.37 (5H, m); 6.35 (1H, d); 5.91-6.08 (3H, m); 5.72 (1H, brs); 4.79 (1H, brs); 3.90 (3H, s); 3.83 (2H, m); 3.61 (5H, m).

Example 270 Preparation of 3-methoxy-5-((2-(1-methyl-1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)benzyl acetate.

Step 1 To a solution of (3-amino-5-methoxyphenyl)methanol (0.300 g, 1.958 mmol), triethylamine (0.817 ml, 5.894 mmol) and DMAP (0.024 g, 0.196 mmol) in dichloromethane (10 ml), acetic acid was added dropwise anhydride (0.184 ml, 1.965 mmol). The reaction mixture was stirred at room temperature for 1.5 h and the reaction mixture was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15-70%) in heptane gave 0.314 g (82%) of 3-amino-5-methoxybenzyl acetate as an oil. ESI/APCI(+): 196 (M+H).

Step 2 3-Methoxy-5-((2-(1-methyl-1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)benzyl acetate was prepared according to General Procedure C from 2-chloro-1- (1-methyl-1H-indol-3-yl)-2-phenylethanone (0.080 g, 0.282 mmol), triethylamine (0.078 ml, 0.564 mmol) and 3-amino-5-methoxybenzyl acetate (0.110 g, 0.564 mmol) in acetonitrile (1 ml) irradiated in a microwave oven at 150° C. for 1 hour. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane gave 0.057 g (46%) of the desired compound as an orange solid. ESI/APCI(+): 443 (M+H); 465 (M + Na).

- 127 040588

Example 271 Preparation of 2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(1-methyl-III-indol-3-yl)2-phenylethanone.

To a solution of 3-methoxy-5-((2-(1-methyl-1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)benzyl acetate (0.057 g, 0.129 mmol) in THF (1 .5 ml) and methanol (1.5 ml) was added potassium carbonate (0.036 g, 0.258 mmol). After stirring at room temperature for 3 hours, the reaction mixture was diluted with dichloromethane and filtered through a Celite pad. The filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30-100%) in heptane followed by precipitation from diethyl ether gave 0.020 g (38%) of 2-((3(hydroxymethyl)-5-methoxyphenyl)amino)-1-(1- methyl-1H-indol-3-yl)-2-phenylethanone as a beige solid. ESI/APCI(+): 401 (M+H). ESI/APCI(-): 399 (M-H). 1H NMR (DMSO-d ₆ ) δ 8.92 (1H, s); 8.17 (1H, d); 7.63 (2H, d); 7.54 (1H, d); 7.11-7.35 (5H, m); 6.39 (1H, s); 6.29 (1H, d); 6.24 (1H, s); 6.12 (1H, s); 5.99 (1H, d); 4.99 (1H, t); 4.29 (2H, d); 3.90 (3H, s); 3.62 (3H, s).

Example 272 Preparation of 1-(isoquinolin-4-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone

1-(Isoquinolin-4-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was obtained according to the general procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-i chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1 ml), isoquinoline-4-carbaldehyde (0.157 g, 0.999 mmol) and a solution of N-benzylidene-3-methoxyaniline (0.999 mmol) in ethanol (1 ml) heated at 70°C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20100%) in heptane followed by precipitation from diethyl ether gave 0.002 g (1%) of the desired compound as white solid. ESI/APCI(+): 369 (M+H). ESI/APCI(-): 367 (M-H).

Example 273 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(5-methylpyridin-3yl)ethanone

Step 1 A solution of 3-methoxy-N-((5-methylpyridin-3-yl)methylene)aniline in ethanol was prepared by heating a solution of 5-methylnicotinaldehyde (0.105 g, 0.867 mmol) and 3-methoxyaniline (0.111 ml, 0.983 mmol) in ethanol (0.5 ml) at 60° C. for 24 hours. Imine formation was quantitative and the solution was used without further purification.

Step 2. 1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(5-methylpyridin-3-yl)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.130 g, 0.482 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (0.5 ml), tert-butyl-3-formyl-1H- indole 1-carboxylate (0.230 g, 0.938 mmol) and a solution of 3-methoxy-N-((5-methylpyridin-3-yl)methylene)aniline (0.867 mmol) in ethanol (1 ml), heated at 60°C for 96 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (50-100%) in heptane followed by precipitation from diethyl ether gave 0.029 g (9%) of the desired compound as a white solid. ESI/APCI(+): 372 (M+H). ESI/APCI(-): 370 (M-H).

Example 274 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(5-methoxypyridin-2yl)ethanone

Step 1 A solution of 3-methoxy-N-((5-methoxypyridin-2-yl)methylene)aniline in ethanol was prepared by heating a solution of 5-methoxypicolinaldehyde (0.137 g, 0.999 mmol) and meta-anisidine (0.112 ml, 1.000 mmol) in ethanol (1 ml) at 60°C overnight. Imine formation was quantitative and the solution was used without further purification. ESI/APCI(+): 243 (M+H); 265 (M + Na).

Step 2. 1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(5-methoxypyridin-2-yl)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1.5 ml), tert-butyl-3-formyl-1H-indole 1-carboxylate ( 0.245 g, 0.999 mmol) and a solution of 3-methoxy-N-((5-methoxypyridin-2-yl)methylene)aniline (0.999 mmol) in ethanol (1 ml), heated at 70° C. overnight. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in dichloromethane. Further purification by flash chromatography on silica gel using a gradient of ethyl acetate (30-100%) in heptane followed by precipitation from diethyl ether and heptane gave 0.139 g (36%) of the desired compound as a beige solid. ESI/APCI(+): 388 (M+H). ESI/APCI(-): 386 (M-H). 1H NMR (DMSO-d6) δ 12.07 (1H, br s); 8.71 (1H, d); 8.22 (1H, d); 8.15 (1H, d); 7.53 (1H, d); 7.46 (1H, d); 7.33 (1H, dd); 7.12-7.25 (2H, m); 6.92 (1H, t); 6.28-6.45 (3H, m); 6.01-6.17 (2H, m); 3.75 (3H, s); 3.63 (3H, s).

Example 275 Preparation of 2-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)-1-(1H-indol-3-yl)-2(( 3-methoxyphenyl)amino)ethanone.

Step 1 To a solution of morpholine-3-carboxylic acid hydrochloride (1.000 g, 5.967 mmol) in water (3 ml) cooled to 0°C was added sodium nitrite (0.553 g, 8.015 mmol) in portions. The reaction mixture was stirred at 0° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was taken up in acetone. The solid was filtered. The filtrate was concentrated under reduced pressure. The residue was co-evaporated with THF to give 4-nitrosomorpholine-3 carboxylic acid as a pale yellow foam which was used in the next step without further purification. ESI/APCI(-): 159 (M-H).

Step 2. To a solution of 4-nitrosomorpholine-3-carboxylic acid (5.967 mmol) in THF (25 ml), cooled to 0°C, was added dropwise a solution of trifluoroacetic anhydride (0.850 ml, 6.018 mmol) in THF ( 2 ml). The reaction mixture was stirred at 0°C for 5 h and at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (25 ml) and stirred with potassium carbonate. The solid was filtered through celite. The filtrate was concentrated under reduced pressure to give 6,7-dihydro-4H-[1,2,3]oxadiazolo[4,3c][1,4]oxazine-8-ium-3-olate as a pale brown wax which used in the next step without purification. ESI/APCI (+): 143 (M+H).

Step 3. To a solution of 6,7-dihydro-4H-[1,2,3]oxadiazolo[4,3-c][1,4]oxazine-8-ium-3-olate (5.967 mmol) in xylone (20 ml) ethyl propiolate (0.650 ml, 6.414 mmol) was added. The reaction mixture was heated at 140° C. for 5 hours. Ethyl propiolate (0.500 ml, 4.934 mmol) was added again and the reaction mixture was heated at 140° C. for 16 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification by flash chromatography on silica gel using ethyl acetate (50%) in heptane as eluent gave 0.638 g (55% over 3 steps) of ethyl 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine -2-carboxylate as a yellow solid. ESI/APCI (+): 197 (M+H). ¹ H NMR (DMSO4) δ 6.55 (1H, s); 4.80 (1H, s), 4.28 (2H, q); 4.18 (1H, t); 4.08 (2H, t); 1.27 (3H, t).

Step 4 To a solution of ethyl 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxylate (0.327 g, 1.667 mmol) in THF (5 mL) cooled to - 78°C, lithium aluminum hydride (0.100 g, 2.635 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight. Water was added and the reaction mixture was stirred for 10 minutes. After addition of magnesium sulfate, stirring was continued for 5 minutes. The reaction mixture was filtered and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give 0.245 g (95%) of (6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)methanol as a yellow oil. ESI/APCI (+): 155 (M+H). ¹ H NMR (DMSO-d ₆ ) δ 5.97 (1H, s); 4.99 (1H, t); 4.75 (2H, s); 4.36 (1H, d); 4.02 (4H, s).

Step 5 To a solution of (6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)methanol (0.237 g, 1.537 mmol) in dichloroethane (12 ml) was added manganese dioxide (1.210 g, 13.92 mmol). The reaction mixture was stirred at 60° C. for 1 hour and at room temperature for 18 hours. The reaction mixture was filtered through celite. The solid was washed with dichloromethane and ethyl acetate. The filtrate was concentrated under reduced pressure to give 0.201 g (86%) of 6,7-dihydro-4H-pyrazolo[5,1c][1,4]oxazine-2-carbaldehyde as an orange solid. ESI/APCI (+): 153 (M+H).

Step 6 A solution of N-((6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)methylene)-3-methoxyaniline in ethanol was prepared by heating a solution of 6.7 -dihydro-4H-nirαzolo[5,1-c][1,4]oxazin-2carbaldehyde (0.102 g, 0.670 mmol) and 3-methoxyaniline (0.078 ml, 0.690 mmol) in ethanol (0.5 ml) at 60° C for 18 hours. Imine formation was quantitative and the solution was used without further purification.

Step 7. 2-(6,7-Dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)-1-(1H-indol-3-yl)-2-(( 3-Methoxyphenyl)amino)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.089 g, 0.330 mmol) and triethylamine (0.070 ml, 0.502 mmol) in ethanol (0.5 ml), tert-butyl-3-formyl-1H-indole-1-carboxylate (0.193 g, 0.787 mmol) and K-((6,7-dihydro4H-pyrazolo[5,1-c][ 1,4]oxazin-2-yl)methylene)-3-methoxyaniline (0.670 mmol) in ethanol (1 ml) heated at 60°C for 24 h. Purification by flash chromatography on silica gel using an ethyl acetate gradient (20- 100%) in heptane followed by precipitation from diethyl ether gave 0.087 g (32%) of the desired compound as a white solid. ESI/APCI(+): 403 (M+H). ESI/APCI(-): 401 (M-H).

Example 276 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(5-methoxypyridin-3yl)ethanone

Step 1. A solution of 3-methoxy-N-((5-methoxypyridin-3-yl)methylene)aniline in ethanol was prepared by heating a solution of 5-methoxynicotinaldehyde (0.137 g, 0.999 mmol) and 3-methoxyaniline (0.119 ml, 1.056 mmol) in ethanol (1 ml) at 60° C. for 18 hours. Imine formation was quantitative and the solution was used without further purification. ESI/APCI (+): 243 (M+H).

Step 2. 1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(5-methoxypyridin-3-yl)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.138 g, 0.512 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (0.5 ml), tert-butyl-3-formyl 1H-indol- 1-carboxylate (0.260 g, 1.060 mmol) and a solution of 3-methoxy-N-((5-methoxypyridin-3-yl)methylene)aniline (0.999 mmol) in ethanol (1 ml), heated at 60°C for 24 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (50-100%) in heptane followed by precipitation from methanol gave 0.065 g (17%) of the desired compound as a white solid. ESI/APCI(+): 388 (M+H). ESI/APCI(-): 386 (M-H).

Example 277 Preparation of 2-(4-fluorophenyl)-2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(1Nindol-3-yl)ethanone

- 129 040588

Step 1 A solution of (3-((4-fluorobenzylidene)amino)-5-methoxyphenyl)methanol in ethanol was prepared by heating a solution of 4-fluorobenzaldehyde (0.114 g, 0.919 mmol) and (3-amino-5-methoxyphenyl)methanol (0.130 g, 0.849 mmol) in ethanol (0.5 ml) at 60° C. for 18 hours. Imine formation was quantitative and the solution was used without further purification. ESI/APCI (+): 260 (M+H).

Step 2 2-(4-Fluorophenyl)-2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl -5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.130 g, 0.482 mmol) and triethylamine (0.085 ml, 0.610 mmol) in ethanol (0.5 ml), tert-butyl-3formyl-1H- indole-1-carboxylate (0.220 g, 0.897 mmol) and a solution of (3-((4-fluorobenzylidene)amino)-5methoxyphenyl)methanol (0.849 mmol) in ethanol (1 ml), heated at 60°C for 24 hours. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (40-100%) in heptane. Further purification by flash chromatography on silica gel using isopropanol (2.5%) in dichloromethane as eluent gave 0.051 g (15%) of the desired compound as a yellow foam. ESI/APCI(+): 405 (M+H). ESI/APCI(-): 403 (M-H).

Example 278 Preparation of 5-(2-(1H-indol-3-yl)-1-((3-methoxyphenyl)amino)-2-oxoethyl)picolinonitrile

Step 1 To a solution of 6-bromonicotinaldehyde (0.500 g, 2.688 mmol) in DMF (5 ml) was added copper (I) cyanide (0.361 g, 4.031 mmol) and the mixture was heated to 120°C. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered through a Celite pad. The organic phase was washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (0-80%) in heptane to give 0.161 g (45%) of 5-formylpicolinonitrile as a pink solid. 1H NMR (CDCl ₃ ) δ 10.21 (1H, s); 9.19 (1H, s); 8.33 (1H, dd); 7.90 (1H, d); 7.27 (1H, s).

Step 2 5-(((3-Methoxyphenyl)imino)methyl)picolinonitrile was quantified according to General Procedure I from 5-formylpicolinonitrile (0.132 g, 0.999 mmol) and 3-methoxyaniline (0.112 mL, 1.001 mmol).

Step 3 5-(2-(1H-Indol-3-yl)-1-((3-methoxyphenyl)amino)-2-oxoethyl)picolinonitrile was prepared according to General Procedure L from a mixture of 3-benzyl-5-(2- hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1H-indole-1-carboxylate (0.245 g , 0.999 mmol) and a solution of 5-(((3-methoxyphenyl)imino)methyl)picolinonitrile (0.999 mmol) in ethanol (1 ml) heated at 70°C for 3 days. The residue was purified by silica gel flash chromatography using a gradient of ethyl acetate (0-100%) in heptane. Further purification by flash chromatography on silica gel using ethyl acetate (42%) in heptane as eluent gave 0.049 g (12%) of the desired compound as a yellow solid. ESI/APCI(+): 383 (M+H). ESI/APCI(-): 381 (M-H).

Example 279 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanone

Step 1 A solution of 3-methoxy-N-((6-(trifluoromethyl)pyridin-3-yl)methylene)aniline in ethanol was prepared by heating a solution of 6-(trifluoromethyl)nicotinaldehyde (0.175 g, 0.999 mmol) and metaanisidine (0.112 ml , 1,000 mmol) in ethanol (1 ml) at 60°C overnight. Imine formation was quantitative and the solution was used without further purification. ESI/APCI(+):281 (M+H).

Step 2. 1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(6-trifluoromethyl)pyridin-3-yl)ethanone was prepared according to general procedure K from a mixture of 3-benzyl -5-(2-hydroxyethyl)-4-methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1.5 ml), tert-butyl-3-formyl 1H-indole-1- carboxylate (0.245 g, 0.999 mmol) and a solution of 3-methoxy-N-((6-(trifluoromethyl)pyridin-3yl)methylene)aniline (0.999 mmol) in ethanol (1 ml), heated at 70° C. overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15-70%) in heptane followed by precipitation from dichloromethane and heptane gave 0.125 g (29%) of the desired compound as a beige solid. ESI/APCI(+): 426 (M+H). ESI/APCI(-): 424 (M-H). ¹ H NMR (DMSO-d ₆ ) δ 12.28 (1H, br s); 9.07 (1H, s); 8.96 (1H, s); 8.27 (1H, d); 8.17 (1H, d); 7.89 (1H, d); 7.50 (1H, d); 7.16-7.29 (2H, m); 6.96 (1H, t); 6.67 (1H, d); 6.41-6.52 (2H, m); 6.36 (lH, d); 6.16 (lH, d); 3.65 (3H, s).

Example 280 Preparation of 1-(6-fluoro-1H-indol-3-yl)-2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-2-phenylethanone

1-(6-Fluoro-1H-indol-3-yl)-2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-2-phenylethanone was obtained according to general procedure K from a mixture of 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1.5 ml), tert-butyl-6-fluoro-3-formyl1H-indole- 1-carboxylate (0.263 g, 0.999 mmol) and a solution of 2-(3-(benzylideneamino)-5-methoxyphenoxy)ethanol (0.999 mmol) in ethanol (1 ml), heated at 70° C. overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in dichloromethane followed by precipitation from diethyl ether gave 0.025 g (6%) of the desired compound as a beige solid. ESI/APCI(+): 435 (M+H). ESI/APCI(-): 433 (M-H). 1H NMR (DMSO-d ₆ ) δ 12.19 (1H, br s); 8.90

- 130 040588 (1H, s); 8.13 (1H, dd); 7.62 (2H, d); 7.12-7.35 (5H, m); 7.05 (1H, t); 6.34 (1H, d); 5.96-6.11 (3H, m); 5.71(1H,

s); 4.78 (1H, t); 3.83 (2H, m); 3.64 (2H, m); 3.60 (3H, s).

Example 281 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyridazin-3-yl)ethanone

Step 1 A mixture of 3-methylpyridazine (1.830 ml, 20.03 mmol), benzaldehyde (4.080 ml, 40.08 mmol)) and zinc chloride (0.546 g, 4.006 mmol) was heated at 150°C for 2.5 h in sealed test tube. After cooling to room temperature, the reaction mixture was diluted with dichloromethane and washed with 1N. sodium hydroxide solution. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15-70%) in dichloromethane gave 2.820 g (77%) of 3-styrylpyridazine as a pale brown solid. ESI/APCI(+): 183 (M+H).

Stage 2. Mixture of 3-styrylpyridazine (0.600 g, 3.293 mmol), sodium periodate (1.410 g, 6.592 mmol) and 2.5% solution of osmium tetroxide in tert-butanol (4.500 ml, 0.494 mmol) in a mixture of acetone (6 ml) , tert-butanol (6 ml) and water (6 ml) were stirred at room temperature for 2 days. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15-70%) in dichloromethane gave 0.264 g (74%) of pyridazine-3-carbaldehyde as a light brown solid. ESI/APCI(+): 109 (M+H).

Step 3 A solution of 3-methoxy-N-(pyridazin-3-ylmethylene)aniline in ethanol was prepared by heating a solution of pyridazin-3-carbaldehyde (0.108 g, 0.999 mmol) and meta-anisidine (0.112 ml, 1.000 mmol) in ethanol ( 1 ml) at 60°C all night. Imine formation was quantitative and the solution was used without further purification. ESI/APCI(+):214 (M+H).

Step 4 1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyridazin-3-yl)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5-( 2-hydroxyethyl)-4-methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1.5 ml), tert-butyl-3-formyl-1H-indole 1-carboxylate (0.245 g , 0.999 mmol) and a solution of 3-methoxy-N-(pyridazin-3-ylmethylene)aniline (0.999 mmol) in ethanol (1 ml), heated at 70°C overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15-70%) in dichloromethane followed by precipitation from ethyl acetate gave 0.080 g (22%) of the desired compound as a beige solid. ESI/APCI(+): 359 (M+H). 1H NMR (DMSO-d6) δ 12.22 (1H, br s); 9.11 (1H, d); 8.83 (1H, s); 8.12 (1H, m); 7.78 (1H, m); 7.66 (1H, dd); 7.50 (1H, d); 7.16-7.30 (2H, m); 6.96 (1H, t); 6.68 (1H, d); 6.39 (3H, m); 6.17 (1H, d); 3.65 (3H, s).

Example 282 Preparation of 2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(7-methyl-1H-indol-3-yl)2-phenylethanone

2-((3-(Hydroxymethyl)-5-methoxyphenyl)amino)-1-(7-methyl-1H-indol-3-yl)-2-phenylethanone was obtained according to the general procedure K from a mixture of 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1.5 ml), tert-butyl-3-formyl-7-methyl1H-indole- 1-carboxylate (0.259 g, 0.999 mmol) and a solution of (3-(benzylideneamino)-5-methoxyphenyl)methanol (0.999 mmol) in ethanol (1 ml) heated at 70° C. overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in dichloromethane followed by precipitation from ethyl acetate gave 0.080 g (20%) of the desired compound as a beige solid. ESI/APCI(+): 401 (M+H). ESI/APCI(-): 399 (M-H). 1H NMR (DMSO-d6) δ 12.08 (1H, br s); 8.87 (1H, d); 7.98 (1H, d); 7.63 (2H, d); 7.22-7.33 (2H, m); 7.12-7.22 (1H, m); 7.03-7.11 (1H, m); 6.96-7.03 (1H, m); 6.41 (1H, s); 6.22-6.32 (2H, m); 6.07-6.17 (2H, m); 4.97 (1H, t); 4.30 (2H, d); 3.62 (3H, s); 2.47 (3H, s).

Example 283 Preparation of 2-((2,6-dimethoxypyridin-4-yl)amino)-1-(1H-indol-3-yl)-2-phenylethanone

2-((2,6-Dimethoxypyridin-4-yl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure E from 2-bromo-1-(1H-indol-3 -yl)-2-phenylethanone (0.042 g, 0.134 mmol) and 2,6-dimethoxy-4-pyridinamine (0.103 g, 0.668 mmol) in acetonitrile (0.6 ml) microwaved at 100°C for 30 min , at 120°C for 15 min and at 130°C for 35 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-60%) in heptane gave 0.021 g (41%) of the desired product as a white powder. ESI/APCI(+): 388 (M+H). ESI/APCI(-): 386 (M-H). 1H NMR (DMSO-d ₆ ) δ 12.16 (1H, br s); 8.88 (1H, d); 8.15 (1H, d); 7.61 (2H, m); 7.45 (1H, d); 7.1-7.35 (7H, m); 6.13 (1H, d); 5.85 (2H, s); 3.69 (6H, s).

Example 284 Preparation of 2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(6methylpyridin-3-yl)ethanone

Step 1. A solution of (3-methoxy-5-(((6-methylpyridin-3-yl)methylene)amino)phenyl)methanol in ethanol was prepared by heating a solution of 6-fluoronicotinaldehyde (0.098 g, 0.809 mmol) and (3-amino -5methoxyphenyl)methanol (0.124 g, 0.810 mmol) in ethanol (0.7 ml) at 60° C. for 24 hours. Imine formation was quantitative and the solution was used without further purification. ESI/APCI (+): 257 (M+H).

Step 2. 2-((3-(Hydroxymethyl)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(6-methylpyridin-3yl)ethanone was prepared according to general procedure K from mixture 3 -benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3ium chloride (0.110 g, 0.408 mmol) and triethylamine (0.080 ml, 0.574 mmol) in ethanol (0.5 ml), tert-butyl- 131 040588

3-formyl-1H-indole-1-carboxylate (0.210 g, 0.856 mmol) and a solution of (3-methoxy-5-(((6-methylpyridin-3yl)methylene)amino)phenyl)methanol (0.809 mmol) in ethanol ( 1 ml), heated at 60° C. for 96 hours. The residue was purified by flash chromatography on silica gel using a gradient of methanol (1-15%) in ethyl acetate. Further purification by flash chromatography on silica gel using a gradient of methanol (0-5%) in ethyl acetate gave 0.056 g (17%) of the desired compound. ESI/APCI(+): 402 (M+H). ESI/APCI(-): 400 (M-H).

Example 285 Preparation of 2-(5-fluoropyridin-3-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone

Step 1 A solution of N-((5-fluoropyridin-3-yl)methylene)-3-methoxyaniline in ethanol was prepared by heating a solution of 5-fluoronicotinaldehyde (0.125 g, 0.999 mmol) and meta-anisidine (0.112 ml, 1.000 mmol) in ethanol (1 ml) at 60°C overnight. Imine formation was quantitative and the solution was used without further purification. ESI/APCI(+):231 (M+H).

Step 2 2-(5-Fluoropyridin-3-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1.5 ml), tert-butyl-3-formyl-1H-indole 1-carboxylate ( 0.245 g, 0.999 mmol) and a solution of K-((5-fluoropyridin-3-yl)methylene)-3-methoxyaniline (0.999 mmol) in ethanol (1 ml), heated at 70° C. overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15-70%) in dichloromethane followed by precipitation from diethyl ether gave 0.161 g (43%) of the desired compound as a beige solid. ESI/APCI(+): 376 (M+H). ESI/APCI(-): 374 (M-H). 1H NMR (DMSO-d6) δ 12.26 (1H, br s); 8.95 (1H, d); 8.78 (1H, s); 8.43 (1H, d); 8.17 (1H, d); 7.91 (1H, d); 7.50 (1H, d); 7.15-7.29 (2H, m); 6.96 (1H, t); 6.58 (1H, d); 6.40-6.50 (2H, m); 6.27 (1H, d); 6.16 (1H, d); 3.65 (3H, s).

Example 286 Enantiomeric separation of 1-(5-fluoro-1H-indol-3-yl)-2-(6-methoxypyridin-3-yl)-2((5-methoxypyridin-3-yl)amino)ethanone gave (- )-1 -(5-fluoro-1 H-indol-3-yl)-2-(6-methoxypyridin-3 yl)-2-((5-methoxypyridin-3 -yl)amino)ethanone and (+)- 1-(5-Fluoro-1H-indol-3-yl)-2-(6-methoxypyridin-3-yl)-2-((5-methoxypyridin-3-yl)amino)ethanone.

1-(5-Fluoro-1H-indol-3-yl)-2-(6-methoxypyridin-3-yl)-2-((5-methoxypyridin-3-yl)amino)ethanone (0.064 g) was separated into its enantiomers and purified by preparative HPLC (ChiralPak column; method 6). Under these conditions, 0.015 g of the faster eluting enantiomer (t _r = 9.7 min; ee = 90%) and 0.013 g of the slower eluting enantiomer (t _r = 12.5 min; ee = 96%) were obtained. ).

Example 287 Enantiomeric separation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2(pyrazolo[1,5-a]pyridin-2-yl)ethanone gave (-)- 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2(pyrazolo[1,5-a]pyridin-2-yl)ethanone and (+)-1-(1H- indol-3-yl)-2-((3-methoxyphenyl)amino)-2(pyrazolo[1,5-a]pyridin-2-yl)ethanone.

1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(pyrazolo[1,5-a]pyridin-2-yl)ethanone (0.029 g) was separated into its enantiomers and purified by preparative HPLC (ChiralPak column; method 7). Under these conditions, 0.008 g of the faster eluting enantiomer (tr = 9.3 min; ee = 98%) and 0.008 g of the slower eluting enantiomer (t _r = 12.9 min; ee = 94%) were obtained. .

Example 288 Enantiomeric resolution of 2-((3,5-dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2phenylethanone gave (-)-2-((3,5-dimethoxyphenyl)amino)-1 -(1H-indol-3-yl)-2-phenylethanone and (+)-2((3,5-dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone.

2-((3,5-Dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone (0.050 g) was separated into its enantiomers and purified by preparative HPLC (ChiralPak column; method 7). Under these conditions, 0.016 g of the faster eluting enantiomer (t _r = 8.1 min; e.i. = 96%) and 0.012 g of the slower eluting enantiomer (t _r = 17.9 min; e.i. = 96%) were obtained. ).

Example 289 Preparation of 2-(benzo[d]oxazol-2-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone

Step 1 A solution of 2-methylbenzo[d]oxazole (1.020 g, 7.661 mmol) and N,N-dimethylformamide dimethyl acetal (1.230 g, 10.32 mmol) in DMF (8 ml) was heated at 140°C for 18 h. the mixture was concentrated under reduced pressure to give 1.170 g (81%) of 2-(benzo[d]oxazol-2-yl)K,K-dimethylethenamine as a brown solid. ESI/APCI (+): 189 (M+H). 1H NMR (DMSO-d6) δ 7.64 (1H, d); 7.42 (1H, d); 7.38 (1H, d); 7.19 (1H, t); 7.09 (1H, t); 5.00 (1H, d); 2.95 (6H, s).

Step 2 To a solution of 2-(benzo[d]oxazol-2-yl)-N,N-dimethylethenamine (0.233 g, 1.238 mmol) in THF (3.8 ml) heated at 45°C was added a 1M solution of periodiodate sodium in water (3.800 ml, 3.800 mmol). The reaction mixture was stirred at 45° C. for 1 hour. After cooling to room temperature, the precipitate was filtered and washed with ethyl acetate. The filtrate was washed with 1M sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-25%) in heptane gave 0.079 g (43%) of benzo[d]oxazole-2-carbaldehyde as a yellow oil ESI/APCI (+): 148 (M+H ). 1H NMR (DMSO-d ₆ ) δ 9.92 (1H, s); 8.02 (1H, d); 7.93 (1H, d); 7.67 (1H, t); 7.56 (1H, t).

- 132 040588

Step 3 A solution of N-(benzo[d]oxazol-2-ylmethylene)-3-methoxyaniline in ethanol was prepared by heating a solution of benzo[d]oxazol-2-carbaldehyde (0.100 g, 0.680 mmol) and 3-methoxyaniline (0.078 ml , 0.698 mmol) in ethanol (0.5 ml) at 60° C. for 5 hours. Imine formation was quantitative and the solution was used without further purification. ESI/APCI (+): 253 (M+H).

Step 4 2-(Benzo[d]oxazol-2-yl)-1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)ethanone was prepared according to General Procedure K from a mixture of 3-benzyl -5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.095 g, 0.352 mmol) and triethylamine (0.070 ml, 0.502 mmol) in ethanol (0.5 ml), tert-butyl-3-formyl- N-indole 1-carboxylate (0.189 g, 0.771 mmol) and a solution of N-(benzo[d]oxazol-2-ylmethylene)-3-methoxyaniline (0.680 mmol) in ethanol (1 ml), heated at 60°C for 16 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (50-100%) in heptane followed by precipitation from methanol gave 0.028 g (10%) of the desired compound as a yellow solid. ESI/APCI(+): 398 (M+H). ESI/APCI(-): 396 (M-H).

Example 290 Preparation of 2-((3-methoxyphenyl)amino)-1-(7-methyl-1H-indol-3-yl)-2-(pyrazolo[1,5a]pyridin-2-yl)ethanone

2-((3-Methoxyphenyl)amino)-1-(7-methyl-1H-indol-3-yl)-2-(pyrazolo[1,5-a]pyridin-2-yl)ethanone was prepared according to the general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.095 g, 0.352 mmol) and triethylamine (0.070 ml, 0.502 mmol) in ethanol (0.5 ml), tert-butyl -3-formyl-7methyl-III-indole-1-carboxylate (0.195 g, 0.752 mmol) and a solution of 3-methoxy-N-(pyrazolo[1,5-a]pyridin-2ylmethylene)aniline (0.704 mmol) in ethanol ( 1 ml) heated at 60° C. for 16 hours. Purification by silica gel flash chromatography using a gradient of ethyl acetate (10-60%) in heptane gave 0.034 g (12%) of the desired compound as a yellow oil. ESI/APCI(+): 411 (M+H). ESI/APCI(-): 409 (M-H).

Example 291 Preparation of 1-(benzo[d]isoxazol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone

Step 1 To a solution of benzo[d]isoxazole-3-carboxylic acid (0.500 g, 3.065 mmol) in THF (20 mL) was added N,O-dimethylhydroxylamine hydrochloride (0.359 g, 3.680 mmol), 1-(3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride (1.180 g, 6.155 mmol) and pyridine (0.500 ml, 6.195 mmol). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure.

The residue was partitioned between ethyl acetate. The phases were separated. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane gave 0.225 g (36%) of N-methoxy-N-methylbenzo[d]isoxazole-3-carboxamide as a white solid. ESI/APCI(+): 207 (M+H).

Step 2 To a solution of N-methoxy-N-methylbenzo[d]isoxazole-3-carboxamide (0.100 g, 0.485 mmol) in THF (5 ml) cooled to 0°C was added a 1M solution of benzylmagnesium chloride in THF (1.450 ml, 1.450 mmol). The reaction mixture was stirred at 0°C for 2 h and at room temperature overnight. After cooling to 0°C, the reaction was quenched by adding water. The reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane gave 0.052 g (45%) of 1-(benzo[d]isoxazol-3-yl)-2-phenylethanone as a beige solid. ESI/APCI(+): 238 (M+H). ESI/APCI(+): 236 (M-H).

Step 3. 1-(Benzo[d]isoxazol-3-yl)-2-bromo-2-phenylethanone was prepared according to general procedure P from a solution of 1-(benzo[d]isoxazol-3-yl)-2-phenylethanone (0.080 g, 0.337 mmol) in THF (3.5 ml) and a solution of phenyltrimethylammonium tribromide (0.140 g, 0.371 mmol) in THF (4.5 ml). The reaction mixture was stirred at 0°C for 1 h and at room temperature overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane gave 0.092 g (86%) of 1(benzo[d]isoxazol-3-yl)-2-bromo-2-phenylethanone as a yellow solid .

Step 4 1-(Benzo[d]isoxazol-3-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone was prepared according to General Procedure E from 1-(benzo[d]isoxazol-3-yl) -2-bromo-2-phenylethanone (0.044 g, 0.114 mmol) and metaanisidine (0.127 ml, 1.134 mmol) in acetonitrile (0.5 ml) irradiated in a microwave oven at 100°C for 15 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane followed by purification by preparative HPLC (XBridge column; method 1) gave 0.004 g (9%) of the desired compound as a yellow solid. ESI/APCI(+): 359 (M+H).

Example 292 Preparation of 2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(7-methyl-1H-indol-3yl)-2-phenylethanone

2-((3-(2-Hydroxyethoxy)-5-methoxyphenyl)amino)-1-(7-methyl-1H-indol-3-yl)-2-phenylethanone was obtained according to general procedure K from a mixture of 3-benzyl- 5-(2-hydroxyethyl)-4-methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1.5 ml), tert-butyl-3-formyl-7-methyl1H-indole -1-carboxylate (0.259 g, 0.999 mmol) and a solution of 2-(3-(benzylideneamino)-5-methoxyphenoxy)ethanol (0.999 mmol) in ethanol (1 ml), heated at 70° C. overnight. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in dichloromethane. Further purification by flash chromatography on silica gel using a gradient of ethyl acetate (30-100%) in heptane followed by purification by preparative HPLC (XBridge column; method 1) gave 0.012 g (3%) of the desired compound as a white solid. ESI/APCI(+): 431 (M+H). ESI/APCI(-): 429

- 133 040588 (M-N). ¹ H NMR (DMSO-d ₆ ) δ 12.09 (1H, br s); 8.89 (1H, d); 7.98 (1H, d); 7.62 (2H, d); 7.22-7.36 (2H, m);

7.13-7.22 (1H, m); 7.03-7.11 (1H, m); 6.95-7.03 (1H, m); 6.32 (1H, d); 6.10 (1H, d); 6.05 (2H, br s); 5.71(1H,

s); 4.78 (1H, t); 3.83 (2H, m); 3.62-3.71 (2H, m); 3.61 (3H, s); 2.48 (3H, s).

Example 293 Preparation of 2-((3-methoxyphenyl)amino)-2-(6-methoxypyridin-3-yl)-1-(7-methyl-1Nindol-3-yl)ethanone

2-((3-Methoxyphenyl)amino)-2-(6-methoxypyridin-3-yl)-1-(7-methyl-1 H-indol-3-yl)ethanone was obtained according to general procedure K from a mixture of 3-benzyl -5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.126 g, 0.467 mmol) and triethylamine (0.090 ml, 0.646 mmol) in ethanol (0.5 ml), tert-butyl-3-formyl- 7methyl-1H-indole-1-carboxylate (0.241 g, 0.929 mmol) and a solution of 3-methoxy-N-((6-methoxypyridin-3yl)methylene)aniline (0.875 mmol) in ethanol (1 ml), heated at 60° C for 98 hours Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-50%) in heptane gave 0.055 g (16%) of the desired compound as a white solid. ESI/APCI(+): 402 (M+H). ESI/APCI(-): 400 (M-H).

Example 294 Preparation of 2-(6-fluoropyridin-3-yl)-2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1(1H-indol-3-yl)ethanone

Step 1 A solution of (3-(((6-fluoropyridin-3-yl)methylene)amino)-5-methoxyphenyl)methanol in ethanol was prepared by heating a solution of 6-fluoronicotinaldehyde (0.110 g, 0.879 mmol) and (3-amino- 5-methoxyphenyl)methanol (0.140 g, 0.914 mmol) in ethanol (0.5 ml) at 60° C. for 5 hours. Imine formation was quantitative and the solution was used without further purification. ESI/APCI (+): 261 (M+H).

Step 2. 2-(6-Fluoropyridin-3-yl)-2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-1-(1H-indol-3yl)ethanone was prepared according to the general procedure K from the mixture 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3ium chloride (0.121 g, 0.448 mmol) and triethylamine (0.090 ml, 0.646 mmol) in ethanol (0.5 ml), tert-butyl 3-formyl-1H -indole-1-carboxylate (0.235 g, 0.958 mmol) and a solution of (3-(((6-fluoropyridin-3-yl)methylene)amino)-5-methoxyphenyl)methanol (0.879 mmol) in ethanol (1 ml), heated at 60°C for 16 hours. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane. Further purification by flash chromatography on silica gel using a gradient of methanol (0-4%) in dichloromethane gave 0.038 g (11%) of the desired compound as a yellow oil. ESI/APCI(+): 406 (M+H). ESI/APCI(-): 404 (M-H).

Example 295 Preparation of 1-(5-fluoro-1H-indol-3-yl)-2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)2-(pyridin-3-yl)ethanone

1-(5-Fluoro-1H-indol-3-yl)-2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-2-(pyridin-3-yl)ethanone was prepared according to General Procedure L from a mixture 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.126 g, 0.467 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (0.5 ml), tert-butyl-5 -fluoro-3formyl-1H-indole-1-carboxylate (0.259 g, 0.984 mmol) and a solution of (3-methoxy-5-((pyridin-3ylmethylene)amino)phenyl)methanol (0.953 mmol) in ethanol (1 ml), heated at 60° C. for 96 hours. Purification by silica gel flash chromatography using a gradient of methanol (0-7%) in dichloromethane followed by precipitation from dichloromethane gave 0.100 g (26%) of the desired compound as a white solid. ESI/APCI(+): 406 (M+H). ESI/APCI(-): 404 (M-H).

Example 296 Preparation of 2-((3,5-dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(6-methoxypyridin-3yl)ethanone

2-((3,5-Dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(6-methoxypyridin-3-yl)ethanone was obtained according to general procedure K from a mixture of 3-benzyl-5- (2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.125 g, 0.463 mmol) and triethylamine (0.090 ml, 0.646 mmol) in ethanol (0.5 ml), tert-butyl-3-formyl-1H-indole1 -carboxylate (0.260 g, 1.060 mmol) and a solution of 3,5-dimethoxy-K-((6-methoxypyridin-3-yl)methylene)aniline (0.912 mmol) in ethanol (1 ml), heated at 60°C for 16 h. tert-Butyl 3-formyl-1H-indole-1-carboxylate (0.127 g, 0.518 mmol) was added and the reaction mixture was heated at 60° C. for 24 h. Purification by silica gel flash chromatography using an ethyl acetate (1060% ) in heptane followed by purification by preparative HPLC (XBridge column; method 2) gave 0.008 g (2%) of the desired compound as a brown solid.

ESI/APCI(+): 418 (M+H). ESI/APCI(-): 416 (M-H).

Example 297 Preparation of 2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2(pyrazolo[1,5-a]pyridin-2-yl )ethanone.

Step 1. A solution of 2-(3-methoxy-5-((pyrazolo[1,5-a]pyridin-2-ylmethylene)amino)phenoxy)ethanol in ethanol was obtained by heating a solution of pyrazolo[1,5-a]pyridine- 2-carbaldehyde (0.073 g, 0.499 mmol) and 2-(3-amino-5-methoxyphenoxy)ethanol (0.092 g, 0.502 mmol) in ethanol (1 ml) at 60°C for 6 h. Imine formation was quantitative and the solution was used without further purification. ESI/APCI(+):312 (M+H).

Step 2. 2-((3-(2-Hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(pyrazolo[1,5a]pyridin-2-yl)ethanone prepared according to the general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.067 g, 0.248 mmol) and triethylamine (0.035 ml, 0.252 mmol) in ethanol (1 ml), tert-butyl-3- formyl 1H-indole-1-carboxylate (0.123 g, 0.501 mmol) and 2-(3-methoxy-5-134 040588 ((pyrazolo[1,5-a]pyridin-2-ylmethylene)amino)phenoxy)ethanol solution (0.499 mmol) in ethanol (0.5 ml) heated at 70° C. overnight. The residue was purified by silica gel flash chromatography using a gradient of methanol (1-10%) in dichloromethane. Further purification by preparative HPLC (XBridge column; method 5) followed by precipitation from diethyl ether gave 0.010 g (4%) of the desired compound as a light brown solid. ESI/APCI(+): 457 (M+H). ESI/APCI(-): 455 (MH). 1H NMR (DMSO-d6) δ 12.10 (1H, br s); 8.80 (1H, brs); 8.61 (1H, d); 8.19 (1H, d); 7.61 (1H, d); 7.48 (1H, d); 7.08-7.29 (3H, m); 6.82 (1H, t); 6.65 (1H, s); 6.29 (2H, s); 6.10 (2H, s); 5.75 (1H, s); 4.81 (1H, t); 3.85 (2H, m); 3.67 (2H,m); 3.63 (3H, s).

Example 298 Preparation of 2-((3,5-dimethoxyphenyl)amino)-1-(7-methyl-1H-indol-3-yl)-2-phenylethanone

Step 1 1-(7-Methyl-1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure O from a solution of 7-methylindole (0.500 g, 3.811 mmol) in dichloromethane (16 mL), 1M diethylaluminum chloride solution in hexane (5.790 ml, 5.790 mmol) and a solution of phenylacetyl chloride (0.762 ml, 5.718 mmol) in dichloromethane (16 ml). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane gave 0.320 g (34%) of the desired compound as a beige solid. ESI/APCI(+): 250 (M+H). ESI/APCI(-): 248 (M-H).

Step 2. 2-Bromo-1-(7-methyl-1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure P from a solution of 1-(7-methyl-1H-indol-3-yl)-2 -phenylethanone (0.200 g, 0.802 mmol) in THF (5.5 ml) and a solution of phenyltrimethylammonium tribromide (0.332 g, 0.882 mmol) in THF (7 ml). The reaction mixture was stirred at 0°C for 1 h and at room temperature overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane gave 0.314 g (99%) of the desired compound as a brown solid. ESI/APCI(+): 328, 330 (M+H). ESI/APCI(-): 326, 328 (M-H).

Step 3 2-((3,5-Dimethoxyphenyl)amino)-1-(7-methyl-1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure E from 2-bromo-1-(7- methyl-1H-indol-3-yl)-2-phenylethanone (0.120 g, 0.366 mmol) and 3,5-dimethoxyaniline (0.280 g, 1.828 mmol) in acetonitrile (1.5 ml) irradiated in a microwave oven at 100° C for 5 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane gave 0.042 g (29%) of 2-((3,5-dimethoxyphenyl)amino)-1-(7-methyl-1Hindol-3-yl )-2-phenylethanone as a white solid. ESI/APCI(+): 401 (M+Na). ESI/APCI(-): 399 (M-H). ¹ H NMR (DMSO-d6) δ 12.08 (1H, br s); 8.88 (1H, d); 7.98 (1H, d); 7.63 (2H, d); 7.23-7.34 (2H, m); 7.18 (1H, d); 7.03-7.12 (1H, m); 6.96-7.03 (1H, m); 6.34 (1H, d); 6.10 (1H, d); 6.06 (2H, d); 5.71 (1H, m); 3.61 (6H, s); 2.48 (3H, s).

Example 299 Preparation of 2-((3,5-dimethoxyphenyl)amino)-1-(1-methyl-1H-indol-3-yl)-2-phenylethanone

Step 1 To a solution of phenylacetic acid (0.500 g, 3.672 mmol) in dichloromethane (7 ml) was added a solution of 1H-benzotriazole (1.360 g, 11.42 mmol) and thionyl chloride (0.294 ml, 4.053 mmol) in dichloromethane (7 ml). The reaction mixture was stirred at room temperature for 1 hour. The white precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was partitioned between dichloromethane and saturated sodium carbonate solution. The phases were separated. The organic phase was washed with saturated sodium carbonate solution, water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 0.812 g (93%) of 1-(1Hbenzo[d][1,2,3]triazole-1- yl)-2-phenylethanone as a yellow solid. 1H NMR (CDCl ₃ ) δ 8.27 (1H, d); 8.12 (1H, d); 7.65 (1H, t); 7.25-7.5 (6H, m); 4.74 (2H, s).

Step 2 1-(1-Methyl-1H-indol-3-yl)-2-phenylethanone was prepared according to the 2 different procedures described herein as Method A and Method B.

Method A To a solution of N-methylindole (0.300 g, 2.287 mmol) and 1-(1H-benzo[d][1,2,3]triazol-1-yl)-2phenylethanone (0.434 g, 1.829 mmol) in dichloromethane ( 19 ml), cooled to 0° C., aluminum trichloride (0.381 g, 2.857 mmol) was added in portions. The reaction mixture was stirred at room temperature for 3 hours. Methanol was added and the reaction mixture was concentrated under reduced pressure. The residue was partitioned between dichloromethane and saturated sodium carbonate solution. The phases were separated. The organic phase was washed with saturated sodium carbonate solution, water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-70%) in heptane gave 0.266 g (58%) of 1-(1-methyl-1H-indol-3-yl)-2-phenylethanone as a rose oil. ESI/APCI(+): 250 (M+H); 272 (M + Na). 1H NMR (DMSO-d6) δ 8.56 (1H, s); 8.18 (1H, d); 7.54 (1H, d); 7.2-7.4 (7H, m); 4.11 (2H, s); 3.89 (3H, s).

Method B. 1-(1-Methyl-1H-indol-3-yl)-2-phenylethanone was prepared according to the general procedure O from a solution of N-methylindole (0.300 g, 2.287 mmol) in dichloromethane (11.5 ml), 1M solution diethylaluminum chloride in hexane (3.960 ml, 3.960 mmol) and a solution of phenylacetyl chloride (0.518 ml, 3.887 mmol) in dichloromethane (11.5 ml). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-60%) in heptane gave 0.350 g (76%) of the desired product as a pink powder.

- 135 040588

Step 3. 2-Bromo-1-(1-methyl-1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure P from a solution of 1-(1-methyl-1H-indol-3-yl)-2 -phenylethanone (0.256 g, 1.027 mmol) in THF (11 ml) and a solution of phenyltrimethylammonium tribromide (0.448 g, 1.192 mmol) in THF (13.5 ml). The reaction mixture was stirred at 0° C. for 1 h and at room temperature for 2 h. Purification by silica gel flash chromatography using a gradient of ethyl acetate (20-50%) in heptane gave 0.302 g (90%) of the desired product as a pink solid . ESI/APCI(+): 328, 330 (M+H). 1H NMR (DMSO-d6) δ 8.69 (1H, s); 8.20 (1H, d); 7.67 (2H, m); 7.57 (1H, d); 7.0-7.4 (5H, m); 6.73 (1H, s); 3.88 (3H, s).

Step 4 2-((3,5-Dimethoxyphenyl)amino)-1-(1-methyl-1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure E from 2-bromo-1-(1- methyl-1H-indol-3-yl)-2-phenylethanone (0.050 g, 0.152 mmol) and 3,5-dimethoxyaniline (0.116 g, 0.757 mmol) in acetonitrile (0.7 ml) irradiated in a microwave oven at 100° C for 10 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-60%) in heptane gave 0.051 g (84%) of the desired product as a white powder. ESI/APCI(+): 401 (M+H); 423 (M + Na). ESI/APCI(-): 399 (M-H). ¹ H NMR (DMSO^) δ 8.93 (1H, s); 8.17 (1H, d); 7.61 (2H, m); 7.55 (1H, d); 7.1-7.3 (4H, m); 6.36 (1H, d); 3.88 (3H, s).

Example 300 Preparation of 2-((3,5-dimethoxyphenyl)amino)-1-(7-(2-hydroxyethyl)-1H-indol-3-yl)-2phenylethanone

Step 1 To a suspension of 1H-indole-7-carboxaldehyde (1.000 g, 6.889 mmol) and methyltriphenylphosphonium bromide (2.960 g, 8.286 mmol) in THF (40 ml) cooled to 0°C, a solution of potassium tert-butoxide was added dropwise (1.170 g, 10.43 mmol) in THF (10 ml). The reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into ice/water and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-50%) in heptane gave 0.914 g of 7-vinyl-1H-indole as a pink oil. ESI/APCI(+): 144 (M+H).

Step 2 To a solution of 7-vinyl-1H-indole (0.914 g, 6.383 mmol) in THF (37 ml) cooled to 0°C was added dropwise a 1M solution of borane-tetrahydrofuran complex in THF (6.400 ml; 6.400 mmol) . The reaction mixture was stirred at room temperature for 2.5 hours. A 10% sodium hydroxide solution (3.100 mL, 7.750 mmol) was added dropwise followed by a 30% hydrogen peroxide solution in water (0.869 mL, 9.837 mmol). The reaction mixture was stirred at room temperature for 4 hours. Saturated ammonium chloride solution was added. After 5 minutes at room temperature, the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2070%) in heptane gave 0.490 g (44% over two steps) of 2-(1H-indol-7-yl)ethanol as a brown oil. ESI/APCI(+): 162 (M+H). ESI/APCI(-): 160 (M-H). 1H NMR (DMSO-d ₆ ) δ 11.00 (1H, br s); 7.35 (1H, m); 7.28 (1H, t); 6.90 (2H, m); 6.40 (1H, m); 4.67 (1H, t); 3.70 (2H, q); 2.98 (2H, t).

Step 3 7-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1H-indole was prepared according to the general procedure N from 2-(1H-indol-7-yl)ethanol (0.200 g, 1.241 mmol), DBU ( 0.280 ml, 1.876 mmol) and TBDMSCl (0.412 g, 2.734 mmol) in THF (4.6 ml). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-80%) in heptane gave 0.288 g (84%) of the desired product as an orange oil.

ESI/APCI(+): 276 (M+H). 1H NMR (DMSO-d ₆ ) δ 11.12 (1H, br s); 7.48 (1H, m); 7.39 (1H, t); 7.00 (2H, m); 6.51 (1H, m); 3.97 (2H, t); 3.14 (2H, t); 0.91 (9H, s); 0.00 (6H, s).

Step 3. 1-(7-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1H-indol-3-yl)-2-phenylethanone was obtained according to the general procedure O from a solution of 7-(2-((mpem- butyldimethylsilyl)oxy)ethyl)-1H-indole (0.193 g, 0.701 mmol) in dichloromethane (3.5 ml), a 1M solution of diethylaluminum chloride in hexane (1.200 ml, 1.200 mmol) and a solution of phenylacetyl chloride (0.156 ml, 1.171 mmol) in dichloromethane (3.5 ml). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-70%) in heptane gave 0.179 g (65%) of the desired product as a pink powder. ESI/APCI(+): 394 (M+H); 416 (M+Na). ESI/APCI(-): 392 (M-H). 1H NMR (DMSO-d6) δ 12.11 (1H, br s); 8.64 (1H, s); 8.17 (1H, d); 7.3-7.5 (5H, m); 7.17-7.26 (2H, m); 4.30 (2H, s); 4.01 (2H, t); 3.21 (2H, t); 0.93 (9H, s); 0.00 (6H, s).

Step 4. 2-Bromo-1-(7-(2-hydroxyethyl)-1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure P from a solution of 1-(7-(2-((tert-butyldimethylsilyl )oxy)ethyl)-1H-indol-3-yl)-2-phenylethanone (0.064 g, 0.163 mmol) in THF (2 ml) and a solution of phenyltrimethylammonium tribromide (0.074 g, 0.197 mmol) in THF (2.4 ml) . The reaction mixture was stirred at 0° C. for 1 h and at room temperature for 3 h. Purification by flash chromatography on silica gel using a gradient of methanol (0-10%) in dichloromethane gave 0.045 g (77%) of the desired product as a beige solid. ESI/APCI(+): 358, 360 (M+H). ESI/APCI(-): 356, 358 (M-H).

Step 5 2-((3,5-Dimethoxyphenyl)amino)-1-(7-(2-hydroxyethyl)-1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure E from 2-bromo- 1-(7-(2-hydroxyethyl)-1H-indol-3-yl)-2-phenylethanone (0.045 g, 0.126 mmol) and 3,5-dimethoxyaniline (0.194 g, 1.266 mmol) in acetonitrile (0.8 ml ) irradiated in a microwave oven at 100°C for 5 min. Purification by flash chromatography on silica gel with

Using a gradient of methanol (0-10%) in dichloromethane, 0.033 g (61%) of the desired product was obtained as a green powder. ESI/APCI(+): 431 (M+H); 453 (M + Na). ESI/APCI(-): 429 (M-H). ¹ H NMR (DMSOd6) δ 12.06 (1H, br s); 8.86 (1H, s); 8.01 (1H, d); 7.63 (2H, m); 7.28 (2H, m); 7.0-7.2 (3H, m); 6.33 (1H, d); 6.10 (1H, d); 6.05 (2H, d); 5.71 (1H, s); 4.69 (1H, brs); 3.69 (2H, t); 3.61 (6H, s); 3.00 (2H, t).

Example 301 Preparation of 2-((3,5-dimethoxyphenyl)amino)-2-(4-fluorophenyl)-1-(1-methyl-1H-indazol-3yl)ethanone

2-((3,5-Dimethoxyphenyl)amino)-2-(4-fluorophenyl)-1-(1-methyl-1H-indazol-3-yl)ethanone was prepared according to general procedure L from a mixture of 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1 ml), 1-methyl-1H-indazole-3-carbaldehyde ( 0.160 g, 0.999 mmol) and a solution of N-(4-fluorobenzylidene)-3,5-dimethoxyaniline (0.999 mmol) in ethanol (1 ml) heated at 70°C for 24 hours. Purification by flash chromatography on silica gel using gradient of ethyl acetate (0-100%) in heptane followed by crystallization from dichloromethane gave 0.062 g (15%) of the desired compound as a white solid. ESI/APCI(+): 420 (M+H). ESI/APCI(-): 418 (M-H). 1H NMR (DMSO-d6) δ 8.14 (1H, d); 7.82 (1H, d); 7.63 (2H, dd); 7.53 (1H, t); 7.33-7.44 (1H, m); 7.16 (2H, t); 6.57 (1H, d); 6.43 (1H, d); 5.95 (2H, brs); 5.75 (1H, s); 4.26 (3H, s); 3.60 (6H, s).

Example 302 Preparation of 2-((3,5-dimethoxyphenyl)amino)-2-(4-fluorophenyl)-1-(7-methyl-1H-indol-3yl)ethanone

Step 1 To a solution of 2-(4-fluorophenyl)acetic acid (0.500 g, 3.244 mmol) in dichloromethane (5 ml) was added oxalyl chloride (0.550 ml, 6.282 mmol) and DMF (1 drop). The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was co-evaporated with toluene to give quantitatively 2-(4-fluorophenyl)acetyl chloride, which was used in the next step without further purification.

Step 2 2-(4-Fluorophenyl)-1-(7-methyl-1H-indol-3-yl)ethanone was prepared according to General Procedure O from a solution of 7-methyl-1H-indole (0.280 g, 2.135 mmol) in dichloromethane (8.5 ml), a 1M solution of diethylaluminum chloride in hexane (4.300 ml, 4.300 mmol) and a solution of 4-(2-fluorophenyl)acetyl chloride (3.244 mmol) in dichloromethane (8.5 ml). Purification by precipitation from diethyl ether gave 0.188 g (33%) of the desired compound as a beige solid. ESI/APCI(+): 268 (M+H). ESI/APCI(-): 266 (M-H).

Step 3. 2-Bromo-2-(4-fluorophenyl)-1-(7-methyl-1H-indol-3-yl)ethanone was prepared according to general procedure P from a solution of 2-(4-fluorophenyl)-1-(7 -methyl-1-H-indol-3-yl)ethanone (0.186 g, 0.696 mmol) in THF (5 ml) and a solution of phenyltrimethylammonium tribromide (0.296 g, 0.787 mmol) in THF (6 ml). The reaction mixture was stirred at 0° C. for 1 h and at room temperature for 4 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-30%) in heptane gave 0.225 g (93%) of the desired compound as a brown solid. ESI/APCI (+): 346, 348 (M+H). ESI/APCI (-): 344, 346 (M-H).

Step 4: A mixture of 2-bromo-2-(4-fluorophenyl)-1-(7-methyl-1H-indol-3-yl)ethanone (0.050 g, 0.144 mmol) and 3,5-dimethoxyaniline (0.047 g, 0.307 mmol) in acetonitrile (1 ml) was stirred at room temperature for 72 hours. The reaction mixture was diluted with ethyl acetate and washed with 1M sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-40%) in heptane gave 0.054 g (89%) of 2-((3,5-dimethoxyphenyl)amino)-2-(4-fluorophenyl)-1(7- methyl-1H-indol-3-yl)ethanone as a white solid. ESI/APCI (+): 419 (M+H). ESI/APCI (-): 417 (M-H).

Example 303 Preparation of 2-((3-(2-(tert-butoxy)ethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)2-(pyridin-3-yl)ethanone.

Step 1: A mixture of (pyridin-3-yl)acetic acid hydrochloride (1.850 g, 10.67 mmol) and acetic anhydride (1.000 ml, 10.68 mmol) was heated in a sealed tube at 85°C for 1 hour. Indole was added (1.250 g, 10.7 mmol). The reaction mixture was heated at 85°C for 20 min and at 105°C for 30 min. After cooling to room temperature, the reaction mixture was turned into a base with saturated sodium bicarbonate solution and was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (1-10%) in dichloromethane gave 0.674 g (27%) of 1-(1H-indol-3-yl)-2(pyridin-3-yl)ethanone as a beige solid substances. ESI/APCI(+): 237 (M+H). ESI/APCI(-): 235 (M-H).

Step 2. 2-Bromo-1-(1H-indol-3-yl)-2-(pyridin-3-yl)ethanone was prepared according to general procedure P from a solution of 1-(1H-indol-3-yl)-2- (pyridin-3-yl)ethanone (0.570 g, 2.412 mmol) in THF (17 ml) and a solution of phenyltrimethylammonium tribromide (0.997 g, 2.652 mmol) in THF (22 ml). The reaction mixture was stirred at room temperature overnight. Purification by flash chromatography on silica gel using a gradient of methanol (1-10%) in dichloromethane gave 0.275 g (36%) of the desired compound as a brown solid. ESI/APCI(+): 315, 317 (M+H).

Step 3 Mixture of 2-bromo-1-(1H-indol-3-yl)-2-(pyridin-3-yl)ethanone (0.060 g, 0.190 mmol) and 3-(2-137 040588 (tert-butoxy) ethoxy)-5-methoxyaniline (0.091 g, 0.381 mmol) in acetonitrile (1 mL) was stirred at room temperature for 24 hours. The reaction mixture was diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (1-10%) in dichloromethane gave 0.041 g of 2-((3-(2-(tert-butoxy)ethoxy)-5-methoxyphenyl)amino)-1-(1H- indol-3yl)-2-(pyridin-3-yl)ethanone as a beige solid. ESI/APCI(+): 474 (M+H), 496 (M+Na). ESI/APCI(-): 472 (M-H).

Example 304 Preparation of 2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2(pyridin-3-yl)ethanone

2-((3-(2-(tert-Butoxy)ethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(pyridin-3-yl)ethanone (0.040 g , 0.084 mmol) was dissolved in a 4N solution of hydrogen chloride in dioxane (3.000 ml, 12.00 mmol). The reaction mixture was stirred at room temperature for 6 hours and partially concentrated under reduced pressure. The residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The phases were separated. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (1-15%) in dichloromethane followed by purification by preparative HPLC (XBridge column; method 5) gave 0.015 g (42%) 2-((3-(2-hydroxyethoxy)-5 -methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(pyridin-3-yl)ethanone as a beige solid. ESI/APCI(+): 418 (M+H). ESI/APCI(-): 416 (M-H). ¹ H NMR (DMSO-d ₆ ) δ 12.22 (1H, br s); 8.94 (1H, s); 8.87 (1H, s); 8.40 (1H, d); 8.16 (1H, d); 7.95 (1H, d); 7.48 (1H, d); 7.32 (1H, dd); 7.14-7.27 (2H, m); 6.47 (1H, d); 6.17 (1H, d); 6.06 (2H, s); 5.70-5.79 (1H, m); 4.79 (1H, t); 3.76-3.93 (2H, m); 3.62-3.71 (2H, m); 3.61 (3H, s).

Example 305 Preparation of 1-(6-fluoro-1H-indol-3-yl)-2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)2-(pyridin-3-yl)ethanone

1-(6-Fluoro-1H-indol-3-yl)-2-((3-(hydroxymethyl)-5-methoxyphenyl)amino)-2-(pyridin-3-yl)ethanone was prepared according to General Procedure L from a mixture 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1 ml), tert-butyl-6-fluoro -3formyl-1H-indole-1-carboxylate (0.263 g, 0.999 mmol) and a solution of (3-methoxy-5-((pyridin-3ylmethylene)amino)phenyl)methanol (0.999 mmol) in ethanol (1 ml), heated at 70°C for 4 days. Purification by flash chromatography on silica gel using a gradient of methanol (0-12%) in dichloromethane followed by preparative TLC using methanol (10%) in dichloromethane as eluent gave 0.029 g (7%) of the desired compound. ESI/APCI(+): 406 (M+H). ESI/APCI(): 404 (M-H).

Example 306 Preparation of 2-((2-fluoro-3,5-dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone

Step 1. To a solution of 3,5-dimethoxyaniline (0.200 g, 1.306 mmol) in dichloromethane (5 ml) was added N-fluoro-2,4,6-trimethylpyridinium triflate (0.377 g, 1.303 mmol) and the reaction mixture was heated at 100° From all night. After cooling to room temperature, water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15-70%) in heptane gave 0.068 g (30%) of 2-fluoro-3,5-dimethoxyaniline as a white solid. ESI/APCI(+): 172 (M+Na). 1H NMR (DMSO-d6) δ 5.94 (1H, dd); 5.89 (1H, dd); 3.73 (3H, s); 3.63 (3H, s).

Step 2 2-((2-Fluoro-3,5-dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure C from 2-bromo-1-(1H- indol-3-yl)-2-phenylethanone (0.120 g, 0.382 mmol), 2-fluoro3,5-dimethoxyaniline (0.065 g, 0.382 mmol) and triethylamine (0.106 ml, 0.764 mmol) in acetonitrile (0.5 ml), irradiated in a microwave oven at 100°C for 15 minutes and at 120°C for 10 minutes. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15-70%) in heptane followed by purification by preparative HPLC (XBridge column; method 2) gave 0.058 g (37%) of the desired compound as a white solid. ESI/APCI(+): 405 (M+H). ESI/APCI(-): 403 (M-H). 1H NMR (DMSO-d6) δ 12.20 (1H, br s); 8.87 (1H, s); 8.15 (1H, d); 7.62 (2H, d); 7.47 (1H, d); 7.24-7.34 (2H, m); 7.13-7.23 (3H, m); 6.21 (1H, d); 6.13 (1H, dd); 5.98 (1H, dd); 5.72-5.81 (1H, m); 3.75 (3H, s); 3.63 (3H, s).

Example 307 Preparation of 2-((3,5-dimethoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(6-methylpyridin-3yl)ethanone

Step 1 A mixture of 2-(6-methylpyridin-3-yl)acetic acid (0.150 g, 0.992 mmol) in acetic anhydride (0.094 ml, 0.996 mmol) was irradiated at 85° C. for 1 hour in a microwave oven. 1Hindole (0.116 g, 0.990 mmol) was added and the reaction mixture was irradiated at 85° C. for 60 min in a microwave oven. The reaction mixture was diluted with ethyl acetate and washed with 1M sodium bicarbonate solution. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (0-7%) in dichloromethane gave 0.057 g (23%) of 1-(1H-indol-3-yl)-2-(6methylpyridin-3-yl)ethanone as a beige solid. ESI/APCI(+): 251 (M+H). ESI/APCI (-): 249 (M-H).

Stage 2. 2-Bromo-1-(1H-indol-3-yl)-2-(6-methylpyridin-3-yl)ethanone was obtained according to the general

- 138 040588 procedure P from a solution of 1-(1H-indol-3-yl)-2-(6-methylpyridin-3-yl)ethanone (0.084 g, 0.336 mmol) in

THF (5 ml) and a solution of phenyltrimethylammonium tribromide (0.145 g, 0.386 mmol) in THF (2 ml). The reaction mixture was stirred at 0° C. for 1 h and at room temperature for 4 h. Purification by flash chromatography on silica gel using a gradient of methanol (0-5%) in dichloromethane gave 0.039 g (35%) of the desired compound. ESI/APCI(+): 329, 331 (M+H). ESI/APCI(-): 327, 329 (M-H).

Step 3: A mixture of 2-bromo-1-(1H-indol-3-yl)-2-(6-methylpyridin-3-yl)ethanone (0.038 g, 0.115 mmol) and 3,5-dimethoxyaniline (0.036 g, 0.235 mmol) in acetonitrile (0.8 ml) was stirred at room temperature for 96 h. The reaction mixture was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (0-5%) in dichloromethane followed by purification by preparative HPLC (XBridge column; Method 2) gave 0.020 g (43%) 2-((3,5dimethoxyphenyl)amino)-1- (III-indol-3-yl)-2-(6-methylpyridin-3-yl)ethanone as a yellow solid. ESI/APCI(+): 402 (M+H). ESI/APCI(-): 400 (M-H).

Example 308 Preparation of 2-((4,6-dimethoxypyrimidin-2-yl)amino)-1-(1H-indol-3-yl)-2-phenylethanone

To a solution of 2-bromo-1-(1H-indol-3-yl)-2-phenylethanone (0.050 g, 0.159 mmol) in acetonitrile (0.5 ml) was added 4,6-dimethoxypyrimidin-2-amine (0.123 g, 0.793 mmol) and the mixture was irradiated at 130°C for 20 min in a microwave oven. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (0-70%) in heptane. Further purification by solid phase extraction on a C18 reverse phase column using a gradient of acetonitrile (30-100%) in water gave 0.010 g (16%) of 2-((4,6-dimethoxypyrimidin-2-yl)amino)-1-( 1H-indol-3-yl)-2-phenylethanone. ESI/APCI(+): 389 (M+H). ESI/APCI(-): 387 (M-H).

Example 309 Preparation of 1-(1H-indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(ortho-tolyl)ethanone

Step 1 3-Methoxy-N-(2-methylbenzylidene)aniline was quantified according to General Procedure I from 2-methylbenzaldehyde (0.116 mL, 1.003 mmol) and 3-methoxyaniline (0.112 mL, 1.001 mmol). ESI/APCI(+): 226 (M+H).

Step 2 1-(1H-Indol-3-yl)-2-((3-methoxyphenyl)amino)-2-(ortho-tolyl)ethanone was prepared according to General Procedure L from a mixture of 3-benzyl-5-(2- hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1 ml), tert-butyl-3-formyl-1H-indole-1-carboxylate (0.245 g , 0.999 mmol) and a solution of 3-methoxy-N-(2-methylbenzylidene)aniline (1.001 mmol) in ethanol (1 ml), heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane followed by precipitation from diethyl ether gave 0.056 g (15%) of the desired compound as a white solid. ESI/APCI(+): 371 (M+H). ESI/APCI(-): 369 (M-H).

Example 310 Preparation of 2-((3-(2-(tert-butoxy)ethoxy)-5-methoxyphenyl)amino)-2-(4-fluorophenyl)-1(1H-indol-3-yl)ethanone.

Step 1 2-(4-Fluorophenyl)-1-(1H-indol-3-yl)ethanone was prepared according to General Procedure O from a solution of 1H-indole (0.234 g, 1.997 mmol) in dichloromethane (10 mL), 1M diethylaluminum solution chloride in hexane (3.000 ml, 3.000 mmol) and a solution of 2-(4-fluorophenyl)acetyl chloride (0.411 ml, 3.001 mmol) in dichloromethane (1 ml). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-80%) in heptane gave 0.324 g (64%) of the desired product. ESI/APCI(+): 254 (M+H). ESI/APCI(-): 252 (M-H).

Step 2. 2-Bromo-2-(4-fluorophenyl)-1-(1H-indol-3-yl)ethanone was prepared according to general procedure R from a solution of 2-(4-fluorophenyl)-1-(1H-indol-3 -yl)ethanone (0.320 g, 1.263 mmol) in THF (8.5 ml) and a solution of phenyltrimethylammonium tribromide (0.522 g, 1.389 mmol) in THF (5 ml). The reaction mixture was stirred at 0°C for 1 h and at room temperature overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-80%) in heptane gave quantitatively the desired product as a crude brown solid. ESI/APCI(-): 330, 332 (M-H).

Step 3. 2-((3-(2-(tert-Butoxy)ethoxy)-5-methoxyphenyl)amino)-2-(4-fluorophenyl)-1-(1H-indol-3yl)ethanone was obtained according to the general procedure C from 2-bromo-2-(4-fluorophenyl)-1-(1H-indol-3-yl)ethanone (0.200 g, 0.602 mmol), 3-(2-(tert-butoxy)ethoxy)-5- methoxyaniline (0.200 g, 0.836 mmol) and triethylamine (0.168 ml, 1.212 mmol) in acetonitrile (1 ml) irradiated in a microwave oven at 100°C for 15 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10100%) in heptane gave 0.153 g (52%) of the desired compound as a brown solid. ESI/APCI(+): 491 (M+H). ESI/APCI(-): 489 (M-H).

Example 311 Preparation of 2-(4-fluorophenyl)-2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1Nindol-3-yl)ethanone

2-((3-(2-(tert-Butoxy)ethoxy)-5-methoxyphenyl)amino)-2-(4-fluorophenyl)-1-(1H-indol-3-yl)ethanone (0.150 g, 0.306 mmol) was dissolved in 4N. a solution of hydrogen chloride in dioxane (3.000 ml, 12.00 mmol) with stirring at room temperature for 16 hours. The reaction was quenched by adding saturated sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated under

- 139 040588 reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30-100%) in heptane gave 0.052 g (39%) of 2-(4-fluorophenyl)-2-((3-(2-hydroxyethoxy)-5methoxyphenyl)amino)- 1-(1H-indole-3-schftanone. ESI/ApCI(+): 435 (M+H). ESI/aPcI(-): 433 (M-H).

Example 312 Preparation of 2-((3,5-dimethoxyphenyl)amino)-1-(5-(hydroxymethyl)-1H-indol-3-yl)-2phenylethanone

Step 1 5-(((tert-Butyldimethylsilyl)oxy)methyl)-1H-indole was prepared according to General Procedure N from (1H-indol-5-yl)methanol (1.000 g, 6.785 mmol), DBU (1.520 ml, 10 .18 mmol) and TBDMSCl (2.250 g, 14.93 mmol) in THF (25 ml). Purification by flash chromatography on silica gel using a gradient of dichloromethane (5-50%) in heptane gave 1.540 g (86%) of the desired compound as a beige solid.

Step 2 1-(5-(((tert-Butyldimethylsilyl)oxy)methyl)-1H-indol-3-yl)-2-chloro-2-phenylethanone was prepared according to General Procedure A from 5-(((tert-butyldimethylsilyl )oxy)methyl)-1H-indole (0.700 g, 2.675 mmol), pyridine (0.210 ml, 2.602 mmol) and α-chlorophenylacetyl chloride (0.386 ml, 2.678 mmol) in toluene (2 ml). The resulting extraction residue was purified by silica gel flash chromatography using a gradient of ethyl acetate (15-100%) in heptane to give 0.550 g (50%) of the desired compound as a white solid.

Step 3 2-((3,5-Dimethoxyphenyl)amino)-1-(5-(hydroxymethyl)-1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure E from 1-(5-(( (tert-Butyldimethylsilyl)oxy)methyl)-1H-indol-3-yl)-2chloro-2-phenylethanone (0.300 g, 0.724 mmol) and 3,5-dimethoxyaniline (1.110 g, 7.246 mmol) in acetonitrile (3 ml) irradiated in a microwave oven at 130°C for 30 min. The residue was purified by silica gel flash chromatography using a gradient of ethyl acetate (15-100%) in heptane. Further purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in dichloromethane followed by purification by preparative HPLC (XBridge column; method 2) gave 0.019 g (5%) of the desired compound as a white solid. ESI/APCI(+): 417 (M+H). ESI/APCI(-): 415 (M-H). 1H NMR (DMSO-d ₆ ) δ 12.08 (1H, br s); 8.87 (1H, s); 8.15 (1H, s); 7.64 (2H, d); 7.41 (1H, d); 7.257.35 (2H, m); 7.12-7.24 (2H, m); 6.33 (1H, d); 5.98-6.15 (3H, m); 5.73 (1H, s); 5.11 (1H, t); 4.56 (2H, d); 3.63 (6H, s).

Example 313 Preparation of 2-((3,5-dimethoxyphenyl)amino)-1-(4-(hydroxymethyl)-1H-indol-3-yl)-2phenylethanone

Step 1 4-(((tert-Butyldimethylsilyl)oxy)methyl)-1H-indole was prepared according to General Procedure N from (1H-indol-4-yl)methanol (1.000 g, 6.785 mmol), DBU (1.520 ml, 10 .18 mmol) and TBDMSCl (2.250 g, 14.93 mmol) in THF (25 ml). Purification by flash chromatography on silica gel using a gradient of dichloromethane (15-70%) in heptane gave 1.650 g (93%) of the desired compound as a white solid.

Step 2 To a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)-1H-indole (1.000 g, 3.825 mmol) and pyridine (0.300 ml, 3.717 mmol) in toluene (10 ml) heated at 55°C , α-chlorophenylacetyl chloride (0.552 mL, 3.825 mmol) was added dropwise. The reaction mixture was heated at 55° C. for 1 hour. After cooling to room temperature, water and methanol were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15-70%) in heptane gave 0.648 g (41%) of 1-(4-(((tert-butyldimethylsilyl)oxy)methyl)-1H-indol-3-yl) -2-chloro-2-phenylethanone as a brown oil and 0.317 g (28%) 2-chloro-1-(4(hydroxymethyl)-1H-indol-3-yl)-2-phenylethanone.

Step 3 2-((3,5-Dimethoxyphenyl)amino)-1-(4-(hydroxymethyl)-1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure E from 2-chloro-1-( 4-(hydroxymethyl)-1H-indol-3-yl)-2-phenylethanone (0.150 g, 0.500 mmol) and 3,5-dimethoxyaniline (0.767 g, 5.007 mmol) in acetonitrile (3 ml) irradiated in a microwave oven at 130°C for 15 min. The residue was purified by silica gel flash chromatography using a gradient of ethyl acetate (2-40%) in heptane. Further purification by preparative HPLC (XBridge column; method 2) followed by precipitation from dichloromethane gave 0.028 g (14%) of the desired compound as a white solid. ESI/APCI(+): 417 (M+H). ESI/APCI(-): 415 (MH). 1H NMR (DMSO-d ₆ ) δ 12.24 (1H, br s); 8.96 (1H, s); 7.60 (3H, d); 7.25-7.43 (4H, m); 7.20 (2H, m); 6.36 (1H, d); 6.17 (1H, d); 6.08 (2H, s); 4.94-5.15 (2H, m); 4.65 (1H, dd); 3.64 (6H, s).

Example 314 Preparation of 2-((3,5-dimethoxyphenyl)amino)-1-(5-(3-hydroxypropyl)-1H-indol-3-yl)2-phenylethanone

Step 1 To a mixture of 1H-indole-5-carboxaldehyde (4.790 g, 33.00 mmol) and potassium carbonate (11.40 g, 82.48 mmol) in THF (90 ml) was added methyl diethylphosphonoacetate (8.700 ml, 47.40 mmol). The reaction mixture was heated at reflux for 24 h and concentrated under reduced pressure. The residue was taken up in water, 1N. hydrochloric acid solution and diethyl ether. The orange precipitate was filtered off. The phases of the filtrate were separated. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-40%) in heptane gave 2.350 g (35%) of methyl 3-(1H-indol-5yl)acrylate as a white solid. ESI/APCI(-): 200 (M-H). 1H NMR (DMSO-d6) δ 8.32 (1H, br s);

7.85 (1H, d); 7.81 (1H, s); 7.43 (1H, dd); 7.38 (1H, d); 7.24 (1H, t); 6.59 (1H, brs); 6.42 (1H, d); 3.81 (3H, s).

Step 2 To a solution of methyl 3-(1H-indol-5-yl)acrylate (2.000 g, 9.939 mmol) in methanol (20 ml) was added 10% palladium on charcoal (0.530 g, 0.489 mmol). The suspension was stirred at room temperature under a hydrogen atmosphere for 24 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give 1.820 g (90%) of methyl 3-(1Hindol-5-yl)propanoate as a white solid . ESI/APCI(+): 204 (M+H).

Step 3 To a solution of methyl 3-(1H-indol-5-yl)propanoate (1.820 g, 8.955 mmol) in a mixture of THF (30 ml) and ethanol (7.5 ml) was added a 4M solution of lithium borohydride in THF (5.000 ml, 20.00 mmol). The reaction mixture was stirred at room temperature overnight. After cooling to 0° C., the reaction was quenched by adding a saturated ammonium chloride solution. The reaction mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-40%) in heptane gave 1.400 g (89%) of 3-(1H-indol-5-yl)propan-1-ol as a colorless oil. ESI/APCI(+): 176 (M+H).

Step 4 5-(3-((tert-Butyldimethylsilyl)oxy)propyl)-1H-indole was prepared according to General Procedure N from 3-(1H-indol-5-yl)propan-1-ol (0.200 g, 1.141 mmol ), DBU (0.255 ml, 1.708 mmol) and TBDMSCl (0.378 g, 2.508 mmol) in THF (4 ml). Purification by flash chromatography on silica gel using a gradient of dichloromethane (15-70%) in heptane gave 0.313 g (95%) of the desired compound as an oil. ESI/APCI(+): 290 (M+H).

Step 5 To a solution of 5-(3-((tert-butyldimethylsilyl)oxy)propyl)-1H-indole (0.310 g, 1.071 mmol) in dichloromethane (4 ml) cooled to 0°C was added a 1M solution of diethylaluminum chloride in THF (1.630 ml, 1.630 mmol). The mixture was stirred at 0°C for 30 min and a solution of phenylacetyl chloride (0.214 ml, 1.606 mmol) in dichloromethane (4 ml) was added dropwise. The resulting solution was stirred at 0° C. for 2 hours. The reaction was quenched by adding a mixture of water and saturated sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-100%) in heptane gave 0.071 g (23%) of 1-(5-(3-hydroxypropyl)-III-indol-3-yl)-2-phenylethanone as a white solid substances. ESI/APCI(+): 294 (M+H); 316 (M + Na). ESI/APCI(-): 292 (M-H).

Step 6 2-Bromo-1-(5-(3-hydroxypropyl)-1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure P from a solution of 1-(5-(3-hydroxypropyl)-1H- indol-3-yl)-2-phenylethanone (0.088 g, 0.300 mmol) in THF (2.5 ml) and a solution of phenyltrimethylammonium tribromide (0.124 g, 0.330 mmol) in THF (2.5 ml). The reaction mixture was stirred at 0°C for 1 h and at room temperature overnight. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in dichloromethane gave 0.096 g (86%) of the desired compound as a beige solid. ESI/APCI(+): 372, 374 (M+H); 394, 396 (M+Na). ESI/APCI(-): 370, 372 (M-H).

Step 7 Mixture of 2-bromo-1-(5-(3-hydroxypropyl)-1H-indol-3-yl)-2-phenylethanone (0.100 g, 0.269 mmol), 3,5-dimethoxyaniline (0.205 g, 1.345 mmol ) and triethylamine (0.075 ml, 0.541 mmol) in acetonitrile (2 ml) was stirred at room temperature for 2 days. Added 1n. hydrochloric acid solution and the reaction mixture were extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in dichloromethane gave 0.071 g (59%) of 2-((3,5-dimethoxyphenyl)amino)-1-(5(3-hydroxypropyl)-1H- indol-3-yl)-2-phenylethanone as a beige solid. ESI/APCI(+): 445 (M+Na). ESI/APCI(-): 443 (M-H). ¹ H NMR (DMSO-d ₆ ) δ 12.06 (1H, br s); 8.86 (1H, brs); 8.01 (1H, s); 7.65 (2H, d); 7.38 (1H, d); 7.31 (2H, t); 7.16-7.25 (1H, m); 7.08 (1H, d); 6.32 (1H, brs); 6.06 (3H, brs); 5.74 (1H, brs); 4.45 (1H, brs); 3.63 (6H, s); 3.43 (2H, m); 2.69 (2H, t); 1.65-1.85 (2H, m).

Example 315 Preparation of 2-((3-(2-(tert-butoxy)ethoxy)-5-methoxyphenyl)amino)-1-(5-fluoro-1Hindol-3-yl)-2-phenylethanone

Step 1 1-(5-Fluoro-1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure O from a solution of 5-fluoro-1H-indole (0.680 g, 5.032 mmol) in dichloromethane (20 ml), 1M solution of diethylaluminum chloride in hexane (7.600 ml, 7.600 mmol) and a solution of phenylacetyl chloride (1.000 ml, 7.504 mmol) in dichloromethane (20 ml). Purification by precipitation from ethyl acetate gave 0.820 g (64%) of the desired compound as a white solid. ESI/APCI(+): 254 (M+H). ESI/APCI(-): 252 (M-H).

Step 2. 2-Bromo-1-(5-fluoro-1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure P from a solution of 1-(5-fluoro-1H-indol-3-yl)-2 -phenylethanone (0.800 g, 3.159 mmol) in THF (22 ml) and a solution of phenyltrimethylammonium tribromide (1.310 g, 3.485 mmol) in THF (25 ml). The reaction mixture was stirred at 0° C. for 1 h and at room temperature for 4 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-70%) in heptane gave 1.040 g

- 141 040588 (99%) of the desired compound as a white solid. ESI/APCI(+): 332, 334 (M+H). ESI/APCI(-):

330, 332 (M-H).

Step 3. Solution of 2-bromo-1-(5-fluoro-1H-indol-3-yl)-2-phenylethanone (0.100 g, 0.301 mmol), 3-(2(tert-butoxy)ethoxy)-5-methoxyaniline (0.075 g, 0.313 mmol) and triethylamine (0.085 ml, 0.610 mmol) in acetonitrile (0.45 ml) were stirred at room temperature for 7 days. The reaction mixture was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-50%) in heptane gave 0.101 g (68%) of 2-((3-(2-(tert-butoxy)ethoxy)-5methoxyphenyl)amino)-1-( 5-fluoro-1H-indol-3-yl)-2-phenylethanone as an oil. ESI/APCI(+): 491 (M+H). ESI/APCI(-): 489 (M-H).

Example 316 Preparation of 1-(5-fluoro-1H-indol-3-yl)-2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-2-phenylethanone

2-((3-(2-tert-Butoxy)ethoxy)-5-methoxyphenyl)amino)-1-(5-fluoro-1H-indol-3-yl)-2-phenylethanone (0.101 g, 0.206 mmol) was dissolved in 4n. a solution of hydrogen chloride in dioxane (2.000 ml, 8.000 mmol). The reaction mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and 1M sodium bicarbonate solution. The phases were separated. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (50-100%) in heptane gave 0.060 g (67%) of 1-(5-fluoro-N-indol-3-yl)-2-((3-(2hydroxyethoxy) -5-methoxyphenyl)amino)-2-phenylethanone as a solid. ESI/APCI(+): 435 (M+H). ESI/APCI (-): 433 (M-H).

Example 317 Preparation of 2-((4-fluoro-3-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone

A solution of 2-bromo-1-(1H-indol-3-yl)-2-phenylethanone (0.048 g, 0.153 mmol), 4-fluoro-3-methoxyaniline (0.026 g, 0.184 mmol) and triethylamine (0.030 ml, 0.215 mmol ) in acetonitrile (0.5 ml) was stirred at 50° C. for 16 h and at room temperature for 96 h. The reaction mixture was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-40%) in heptane gave 0.054 g (94%) of 2-((4-fluoro-3-methoxyphenyl)amino)-1-(1H-indol-3yl)- 2-phenylethanone as a beige foam. ESI/APCI(+): 375 (M+H). ESI/APCI(-): 373 (M-H).

Example 318 Preparation of 2-((3,5-dimethoxyphenyl)amino)-1-(4-(3-hydroxypropyl)-1H-indol-3-yl)2-phenylethanone

Step 1 To a solution of 1H-indole-4-carbaldehyde (1.000 g, 6.889 mmol) and methyl-2-(diethoxyphosphoryl)acetate (1.511 ml, 8.268 mmol) in THF (15 ml) was added potassium carbonate (2.380 g, 17. 22 mmol). The reaction mixture was heated under reflux for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between diethyl ether and water. The phases were separated. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-60%) in heptane gave 1.059 g (76%) of methyl 3-(1H-indol-4yl)acrylate as an oil. ESI/APCI(-): 200 (M-H).

Step 2 To a solution of methyl 3-(1H-indol-4-yl)acrylate (1.059 g, 5.263 mmol) in methanol was added 10% palladium on carbon (0.560 g, 5.262 mmol). The suspension was stirred under a hydrogen atmosphere at room temperature for 16 hours. The reaction mixture was filtered through a Celite pad. The solid was washed with ethanol and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-60%) in heptane gave 0.936 g (88%) of methyl 3-(1H-indol-4-yl)propanoate. ESI/APCI(+): 204 (M+H).

Step 3 To a solution of methyl 3-(1H-indol-4-yl)propanoate (0.935 g, 4.601 mmol) in a mixture of THF (15 ml) and ethanol (4 ml) was added lithium borohydride (0.230 g, 10.58 mmol ). The reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched by adding saturated ammonium chloride solution and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 0.730 g (91%) of 3-(1H-indol-4-yl)propan-1-ol as milk oil. ESI/APCI(+): 176 (M+H). ESI/APCI(-): 174 (M-H).

Step 4 4-(3-((tert-Butyldimethylsilyl)oxy)propyl)-1H-indole was prepared according to General Procedure N from 3-(1H-indol-4-yl)propan-1-ol (0.300 g, 1.712 mmol ), TBDMSC1 (0.568 g, 3.769 mmol) and DBU (0.387 ml, 2.568 mmol) in THF (6 ml). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-60%) in heptane gave 0.388 g (78%) of the desired compound. ESI/APCI(+): 290 (M+H). ESI/APCI(-): 288 (M-H).

Step 5. 1-(4-(3-((tert-Butyldimethylsilyl)oxy)propyl)-1H-indol-3-yl)-2-phenylethanone was obtained according to the general procedure O from a solution of 4-(3-((mpem- butyldimethylsilyl)oxy)propyl)-1H-indole (0.385 g, 1.330 mmol) in dichloromethane (7 ml), 1M solution of diethylaluminum chloride in hexane (1.995 ml, 1.995 mmol) and phenylacetyl chloride (0.266 ml, 1.996 mmol). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-60%) in heptane gave 0.090 g (17%) of the desired product as a white solid. ESI/APCI(+): 408 (M+H); 430 (M + Na). ESI/APCI(-): 406 (M-H).

Step 6. 2-Bromo-1-(4-(3-hydroxypropyl)-1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure P from a solution of 1-(4-(3-( (mpem-butyldimethylsilyl)oxy)propyl)-1H-indol-3-yl)-2phenylethanone (0.090 g, 0.221 mmol) in THF (2 ml) and a solution of phenyltrimethylammonium tribromide (0.091 g, 0.243 mmol) in THF (2 ml) . The reaction mixture was stirred at 0°C for 1 h and at room temperature overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-100%) in heptane gave 0.040 g (49%) of the desired product. ESI/APCI(+): 372, 374 (M+H). ESI/APCI(-): 370, 372 (M-H).

Step 7 To a solution of 2-bromo-1-(4-(3-hydroxypropyl)-1H-indol-3-yl)-2-phenylethanone (0.040 g, 0.107 mmol) in acetonitrile (0.5 ml) was added 3, 5-dimethoxyaniline (0.049 g, 0.322 mmol) and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (10-80%) in heptane. Further purification by preparative HPLC (XBridge column; method 2) gave 0.009 g (18%) of 2-((3,5-dimethoxyphenyl)amino)-1-(4-(3-hydroxypropyl)-1H-indol-3yl)-2 -phenylethanone as a white amorphous solid. ESI/APCI(+): 445 (M+H). ESI/APCI(-): 443 (M-H).

Example 319 Preparation of 2-((3,5-dimethoxyphenyl)amino)-1-(7-(2-hydroxyethyl)-1-methyl-1H-indol3-yl)-2-phenylethanone

Step 1 2-(1H-Indol-7-yl)ethyl acetate was prepared according to General Procedure Q from 2-(1H-indol-7yl)ethanol (0.200 g, 1.241 mmol), DMAP (0.310 g, 2.537 mmol) and acetic anhydride (0.310 ml, 3.285 mmol) in dichloromethane (30 ml). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-80%) in heptane gave 0.218 g (86%) of the desired product as a colorless oil. ESI/APCI(+): 204 (M+H); 226 (M + Na). ¹ H NMR (DMSO4;) δ 11.11 (1H, br s); 7.41 (1H, m); 7.33 (1H, t); 6.93 (2H, m); 6.43 (1H, m); 4.29 (2H, t); 3.16 (2H, t); 1.97 (3H, s).

Step 2 To a solution of 2-(1H-indol-7-yl)ethyl acetate (0.118 g, 0.581 mmol) in DMF (4 ml) were added cesium carbonate (0.483 g, 2.965 mmol) and methyl iodide (0.055 ml, 1.767 mmol). After 7 hours at room temperature, cesium carbonate (0.483 g, 2.965 mmol) and methyl iodide (0.055 ml, 1.767 mmol) were added again. The reaction mixture was stirred overnight at room temperature. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-60%) in heptane gave 0.094 g (75%) of 2-(1-methyl-1H-indol-7-yl)ethyl acetate as a yellow oil. ESI/APCI(+): 218 (M+H); 240 (M + Na). 1H NMR (DMSO-d6) δ 7.44 (1H, m); 7.24 (1H, t); 6.95 (2H, m); 6.40 (1H, m); 4.30 (2H, t); 4.04 (3H, s); 3.38 (2H,t); 2.02 (3H, s).

Step 3 2-(1-Methyl-3-(2-phenylacetyl)-1H-indol-7-yl)ethyl acetate was prepared according to the general procedure O from a solution of 2-(1-methyl-1H-indol-7-yl)ethyl acetate (0.094 g, 0.433 mmol) in dichloromethane (2.2 ml), a 1M solution of diethylaluminum chloride in hexane (0.750 ml, 0.750 mmol) and a solution of phenylacetyl chloride (0.098 ml, 0.735 mmol) in dichloromethane (2.2 ml). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-80%) in heptane gave 0.071 g (49%) of the desired product as a purple powder. ESI/APCI(+): 336 (M+H); 358 (M + Na). 1H NMR (DMSO-d ₆ ) δ 8.53 (1H, m); 8.15 (1H, d); 7.1-7.4 (7H, m); 4.31 (2H, t); 4.15 (3H, s); 4.11 (2H, s); 3.40 (2H, t); 2.00 (3H, s).

Step 4 To a suspension of 2-(1-methyl-3-(2-phenylacetyl)-1H-indol-7-yl)ethyl acetate (0.090 g, 0.268 mmol) in a mixture of dioxane (1.4 ml) and water (1, 4 ml) was added 1N. lithium oxide solution. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate. The organic phase was washed with 1N. hydrochloric acid solution, water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (0-10%) in dichloromethane gave 0.069 g (88%) of 1-(7-(2-hydroxyethyl)-1-methyl-1H-indol-3-yl)-2 -phenylethanone in the form of a white foam. ESI/APCI(+): 294 (M+H); 316 (M + Na).

Step 4. 2-Bromo-1-(7-(2-hydroxyethyl)-1-methyl-1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure R from a solution of 1-(7-(2-hydroxyethyl )-1-methyl-1H-indol-3-yl)-2-phenylethanone (0.069 g, 0.235 mmol) in THF (2.9 ml) and a solution of phenyltrimethylammonium tribromide (0.131 g, 0.348 mmol) in THF (3.5 ml). The reaction mixture was stirred at 0° C. for 1 h and at room temperature for 3 h. Purification by flash chromatography on silica gel using a gradient of methanol (0-10%) in dichloromethane gave 0.057 g (65%) of the desired product as a yellow oils. ESI/APCI(+): 372, 374 (M+H). 1H NMR (DMSO-d6) δ 8.62 (1H, m); 8.12 (1H, d); 7.67 (2H, m); 7.35 (3H, m); 7.16 (1H, m); 7.08 (1H, m); 6.70 (1H, s); 4.11 (3H, s); 3.67 (2H,t); 3.19 (2H, t).

Step 5 2-((3,5-Dimethoxyphenyl)amino)-1-(7-(2-hydroxyethyl)-1-methyl-1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure E from 2 -bromo-1-(7-(2-hydroxyethyl)-1-methyl-1H-indol-3-yl)2-phenylethanone (0.052 g, 0.140 mmol) and 3,5-dimethoxyaniline (0.216 g, 1.410 mmol) in acetonitrile (0.8 ml), irradiated in a microwave oven at 100°C for 10 min. The residue was purified by silica gel flash chromatography using a gradient of methanol (0-10%) in dichloromethane. Further purification by flash chromatography on silica gel using an ethyl acetate gradient (40-95%) in

- 143 040588 heptane received 0.042 g (68%) of the desired product in the form of a beige powder. ESI/APCI(+): 445 (M+H);

467 (M + Na). ESI/APCI(-): 443 (M-H). 1H NMR (DMSO-d ₆ ) δ 8.85 (1H, s); 8.09 (1H, d); 7.62 (2H, m); 7.29 (2H, m); 7.0-7.2 (3H, m); 6.34 (1H, d); 6.01 (1H, s); 5.96 (2H, d); 5.72 (1H, s); 4.80 (1H, t); 4.15 (3H, s); 3.68 (2H, q); 3.61 (6H, s); 3.20 (2H, m).

Example 320 Preparation of 2-((3-hydroxy-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone

A mixture of 2-bromo-1-(1H-indol-3-yl)-2-phenylethanone (0.065 g, 0.207 mmol), 3-amino-5-methoxyphenol (0.115 g, 0.828 mmol) and triethylamine (0.058 ml, 0.418 mmol ) in acetonitrile (0.75 ml) was stirred at room temperature for 65 hours. 1N was added. hydrochloric acid solution and the reaction mixture were extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography using a gradient of ethyl acetate (1570%) in heptane. Further purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-20%) in dichloromethane gave 0.033 g (43%) 2-((3-hydroxy-5-methoxyphenyl)amino)-1(1H-indol-3-yl )-2-phenylethanone as a white solid. ESI/APCI(+): 373 (M+H). ESI/APCI(-): 371 (M-H). ¹ H NMR (DMSO-d6) δ 12.12 (1H, br s); 8.93 (1H, brs); 8.85 (1H, s); 8.15 (1H, d); 7.61 (2H, d); 7.46 (1H, d); 7.24-7.35 (2H, m); 7.19 (3H, m); 6.17 (1H, d); 6.00 (1H, d); 5.90 (1H, s); 5.84 (1H, s); 5.58 (1H, s); 3.56 (3H, s).

Example 321 Preparation of 2-((3,5-dimethoxyphenyl)amino)-1-(1-methyl-1H-indol-3-yl)-2-(pyridin-3yl)ethanone

Step 1 To a solution of 3-acetylindole (2.000 g, 12.56 mmol) in DMF (26 ml) cooled to 0°C was added sodium hydride (60% dispersion in mineral oil; 0.552 g, 13.80 mmol) in portions . After 10 min at 0° C., methyl iodide (0.939 mL, 15.08 mmol) was added and the reaction mixture was stirred at room temperature for 23 h. The reaction mixture was poured into ice/water and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-50%) in heptane gave 1.732 g (80%) of 1-(1-methyl-1H-indol-3yl)ethanone as a white powder. ESI/APCI(+): 174 (M+H); 196 (M + Na).

Step 2: A mixture of tris(dibenzylideneacetone)dipalladium (0.030 g, 0.033 mmol), (±) 2,2'-bis(diphenylphosphino)binaphthyl (0.051 g, 0.082 mmol) and sodium tert-butoxide (0.211 g, 2.300 mmol) in THF (3.9 ml) was degassed for 15 minutes with argon. 1-(1-Methyl-1H-indol-3-yl)ethanone (0.200 g, 1.155 mmol), 3-bromopyridine (0.094 ml, 0.862 mmol) and THF (1.9 ml) were added. The reaction mixture was heated at 80° C. for 39 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was washed with 1N. hydrochloric acid solution. The aqueous phase was converted to base with 2N. sodium hydroxide solution and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (0-10%) in dichloromethane gave 0.093 g (39%) of 1-(1methyl-1H-indol-3-yl)-2-(pyridin-3-yl)ethanone. ESI/APCI(+): 251 (M+H); 273 (M + Na). 1H NMR (DMSOd6) δ 8.60 (1H, s); 8.55 (1H, d); 8.44 (1H, dd); 8.17 (1H, d); 7.74 (1H, d); 7.56 (1H, d); 7.2-7.35 (3H, m); 4.20 (2H, s); 3.91 (3H, s).

Step 3 To a solution of 1-(1-methyl-1H-indol-3-yl)-2-(pyridin-3-yl)ethanone (0.051 g, 0.204 mmol) in THF (5 ml) was added pyridinium tribromide (0.130 g , 0.406 mmol). The reaction mixture was heated at 60° C. for 6 hours. 3,5-Dimethoxyaniline (0.312 g, 2.037 mmol) was added and the reaction mixture was refluxed for 2 hours. After cooling to room temperature, the reaction mixture was filtered and the solid was washed with ethyl acetate . The filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The phases were separated. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-90%) in heptane gave 0.043 g (53%) 2-((3,5-dimethoxyphenyl)amino)-1-(1-methyl-1H-indol-3-yl )-2-(pyridin-3-yl)ethanone as a yellow solid. ESI/APCI(+): 402 (M+H); 424 (M + Na). ESI/APCI(-): 400 (M-H). ¹ H NMR (DMSO-d6) δ 9.02 (1H, s); 8.94 (1H, d); 8.46 (1H, dd); 8.22 (1H, d); 8.02 (1H, d); 7.62 (1H, d); 7.27-7.41 (3H, m); 6.55 (1H, d); 6.14 (1H, d); 6.10 (2H, d); 5.80 (1H, s); 3.97 (3H, s); 3.68 (6H, s).

Example 322 Preparation of 2-((3-(3-hydroxypropoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2phenylethanone

Step 1 To a mixture of 3-amino-5-methoxyphenol (1.000 g, 7.186 mmol) and cesium carbonate (4.680 g, 14.37 mmol) in DMF (24 ml) was added 3-bromopropan-1-ol (1.100 g, 7.914 mmol). The reaction mixture was stirred at 60° C. for 20 hours. After cooling to 0° C., saturated sodium bicarbonate solution was added and the reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15-100%) in heptane gave 0.758 g (53%) of 3-(3-amino-5-methoxyphenoxy)propan-1-ol as an oil. ESI/APCI(+): 198 (M+H).

- 144 040588

Step 2: A mixture of 2-bromo-1-(1H-indol-3-yl)-2-phenylethanone (0.100 g, 0.318 mmol), 3-(3-amino-5methoxyphenoxy)propan-1-ol (0.063 g, 0.319 mmol) and triethylamine (0.088 ml, 0.635 mmol) in acetonitrile (2 ml) was stirred at room temperature for 2 days. 3-(3-Amino-5methoxyphenoxy)propan-1-ol (0.063 g, 0.319 mmol) was added again and stirring was continued at room temperature for 2 days. The mixture was diluted with ethyl acetate and washed with 1N. hydrochloric acid solution. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in dichloromethane followed by purification by preparative HPLC (XBridge column; method 5) gave 0.036 g (26%) 2-((3-(3hydroxypropoxy)-5-methoxyphenyl)amino )-1-(1H-indol-3-yl)-2-phenylethanone as a white solid. ESI/APCI(+): 431 (M+H). ESI/APCI(-): 429 (M-H). ¹ H NMR (DMSO-d ₆ ) δ 12.14 (1H, br s); 8.90 (1H, s); 8.16 (1H, d); 7.63 (2H, d); 7.46 (1H, d); 7.07-7.36 (5H, m); 6.32 (1H, d); 5.93-6.15 (3H, m); 5.71 (1H, s); 4.51 (1H, t); 3.89 (2H, t); 3.61 (3H, s); 3.51 (2H, m); 1.78 (2H, m).

Example 323 Preparation of 2-((3,5-dimethoxyphenyl)amino)-1-(7-(hydroxymethyl)-1H-indol-3-yl)-2phenylethanone

Step 1: A solution of (1H-indol-7-yl)methanol (0.251 g, 1.705 mmol), imidazole (0.287 g, 4.216 mmol) and TBDMSC1 (0.300 g, 1.990 mmol) in THF (8 ml) was stirred at room temperature in within 4 days. The solid was filtered and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-10%) in heptane gave 0.344 g (77%) of 7-(((tert-butyldimethylsilyl)oxy)methyl)-1H-indole as a colorless oil. 1H NMR (DMSO-d6) δ 10.83 (1H, s); 7.35 (1H, d); 7.23 (1H, t); 7.01 (1H, d); 6.89 (1H, t); 6.35 (1H, dd); 4.91 (2H, s); 0.83 (9H, s); 0.00 (6H, s).

Step 2 1-(7-(((tert-Butyldimethylsilyl)oxy)methyl)-1H-indol-3-yl)-2-chloro-2-phenylethanone was prepared according to General Procedure A from 7-(((tert-butyldimethylsilyl )oxy)methyl)-1H-indole (0.173 g, 0.662 mmol), pyridine (0.060 ml, 0.742 mmol) and α-chlorophenylacetyl chloride (0.095 ml, 0.662 mmol) in toluene (1.5 ml). The resulting extraction residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (0-25%) in heptane to give 0.060 g (22%) of the desired compound as a red-brown solid. ESI/APCI(+): 414, 416 (M+H). ESI/APCI(-): 412, 414 (M-H).

Step 3 2-((3,5-Dimethoxyphenyl)amino)-1-(7-(hydroxymethyl)-1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure E from 1-(7-(( (tert-Butyldimethylsilyl)oxy)methyl)-1H-indol-3-yl)-2chloro-2-phenylethanone (0.060 g, 0.145 mmol) and 3,5-dimethoxyaniline (0.220 g, 1.436 mmol) in acetonitrile (0.5 ml) irradiated at 100°С for 15 min and at 150°С for 15 min. Purification by preparative HPLC (XBridge column; method 2) gave 0.006 g (10%) of the desired compound as a beige solid. ESI/APCI(+): 417 (M+H). ESI/APCI(-): 415 (M-H).

Example 324 Preparation of 2-(3-(2-((5-methoxypyridin-3-yl)amino)-2-phenylacetyl)-1H-indol-7yl)ethyl acetate

Step 1 2-(3-Formyl-1H-indol-7-yl)ethyl acetate was prepared according to General Procedure R from a solution of oxalyl chloride (0.806 ml, 9.207 mmol) in dichloromethane (30 ml), DMF (0.773 ml, 9.984 mmol) and a solution of 2-(1H-indol-7-yl)ethyl acetate (1.560 g, 7.676 mmol) in dichloromethane (5 ml). The residue obtained after concentration of the organic phase under reduced pressure was dried to give crude 2-(3-formyl-1H-indol-7-yl)ethyl acetate as a beige solid which was used without further purification. ESI/APCI(+): 232 (M+H). ESI/APCI(-): 230 (M-H).

Step 2 tert-Butyl 7-(2-acetoxyethyl)-3-formyl-1H-indole-1-carboxylate was prepared according to General Procedure F from 2-(3-formyl-1H-indol-7-yl)ethyl acetate (1.776 g, 7.680 mmol), di-tert-butyl dicarbonate (2.011 g, 9.214 mmol) and DMAP (0.094 g, 0.768 mmol) in acetonitrile (40 ml). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-60%) in heptane gave 1.770 g (70%) of the desired compound as a yellow solid.

Step 3 2-(3-(2-((5-Methoxypyridin-3-yl)amino)-2-phenylacetyl)-1H-indol-7-yl)ethyl acetate was prepared according to general procedure K from a mixture of 3-benzyl-5 - (2-hydroxyethyl) -4-methylthiazol-3-ium chloride (0.120 g, 0.445 mmol) and triethylamine (0.090 ml, 0.646 mmol) in ethanol (0.5 ml), tert-butyl-7- (2 acetoxyethyl) - 3-formyl-1H-indole-1-carboxylate (0.273 g, 0.824 mmol) and a solution of N-benzylidene-5methoxypyridine-3-amine (0.857 mmol) in ethanol (1 ml) heated at 60°C for 72 hours. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-100%) in heptane gave 0.148 g (41%) of the desired compound as a yellow oil. ESI/APCI(+): 444 (M+H). ESI/APCI(-): 442 (M-H).

Example 325 Preparation of 1-(7-(2-hydroxyethyl)-1H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)2-phenylethanone

-(7-(2-Hydroxyethyl)-1H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2-phenylethanone was prepared according to General Procedure S from a solution of 2-(3-( 2-((5-Methoxypyridin-3-yl)amino)-2-phenylacetyl)-1Nindol-7-yl)ethyl acetate (0.148 g, 0.334 mmol) in a mixture of THF (2 ml) and methanol (2 ml) and potassium carbonate (0.095 g, 0.689 mmol). The reaction mixture was stirred at room temperature for 3 h.

- 145 040588

Purification by flash chromatography on silica gel using a gradient of methanol (0-6%) in dichloromethane followed by precipitation from dichloromethane gave 0.037 g (28%) of the desired compound as a brown powder. ESI/APCI(+): 402 (M+H).

Example 326 Preparation of 2-((3,5-dimethoxyphenyl)amino)-1-(7-(2-(dimethylamino)ethyl)-1H-indol-3yl)-2-phenylethanone

Step 1 To a solution of 1-(7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indol-3-yl)-2-phenylethanone (0.178 g, 0.452 mmol) in dichloromethane (7 ml) was added 4N solution of hydrogen chloride in dioxane (1.600 ml, 6.400 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane and washed with water. The organic phase was washed with saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (40-80%) in heptane gave 0.102 g (81%) of 1-(7-(2-hydroxyethyl)1H-indol-3-yl)-2-phenylethanone. ESI/APCI(+): 280 (M+H); 302 (M + Na). ESI/APCI(-): 278 (M-H).

Step 2 Triethylamine (0.074 ml, 0.534 mmol) and mesyl chloride (0.032 ml, 0.413 mmol). The reaction mixture was stirred at room temperature for 4 hours. A 2N solution of dimethylamine in THF (2.100 mL, 4.200 mmol) was added gradually over 4 days at room temperature. The reaction mixture was then partially concentrated under reduced pressure to remove dichloromethane. A 2N solution of dimethylamine in THF (1.000 ml, 2.000 mmol) was added and the reaction mixture was heated at 60°C for 6 h. A 2N solution of dimethylamine in THF (1.000 ml, 2.000 mmol) was added and the reaction mixture was stirred overnight at room temperature . The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The phases were separated. The organic phase was washed several times with 2N hydrochloric acid. The acidic aqueous phases were combined, basified with 2N sodium hydroxide solution and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 0.064 g (57%) 1-(7-(2-(dimethylamino)ethyl)-1H-indol-3-yl)- 2-phenylethanone as an orange oil, which was used in the next step without further purification. ESI/APCI(+): 307 (M+H); 329 (M + Na). ESI/APCI(-): 305 (M-H).

Step 3 To a solution of 1-(7-(2-(dimethylamino)ethyl)-1H-indol-3-yl)-2-phenylethanone (0.063 g, 0.206 mmol) in THF (2.5 ml) cooled to 0 °C, a solution of phenyltrimethylammonium tribromide (0.110 g, 0.292 mmol) in THF (3 ml) was added. The reaction mixture was stirred at 0° C. for 1 h and at room temperature for 5 h. 3,5-Dimethoxyaniline (0.154 g, 1.005 mmol) was added. The reaction mixture was refluxed for 2 h and stirred overnight at room temperature. 3,5-Dimethoxyaniline (0.051 g, 0.553 mmol) was added and the reaction mixture was stirred at room temperature for 65 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The phases were separated. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (2-10%) in dichloromethane followed by preparative TLC using methanol (10%) in dichloromethane as eluent gave 0.029 g (31%) of 2((3,5-dimethoxyphenyl )amino)-1-(7-(2-(dimethylamino)ethyl)-1H-indol-3-yl)-2-phenylethanone as a beige powder. ESI/APCI(+): 458 (M+H). ESI/APCI(-): 456 (M-H). ¹ H NMR (DMSO-d ₆ ) δ 12.24 (1H, br s); 8.89 (1H, s); 8.04 (1H, d); 7.64 (2H, m); 7.29 (1H, t); 7.05-7.2 (4H, m); 6.34 (1H, d); 6.10 (1H, d); 6.06 (2H, d); 5.72 (1H, s); 3.68 (6H, s); 3.08 (2H, m); 2.79 (2H, m); 2.43 (6H, m).

Example 327 Preparation of 2-((3-hydroxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone

A suspension of 2-bromo-1-(1H-indol-3-yl)-2-phenylethanone (0.098 g, 0.312 mmol) and 3-aminophenol (0.068 g, 0.623 mmol) in acetonitrile (1 ml) was stirred at room temperature for 24 hours The reaction mixture was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-50%) in heptane gave 0.065 g (61%) of 2-((3hydroxyphenyl)amino)-1-(1H-indol-3-yl)-2-phenylethanone in as a beige solid. ESI/APCI(+): 343 (M+H). ESI/APCI(-): 341 (M-H).

Example 328 Preparation of ethyl 4-(3-((2-(1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)-5-methoxyphenoxy)butanoate

Step 1 To a solution of 3-amino-5-methoxyphenol (0.500 g, 3.593 mmol) in THF (10 ml) was added ditert-butyl dicarbonate (0.863 g, 3.954 mmol) in THF (2 ml). The reaction mixture was refluxed overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane gave 0.427 g (50%) of tert-butyl-(3-hydroxy-5-methoxyphenyl)carbamate as an oil. ESI/APCI(+): 240 (M+H).

Step 2: Mixture of tert-butyl (3-hydroxy-5-methoxyphenyl)carbamate (0.200 g, 0.836 mmol), potassium carbonate (0.231 g, 1.671 mmol), ethyl 4-bromobutyrate (0.245 g, 1.256 mmol) and potassium iodide (0.014 g, 0.084 mmol) in acetone (5 ml) was stirred at 60° C. for 65 h. After cooling to room temperature, water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane gave 0.189 g (64%) of ethyl 4-(3-((tert-butoxycarbonyl)amino)-5-methoxyphenoxy)butanoate as an oil. ESI/APCI(+): 354 (M+H); 376 (M + Na).

Step 3 Ethyl 4-(3-((tert-butoxycarbonyl)amino)-5-methoxyphenoxy)butanoate (0.104 g, 0.294 mmol) was dissolved in 4N. a solution of hydrogen chloride in dioxane (3.000 ml, 12.00 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was partially concentrated. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The phases were separated. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15-70%) in heptane gave 0.054 g (72%) of ethyl 4-(3-amino-5-methoxyphenoxy)butanoate as an orange oil.

Step 3 Ethyl 4-(3-((2-(1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)-5-methoxyphenoxy)butanoate was prepared according to General Procedure C from 2-bromo -1-(1H-indol-3-yl)-2-phenylethanone (0.102 g, 0.324 mmol), ethyl 4-(3-amino-5-methoxyphenoxy)butanoate (0.082 g, 0.324 mmol) and triethylamine (0.090 ml , 0.647 mmol) in acetonitrile (2 ml), irradiated in a microwave oven at 100°C for 20 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane followed by precipitation from diethyl ether gave 0.057 g (36%) of the desired compound as a white solid. ESI/APCI(+): 487 (M+H). ESI/APCI(-): 485 (M-H).

Example 329 Preparation of 2-((3-(2-(tert-butoxy)ethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)2-(para-tolyl)ethanone

Step 1. 1-(1H-Indol-3-yl)-2-(para-tolyl)ethanone was prepared according to the general procedure O from a solution of 1H-indole (0.350 g, 2.988 mmol) in dichloromethane (15 ml), 1M diethylaluminum solution chloride in hexane (3.880 ml, 3.880 mmol) and a solution of 2-(para-tolyl)acetyl chloride (0.655 g, 3.884 mmol) in dichloromethane (2 ml). The residue obtained after extraction was purified by precipitation from dichloromethane to give 0.417 g (56%) of the desired compound as a white solid. ESI/APCI(+): 250 (M+H). ESI/APCI(-): 248 (M-H).

Step 2. 2-Bromo-1-(1H-indol-3-yl)-2-(para-tolyl)ethanone was obtained according to the general procedure P from a solution of 1-(1H-indol-3-yl)-2-(para -tolyl)ethanone (0.417 g, 1.673 mmol) in THF (11 ml) and phenyltrimethylammonium tribromide (0.692 g, 1.840 mmol). The reaction mixture was stirred at room temperature overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-80%) in heptane gave 0.642 g of crude 2-bromo-1-(1H-iidol-3-yl)-2-(para-tolyl)ethanone as a pink solid substance that was used in the next step without further purification. ESI/APCI(+): 328, 330 (M+H). ESI/APCI(-): 326, 328 (M-H).

Stage 3. 2-((3-(2-(tert-Butoxy)ethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(para-tolyl)ethanone was obtained according to the general procedure C from 2-bromo-1-(1H-indol-3-yl)-2-(para-tolyl)ethanone (0.075 g, 0.228 mmol), 3-(2-(tert-butoxy)ethoxy)-5- methoxyaniline (0.060 g, 0.251 mmol) and triethylamine (0.064 ml, 0.456 mmol) in acetonitrile (0.5 ml) irradiated in a microwave oven at 100°C for 15 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-80%) in heptane gave 0.058 g (52%) of the desired compound as a brown solid. ESI/APCI(+): 487 (M+H). ESI/APCI(-): 485 (M-H).

Example 330 Preparation of 2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2(para-tolyl)ethanone

2-((3-(2-(tert-Butoxy)ethoxy)-5-methoxyphenyl)amino)-1-(1 H-indol-3-yl)-2-(para-tolyl)ethanone (0.058 g, 0.119 mmol) was dissolved in 4N. a solution of hydrogen chloride in dioxane (1.5 ml, 6,000 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (50-100%) in heptane gave 0.030 g (58%) of 2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1H-indole -3-yl)-2-(para-tolyl)ethanone as a solid. ESI/APCI(+): 431 (M+H). ESI/APCI(-): 429 (M-H). 1H NMR (DMSO-d6) δ 8.85 (1H, s); 8.15 (1H, d); 7.40-7.56 (3H, m); 7.12-7.27 (2H, m); 7.08 (2H, d); 6.27 (1H, d); 6.03 (3H, brs); 5.70 (1H, s); 4.79 (1H, t); 3.83 (2H, d); 3.58-3.68 (5H, m); 2.20 (3H, s).

Example 331 Preparation of 2-((3,5-dimethoxyphenyl)amino)-1-(5-(2-hydroxyethyl)-1H-indol-3-yl)-2phenylethanone

Step 1 To a solution of 1H-indole-5-carbaldehyde (5.000 g, 34.45 mmol) in THF (200 ml) cooled to 0°C was added methyltriphenylphosphonium bromide (14.77 g, 41.33 mmol) and a solution potassium tert-butoxide (5.800 g, 51.67 mmol) in THF (50 ml). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was partially concentrated under reduced pressure. The residue was poured into ice/water and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane gave 3.110 g (63%) of 5-vinyl-1H-indole as a beige solid. ESI/APCI(+): 144 (M+H). ESI/APCI(-): 142 (M-H).

Step 2 To a solution of 5-vinyl-1H-indole (2.960 g, 20.67 mmol) in THF (100 ml) was added dropwise a 1M solution of borane-tetrahydrofuran complex in THF (20.70 ml, 20.70 mmol) and the reaction mixture was stirred for 2.5 hours.

10% sodium hydroxide solution (8.240 ml, 24.83 mmol) and 30% hydrogen peroxide solution (2.350 ml, 24.83 mmol) were added successively and the reaction mixture was stirred at room temperature for 3.5 h. ammonium chloride. The reaction mixture was vigorously stirred for 5 min and partitioned between ethyl acetate and water. The phases were separated. The organic phase was washed with brine and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30-100%) in heptane gave 2.310 g (66%) of 2-(1H-indol-5-yl)ethanol as an oil. ESI/APCI(+):162(M+H); 184 (M + Na).

Step 3 5-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1H-indole was prepared according to General Procedure N from 2-(1H-indol-5-yl)ethanol (0.464 g, 2.878 mmol), TBDMSCl ( 0.954 g, 6.330 mmol) and DBU (0.651 ml, 4.319 mmol) in THF (10 ml). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-16%) in heptane gave 0.582 g (73%) of the desired compound as a yellow oil. ESI/APCI(+): 276 (M+H).

Step 4. 1-(5-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1H-indol-3-yl)-2-phenylethanone was obtained according to the general procedure O from a solution of 5-(2-((tert- butyldimethylsilyl)oxy)ethyl)-1H-indole (0.580 g, 2.106 mmol) in dichloromethane (15 ml), a 1M solution of diethylaluminum chloride in hexane (2.740 ml, 2.740 mmol) and a solution of phenylacetyl chloride (0.365 ml, 2.739 mmol) in dichloromethane ( 2 ml). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-80%) in heptane gave 0.182 (22%) of the desired compound. ESI/APCI(+): 394 (M+H). ESI/APCI(-): 392 (M-H).

Step 5. 2-Bromo-1-(5-(2-hydroxyethyl)-1H-indol-3-yl)-2-phenylethanone was prepared according to general procedure P from a solution of 1-(5-(2-((tert-butyldimethylsilyl )oxy)ethyl)-1H-indol-3-yl)-2-phenylethanone (0.182 g, 0.462 mmol) in THF (3 ml) and phenyltrimethylammonium tribromide (0.191 g, 0.509 mmol). The reaction mixture was stirred at room temperature overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-100%) in heptane gave 0.083 g (50%) of the desired compound as a brown solid. ESI/APCI(+): 358, 360 (M+H). ESI/APCI(-): 356, 358 (M-H).

Step 6 2-((3,5-Dimethoxyphenyl)amino)-1-(5-(2-hydroxyethyl)-1H-indol-3-yl)-2-phenylethanone was prepared according to General Procedure E from 2-bromo-1 -(5-(2-hydroxyethyl)-1H-indol-3-yl)-2-phenylethanone (0.040 g, 0.112 mmol) and 3,5-dimethoxyaniline (0.086 g, 0.558 mmol) in acetonitrile (0.5 ml) irradiated in a microwave oven at 100°C for 15 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-100%) in heptane gave 0.032 g (65%) of the desired compound as a gray solid. ESI/APCI(+): 431 (M+H). ESI/APCI(-): 429 (M-H).

Example 332 Preparation of 2-((3,5-dimethoxyphenyl)amino)-2-(4-fluorophenyl)-1-(7-(2-hydroxyethyl)-1Nindol-3-yl)ethanone.

Stage 1. 1-(7-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1H-indol-3-yl)-2-(4-fluorophenyl)ethanone was obtained according to the general procedure O from a solution of 7-(2 -((tert-butyldimethylsilyl)oxy)ethyl)-1H-indole (0.434 g, 1.576 mmol) in dichloromethane (9 ml), 1M solution of diethylaluminum chloride in hexane (2.048 ml, 2.048 mmol) and 2-(4-fluorophenyl) acetyl chloride (0.353 g, 2.048 mmol) in dichloromethane (1 ml). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-100%) in heptane gave 0.149 g (23%) of the desired compound. ESI/APCI(+): 412 (M+H). ESI/APCI(-): 410 (M-H). 0.137 g (29%) of 2-(4-fluorophenyl)-1-(7-(2-hydroxyethyl)-1H-indol-3-yl)ethanone was also isolated.

Step 2. 2-Bromo-2-(4-fluorophenyl)-1-(7-(2-hydroxyethyl)-1H-indol-3-yl)ethanone was prepared according to general procedure P from a solution of 2-(4-fluorophenyl)- 1-(7-(2-hydroxyethyl)-1H-indol-3-yl)ethanone (0.137 g, 0.461 mmol) in THF (3 mL) and phenyltrimethylammonium tribromide (0.203 g, 0.540 mmol). The reaction mixture was stirred at room temperature overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30-100%) in heptane gave 0.097 g (56%) of the desired compound. ESI/APCI(+): 376, 378 (M+H). ESI/APCI(-): 374, 376 (M-H).

Step 3 2-((3,5-Dimethoxyphenyl)amino)-2-(4-fluorophenyl)-1-(7-(2-hydroxyethyl)-1H-indol-3yl)ethanone was prepared according to General Procedure E from 2 -bromo-2-(4-fluorophenyl)-1-(7-(2-hydroxyethyl)-1Nindol-3-yl)ethanone (0.050 g, 0.133 mmol) and 3,5-dimethoxyaniline (0.102 g, 0.665 mmol) in acetonitrile (0.5 ml), irradiated in a microwave oven at 100°C for 15 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-100%) in heptane gave 0.036 g (58%) of the desired compound as a solid. ESI/APCI(+): 449 (M+H). ESI/APCI(-): 447 (M-H). 1H NMR (DMSO-d6) δ 8.86 (1H, s); 8.01 (1H, d); 7.66 (2H, dd); 6.99-7.20 (4H, m); 6.35 (1H, d); 6.12 (1H, d); 6.05 (2H, d); 5.72 (1H, s); 3.69 (2H, t); 3.62 (6H, s); 3.02 (2H, t).

Example 333 Preparation of 3-(3-(2-((5-methoxypyridin-3-yl)amino)-2-phenylacetyl)-1H-indol-5-148040588yl)propyl acetate.

Step 1 3-(1H-Indol-5-yl)propyl acetate was prepared according to General Procedure Q from 3-(1H-indol-5yl)propan-1-ol (1.400 g, 7.989 mmol), DMAP (0.976 g, 8.185 mmol ) and acetic anhydride (1.900 ml, 20.14 mmol) in dichloromethane (150 ml). Purification by flash chromatography on silica gel using dichloromethane as eluent gave 1.590 g (92%) of the desired compound as a colorless oil. ESI/APCI(+): 218 (M+H).

Step 2 3-(3-Formyl-1H-indol-5-yl)propyl acetate was prepared according to General Procedure R from a solution of oxalyl chloride (0.800 ml, 9.139 mmol) in dichloromethane (40 ml), DMF (0.750 ml, 9.687 mmol) and a solution of 3-(1H-indol-5-yl)propyl acetate (1.590 g, 7.318 mmol) in dichloromethane (15 ml). The residue obtained after concentration of the organic phase under reduced pressure was dried to give 1.700 g (95%) of the desired compound as a beige solid, which was used without further purification. ESI/APCI(+): 246 (M+H). ESI/APCI(-): 244 (M-H).

Step 3 tert-Butyl 5-(3-acetoxypropyl)-3-formyl-1H-indole-1-carboxylate was prepared according to General Procedure F from 3-(3-formyl-1H-indol-5-yl)propyl acetate (1.710 g, 6.931 mmol), di-tert-butyl dicarboxylate (1.820 g, 8.339 mmol) and DMAP (0.090 g, 0.737 mmol) in acetonitrile (35 mL) to give 2.350 g (98%) of the desired product as a pale yellow solid. ESI/APCI(+): 346 (M+H). ¹ H NMR (DMSO-d6) δ 10.06 (1H, s); 8.63 (1H, s); 8.02 (1H, d); 7.98 (1H, s); 7.31 (1H, dd); 3.99 (2H, t); 2.76 (2H, t); 2.01 (3H, s); 1.92 (2H, m); 1.66 (9H, s).

Step 4 3-(3-(2-((5-Methoxypyridin-3-yl)amino)-2-phenylacetyl)-1H-indol-5-yl)propyl acetate was prepared according to General Procedure K from a mixture of 3-benzyl-5 - (2-hydroxyethyl) -4-methylthiazol-3-ium chloride (0.132 g, 0.489 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (0.5 ml), tert-butyl-5- (3acetoxypropyl) - 3-formyl-1H-indole-1-carboxylate (0.340 g, 0.984 mmol) and a solution of N-benzylidene-5methoxypyridine-3-amine (0.980 mmol) in ethanol (1 ml), heated at 60°C for 72 hours. Purification by flash chromatography on silica gel using a gradient of methanol (0-5%) in dichloromethane gave 0.224 g (50%) of the desired compound as a yellow oil. ESI/APCI(+): 458 (M+H). ESI/APCI(-): 456 (M-H).

Example 334 Preparation of 1-(5-(3-hydroxypropyl)-1H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2-phenylethanone

-(5-(3-Hydroxypropyl)-1 H-indol-3 -yl)-2-((5-methoxypyridin-3-yl)amino)-2-phenylethanone was obtained according to the general procedure S from a solution of 3-(3 -(2-(5-methoxypyridin-3-yl)amino)-2-phenylacetyl)1H-indol-5-yl)propyl acetate (0.224 g, 0.490 mmol) in THF (3 ml) and methanol (3 ml) and carbonate potassium (0.135 g, 0.977 mmol). The reaction mixture was heated at 45° C. for 3 hours. Purification by silica gel flash chromatography using a gradient of methanol (0-7%) in dichloromethane followed by precipitation from dichloromethane gave 0.072 g (35%) of the desired compound as a white solid. ESI/APCI(+): 416 (M+H). ESI/APCI(-): 414 (M-H).

Example 335 Preparation of 2-(3-fluorophenyl)-2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1Nindol-3-yl)ethanone

Step 1 2-(3-Fluorophenyl)-1-(1H-indol-3-yl)ethanone was prepared according to General Procedure O from a solution of 1H-indole (0.292 g, 2.492 mmol) in dichloromethane (15 mL), 1M diethylaluminum solution chloride in hexane (3.240 ml, 3.240 mmol) and a solution of 2-(3-fluorophenyl)acetyl chloride (0.559 g, 3.184 mmol) in dichloromethane (2 ml). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (10-80%) in heptane gave 0.459 g (73%) of the desired compound as a solid. ESI/APCI(+): 254 (M+H). ESI/APCI(-): 252 (M-H).

Step 2. 2-Bromo-2-(3-fluorophenyl)-1-(1H-indol-3-yl)ethanone was prepared according to general procedure P from a solution of 2-(3-fluorophenyl)-1-(1H-indol-3 -schftanone (0.459 g, 1.812 mmol) in THF (12 mL) and phenyltrimethylammonium tribromide (0.749 g, 1.994 mmol) Purification by silica gel flash chromatography using a gradient of ethyl acetate (10-80%) in heptane gave 0.466 g (77% ) of the desired compound as a brown solid ESI/APCI(+): 332.334 (M+H) ESI/APCI(-): 330.332 (M-H).

Step 3 To a solution of 2-bromo-2-(3-fluorophenyl)-1-(1H-indole-3-sphthanone (0.054 g, 0.164 mmol) and triethylamine (0.046 ml, 0.328 mmol) in acetonitrile (0.3 ml ) was added 2-(3-amino-5-methoxyphenoxy)ethanol (0.030 g, 0.164 mmol).The reaction mixture was stirred at room temperature for 4 days and concentrated under reduced pressure.The residue was purified by flash chromatography on silica gel using an ethyl acetate gradient ( 10-100%) in heptane Further purification by silica gel flash chromatography using a gradient of methanol (2-8%) in dichloromethane gave 0.030 g (42%) 2-(3-fluorophenyl)-2-((3-(2 -hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3yl)ethanone as a yellow solid.

ESI/APCI(+): 435 (M+H). ESI/APCI(-): 433 (M-H).

Example 336 Preparation of 2-(3-(2-(5-methoxypyrazin-2-yl)-2-((5-methoxypyridin-3-yl)amino)acetyl)-1H-indol-7-yl)ethyl acetate.

Step 1. A solution of 5-methoxy-N-((5-methoxypyrazin-2-yl)methylene)pyridine-3-amine in ethanol was prepared by heating a solution of 5-methoxypyrazine-2-carbaldehyde (0.130 g, 0.941 mmol) and 5-methoxypyridine- 3-amine (0.133 g, 1.071 mmol) in ethanol (0.5 ml) at 60°C for 16 hours. Formation

- 149 040588 imine was quantitative and the solution was used without further purification. ESI/APCI(+): 245 (M+H).

Step 2 2-(3-(2-(5-Methoxypyrazin-2-yl)-2-((5-methoxypyridin-3-yl)amino)acetyl)-1H-indol-7yl)ethyl acetate was prepared according to General Procedure L from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.717 ml, 0.500 mmol) in ethanol (1 ml), tert-butyl-7-( 2-acetoxyethyl)-3-formyl-1H-indole-1-carboxylate (0.331 g, 0.998 mmol) and a solution of 5-methoxy-N-((5-methoxypyrazin-2-yl)methylene)pyridine-3-amine (0.999 mmol) in ethanol (1 ml), heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of methanol (0-7%) in dichloromethane gave 0.281 g (59%) of the desired compound as a beige solid. ESI/APCI(+): 476 (M+H). ESI/APCI(-): 474 (M-H).

Example 337 Preparation of 1-(7-(2-hydroxyethyl)-1H-indol-3-yl)-2-(5-methoxypyrazin-2-yl)-2-((5methoxypyridin-3-yl)amino)ethanone.

-(7-(2-Hydroxyethyl)-1H-indol-3-yl)-2-(5-methoxypyrazin-2-yl)-2-((5-methoxypyridin-3-yl)amino)ethanone was obtained according to the general procedure S from a solution of 2-(3-(2-(5-methoxypyrazin-2-yl)-2-((5methoxypyridin-3-yl)amino)acetyl)-1H-indol-7-yl)ethyl acetate (0.280 g, 0.589 mmol) in a mixture of THF (4 ml) and methanol (4 ml) and potassium carbonate (0.163 g, 1.178 mmol). The reaction mixture was stirred at room temperature for 16 hours. Purification by silica gel flash chromatography using a gradient of methanol (1-10%) in dichloromethane gave 0.084 g (33%) of the desired compound as a solid. ESI/APCI(+): 434 (M+H). ESI/APCI(-): 432 (M-H). 1H NMR (DMSO-d6) δ 8.76 (1H, s); 8.53 (1H, s); 8.26 (1H, s); 8.02 (1H, d); 7.87 (1H, d); 7.55 (1H, d); 7.04-7.19 (2H, m); 6.85 (1H, s); 6.69 (1H, d); 6.37 (1H, d); 3.86 (3H, s); 3.66-3.77 (5H, m); 3.03 (2H, t).

Example 338 Preparation of 2-(3-(2-((5-methoxypyridin-3-yl)amino)-2-(pyrazolo[1,5-a]pyridin-2yl)acetyl)-1 H-indol-7- yl)ethyl acetate.

Stage 1. A solution of 5-methoxy-N-(pyrazolo[1,5-a]pyridin-2-ylmethylene)pyridine-3-amine in ethanol was obtained by heating a solution of pyrazolo[1,5-a]pyridine-2-carbaldehyde ( 0.139 g, 0.951 mmol) and 5-methoxypyridine-3-amine (0.121 g, 0.975 mmol) in ethanol (0.5 ml) at 60° C. for 5.5 h. Imine formation was quantitative and the solution was used without further purification. ESI/APCI(+): 253 (M+H).

Step 2. 2-(3-(2-((5-Methoxypyridin-3-yl)amino)-2-(pyrazolo[1,5-a]pyridin-2-yl)acetyl)-1Nindol-7-yl) ethyl acetate was prepared according to the general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.550 mmol) in ethanol (1 ml), t -butyl-7-(2-acetoxyethyl)-3-formyl-1H-indole-1-carboxylate (0.331 g, 0.998 mmol) and a solution of 5-methoxy-K-(pyrazolo[1,5-a]pyridine-2- ylmethylene)pyridine-3-amine (0.999 mmol) in ethanol (1 ml) heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of methanol (0-7%) in dichloromethane gave 0.130 g (27%) of the desired compound as a red oil. ESI/APCI(+): 484 (M+H). ESI/APCI(-): 482 (M-H).

Example 339 Preparation of 1-(7-(2-hydroxyethyl)-1H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)2-(pyrazolo[1,5-a]pyridine -2-yl)ethanone.

1-(7-(2-Hydroxyethyl)-1H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2-(pyrazolo[1,5-а]pyridin-2- yl)ethanone was prepared according to general procedure S from a solution of 2-(3-(2-((5-methoxypyridin-3yl)amino)-2-(pyrazolo[1,5-a]pyridin-2-yl)acetyl)-1H -indol-7-yl)ethyl acetate (0.130 g, 0.269 mmol) in THF (2 ml) and methanol (2 ml) and potassium carbonate (0.074 g, 0.538 mmol). The reaction mixture was stirred at room temperature for 16 hours. Purification by flash chromatography on silica gel using a gradient of methanol (1-10%) in dichloromethane gave 0.053 g (44%) of the desired compound as a solid. ESI/APCI(+): 442 (M+H). ESI/APCI(-): 440 (M-H). 1H NMR (DMSO-d ₆ ) δ 12.05 (1H, br s); 8.77 (1H, s); 8.60 (1H, d); 8.03 (1H, d); 7.89 (1H, d); 7.59 (1H, d); 7.51 (1H, d); 7.00-7.23 (3H, m); 6.766.91 (2H, m); 6.55-6.68 (2H, m); 6.42 (1H, d); 4.70 (1H, brs); 3.61-3.79 (5H, m); 3.01 (2H, t).

Example 340 Preparation of 2-(3-(2-(5-fluoropyridin-3-yl)-2-((5-methoxypyridin-3-yl)amino)acetyl)1 H-indol-7-yl)ethyl acetate.

Step 1 A solution of N-((5-fluoropyridin-3-yl)methylene)-5-methoxypyridin-3-amine in ethanol was prepared by heating a solution of 5-fluoronicotinaldehyde (0.125 g, 0.999 mmol) and 5-methoxypyridin-3-amine (0.124 g, 0.999 mmol) in ethanol (0.5 ml) at 60° C. for 4 h. Imine formation was quantitative and the solution was used without further purification.

Step 2 2-(3-(2-(5-Fluoropyridin-3-yl)-2-((5-methoxypyridin-3-yl)amino)acetyl)-1H-indol-7yl)ethyl acetate was prepared according to the general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.500 mmol) in ethanol (1 ml), tert-butyl-7-( 2-acetoxyethyl)-3-formyl-1H-indole-1-carboxylate (0.331 g, 0.998 mmol) and a solution of K-((5-fluoropyridin-3-yl)methylene)-5-methoxypyridine-3-amine (0.999 mmol ) in ethanol (1 ml) heated at 70°C for 2 days. Purification by precipitation from dichloromethane gave 0.254 g (55%) of the desired compound as a white solid. ESI/APCI(+): 463 (M+H). ESI/APCI(-): 461 (M-H).

Example 341 Preparation of 2-(5-fluoropyridin-3-yl)-1-(7-(2-hydroxyethyl)-1H-indol-3-yl)-2-((5-150 040588 methoxypyridin-3-yl) amino)ethanone.

2-(5-Fluoropyridin-3-yl)-1-(7-(2-hydroxyethyl)-1H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)ethanone was obtained according to the general procedure S from a solution of 2-(3-(2-(5-fluoropyridin-3-yl)-2-((5methoxypyridin-3-yl)amino)acetyl)-1H-indol-7-yl)ethyl acetate (0.190 g, 0.411 mmol) in a mixture of THF (3 ml) and methanol (3 ml) and potassium carbonate (0.114 g, 0.822 mmol). The reaction mixture was stirred at room temperature for 16 hours. Purification by flash chromatography on silica gel using a gradient of methanol (1-10%) in dichloromethane gave 0.074 g (43%) of the desired compound as a white solid. ESI/APCI(+): 421 (M+H). ESI/APCI(-): 419 (M-H). ¹ H NMR (DMSO-d6) δ 8.93 (1H, s); 8.79 (1H, s); 8.44 (1H, d); 8.02 (1H, d); 7.83-7.96 (2H, m); 7.55 (1H, d); 7.03-7.21 (2H, m); 6.79-6.93 (2H, m); 6.36 (1H, d); 3.65-3.79 (5H, m); 3.03 (2H, t).

Example 342 Preparation of 2-(3-(2-((5-methoxypyridin-3-yl)amino)-2-phenylacetyl)-1H-indol-5yl)ethyl acetate

Step 1 2-(1H-Indol-5-yl)ethyl acetate was prepared according to General Procedure Q from 2-(1H-indol-5yl)ethanol (2.310 g, 14.33 mmol), DMAP (3.500 g, 28.66 mmol ) and acetic anhydride (3.500 ml, 37.26 mmol) in dichloromethane (250 ml). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15-70%) in heptane gave 2.580 g (89%) of the desired compound as an oil.

Step 2 2-(3-Formyl-1H-indol-5-yl)ethyl acetate was prepared according to General Procedure R from a solution of oxalyl chloride (1.330 ml, 15.23 mmol) in dichloromethane (8 ml), DMF (1.180 ml, 15. 23 mmol) and a solution of 2-(1H-indol-5-yl)ethyl acetate (2.580 g, 12.69 mmol) in dichloromethane (20 ml). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (30-100%) in heptane gave 2.780 g (95%) of the desired compound as a beige solid. ESI/APCI(+): 232 (M+H); 254 (M + Na). ESI/APCI(-): 230 (M-H).

Step 3 tert-Butyl 5-(2-acetoxyethyl)-3-formyl-1H-indole-1-carboxylate was prepared according to General Procedure F from 2-(3-formyl-1H-indol-5-yl)ethyl acetate (2.780 g, 12.02 mmol), di-tert-butyl dicarbonate (2.150 g, 14.43 mmol) and DMAP (0.294 g, 2.406 mmol) in acetonitrile (50 ml). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane gave 3.940 (99%) of the desired compound as a beige solid. ESI/APCI(+): 354 (M+Na).

Step 4 2-(3-(2-((5-Methoxypyridin-3-yl)amino)-2-phenylacetyl)-1H-indol-5-yl)ethyl acetate was prepared according to general procedure K from a mixture of 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1.5 ml), tert-butyl-5-(2acetoxyethyl)-3-formyl- 1H-indole-1-carboxylate (0.331 g, 0.999 mmol) and a solution of N-benzylidene-5methoxypyridine-3-amine (0.996 mmol) in ethanol (1 ml), heated at 70° C. overnight. Purification by flash chromatography on silica gel using a gradient of methanol (1-10%) in dichloromethane gave 0.216 g (49%) of the desired compound as a solid. ESI/APCI(+): 444 (M+H). ESI/APCI(-): 442 (M-H).

Example 343 Preparation of 1-(5-(2-hydroxyethyl)-1H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)2-phenylethanone

1-(5-(2-Hydroxyethyl)-1H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2-phenylethanone was obtained according to the general procedure S from a solution of 2-(3- (2-((5-Methoxypyridin-3-yl)amino)-2-phenylacetyl)-1Nindol-5-yl)ethyl acetate (0.216 g, 0.487 mmol) in THF (5 ml) and methanol (5 ml) and potassium carbonate (0.135 g, 0.977 mmol). The reaction mixture was stirred at room temperature for 3 hours. Purification by silica gel flash chromatography using a gradient of methanol (1-10%) in dichloromethane followed by precipitation from acetonitrile gave 0.075 g (38%) of the desired compound as a beige solid. ESI/APCI(+): 402 (M+H). ESI/APCI(-): 400 (M-H). 1H NMR (DMSO-d6) δ 12.10 (1H, br s); 8.86 (1H, s); 8.02 (1H, s); 7.85 (1H, d); 7.66 (2H, d); 7.51 (1H, d); 7.38 (1H, d); 7.26-7.35 (2H, m); 7.17-7.25 (1H, m); 7.09 (1H, d); 6.79 (1H, s); 6.68 (1H, d); 6.17 (1H, d); 4.62 (1H, t); 3.72 (3H, s); 3.54-3.66 (2H, m); 2.80 (2H, t).

Example 344 Preparation of 2-(3-(2-(5-methoxypyrazin-2-yl)-2-((5-methoxypyridin-3-yl)amino)acetyl)-1H-indol-5-yl)ethyl acetate.

2-(3-(2-(5-Methoxypyrazin-2-yl)-2-((5-methoxypyridin-3-yl)amino)acetyl)-1H-indol-5-yl)ethyl acetate was obtained according to the general procedure K from mixtures of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1.5 ml), tert-butyl-5(2- acetoxyethyl)-3-formyl-1H-indole-1-carboxylate (0.331 g, 0.999 mmol) and a solution of 5-methoxy-N-((5methoxypyrazin-2-yl)methylene)pyridine-3-amine (0.999 mmol) in ethanol (1 ml) heated at 70°C overnight. Purification by flash chromatography on silica gel using a gradient of methanol (1-10%) in dichloromethane gave 0.311 g (65%) of the desired compound as a solid. ESI/APCI(+): 476 (M+H). ESI/APCI(-): 474 (M-H).

Example 345 Preparation of 1-(5-(2-hydroxyethyl)-1H-indol-3-yl)-2-(5-methoxypyrazin-2-yl)-2-((5methoxypyridin-3-yl)amino)ethanone.

1-(5-(2-Hydroxyethyl)-1H-indol-3-yl)-2-(5-methoxypyrazin-2-yl)-2-((5-methoxypyridin-3-yl)amino)ethanone was obtained according to the general procedure S from a solution of 2-(3-(2-(5-methoxypyrazin-2-yl)-2-((5

- 151 040588 methoxypyridin-3-yl)amino)acetyl)-1H-indol-5-yl)ethyl acetate (0.311 g, 0.654 mmol) in THF (7.5 ml) and methanol (7.5 ml) and potassium carbonate ( 0.181 g, 1.210 mmol). The reaction mixture was stirred at room temperature for 3 hours. Purification by silica gel flash chromatography using a gradient of methanol (1-10%) in dichloromethane followed by precipitation from acetonitrile gave 0.165 g (58%) of the desired compound as a beige solid. ESI/APCI(+): 434 (M+H). ESI/APCI(-): 432 (M-H). 1H NMR (DMSO-d6) δ 12.10 (1H, br s); 8.75 (1H, s); 8.52 (1H, s); 8.26 (1H, s); 8.01 (1H, s); 7.86 (1H, d); 7.56 (1H, d); 7.40 (1H, d); 7.11 (1H, d); 6.84 (1H, brs); 6.68 (1H, d); 6.33 (1H, d); 4.64 (1H, t); 3.86 (3H, s); 3.74 (3H, s); 3.55-3.67 (2H, m); 2.81 (2H, t).

Example 346 Preparation of 2-(3-(2-((5-methoxypyridin-3-yl)amino)-2-(pyrazolo[1,5-a]pyridin-2yl)acetyl)-1 H-indol-5 - yl)ethyl acetate.

2-(3-(2-((5-Methoxypyridin-3-yl)amino)-2-(pyrazolo[1,5-a]pyridin-2-yl)acetyl)-1H-indol-5yl)ethyl acetate was obtained according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1.5 ml), tert-butyl-5- (2-acetoxyethyl)-3-formyl-1H-indole-1-carboxylate (0.331 g, 0.999 mmol) and a solution of 5-methoxy-N-(pyrazolo[1,5-a]pyridin-2-ylmethylene)pyridin-3-amine (0.999 mmol) in ethanol (1 ml) heated at 70°C overnight. Purification by flash chromatography on silica gel using a gradient of methanol (1-10%) in dichloromethane gave 0.218 g (45%) of the desired compound as a solid. ESI/APCI(+): 484 (M+H). ESI/APCI(-): 482 (M-H).

Example 347 Preparation of 1-(5-(2-hydroxyethyl)-1H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)2-(pyrazolo[1,5-a]pyridine -2-yl)ethanone.

1-(5-(2-Hydroxyethyl)-1H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2-(pyrazolo[1,5-a]pyridin-2- yl)ethanone was prepared according to general procedure S from a solution of 2-(3-(2-((5-methoxypyridin-3yl)amino)-2-(pyrazolo[1,5-a]pyridin-2-yl)acetyl)-1H -indol-5-yl)ethyl acetate (0.218 g, 0.451 mmol) in THF (5 ml) and methanol (5 ml) and potassium carbonate (0.124 g, 0.904 mmol). The reaction mixture was stirred at room temperature for 3 hours. Purification by flash chromatography on silica gel using a gradient of methanol (1-10%) in dichloromethane followed by precipitation from ethanol gave 0.077 g (39%) of the desired compound as a pink solid. ESI/APCI(+): 442 (M+H). ESI/APCI(-): 440 (M-H). 1H NMR (DMSO-d6) δ 11.95 (1H, br s); 8.68 (1H, s); 8.52 (1H, d); 7.94 (1H, s); 7.81 (1H, d); 7.52 (1H, d); 7.44 (1H, d); 7.29 (1H, d); 7.04-7.15 (1H, m); 7.01 (1H, d); 6.68-6.83 (2H, m); 6.58 (1H, s); 6.52 (1H, d); 6.31 (1H, d); 4.55 (1H, t); 3.64 (3H, s); 3.46-3.58 (2H, m); 2.72 (2H, t).

Example 348 Preparation of 2-(3-(2-(4-fluorophenyl)-2-((5-methoxypyridin-3-yl)amino)acetyl)-1Nindol-7-yl)ethyl acetate.

Step 1 A solution of N-(4-fluorobenzylidene)-5-methoxypyridine-3-amine in ethanol was prepared by heating a solution of 4-fluorobenzaldehyde (0.120 g, 0.967 mmol) and 5-methoxypyridine-3-amine (0.121 g, 0.975 mmol) in ethanol (0.5 ml) at 60° C. for 20 hours. Imine formation was quantitative and the solution was used without further purification.

Step 2. 2-(3-(2-(4-Fluorophenyl)-2-((5-methoxypyridin-3-yl)amino)acetyl)-1H-indol-7-yl)ethyl acetate was obtained according to the general procedure K from a mixture 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1 ml), tert-butyl-7-( 2acetoxyethyl)-3-formyl-1H-indole-1-carboxylate (0.331 g, 0.998 mmol) and a solution of K-(4-fluorobenzylidene)-5-methoxypyridin-3-amine (0.999 mmol) in ethanol (1 ml), heated at 70°C for 2 days. Purification by flash chromatography on silica gel using a gradient of methanol (0-7%) in dichloromethane gave 0.191 g (41%) of the desired compound as a beige solid. ESI/APCI(+): 462 (M+H). ESI/APCI(-): 460 (M-H).

Example 349 Preparation of 2-(4-fluorophenyl)-1-(7-(2-hydroxyethyl)-1H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)ethanone

2-(4-Fluorophenyl)-1-(7-(2-hydroxyethyl)-1 H-indol-3 -yl)-2-((5-methoxypyridin-3-yl)amino)ethanone was obtained according to the general procedure S from a solution of 2-(3-(2-(4-fluorophenyl)-2-((5-methoxypyridin-3yl)amino)acetyl)-1H-indol-7-yl)ethyl acetate (0.190 g, 0.412 mmol) in a mixture of THF ( 3 ml) and methanol (3 ml) and potassium carbonate (0.114 g, 0.823 mmol). The reaction mixture was stirred at room temperature for 16 hours. Purification by flash chromatography on silica gel using a gradient of methanol (1-10%) in dichloromethane followed by purification by preparative HPLC (XBridge column; method 5) gave 0.038 g (22%) of the desired compound in the form of a yellow powder. ESI/APCI(+): 420 (M+H). ESI/APCI(-): 418 (M-H).

Example 350 Preparation of 4-(3-((2-(1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)-5-methoxyphenoxy)butanoic acid.

To a solution of ethyl 4-(3-((2-(1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)-5-methoxyphenoxy)butanoate (0.050 g, 0.103 mmol) in dioxane ( 3 ml) was added 1N. sodium hydroxide solution (0.308 ml, 0.308 mmol). The reaction mixture was stirred at room temperature for 4 days. Added 1n. hydrochloric acid solution and the reaction mixture were extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by preparative HPLC (XBridge column;

- 152 040588 method 2) followed by flash chromatography on silica gel using a gradient of methanol (1-7%) in dichloromethane gave 0.009 g (19%) 4-(3-((2-(1H-indol-3-yl )-2-oxo-1-phenylethyl)amino)-5-methoxyphenoxy)butanoic acid as a beige solid. ESI/APCI(+): 459 (M+H). ESI/APCI(-): 457 (M-H). ¹ H NMR (DMSO-d6) δ 12.14 (1H, br s); 8.89 (1H, s); 8.16 (1H, d); 7.63 (2H, d); 7.46 (1H, d); 7.25-7.35 (2H, m); 7.12-7.24 (3H, m); 6.31 (1H, d); 5.99-6.12 (3H, m); 5.71 (1H, s); 3.84 (2H, t); 3.61 (3H, s); 2.73 (1H, brs); 2.32 (2H, t); 1.86 (2H, m).

Example 351 Preparation of 2-(3-(2-((3,5-dimethoxyphenyl)amino)-2-(pyrazolo[1,5-a]pyridin-2-yl)acetyl)-1 H-indol-5- yl)ethyl acetate.

2-(3-(2-((3,5-Dimethoxyphenyl)αmino)-2-(nirαzolo[1,5-α]nurudin-2-yl)αcetyl)-1H-indol-5-yl)ethyl acetate was obtained according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (0.135 g, 0.500 mmol) and triethylamine (0.070 ml, 0.505 mmol) in ethanol (1.5 ml), tert-butyl- 5(2-acetoxyethyl)-3-formyl-1H-indole-1-carboxylate (0.331 g, 0.999 mmol) and 3,5-dimethoxy-N(pyrazolo[1,5-a]pyridin-2-ylmethylene)aniline solution (0.999 mmol) in ethanol (1 ml) heated at 70°C overnight. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in dichloromethane gave 0.250 g (50%) of the desired compound as an oil. ESI/APCI(+): 513 (M+H). ESI/APCI(-): 511 (M-H).

Example 352 Preparation of 2-((3,5-dimethoxyphenyl)amino)-1-(5-(2-hydroxyethyl)-1H-indol-3-yl)-2(pyrazolo[1,5-a]pyridine-2 -yl)ethanone.

2-((3,5-Dimethoxyphenyl)amino)-1-(5-(2-hydroxyethyl)-1H-indol-3-yl)-2-(pyrazolo[1,5-a]pyridin2-yl)ethanone was obtained according to the general procedure S from a solution of 2-(3-(2-((3,5-dimethoxyphenyl)amino)-2(pyrazolo[1,5-a]pyridin-2-yl)acetyl)-1H-indol-5- yl)ethyl acetate (0.250 g, 0.488 mmol) in THF (5 ml) and methanol (5 ml) and potassium carbonate (0.135 g, 0.977 mmol). The reaction mixture was stirred at room temperature for 3 hours. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15-70%) in dichloromethane followed by precipitation from ethanol gave 0.086 g (37%) of the desired compound as a beige solid. ESI/APCI(+): 471 (M+H). ESI/APCI(-): 469 (M-H). ¹ H NMR (DMSO-d6) δ 11.99 (1H, br s); 8.74 (1H, s); 8.58 (1H, d); 8.01 (1H, s); 7.59 (1H, d); 7.36 (1H, d); 7.00-7.20 (2H, m); 6.80 (1H, t); 6.64 (1H, s); 6.26 (2H, s); 6.09 (2H, s); 5.74 (1H, s); 4.62 (1H, t); 3.62 (6H, s); 3.58 (2H, m); 2.79 (2H, t).

Example 353 Preparation of 3-(3-(2-((5-methoxypyridin-3-yl)amino)-2-(pyrazolo[1,5-a]pyridin-2yl)acetyl)-1 H-indol-5 - yl) propyl acetate.

3-(3-(2-((5-Methoxypyridin-3-yl)amino)-2-(pyrazolo[1,5-a]pyridin-2-yl)acetyl)-1H-indol-5yl)propyl acetate was obtained according to general procedure K from a mixture of 3-benzyl-5-(2-hydroxyethyl)-4methylthiazol-3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (0.5 ml), t- butyl 5-(3-acetoxypropyl)-3-formyl-1H-indole-1-carboxylate (0.353 g, 1.022 mmol) and a solution of 5-methoxy-N-(pyrazolo[1,5-a]pyridin-2-ylmethylene )pyridine-3-amine (0.951 mmol) in ethanol (2 ml) heated at 60°C for 72 h. Purification by flash chromatography on silica gel using a gradient of methanol (0-5%) in dichloromethane gave 0.233 g (46 %) of the desired compound as a brown solid. ESI/APCI(+): 498 (M+H). ESI/APCI(-): 496 (M-H).

Example 354 Preparation of 1-(5-(3-hydroxypropyl)-1H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2-(pyrazolo[1,5-a] pyridin-2-yl)ethanone.

To a solution of 3-(3-(2-((5-methoxypyridin-3-yl)amino)-2-(pyrazolo[1,5-a]pyridin-2-yl)acetyl)-1Nindol-5-yl)propyl acetate (0.233 g, 0.468 mmol) in a mixture of methanol (3 ml), THF (3 ml) and water (0.5 ml) was added potassium carbonate (0.135 g, 0.977 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed with citric acid buffer (pH 5). The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (0-7%) in dichloromethane followed by purification by preparative HPLC (XBridge column; method 3) gave 0.040 g (19%) 1-(5-(3-hydroxypropyl)-1H- indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)-2(pyrazolo[1,5-a]pyridin-2-yl)ethanone as a beige solid. ESI/APCI(+): 456 (M+H). ESI/APCI(-): 454 (M-H).

Example 355 Preparation of 3-(3-(2-(5-methoxypyrazin-2-yl)-2-((5-methoxypyridin-3-yl)amino)acetyl)-1H-indol-5-yl)propyl acetate.

3-(3-(2-(5-Methoxypyrazin-2-yl)-2-((5-methoxypyridin-3-yl)amino)acetyl)-1H-indol-5-yl)propyl acetate was obtained according to the general procedure K from mixtures of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol3-ium chloride (0.135 g, 0.500 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (0.5 ml), tert-butyl-5-(3 -acetoxypropyl)-3-formyl-1H-indole-1-carboxylate (0.340 g, 0.984 mmol) and a solution of 5methoxy-N-((5-methoxypyrazin-2-yl)methylene)pyridine-3-amine (0.941 mmol) in ethanol (1 ml) heated at 60° C. for 48 h. Purification by flash chromatography on silica gel using a gradient of methanol (0-5%) in dichloromethane gave 0.397 g (64%) of the desired compound as a brown solid. ESI/APCI(+): 490 (M+H). ESI/APCI(-): 488 (M-H).

- 153 040588

Example 356 Preparation of 1-(5-(3-hydroxypropyl)-III-indol-3-yl)-2-(5-methoxypyrazin-2-yl)-2-((5methoxypyridin-3-yl)amino)ethanone.

1-(5-(3-Thydroxypropyl)-III-indol-3-yl)-2-(5-methoxypyrazin-2-yl)-2-((5-methoxypyridin-3yl)amino)ethanone was obtained according to the general procedure S from solution 3-(3-(2-(5-methoxypyrazin-2-yl)-2((5-methoxypyridin-3-yl)amino)acetyl)-1H-indol-5-yl)propyl acetate (0.297 g, 0.607 mmol) in THF (4 ml) and methanol (4 ml) and potassium carbonate (0.171 g, 1.237 mmol). The reaction mixture was heated at 45° C. for 5 hours. Purification by flash chromatography on silica gel using a gradient of methanol (0-10%) in dichloromethane gave 0.090 g (33%) of the desired product as a pale yellow solid. ESI/APCI(+): 448 (M+H).

Example 357 Preparation of 2-((3,5-dimethoxyphenyl)amino)-1-(7-(2-(methylsulfonyl)ethyl)-1H-indol3-yl)-2-phenylethanone

Step 1: Triethylamine (0.065 ml, 0.498 mmol) and mesyl chloride (0.028 ml, 0.468 mmol). The reaction mixture was stirred at room temperature for 5 hours. Water was added and the phases were separated. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give quantitatively 2-(3-(2-phenylacetyl)-1H-indol-7-yl)ethyl methanesulfonate which was used without further purification . ESI/APCI(+): 358 (M+H).

To a solution of 2-(3-(2-phenylacetyl)-1H-indol-7-yl)ethylmethanesulfonate (0.319 mmol) in methanol (3.6 ml) was added sodium thiomethoxide (0.045 g, 0.642 mmol). After 18 hours at room temperature, sodium thiomethoxide (0.045 g, 0.642 mmol) was added again. The reaction mixture was stirred at room temperature for 8.5 hours. After sodium thiomethoxide (0.018 g, 0.257 mmol) was added, stirring was continued at room temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (15-50%) in heptane gave 0.041 g (42%) of 1-(7-(2-(methylthio)ethyl)-1H-indol-3-yl)-2-phenylethanone in the form of a white powder. ESI/APCI(+): 310 (M+H). ESI/APCI(-): 308 (M-H).

Step 2 To a solution of 1-(7-(2-(methylthio)ethyl)-1H-indol-3-yl)-2-phenylethanone (0.087 g, 0.236 mmol) in dichloromethane (1 ml) cooled to 0°C , 3-chloroperoxybenzoic acid (0.125 g, 0.507 mmol) was added in portions. After 2 hours at room temperature, 3-chloroperoxybenzoic acid (0.040 g, 0.174 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (40-90%) in heptane gave 0.037 g (46%) of 1-(7-(2(methylsulfonyl)ethyl)-1H-indol-3-yl)-2-phenylethanone in the form of a white powder.

ESI/APCI(+): 342 (M+H); 364 (M + Na). ESI/APCI(-): 340 (M-H).

Step 3 To a solution of 1-(7-(2-(methylsulfonyl)ethyl)-1H-indol-3-yl)-2-phenylethanone (0.037 g, 0.108 mmol) in THF (1.3 ml) cooled to 0 °C, a solution of phenyltrimethylammonium tribromide (0.058 g, 0.154 mmol) in THF (1.6 ml) was added. The reaction mixture was stirred at 0° C. for 1 h and at room temperature for 4 h. 3,5-dimethoxyaniline (0.167 g, 1.090 mmol) was added. The reaction mixture was refluxed for 3 hours and stirred overnight at room temperature. The reaction mixture was filtered and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was divided between ethyl acetate and 1N. hydrochloric acid solution. The phases were separated. The organic phase was washed with saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using ethyl acetate (40-90%) in heptane gave 0.035 g (66%) 2-((3,5-dimethoxyphenyl)amino)-1-(7-(2(methylsulfonyl)ethyl)- 1H-indol-3-yl)-2-phenylethanone as a beige powder. ESI/APCI(+): 493 (M+H); 515 (M+Na). ESI/APCI(-): 491 (MH). ¹ H NMR (DMSO-d6) δ 12.22 (1H, br s); 8.93 (1H, s); 8.06 (1H, t); 7.63 (2H, m); 7.26 (2H, m); 7.13-7.20 (3H, m); 6.35 (1H, d); 6.11 (1H, d); 6.06 (2H, s); 5.71 (1H, s); 3.61 (6H, s); 3.47 (2H, m); 3.33 (2H, m); 3.02 (3H, s).

Example 358 Preparation of 2-((3,5-dimethoxyphenyl)amino)-2-(4-fluorophenyl)-1-(5-(3-hydroxypropyl)1 H-indol-3-yl)ethanone.

Step 1. 1-(5-(3-((tert-Butyldimethylsilyl)oxy)propyl)-1H-indol-3-yl)-2-(4-fluorophenyl)ethanone was obtained according to the general procedure O from a solution of 5-(3 -((tert-butyldimethylsilyl)oxy)propyl)-1Hindole (0.130 g, 0.449 mmol) in dichloromethane (2.5 ml), 1M solution of diethylaluminum chloride in hexane (0.584 ml, 0.584 mmol) and a solution of 2-(4-fluorophenyl )acetyl chloride (0.101 g, 0.584 mmol) in dichloromethane (1 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-100%) in heptane gave 0.042 g (22%) of the desired compound. ESI/APCI(+): 426 (M+H). ESI/APCI(-): 424 (M-H).

Step 2. 2-Bromo-2-(4-fluorophenyl)-1-(5-(3-hydroxypropyl)-1H-indol-3-yl)ethanone was prepared according to the general procedure R from a solution of 1-(5 -(3-((tert-butyldimethylsilyl)oxy)propyl)-1H-indol-3-yl)2-(4-fluorophenyl)ethanone (0.042 g, 0.099 mmol) in THF (1 ml) and phenyltrimethylammonium tribromide (0.045 g , 0.118 mmol). Purification by flash chromatography on silica gel using a gradient of methanol (110%) in dichloromethane gave 0.020 g (52%) of the desired compound. ESI/APCI(+): 390, 392 (M+H).

ESI/APCI(-): 388, 390 (M-H).

Step 3 2-((3,5-Dimethoxyphenyl)amino)-2-(4-fluorophenyl)-1-(5-(3-hydroxypropyl)-1H-indol-3yl)ethanone was prepared according to General Procedure E from 2- bromo-2-(4-fluorophenyl)-1-(5-(3-hydroxypropyl)1H-indol-3-yl)ethanone (0.020 g, 0.051 mmol) and 3,5-dimethoxyaniline (0.039 g, 0.256 mmol) in acetonitrile (0.5 ml), irradiated in a microwave oven at 100°C for 15 min. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (20-100%) in heptane gave 0.008 g (34%) of the desired compound as a solid. ESI/APCI(+): 463 (M+H). ESI/APCI(-): 461 (M-H).

Example 359 Preparation of 3-(3-(2-(4-fluorophenyl)-2-((5-methoxypyridin-3-yl)amino)acetyl)-1Hindol-5-yl)propyl acetate

3-(3-(2-(4-Fluorophenyl)-2-((5-methoxypyridin-3-yl)amino)acetyl)-1H-indol-5-yl)propyl acetate was prepared according to general procedure K from a mixture of 3-benzyl -5-(2-hydroxyethyl)-4-methylthiazol-3-yl chloride (0.133 g, 0.486 mmol) and triethylamine (0.100 ml, 0.717 mmol) in ethanol (0.5 ml), tert-butyl-5-(3acetoxypropyl )-3-formyl-1H-indole-1-carboxylate (0.350 g, 1.013 mmol) and a solution of N-(4fluorobenzylidene)-5-methoxypyridine-3-amine (0.967 mmol) in ethanol (1 ml), heated at 60 ° C for 24 hours Purification by flash chromatography on silica gel using a gradient of methanol (0-5%) in dichloromethane gave 0.193 g (40%) of the desired compound as a brown oil. ESI/APCI(+): 476 (M+H). ESI/APCI(-): 474 (M-H).

Example 360 Preparation of 2-(4-fluorophenyl)-1-(5-(3-hydroxypropyl)-1H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)ethanone

2-(4-Fluorophenyl)-1-(5-(3-hydroxypropyl)-1H-indol-3-yl)-2-((5-methoxypyridin-3-yl)amino)ethanone was prepared according to the general procedure S from 3 -(3-(2-(4-fluorophenyl)-2-((5-methoxypyridin-3yl)amino)acetyl)-1H-indol-5-yl)propyl acetate (0.193 g, 0.406 mmol) in THF mixture (3 ml ) and methanol (3 ml) and potassium carbonate (0.117 g, 0.847 mmol). The reaction mixture was heated at 45° C. for 5 hours. Purification by silica gel flash chromatography using a gradient of methanol (0-5%) in dichloromethane followed by precipitation from dichloromethane gave 0.027 g (15%) of the desired product as a white solid. ESI/APCI(+): 434 (M+H). ESI/APCI(-): 432 (M-H).

Example 361 Preparation of 2-((3,5-dimethoxyphenyl)amino)-2-(4-fluorophenyl)-1-(5-(2-hydroxyethyl)-1Nindol-3-yl)ethanone.

Step 1. 2-(4-Fluorophenyl)-1-(5-(2-hydroxyethyl)-1H-indol-3-yl)ethanone was prepared according to the general procedure O from 5-(2-((tert-butyldimethylsilyl)oxy) ethyl)-1H-indole (0.430 g, 1.561 mmol) in dichloromethane (5 ml), a 1M solution of diethylaluminum chloride in hexane (0.322 ml, 0.322 mmol) and a solution of 2-(4fluorophenyl)acetyl chloride (0.322 ml, 2.351 mmol) in dichloromethane (5 ml). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-70%) in heptane gave 0.062 (13%) of the desired compound. ESI/APCI(+): 298 (M+H). ESI/APCI(-): 296 (M-H).

Step 2 To a solution of 2-(4-fluorophenyl)-1-(5-(2-hydroxyethyl)-1H-indol-3-yl)ethanone (0.060 g, 0.202 mmol) in THF (2.5 ml), chilled to 0°C, a solution of phenyltrimethylammonium tribromide (0.106 g, 0.282 mmol) in THF (2.5 ml) was added. The reaction mixture was stirred at 0° C. for 1 h and at room temperature for 5 h. 3,5-Dimethoxyaniline (0.309 g, 2.021 mmol) was added and the reaction mixture was refluxed for 2 h. After cooling to room temperature added 1n. hydrochloric acid solution and the reaction mixture were extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in dichloromethane followed by purification by preparative HPLC (XBridge column; method 2) gave 0.025 g (28%) 2-((3,5dimethoxyphenyl)amino)-2-(4 -fluorophenyl)-1-(5-(2-hydroxyethyl)-1H-indol-3-yl)ethanone as a white solid. ESI/APCI(+): 449 (M+H). ESI/APCI(-): 447 (M-H). ¹ H NMR (DMSO-d6) δ 12.07 (1H, br s); 8.84 (1H, d); 7.99 (1H, s); 7.59-7.72 (2H, m); 7.36 (1H, d); 7.02-7.19 (3H, m); 5.98-6.13 (3H, m); 5.74 (1H, s); 3.62 (6H, s); 3.52-3.60 (2H, m); 2.78 (2H, t).

Without limitation, the following are examples of compounds of the present invention that can be prepared using such protocols as described herein:

4-(3-((1-(4,6-dimethylpyridin-3-yl)-2-(1H-indol-3-yl)-2-oxoethyl)amino)-5-methoxyphenyl)butanoic acid;

2-(6-(hydroxymethyl)pyridin-3-yl)-1-(1H-indol-3-yl)-2-((3-methoxy-5-(2-(methylsulfonyl)ethyl)phenyl)amino)ethanone ;

2-((3,5-dimethoxyphenyl)amino)-1-(5-fluoro-7-(2-hydroxyethyl)-1H-indol-3-yl)-2-(tetrahydrofuran3-yl)ethanone;

2-((3,5-dimethoxyphenyl)amino)-1-(5-((methylsulfonyl)methyl)-1H-indol-3-yl)-2-(tetrahydro-2Hpyran-4-yl)ethanone;

- 155 040588

2-((3,5-dimethoxyphenyl)amino)-1 -(5-(3-(dimethylamino)propyl)-1 H-indol-3-yl)-2-(3,5-dimethylisoxazol-4-yl) ethanone;

2-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-(7-(3-aminopropyl)-III-indol-3-yl)-2-((3 ,5-dimethoxyphenyl)amino)ethanone;

2-(benzo[d]isoxazol-3-yl)-2-((3,5-dimethoxyphenyl)amino)-1-(7-(3-hydroxypropyl)-1H-indol-3yl)ethanone;

3-(3-(2-((3,5-dimethoxyphenyl)amino)-2-(5-phenylisoxazol-3-yl)acetyl)-III-indol-5-yl)propanoic acid;

-(5-(2-aminoethyl)-1H-indol-3-yl)-2-((3,5-dimethoxyphenyl)amino)-2-(5-methyl-1-phenyl-1H-pyrazole-3- yl) ethanone;

1-methyl-4-((2-(5-(2-(methylsulfonyl)ethyl)-1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)pyrrolidin-2-one;

1-(III-indol-3-yl)-2-((3-methoxy-5-((methylamino)methyl)phenyl)amino)-2-(3-methyl-3H-imidazo[4,5b]pyridine- 2-yl)ethanone;

2-(6,7-dihydro-4H-pyrano[3,4-d]thiazol-2-yl)-2-((3-(2-hydroxyethyl)-5-methoxyphenyl)amino)-1-(1Hindole- 3-yl)ethanone;

2-((3 -(2-aminoethoxy)-5-methoxyphenyl)amino)-1 -(1 H-indol-3-yl)-2-(1-methyl-1 H-benzo[d]imidazol2-yl) ethanone;

2-(benzo[d]thiazol-2-yl)-1-(1 H-indol-3-yl)-2-((3-methoxy-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl )amino)ethanone;

2-((3-(difluoromethoxy)phenyl)amino)-1-(1H-indol-3-yl)-2-(thiazolo[4,5-b]pyrazin-2-yl)ethanone;

2-(3-((1-(benzo[b]thiophen-2-yl)-2-(1H-indol-3-yl)-2-oxoethyl)amino)-5-methoxyphenyl)acetic acid;

2-((3-(3-aminopropoxy)-5-methoxyphenyl)amino)-1-(1H-indol-3-yl)-2-(thieno[2,3-b]pyridin-2yl)ethanone;

1-(5-(aminomethyl)-1H-indol-3-yl)-2-((3,5-dimethoxyphenyl)amino)-2-(thiazolo[5,4-c]pyridin-2yl)ethanone;

1-(7-(aminomethyl)-1H-indol-3-yl)-2-((3,5-dimethoxyphenyl)amino)-2-(thiazolo[4,5-c]pyridin-2yl)ethanone;

1-(5-(2-aminoethyl)-1H-indol-3-yl)-2-((3,5-dimethoxyphenyl)amino)-2-(thiazolo[4,5-b]pyridin-2yl)ethanone;

1-(1H-indol-3-yl)-2-((3-methoxy-5-(2-(methylsulfonyl)ethoxy)phenyl)amino)-2-(5-methyl-4,5,6,7tetrahydropyrazolo[ 1,5-a]pyrazin-2-yl)ethanone;

2-((3,5-dimethoxyphenyl)amino)-1-(III-indol-3-yl)-2-(5-methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine- 2-yl)ethanone;

2-((3,5-dimethoxyphenyl)amino)-1-(7-(2-hydroxyethyl)-1H-indol-3-yl)-2-(para-tolyl)ethanone;

2-(4-fluorophenyl)-2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(7-(2-hydroxyethyl)-1H-indol3-yl)ethanone;

2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(5-(2-hydroxyethyl)-1H-indol-3-yl)-2-phenylethanone;

2-((3,5-dimethoxyphenyl)amino)-1-(5-(2-(dimethylamino)ethyl)-1H-indol-3-yl)-2-(4-fluorophenyl)ethanone;

2-((3,5-dimethoxyphenyl)amino)-2-(4-fluorophenyl)-1-(5-(2-hydroxyethyl)-1-methyl-1H-indazol-3yl)ethanone;

2-(4-fluorophenyl)-2-((3-(2-hydroxyethoxy)-5-methoxyphenyl)amino)-1-(1-methyl-1H-indazol-3yl)ethanone;

2-((3,5-dimethoxyphenyl)amino)-1-(5-(2-hydroxyethyl)-1-methyl-1H-indazol-3-yl)-2-(pyrazolo[1,5а]pyridine-2- yl) ethanone;

2-(4-fluorophenyl)-1-(1 H-indol-3-yl)-2-((3-methoxy-5-((methylsulfonyl)methyl)phenyl)amino)ethanone;

2-((3,5-dimethoxyphenyl)amino)-2-(3-methylpyridin-2-yl)-1-(7-((methylsulfonyl)methyl)-1 H-indol3-yl)ethanone and

3-(3-(2-(6-cyanopyridin-2-yl)-2-((3,5-dimethoxyphenyl)amino)acetyl)-1H-indol-5-yl)propanoic acid.

Part B.

Example 362 Antiviral activity of the compounds of the invention.

For dengue virus: Vero-B cells (5×10 ⁴ ) were seeded in 96-well plates. One day later, the culture medium was replaced with 100 µl of assay medium containing a 2x serial dilution of the compound (concentration range: 50-0.004 µg/ml) and 100 µl of dengue virus (DENV) inoculum. After a 2 hour incubation period, the cell monolayer was washed 3 times with assay medium to remove residual unadsorbed virus and the cultures were further incubated for 4 days (DENV-2 NGC), 5 days (DENV-4, Dak HD 34460 strain) or 7 or 8 days (DENV-1, strain

- 156 040588

Djibouti D1/H/IMTSSA/98/606 and DENV-3, prototype strain H87) in the presence of an inhibitor. The supernatant was collected and viral RNA load was determined by quantitative real-time RT-PCR. The 50% effective concentration (EC ₅₀ ), defined as the concentration of a compound required to inhibit viral RNA replication by 50%, was determined using logarithmic interpolation.

The antiviral activity of the compounds against DENV-2 NGC was also tested on adenocarcinoma cells of the human alveolar basal epithelium (A549 cells) using the protocol described above, with the difference that fewer cells were plated per well (2x10 ⁴ cells/well).

For yellow fever virus: Vero-B cells (5x10 ⁴ ) were seeded in 96-well plates. One day later, the culture medium was replaced with 100 µl of assay medium containing 2x serial dilution of the compound (concentration range: 50-0.004 µg/ml) and 100 µl of yellow fever virus (YFV-17D) inoculum. After a 2 hour incubation period, the cell monolayer was washed 3 times with assay medium to remove residual unadsorbed virus, and the cultures were further incubated for 4 days in the presence of an inhibitor. The supernatant was collected and viral RNA load was determined by quantitative real-time RT-PCR. The 50% effective concentration (EC ₅₀ ), defined as the concentration of a compound required to inhibit viral RNA replication by 50%, was determined using logarithmic interpolation.

Quantitative reverse transcriptase PCR (RT-qPCR).

RNA was isolated from 100 μl (or in some cases 150 μl) of the supernatant using the NucleoSpin 96 Virus kit (Macherey-Nagel, Duren, Germany) as described by the manufacturer. TaqMan primer sequences (DENV-For, DENV-Rev, YFV-For, YFV-Rev; Table 2) and TaqMan probes (DENV-Probe and YFV-Probe; Table 2) were selected from non-structural gene 3 (NS3) or NS5 corresponding flaviviruses using Primer Express software (version 2.0; Applied Biosystems, Lennik, Belgium). The TaqMan probe was fluorescently labeled with 6-carboxyfluorescein (FAM) at the 5' end as a reporter dye and with minor groove binding protein (MGB) at the 3' end as a quencher (Table 2). One-step quantitative RT-PCR was performed in a total volume of 25 µl containing 13.9375 µl H ₂ O, 6.25 µl master mix (Eurogentec, Seraing, Belgium), 0.375 µl forward primer, 0.375 µl reverse primer, 1 µl sample, 0.0625 µl reverse transcriptase (Eurogentec) and 3 µl sample. RT-PCR was performed using the ABI 7500 rapid real-time PCR system (Applied Biosystems, Branchburg, New Jersey, USA) under the following conditions: 30 min at 48°C and 10 min at 95°C, followed by 40 cycles of 15 s at 95°C and 1 min at 60°C. Data were analyzed using ABI PRISM 7500 SDS software (version 1,3,1; Applied Biosystems). For absolute quantitation, calibration curves were prepared using 10-fold dilutions of standard preparations of known concentrations.

Table 2. Primers and probes used for real-time RT-PCR

Primer/Sample Sequence (5'->3') ^a Source ¹⁵ Target DENV-For TCGGAGCCGGAGTTTACAAA (SEQ ID N.I) DENV 2 NGC NS3 DENV-Rev TCTTAACGTCCGCCCATGAT (SEQ ID N.2) DENV Probe K4M-ATTCCACACAATGTGGCAT- MGB (SEQ ID N.3) DenS GGATAGACCAGAGATCCTGCTGT (SEQ ID N.4) DENV-1, -3, -4 NS5 DenASl-3 CATTCCATTTTCTGGCGTTC (SEQ ID N.5) DENV-1, -3 DenAS4 CAATCCATCTTGCGGCGCTC (SEQ ID N.6) DENV-4 DEN_l-3 probe ΕΛΛ/CAGCATCATTCCAGGCACAG MGB (SEQ ID N.7) DENV-1, -3 DEN_4 probe K4M-CAACATCAATCCAGGCACAG- MGB (SEQ ID N.8) DENV-4 YFV For TGGCATATTCCAGTCAACCTTCT (SEQ IDN.9) YFV-17D NS3 YFV-Rev GAAGCCCAAGATGGAATCAACT (SEQ IDN.10) YFV Probe K4M-TTCCACACAATGTGGCATGMGB (SEQ ID N il)

a Reporter dye (FAM) and quencher (MGB/TAMRA) elements are shown in bold and italics.

^b The nucleotide sequence and position of primers and probes within the genome were derived from the nucleotide sequence of DENV 2 NGC (GenBank accession number M29095; Irie et al., 1989), dengue virus, serotype 1, strain Djibouti Dl/H/IMTSSA/98/606 ( GenBank accession number AF298808), dengue virus serotype 3, prototype strain H87 (c93130), dengue virus serotype 4, strain Dak HD 34460 (partial only, unpublished sequences available), and YFV-17D (GenBank accession number

- 157 040588

X03700; Rice et al., 1985).

Cytotoxicity assay.

The possible cytotoxic effects of the compounds were evaluated on uninfected resting Vero-B cells. Cells were seeded at 5x10 ⁴ cells/well in a 96-well plate in the presence of two-fold serial dilutions (range 50-0.004 μg/ml) of the compound and incubated for 4 days. The culture medium was removed and 100 µl of 3-(4,5dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium phenazine methosulfate (MTS/PMS;

Promega, Leiden, The Netherlands) on PBS. After a 2 hour incubation period at 37° C. at 498 nm, the absorbance was determined. Cytotoxic activity was calculated using the following formula:

% cell viability = 100χ(OD _compound /OD _CC ), where ODc _Compound and ODcc correspond to the optical density at 498 nm of uninfected cell cultures treated with the compound and the optical density of uninfected untreated cell cultures, respectively. The 50% cytotoxic concentration (ie the concentration that reduces the total number of cells by 50%; CC ₅₀ ) was calculated using linear interpolation.

A similar protocol was used to determine cytotoxicity on A549 cells, with the difference that the cells were seeded at 2x10 ⁴ cells/well.

In table. 3 shows anti-DENV-2 activity on Vero-B cells and cytotoxicity of some exemplary compounds of the present invention.

- 158 040588

Table 3

Code EC ₅ o (mkM) CC ₅ o (mkM) SI Code EC50 (mkM) CC50 (mkM) SI CPD-001 0 08 29 380 CPD-036 0.04 14 333 CPD-002 0 01 16 2307 CPD-037 1.20 19 16 CPD-003 0 11 13 114 CPD-039 2.48 15 6 CPD-004 0 19 eleven 57 CPD-040 4.24 > 129 > 30 CPD-005 0 93 5 6 CPD-041 0.50 14 29 CPD-006 0 75 6 8 CPD-042 12 51 > 138 > 11 CPD-007 253 5 2 CPD-043 0.29 > 126 >440 CPD-008 242 12 5 CPD-044 6 48 65 10 CPD-009 066 4 7 CPD-045 006 > 139 >2183 CPD-010 007 18 244 CPD-046 0 65 17 26 CPD-011 166 23 14 CPD-047 0 42 16 39 CPD-012 0 05 14 297 CPD-048 2.09 > 115 > 54 CPD-013 0.002 9 5726 CPD-049 0.08 > 134 > 1642 CPD-014 0 02 8 354 CPD-050 2.40 87 36 CPD-015 0 02 22 1065 CPD-051 2.47 > 125 > 51 CPD-016 5 01 54 eleven CPD-052 3.72 52 14 CPD-018 0 37 19 52 CPD-053 0.02 18 774 CPD-019 0 14 71 514 CPD-054 2.09 > 115 > 54 CPD-020 0 14 16 114 CPD-055 007 50 759 CPD-021 1 62 > 115 > 70 CPD-056 0 45 > 139 > 312 CPD-022 12 80 77 6 CPD-057 605 15 2 CPD-023 0 30 16 53 CPD-058 2 85 64 22 CPD-024 0 50 14 27 CPD-059 1.25 16 13 CPD-025 0 68 48 69 CPD-060 10 33 > 113 > 10 CPD-026 17 19 > 138 > 8 CPD-061 1.71 59 34 CPD-027 0 13 15 111 CPD-062 0.58 > 134 >230 CPD-028 135 17 > 144 > 1 CPD-063 14 33 > 134 > 9 CPD-029 0 84 65 78 CPD-064 8.75 72 8 CPD-030 009 > 126 > 1412 CPD-065 12 10 90 7 CPD-031 50 19 > 145 >2 CPD-066 6 32 95 15 CPD-032 55 53 > 146 >2 CPD-067 0 04 20 546 CPD-033 9 15 71 8 CPD-068 1 32 12 9 CPD-034 46 49 > 151 > 3 CPD-069 2 13 71 33 CPD-035 2 11 14 7 CPD-070 3.27 90 27

- 159 040588

Code EC ₅ o (mkM) CC50 (mkM) SI Code EC50 (mkM) CC50 (mkM) SI CPD-071 60.85 135 2 CPD-109 0.53 84 159 CPD-072 6.84 68 10 CPD-110 0.58 73 127 CPD-073 2.35 76 32 CPD-111 0.44 > 115 >263 CPD-074 0.81 77 95 CPD-112 3.27 12 4 CPD-075 1.52 102 67 CPD-113 0.49 > 112 >232 CPD-076 3 77 115 31 CPD-114 1 10 52 48 CPD-077 0 04 13 313 CPD-115 10 58 49 5 CPD-078 11 64 109 9 CPD-116 0 14 13 88 CPD-080 0.99 > 124 > 125 CPD-117 3.57 > 133 > 37 CPD-081 10.76 50 5 CPD-118 0.01 13 943 CPD-082 61.85 109 2 CPD-119 0.03 13 372 CPD-083 0.03 26 941 CPD-120 0.02 eleven 674 CPD-084 0.03 > 127 >4185 CPD-121 5.76 60 10 CPD-085 0.07 16 227 CPD-122 0.02 16 785 CPD-086 0.04 12 329 CPD-123 0.05 15 337 CPD-087 0.80 > 128 > 161 CPD-124 0.56 3 5 CPD-088 2.53 > 121 >48 CPD-125 7.19 > 138 > 19 CPD-089 0.67 > 139 >208 CPD-126 0.07 16 241 CPD-090 2.90 13 5 CPD-127 2.15 72 33 CPD-092 0.10 19 184 CPD-128 0.56 63 113 CPD-093 16.79 87 5 CPD-129 1.09 > 108 > 99 CPD-094 0.14 eleven 77 CPD-130 0.03 15 749 CPD-096 2.90 > 121 >42 CPD-131 0.01 13 1779 CPD-097 2.32 12 5 CPD-132 0.05 12 235 CPD-098 1069 > 121 > 11 CPD-133 0 04 19 499 CPD-099 1 76 12 7 CPD-134 0 46 49 106 CPD-100 12 03 42 3 CPD-135 40 66 > 124 > 3 CPD-101 4.90 eleven 2 CPD-136 0.22 > 120 > 545 CPD-102 0.62 65 105 CPD-137 0.05 > 128 >2762 CPD-103 12.43 > 138 > 11 CPD-138 0.27 20 74 CPD-104 0.35 65 186 CPD-139 0.02 20 915 CPD-105 1.23 14 eleven CPD-140 2.15 53 24 CPD-106 8.93 > 120 > 13 CPD-141 1.63 44 27 CPD-107 7.88 20 3 CPD-142 0.10 13 137

- 160 040588

Code EC ₅₀ (mkM) CC ₅₀ (mkM) SI Code EC ₅₀ (mkM) CC50 (mkM) SI CPD-144 006 20 320 CPD-198 0 14 16 119 CPD-146 0 05 25 498 CPD-199 24.90 > 120 >4 CPD-148 007 44 594 CPD-200 2.24 54 24 CPD-149 003 14 554 CPD-201 12.23 74 6 CPD-150 003 105 3956 CPD-202 8.33 104 12 CPD-151 009 > 133 > 1443 CPD-203 0.73 > 134 > 185 CPD-152 009 75 814 CPD-205 0.06 14 244 CPD-153 0 29 > 133 >454 CPD-206 0 02 12 625 CPD-154 006 44 778 CPD-207 3.83 16 4 CPD-155 0 08 15 191 CPD-208 0.37 > 102 >279 CPD-156 0 02 eleven 665 CPD-209 1 12 > 100 > 89 CPD-157 0 05 15 299 CPD-210 0.20 13 68 CPD-158 009 63 746 CPD-211 2.83 >111 > 39 CPD-159 0 11 67 624 CPD-212 0.42 > 110 >260 CPD-170 0 44 26 58 CPD-213 0.06 15 256 CPD-173 0 02 69 3693 CPD-214 0.03 16 469 CPD-174 10.07 61 6 CPD-215 0.16 14 90 CPD-179 5 30 135 26 CPD-216 0 84 > 106 > 127 CPD-180 56.97 > 145 >2 CPD-217 0.25 eleven 44 CPD-181 4 22 > 122 >28 CPD-218 2.39 13 6 CPD-182 301 12 4 CPD-219 0 52 86 166 CPD-183 15.20 86 6 CPD-221 29.28 80 3 CPD-184 22.42 70 3 CPD-222 0.13 > 129 > 1003 CPD-186 4 35 40 9 CPD-223 57.95 > 128 >2 CPD-187 3 18 58 18 CPD-224 0.05 > 134 >2622 CPD-189 0 93 > 145 > 156 CPD-225 0.38 > 134 > 357 CPD-190 1 71 eleven 7 CPD-226 0.07 73 1005 CPD-191 2 58 13 5 CPD-227 027 > 124 >454 CPD-192 5 62 50 9 CPD-228 1.62 13 8 CPD-193 0 72 > 133 > 185 CPD-229 2.40 > 115 >48 CPD-194 0 94 61 65 CPD-230 0 12 21 176 CPD-195 12.73 65 5 CPD-231 1.22 18 15 CPD-196 62.56 > 139 >2 CPD-232 0.10 > 125 > 1206 CPD-197 3 30 > 139 >42 CPD-233 0 01 eleven 817

- 161 040588

Code EC50 (mkM) CC ₅₀ (mkM) SI Code EC50 (mkM) CC ₅₀ (mkM) SI CPD-234 0.05 15 319 CPD-270 0.13 > 128 > 1001 CPD-235 0.004 13 3701 CPD-272 0.47 > 124 >263 CPD-236 0.02 69 4562 CPD-273 0.32 > 122 >382 CPD-237 1.35 > 113 > 84 CPD-274 0.39 100 257 CPD-238 0.04 > 125 > 3548 CPD-275 9.96 > 126 > 13 CPD-239 22.65 > 125 >6 CPD-276 2.62 23 9 CPD-240 0.11 63 578 CPD-277 0.29 16 54 CPD-241 0.04 58 1531 CPD-278 0.27 > 125 >455 CPD-242 0.04 59 1340 CPD-279 0.18 > 124 >682 CPD-243 1.69 13 8 CPD-280 0.78 > 139 > 179 CPD-245 0.08 16 192 CPD-281 0.21 > 128 >612 CPD-246 0.32 16 51 CPD-282 0.26 > 128 >490 CPD-247 0.42 15 37 CPD-283 0.17 56 323 CPD-248 0.56 15 27 CPD-284 0.62 74 120 CPD-249 0.10 53 553 CPD-285 0.04 50 1327 CPD-250 0.22 15 65 CPD-286 1.05 > 126 > 120 CPD-251 0.07 14 195 CPD-287 0.44 > 132 >303 CPD-252 0.48 68 140 CPD-288 0.12 77 620 CPD-254 0.02 13 743 CPD-289 0.06 68 1150 CPD-255 0 04 63 1535 CPD-290 0 88 > 125 > 142 CPD-256 0 19 83 433 CPD-291 006 53 872 CPD-257 045 17 37 CPD-292 006 68 1043 CPD-258 1 47 72 49 CPD-293 0001 65 50498 CPD-259 054 14 26 CPD-294 0 02 41 2598 CPD-260 0 08 > 126 > 1681 CPD-295 003 18 679 CPD-261 0 39 15 40 CPD-296 0 05 31 605 CPD-262 006 71 1099 CPD-297 003 22 668 CPD-263 2 18 13 6 CPD-298 0 42 > 116 >278 CPD-264 0.51 > 124 >244 CPD-299 0.02 62 3136 CPD-265 0.02 > 124 > 5616 CPD-300 1.29 50 39 CPD-266 0.06 > 124 >2222 CPD-301 0.08 89 1097 CPD-267 1.30 79 61 CPD-302 0.65 15 23 CPD-268 0.46 15 34 CPD-303 0.52 71 135 CPD-269 0.48 13 28 CPD-305 0.09 > 116 > 1263

- 162 040588

Code EC ₅₀ (µM) SS ₅₀ (µM) SI Code EC ₅₀ (µM) SS ₅₀ (µM) I SI CPD-307 0.18 > 124 >702 CPD-338 0.01 > 124 > 16618 CPD-309 0.54 74 138 CPD-339 0.09 19 205 CPD-310 0.06 25 454 CPD-340 0.02 > 119 >6223 CPD-311 2.58 77 thirty CPD-341 0.002 12 6121 CPD-312 4.67 69 15 CPD-343 0.19 > 119 >637 CPD-313 0.04 58 1464 CPD-344 0.09 94 1054 CPD-314 0.21 50 240 CPD-345 0.21 106 493 CPD-315 0.05 13 265 CPD-346 0.01 54 9945 CPD-316 0.02 29 1180 CPD-347 0.98 6 6 CPD-317 0.58 88 153 CPD-348 0.10 14 151 CPD-318 0.06 54 967 CPD-350 0.01 46 3462 CPD-319 0.12 20 172 CPD-351 0.11 65 605 CPD-320 0.07 > 124 > 1781 CPD-352 0.29 71 247 CPD-321 0.11 33 310 CPD-353 0.10 56 582 CPD-322 0.02 51 2855 CPD-355 0.03 44 1511 CPD-323 0.35 58 166 CPD-356 0.12 13 113 CPD-324 0.01 thirty 3306 CPD-357 1.35 55 40 CPD-325 0.09 68 731 CPD-358 0.18 63 345 CPD-326 0.001 13 9127 CPD-359 0.10 52 501 CPD-327 0.35 eleven 33 CPD-360 0.04 > 124 > 3541 CPD-328 0.01 13 1231 CPD-361 0.09 50 586 CPD-329 0.01 41 2980 CPD-362 0.09 41 470 CPD-330 4.63 > 139 > 30 CPD-364 1.12 62 55 CPD-331 0.02 14 736 CPD-365 2.03 12 6 CPD-332 0.04 20 527 CPD-366 0.26 78 293 CPD-333 0.04 90 2078 CPD-367 0.04 > 103 >2863 CPD-334 0.07 122 1746 CPD-369 0.01 eleven 1306 CPD-335 0.02 18 909 CPD-37D 0.06 66 1152 CPD-336 0.01 > 123 > 8498 CPD-371 0.03 12 389 CPD-337 0.005 15 3237

In table. 4 shows anti-DENV-l, -DENV-3 and -DENV-4 activity on Vero-B cells of some exemplary compounds of the present invention.

- 163 040588

Table 4

DENV-1 DENV-3 DENV4 DENV-1 DENV-3 DENV-4 Code EC ₅₀ (µM) EC ₅₀ (µM) EC ₅₀ (µM) Code EC ₅₀ (mkM) EC ₅₀ (mkM) EC ₅₀ (mkM) CPD-001 1 60 29 40 4 45 CPD-128 7 50 18 37 ND CPD-002 0 54 <05 27 20 CPD-130 0 35 1 70 7 42 CPD-004 4 53 8 55 ND CPD-131 025 0 68 4 77 CPD-010 1.29 3.54 5.43 CPD-132 2.45 3.47 ND CPD-012 4.42 < 0.5 ND CPD-133 2.25 4.17 ND CPD-013 0.09 < 0.5 1.81 CPD-137 0.67 3.81 2.78 CPD-019 0.67 2.18 8.38 CPD-138 3.21 6.52 ND CPD-020 15.08 ND ND CPD-139 0.6B 0.46 3.81 CPD-025 7.89 12.95 11.76 CPD-142 1.71 3.97 ND CPD-027 2.10 9.90 3.70 CPD-144 2.89 3.08 ND CPD-029 2 82 ND ND CPD-146 069 2 72 4 25 CPD-030 4 80 6 24 13 15 CPD-148 1 65 5 54 2 87 CPD-036 243 3 42 5 85 CPD-149 2 88 4 01 5 72 CPD-043 3 38 5 88 4 76 CPD-150 1 28 107 8 87 CPD-045 0.64 0.87 11.05 CPD-151 0.53 2.10 4.87 CPD-049 2.21 10.54 2.27 CPD-152 2.05 0.99 5.62 CPD-OB 1 5.76 24.23 32.63 CPD-153 6.26 2.26 3.68 CPD-053 1.64 11.18 7.11 CPD-154 3.92 4.40 9.87 CPD-055 1.86 3.38 4.44 CPD-155 2.94 ND ND CPD-056 10.57 69.18 5.92 CPD-156 0.61 2.12 3.37 CPD-067 <05 1 20 ND CPD-157 1 31 0 85 5 10 CPD-077 1 42 207 4 27 CPD-158 2 50 2 19 7 20 CPD-083 054 071 252 CPD-159 1 48 3 16 6 86 CPD-084 <05 2 38 309 CPD-173 30 71 ND ND CPD-086 0.97 1.05 3.57 CPD-193 23.67 18.93 5.44 CPD-087 6.05 ND ND CPD-194 ND ND 18.69 CPD-092 ND 0.93 6.73 CPD-203 5.09 5.06 5.32 CPD-104 3.85 24.02 14.88 CPD-206 0.37 0.67 1.52 CPD-116 4.19 9.30 ND CPD-208 ND 6.65 6.95 CPD-118 0.44 3.68 ND CPD-210 1.03 ND ND CPD-119 069 1 74 291 CPD-212 ND 5 90 264 CPD-120 2 31 5 18 ND CPD-213 081 254 2 85 CPD-122 3 64 8 25 ND CPD-214 0 15 099 4 16 CPD-123 1 60 256 264 CPD-219 ND 22 07 ND CPD-126 2.99 8.50 6.29 CPD-222 1.81 3.27 3.14

ND not defined.

- 164 040588

DENV-1 DENV-3 DENV4 DENV-1 DENV-3 DENV4 Code EC ₅₀ (µM) EC ₅₀ (mkM) EC ₅₀ (mkM) Code EC ₅₀ (mkM) EC ₅₀ (mkM) EC ₅₀ (mkM) CPD-225 ND 299 1 16 CPD-289 0 80 091 1022 CPD-226 0 92 081 8 64 CPD-291 0 80 0 80 8 67 CPD-227 ND 291 7 45 CPD-292 0 83 1 11 708 CPD-229 2.81 42.99 7.55 CPD-293 0.06 0.04 1.15 CPD-230 0.35 3.53 2.56 CPD-294 0.23 0.67 7.21 CPD-232 0.85 2.69 1.15 CPD-295 0.34 1.38 6.29 CPD-233 0.22 1.29 3.09 CPD-296 0.99 1.83 3.31 CPD-234 0.76 2.00 4.19 CPD-297 ND 0.57 6.68 CPD-235 0.09 0.27 3.02 CPD-298 2.02 5.79 4.52 CPD-236 0.17 0.31 2.45 CPD-299 0.50 0.78 3.65 CPD-237 ND ND 8 31 CPD-300 5 29 21 12 4 13 CPD-238 054 1 65 10 17 CPD-301 1 12 0 50 4 25 CPD-240 1 20 2 38 8 73 CPD-303 3 26 ND ND CPD-241 062 062 5 69 CPD-305 0 44 102 256 CPD-242 0.40 0.57 7.87 CPD-307 2.43 ND 11.49 CPD-245 0.70 2.38 3.01 CPD-309 0.62 0.70 2.80 GPD-249 1.13 4.57 1.98 CPD-310 1.11 0.65 9.37 CPD-252 ND 12.56 2.29 CPD-313 0.72 1.11 5.84 CPD-254 0.67 0.80 1.15 CPD-314 1.70 2.80 8.76 CPD-255 0.75 1.66 3.36 CPD-315 0.38 1.01 1.97 CPD-256 6 76 4 49 19 90 CPD-316 0 39 0 32 4 42 CPD-258 ND ND 9 42 CPD-317 4 13 12 84 10 63 CPD-260 6 63 22 63 5 44 CPD-318 0 22 2 32 10 84 CPD-262 2 33 6 73 8 49 CPD-319 2 84 1 70 2 27 CPD-265 0.29 1.64 4.88 CPD-320 0.96 1.17 9.44 CPD-266 0.70 4.32 3.51 CPD-321 0.40 0.32 2.74 CPD-270 1.57 1.87 ND CPD-322 0.30 0.32 3.00 CPD-273 0.58 7.66 8.41 CPD-323 3.62 4.99 ND CPD-278 2.84 13.20 5.80 CPD-324 0.27 0.19 5.32 CPD-279 0.62 0.89 8.66 CPD-325 0.87 1.84 7.16 CPD-281 0 85 5 57 1 12 CPD-326 0 05 009 1 89 CPD-282 1 24 3 12 13 13 CPD-327 1 42 461 2 25 CPD-283 2 83 7 14 7 89 CPD-328 020 0 13 2 84 CPD-285 0 84 2 20 2 31 CPD-329 027 0 32 292 CPD-288 1.90 2.70 6.33 CPD-331 0.39 0.39 3.28

ND not defined.

DENV-1 DENV-3 DENV-4 DENV-1 DENV-3 DENV-4 Code EC ₅ o (mkM) EC50 (mkM) EC ₅ o (mkM) Code EC ₅ o (mkM) EC ₅ o (mkM) EC ₅ o (mkM) CPD-332 0 72 1 35 2 84 CPD-344 ND 0 79 25 90 CPD-333 0 39 0 49 5 92 CPD-345 ND 1 73 294 CPD-334 1 29 081 16 77 CPD-346 ND 0 04 1 27 CPD-335 0.32 0.42 2.38 CPD-348 ND ND 3.75 CPD-336 0.26 0.35 5.77 CPD-350 ND 0.28 3.11 CPD-337 0.09 0.23 0.95 CPD-351 ND 2.02 9.58 CPD-338 0.35 0.25 1.82 CPD-352 ND 3.03 8.60 CPD-339 0.81 0.82 2.93 CPD-353 ND 0.17 7.18 CPD-340 0.18 0.24 6.39 CPD-355 ND 0.30 6.17 CPD-341 ND 0.05 3.36 CPD-359 ND ND 5.48 CPD-343 ND 3 11 ND CPD-360 ND ND 5 78

ND not defined.

- 165 040588

In table. 5 shows anti-YFV activity on Vero-B cells of some exemplary compounds of the invention.

Table 5

Code EUzo (µM) CCzo(µM) SI CPD-001 9.16 43 5 CPD-002 2.81 25 9 CPD-010 < 0.6 12 >22 CPD-012 < 0.5 12 >23 CPD-013 0.52 eleven 20 CPD-019 6.18 56 9 CPD-193 <05 > 133 >250

In table. 6 shows anti-DENV-2 activity on A549 cells of some exemplary compounds of the present invention.

Code EC ₅ o (µM) CCzo (µM) Table 6 SI CPD-010 0 066 16 242 CPD-131 0008 eleven 1447 CPD-236 0 019 65 3428 CPD-242 0 010 47 4642 CPD-255 0 029 59 2030 CPD-293 0003 > 117 >43103 CPD-294 0015 61 4048 CPD-320 0006 > 124 > 22522 CPD-328 0006 12 2140 CPD-334 0 024 85 3536 CPD-336 0005 > 123 > 22523 CPD-338 0 026 > 124 >4808 CPD-340 0 027 > 119 >4425 CPD-346 0008 60 7559 CPD-35O 0008 63 7758 CPD-360 0 027 > 124 >4630

Example 363 In vivo activity of the compounds of the invention against dengue infection.

The mouse model of dengue viremia described in Schul W., Liu W., Xu HY, Flamand M., Vasudevan SG, J. Infect. Dis. 2007, 95(5) 665-74) (incorporated herein by reference), can be used to study the in vivo efficacy of compounds. on day 0 2x106 plaque forming units (pfu) DENV-2 (TSV01 strain) Infected mice (6 or 8 animals per group) were immediately treated with the compound to be tested at at least one or more selected doses via ip, iv or s.c. injection or oral administration and vehicle control for three consecutive days. On day 4, blood samples were collected and viral titers were determined using plaque assay. γ-interferon) described by Tan et al (PLoS Negl. Trop. Dis. 2010, 4(4) and Ann. Acad. Med. Singapore 2011,40 523-32) (incorporated herein by reference) was created for definitions in vivo effect activity of the CPD-242 compound. Female AG129 mice (B&K Universal, UK) aged 7-9 weeks were randomly divided into 3 test groups (n = 4 or 5 per group): 1 infected group that received vehicle only and 2 infected groups that were treated with either test compound CPD-242 (60 mg/kg/day, s.c., twice daily, dissolved in 10% DMSO, 5% Solutol in saline (0.9%)), or Celgosivir reference compound (100 mg/kg/day). day; i.p., twice a day, dissolved in 0.9% NaCl). Mice were subcutaneously inoculated on day 0 with 1x10 ⁷ plaque forming units (b.u.) of the non-mouse adapted DENV-2 strain D2Y98P, a highly infectious strain in AG129 mice that results in severe disease and death within 2 weeks. Infected mice were further treated twice daily for 17 consecutive days with vehicle, Celgosivir or CPD-242. Once the mice showed symptoms of virus-induced paralysis and/or lost >30% body weight, they were euthanized. The results from this in vivo experiment are shown in the Figure and clearly show that treatment of dengue virus-infected AG129 mice with CPD242 results in a very significant slowdown (p: 0.0017) in virus-induced disease (euthanasia day shown).

- 166 -

Claims (35)

CLAIM 1. The compound of formula (B) where the fragment where the wavy line (—) denotes the point of attachment to the carbonyl of the main formula (B), where the specified fragment is unsubstituted; cycle B is selected from where the wavy line (—) denotes the point of attachment to the carbon atom of the basic formula (B) - 167 040588 and where the depicted cycles can be optionally substituted with one, two or three Z ^1a ; R ¹ is selected from C ₃ -7 cycloalkyl, aryl, heterocycle; and where the specified C _3-7 cycloalkyl, aryl and heterocycle is optionally substituted with one, two or three Z ^1b ; R ² is hydrogen; each Z ^1a is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ ² , -OC(=O)Z ³ , =O, -SZ ² , =S, -S(=O)Z ² , -S (=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethoxy, nitro, -NZ ⁴ Z ⁵ , -NZ ⁴ S(=O)2Z ² , -NZ ⁴ C(=O)Z ² , -NZ ⁴ C(=O)NZ ⁴ Z ⁵ , cyano, -C(=O)Z ³ , -C(=O)OZ ² , -C(=O)NZ ⁴ Z ⁵ , -C(=O) H, heteroC _1-6 alkyl, aryl, heterocycle and heterocycle-C^alkyl; and where said heteroC _1-6 alkyl, aryl, heterocycle and heterocycle-C _1-6 alkyl are optionally substituted with one, two or three substituents selected from hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -OCF ₃ , -O-C(O)Me, cyano, nitro, -C(O)OH, -C(O)oC ₁ . ₆ αkyl, -NH ₂ , -NHCH ₃ ; -N(CH ₃ ) ₂ , -NHC(=O)O-C ₁ . ₄ alkyl; -S(O) ₂ C _1-4 α alkyl and -O-C ₁ - ₆ alkyl; each Z ^1b is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ ² , -OC(=O)Z ³ , =O, -SZ ² , =S, -S(=O)Z ² , -S (=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethyl, trifluoromethoxy, nitro, -NZ ⁴ Z ⁵ , -NZ ⁴ C(=O)NZ ⁴ Z ⁵ , cyano, -C(=O )Z ³ , -C(=O)H, C _1-6 alkyl, heteroC _1-6 alkyl, aryl and heterocycle; and wherein said C _1-6 alkyl, heteroC _1-6 alkyl, aryl and heterocycle are optionally substituted with one, two or three substituents selected from hydroxyl, halogen, -SH, =S, trifluoromethyl, -OCF ₃ , -O-C( O) Me, cyano, nitro, -C (O) OH, -C (O) OC ₁ . ₆ alkyl, -NH ₂ , -NHCH ₃ ; -N(CH ₃ ) ₂ , -NH-C(=O)O-C ₁ . ₄ alkyl; -S (O) ₂ C ₁ . ₄ alkyl and -O-C ₁ - ₆ alkyl; each Z ² is independently selected from C _1-6 alkyl, aryl, and heterocycle, wherein said C _1-6 alkyl, aryl, and heterocycle are optionally substituted with one, two, or three substituents selected from hydroxyl, ═O, halogen, —SH, ═S , trifluoromethyl, difluoromethyl, -O-C1 ₆ alkyl, -OCF ₃ , -S (= O) ₂ C _1-4 alkyl, cyano, nitro, -C (= O) OH, -C (= O) O-C _1-4 alkyl, -NH2 and -N(CH ₃ ) ₂ , pyrrolidinyl, piperidinyl and piperazinyl; each Z ³ is independently selected from hydroxyl, C _1-6 alkyl, aryl and heterocycle, wherein said C _1-6 alkyl, aryl and heterocycle are optionally substituted with one, two or three substituents selected from C _1-6 alkyl and -N(CH ₃ ) ₂ ; each Z ⁴ and Z ⁵ is independently selected from hydrogen, C _1-6 alkyl, aryl, C _3-7 cycloalkyl, and heterocycle; or 1-(1H-indol-4-yl)-2-(3-methoxyanilino)-2-phenylethanone; or 1-(4-isoquinolyl)-2-(3-methoxyanilino)-2-phenylethanone; or 1-(1H-indol-3-yl)-2-(3-methoxy-N-methylanilino)-2-phenylethanone; or 3-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-N,N-dimethylbenzamide; or 2-[2-furylmethyl(methyl)amino]-1-(1 H-indol-3-yl)-2-phenylethanone; or N-[2-(1 H-indol-3-yl)-2-oxo-1-phenylethyl]-2-(dimethylamino)-N-(3-methoxyphenyl)acetamide; and its stereoisomers or tautomers or pharmaceutically acceptable salts; where the term heteroalkyl as used herein refers to an acyclic alkyl in which one or more carbon atoms are replaced by an oxygen, nitrogen or sulfur atom, provided that said chain cannot contain two adjacent O atoms or two adjacent S atoms; where the term heterocycle means a saturated, unsaturated or aromatic ring system of 3-18 atoms, including at least one N, O, S or P; the term aryl means an aromatic hydrocarbon radical of 6 to 20 carbon atoms formed by removal of a hydrogen from a carbon atom of the parent aromatic ring system, provided that the compound of formula (B) is not itself 3-(2-(1H-indol-3-yl)-2-oxo-1-phenylethylamino)benzenesulfonamide (CAS number 1211427-21-2); 2-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylamino)-1-(1H-indol-3-yl)-2-phenylethanone (CAS No. 1090733-87- 1); 1-(1H-indol-3-yl)-2-phenyl-2-(m-tolylamino)ethanone (CAS number 1252467-88-1); 2-(4-ethoxy-3-(hydroxymethyl)phenylamino)-1-(1 H-indol-3-yl)-2-phenylethanone (CAS No. 1241127-58-1); 1-(1H-indol-3-yl)-2-[(6-methoxy-3-pyridinyl)amino]-2-phenylethanone (CAS number 1181884-55-8); 1-(1H-indol-3-yl)-2-[(1-methyl-1H-pyrazol-3-yl)amino]-2-phenylethanone (CAS number 1134766-19-0); 2-[(3,5-dimethoxyphenyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone (CAS number 1030232-46-2); 1-(1H-indol-3-yl)-2-phenyl-2-(phenylamino)ethanone (CAS number 1030214-83-5); 1-(1H-indol-3-yl)-2-[[6-(4-morpholinyl)-3-pyridinyl]amino]-2-phenylethanone (CAS number 103021241-9); 2-(3-(difluoromethoxy)-4-methoxyphenylamino)-1-(1H-indol-3-yl)-2-phenylethanone (CAS number 1015662-06-2); 1-(1H-indol-3-yl)-2-phenyl-2-[(3,4,5-trimethoxyphenyl)amino]ethanone (CAS number 1014535-82-0); 2-[(4-fluorophenyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone (CAS number 1014493-63-0); 2-[(4-ethoxy-3-methoxyphenyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone (CAS number 1014422-80-0); 1-[4-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-2-methoxyphenyl]-2-pyrrolidinone (CAS No. - 168 040588 1011119-79-1); 2-[(1-Acetyl-2,3-dihydro-1H-indol-5-yl)amino]-1-(1H-indol-3-yl)-2-phenylethanone (CAS No. 949443-90-7); 1-(1H-indol-3-yl)-2-phenyl-2-[(1-propyl-4-piperidinyl)amino]ethanone (CAS number 941047-24-1); 2-(cyclopentylamino)-1-(1H-indol-3-yl)-2-phenylethanone (CAS number 931079-25-3); 1-(1H-indol-3-yl)-2-[(4-methylphenyl)amino]-2-phenylethanone (CAS number 931016-79-4); 2-(cyclopropylamino)-1-(1H-indole-3-ul)-2-phenylethanone (CAS number 931000-99-6); 2-[(3,4-dihydro-2H-1-benzothiopyran-4-yl)amino]-1-(1H-indol-3-yl)-2-phenylethanone (CAS number 924713-60-0); 2-[(3,4-dimethoxyphenyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone (CAS number 924712-67-4); 2-ethoxy-5-[[2-(1H-indole-3-ul)-2-oxo-1-phenylethyl]amino]-N,N-dimethylbenzenesulfonamide (CAS number 920883-17-6); 6-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-2-methyl-2H-1,4-benzoxazin-3(4H)-one (CAS No. 920834- 07-7); 2-[(3,4-dihydro-2H-1-benzopyran-4-yl)amino]-1-(1H-indol-3-yl)-2-phenylethanone (CAS number 920819-87-0); 4-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]benzolacetonitrile (CAS number 920669-36-9); 1-(III-indol-3-yl)-2-[(4-methoxyphenyl)amino]-2-phenylethanone (CAS number 920601-77-0); 1-(1H-indol-3-yl)-2-phenyl-2-(1,1-dioxotetrahydrothiophen-3-ylamino)ethanone (CAS number 87861992-2); 2-[[3-(hydroxymethyl)phenyl]amino]-1-(1H-indol-3-yl)-2-phenylethanone (CAS number 875166-36-2); 2-[(2,3-dihydro-1,4-benzodioxin-6-yl)amino]-1-(1H-indol-3-yl)-2-phenylethanone (CAS number 874669-99-5); 1-(1H-indol-3-yl)-2-(morpholino(phenyl)methylamino)-2-phenylethanone; 2-(4-(dimethylamino)benzylamino)-1-(1H-indol-3-yl)-2-phenylethanone; 1-(1H-indol-3-yl)-2-(2-methoxybenzylamino)-2-phenylethanone; 1-(1H-indol-3-yl)-2-(3-methoxybenzylamino)-2-phenylethanone; 2-(2-(dimethylamino)-1-phenylethylamino)-1-(1H-indol-3-yl)-2-phenylethanone; 2-(3,4-dimethoxyphenethylamino)-1-(1H-indol-3-yl)-2-phenylethanone; 1-(1H-indol-3-yl)-2-(1-(2-methoxyphenyl)ethylamino)-2-phenylethanone; 1-(1H-indol-3-yl)-2-(4-methoxybenzylamino)-2-phenylethanone; 2-(benzylamino)-1-(1H-indol-3-yl)-2-phenylethanone; 2-[4-[[2-(1H-indole-3-yl)-2-oxo-1-phenylethyl]amino]phenyl]-N,N-dimethylacetamide; 4-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-1,5-dimethyl-2-phenylpyrazol-3-one; (2S)-2-(1,3-benzodioxol-5-ylamino)-1-(1H-indol-3-yl)-2-phenylethanone; (2S)-2-(2,3-dihydro-1,4-benzodioxin-6-ulamino)-1-(1H-indole-3-ul)-2-phenylethanone; (2S)-2-anulino-1-(1H-indol-3-ul)-2-phenylethanone; (2S)-1-(1H-indole-3-ul)-2-(3-metulanulino)-2-phenylethanone; (2S)-1-(1H-indole-3-ul)-2-(3-methoxyanilino)-2-phenylethanone; (2S)-1-(1H-indol-3-yl)-2-(4-methylanilino)-2-phenylethanone; (2S)-1-(1H-indole-3-ul)-2-(4-methoxyanilino)-2-phenylethanone; methyl 4-[[(1S)-2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]benzoate; (2S)-1-(1H-indole-3-ul)-2-phenyl-2-(3,4,5-trimethoxyanilino)ethanone; (2S)-2-(4-ethoxy-3-methoxyanilino)-1-(1H-indol-3-yl)-2-phenylethanone; 2-[4-[[(1S)-2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]phenyl]acetonitrile; (2S)-2-(4-fluoroanilino)-1-(1H-indol-3-yl)-2-phenylethanone; (2R)-2-[(1-acetyl-2,3-dihydroindol-5-yl)amino]-1-(1H-indol-3-ul)-2-phenylethanone; (2S)-2-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylamino)-1-(1H-indol-3-yl)-2-phenuletanone; (2R)-2-(4-fluoroanilino)-1-(1H-indol-3-yl)-2-phenylethanone; 3,4-dihydro-6-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-2(1H)-quinolinone (CAS number 1277962-26-1); 2-[(3-(hydroxymethyl)-4-methoxyphenyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone; 2-(1,3-benzodioxol-5-ylamino)-1-(1H-indol-3-yl)-2-phenylethanone; or 2. Compound of formula (B) - 169 040588 where the fragment is selected from where the wavy line (—) denotes the point of attachment to the carbonyl of the main formula (B); moreover, the specified fragment is optionally substituted with one or two Z ¹ ; cycle B is selected from - 170 040588 where the wavy line (—) denotes the point of attachment to the carbon atom of the basic formula (B) and where the depicted cycles are unsubstituted; R ¹ is selected from C ₃ -7 cycloalkyl, aryl, heterocycle; and wherein said C _3-7 cycloalkyl, aryl and heterocycle are optionally substituted with one, two or three Z ^1b ; R ² is hydrogen; each Z ¹ is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ ² , -OC(=O)Z ³ , =O, -SZ ² , =S, -S(=O)Z ² , -S (=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethyl, trifluoromethoxy, nitro, -NZ ⁴ Z ⁵ , -NZ ⁴ S(=O)2Z ² , -NZ ⁴ C(=O)Z ² , -NZ ⁴ C(=O)OZ ² , -NZ ⁴ C(=O)NZ ⁴ Z ⁵ , cyano, -C(=O)Z ³ , -C(=O)OZ ² , -C(= O)NZ ⁴ Z ⁵ , -C(=O)H, C _1-6 alkyl, heteroC _1-6 alkyl, aryl, heterocycle and heterocycle-C^alkyl; and where said C _1-6 alkyl, heteroC _1-6 alkyl, aryl, heterocycle and heterocycle-Cm alkyl are optionally substituted with one, two or three substituents selected from hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, - OCF ₃ , -О-С(О)Me, cyano, nitro, -С(О)0n, -С(O)OC ₁ . ₆ αkyl, -NH ₂ , -NHCH ₃ ; -N(CH ₃ ) ₂ , -NH-C(=O)O-C ₁ . ₄ alkyl; -S(O) ₂ C ₁ . ₄ alkyl and -O-C ₁ - ₆ alkyl; each Z ^1b is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ ² , -OC(=O)Z ³ , =O, -SZ ² , =S, -S(=O)Z ² , -S (=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethyl, trifluoromethoxy, nitro, -NZ ⁴ Z ⁵ , -NZ ⁴ C(=O)NZ ⁴ Z ⁵ , cyano, -C(=o )z ³ , -C(=O)OZ ² , -C(=O)H, C ₁ . ₆ αkyl, heteroC _1-6 alkyl, aryl and heterocycle; and wherein said C _1-6 alkyl, heteroC _1-6 alkyl, aryl and heterocycle are optionally substituted with one, two or three substituents selected from hydroxyl, halogen, -SH, =S, trifluoromethyl, -OCF ₃ , -O-C( O) Me, cyano, nitro, -C (O) OH, -C (O) OC ₁ . ₆ alkyl, -NH ₂ , -NHCH ₃ ; -N(CH ₃ ) ₂ , -NH-C(=O)O-C ₁ . ₄ alkyl; -S(O) ₂ C ₁ . ₄ alkyl and -O-C^ alkyl; each Z ² is independently selected from C ₁ . ₆ alkyl, aryl, heterocycle and heterocycle-Cm alkyl; wherein said C _1-6 alkyl, aryl, heterocycle and heterocycle-C^alkyl are optionally substituted with one, two or three substituents selected from hydroxyl, ═O, halogen, —SH, ═S, trifluoromethyl, difluoromethyl, —OC ₁ . ₆ alkyl, -OCF ₃ , -S(=O) ₂ C ₁ . ₄ alkyl, cyano, nitro, -C(=O)OH, -C(=O)O-C ₁ - ₄ alkyl, -NH ₂ and -N(CH ₃ ) ₂ , pyrrolidinyl, piperidinyl and piperazinyl; each Z ³ is independently selected from hydroxyl, C ₁ . ₆ alkyl, aryl and heterocycle; wherein said O^alkyl, aryl and heterocycle are optionally substituted with one, two or three substituents selected from C ₁ . ₆ αkyl and -N(CH ₃ ) ₂ ; each Z ⁴ and Z ⁵ is independently selected from hydrogen, C _1-6 alkyl, aryl, C ₃ - ₇ cycloalkyl, and heterocycle; or 1-(1H-indol-3-yl)-2-(3-methoxy-N-methylanilino)-2-phenylethanone; or 3-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-N,N-dimethylbenzamide; or 2-[2-furylmethyl(methyl)amino]-1-(1 H-indol-3-yl)-2-phenylethanone; or N-[2-(1 H-indol-3-yl)-2-oxo-1-phenylethyl]-2-(dimethylamino)-N-(3-methoxyphenyl)acetamide; and its stereoisomers or tautomers or pharmaceutically acceptable salts; where the term heteroalkyl as used herein refers to an acyclic alkyl in which one or more carbon atoms are replaced by an oxygen, nitrogen or sulfur atom, provided that said chain cannot contain two adjacent O atoms or two adjacent S atoms, where the term heterocycle means a saturated, unsaturated or aromatic ring system of 3-18 atoms including at least one N, O, S or P; the term aryl means an aromatic hydrocarbon radical of 6 to 20 carbon atoms formed by removal of a hydrogen from a carbon atom of the parent aromatic ring system, provided that the compound of formula (B) is not itself N-(5-(2-(7-ethyl-1H-indol-3-yl)-2-oxo-1-phenylethylamino)-2-methoxyphenyl)methanesulfonamide; 3-(2-(1H-indol-3-yl)-2-oxo-1-phenylethylamino)benzenesulfonamide; 2-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylamino)-1-(1H-indol-3-yl)-2-phenylethanone; 1-(7-ethyl-1H-indol-3-yl)-2-[(1-methyl-1H-pyrazol-3-yl)amino]-2-phenylethanone; 1-(7-ethyl-1H-indol-3-yl)-2-phenyl-2-[(3,4,5-trimethoxyphenyl)amino]ethanone; 2-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)amino]-1-(7-ethyl-1H-indol-3-yl)-2-phenylethanone; 3,4-dihydro-6-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-2(1H)-quinolinone; 1-(1H-indol-3-yl)-2-phenyl-2-(m-tolylamino)ethanone; 2-(4-ethoxy-3-(hydroxymethyl)phenylamino)-1-(1H-indol-3-yl)-2-phenylethanone; 2-[(1-acetyl-4-piperidinyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone; 1-(1H-indol-3-yl)-2-[(6-methoxy-3-pyridinyl)amino]-2-phenylethanone; 1-(1H-indol-3-yl)-2-[(1-methyl-1H-pyrazol-3-yl)amino]-2-phenylethanone; 2-[(3,5-dimethoxyphenyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone; 1-(1H-indol-3-yl)-2-phenyl-2-(phenylamino)ethanone; 1-(1H-indol-3-yl)-2-[[6-(4-morpholinyl)-3-pyridinyl]amino]-2-phenylethanone; 2-(3-(difluoromethoxy)-4-methoxyphenylamino)-1-(1 H-indol-3-yl)-2-phenylethanone; 1-(1H-indol-3-yl)-2-phenyl-2-[(3,4,5-trimethoxyphenyl)amino]ethanone; 2-[(4-fluorophenyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone; - 171 040588 2-[(4-ethoxy-3-methoxyphenyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone; 1-[4-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-2-methoxyphenyl]-2-pyrrolidinone (CAS No. 1011119-79-1); 2-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)amino]-1-(1H-indol-3-yl)-2-phenylethanone; 1-(1H-indol-3-yl)-2-phenyl-2-[(1-propyl-4-piperidinyl)amino]ethanone; 2-(cyclopentylamino)-1-(1 H-indol-3-yl)-2-phenylethanone; 1-(1H-indol-3-yl)-2-[(4-methylphenyl)amino]-2-phenylethanone; 2-(cyclopropylamino)-1-(1 H-indol-3-yl)-2-phenylethanone; 2-[(3,4-dihydro-2H-1-benzothiopyran-4-yl)amino]-1-(1H-indol-3-yl)-2-phenylethanone; 2-[(3,4-dimethoxyphenyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone; 2-ethoxy-5-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-X,X-dimethylbenzenesulfonamide; 6-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-2-methyl-2H-1,4-benzoxazin-3(4H)-one; 2-[(3,4-dihydro-2H-1-benzopyran-4-yl)amino]-1-(1H-indol-3-yl)-2-phenylethanone; 4-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]benzolacetonitrile; 1-(1H-indol-3-yl)-2-[(4-methoxyphenyl)amino]-2-phenylethanone; 1-(1H-indol-3-yl)-2-phenyl-2-(1,1-dioxotetrahydrothiophen-3-ylamino)ethanone; 2-[[3-(hydroxymethyl)phenyl]amino]-1-(1H-indol-3-yl)-2-phenylethanone; 2-[(2,3-dihydro-1,4-benzodioxin-6-yl)amino]-1-(1H-indol-3-yl)-2-phenylethanone; 1-(1H-indol-3-yl)-2-(morpholino(phenyl)methylamino)-2-phenylethanone; K-[5-[[2-(7-ethyl-1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-2-methylphenyl]methanesulfonamide; N-[5-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-2-methoxyphenyl]methanesulfonamide; 2-[4-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]phenyl]-N,N-dimethylacetamide; 4-[[2-(7-ethyl-1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-1,5-dimethyl-2-phenylpyrazol-3-one; 4-[[2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-1,5-dimethyl-2-phenylpyrazol-3-one; (2S)-2-(1,3-benzodioxol-5-ylamino)-1-(1H-indol-3-yl)-2-phenylethanone; (2S)-2-(2,3-dihydro-1,4-benzodioxin-6-ylamino)-1-(1H-indol-3-yl)-2-phenylethanone; (2S)-2-anilino-1-(1 H-indol-3-yl)-2-phenylethanone; (2S)-1-(1H-indol-3-yl)-2-(3-methylanilino)-2-phenylethanone; (2S)-1-(1H-indol-3-yl)-2-(3-methoxyanilino)-2-phenylethanone; (2S)-1-(1H-indol-3-yl)-2-(4-methylanilino)-2-phenylethanone; (2S)-1-(1H-indol-3-yl)-2-(4-methoxyanilino)-2-phenylethanone; methyl 4-[[( 1S)-2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]benzoate; (2S)-1-(1H-indol-3-yl)-2-phenyl-2-(3,4,5-trimethoxyanilino)ethanone; (2S)-2-(4-ethoxy-3-methoxyαnilino)-1-(1H-indol-3-yl)-2-phenylethαnon; 2-[4-[[(1S)-2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]phenyl]acetonitrile; (2S)-2-(4-fluoroanilino)-1-(1H-indol-3-yl)-2-phenylethanone; (2R)-2-[(1-acetyl-2,3-dihydroindol-5-yl)αmino]-1-(1H-indol-3-yl)-2-phenylethanone; (2S)-1-(7-ethyl-1H-indol-3-yl)-2-phenyl-2-(3,4,5-trimethoxyαnilino)ethαnon; (2S)-2-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylamino)-1-(1H-indol-3-yl)-2-phenylethanone; N-[4-[[(1R)-2-(7-ethyl-1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]phenyl]ethanesulfonamide; 5-[[(1R)-2-(7-ethyl-1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-3H-1,3-benzoxazol-2-one (2R)- 2-(4-fluoroanilino)-1-(1H-indol-3-yl)-2-phenylethanone; N-[5-[[(1R)-2-(7-ethyl-1H-indol-3-yl)-2-oxo-1-phenylethyl]amino]-2-methoxyphenyl]methanesulfonamide; 3,4-dihydro-6-[[2-( 1 H-indol-3 -yl)-2-oxo-1-phenylethyl]amino]-2( 1 H)-quinolinone (CAS number 1277962-26-1); 2-[(3-(hydroxymethyl)-4-methoxyphenyl)amino]-1-(1H-indol-3-yl)-2-phenylethanone; 2-(1,3-benzodioxol-5-ylamino)-1-(1 H-indol-3-yl)-2-phenylethanone; 1-(7-ethyl-1H-indol-3-yl)-2-[3-(hydroxymethyl)anilino]-2-phenylethanone; 1-(7-ethyl-1H-indol-3-yl)-2-[3-(hydroxymethyl)-4-methoxyanilino]-2-phenylethanone; 3. Compound of formula (B) - 172 040588 where the fragment is selected from where the wavy line J) denotes the point of attachment to the carbonyl of the basic formula (B); moreover, the specified fragment is substituted by one or two Z ¹ ; cycle B is selected from where the wavy line J) denotes the point of attachment to the carbon atom of the basic formula (B) and where the indicated cycles are substituted by one, two or three Z ^1a ; R ¹ is selected from C _3-7 cycloalkyl, aryl, heterocycle; and where the specified C _3-7 cycloalkyl, aryl and heterocycle are unsubstituted; R ² is hydrogen; each Z ¹ is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ ² , -OC(=O)Z ³ , =O, -SZ ² , =S, -S(=O)Z ² , -S (=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethyl, trifluoromethoxy, nitro, -NZ4Z ⁵ , -NZ ⁴ S(=O) ₂ Z ² , -NZ4C(=O)Z ² , - NZ4C(=O)-OZ ² , -NZ4C(=O)NZ4Z ⁵ , cyano, -C(=O)Z ³ , -C(=O)OZ ² , - 173 040588 -C(=O)NZ ⁴ Z ⁵ , -C(=O)H, C _1-6 alkyl, heteroC _1-6 alkyl, aryl, heterocycle and heterocycle-C _1-6 alkyl; and wherein said C _1-6 alkyl, heteroC _1-6 alkyl, aryl, heterocycle and heterocycle-C _1-6 alkyl are optionally substituted with one, two or three substituents selected from hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -OCF3, -O-C(O)Me, cyano, nitro, -C(O)OH, -C(O)OC _1-6 αkyl, -NH2, -NHCH3; -N(CH ₃ )2, -NH-C(=O)O-C _1-4 αkyl; -S(O) ₂ C _1-4 alkyl and -O-C _1-6 alkyl; each Z ^1a is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, -OZ ² , -OC(=O)Z ³ , =O, -SZ ² , =S, -S(=O)Z ² , -S (=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethoxy, nitro, -NZ ⁴ Z ⁵ , -NZ ⁴ S(=O)2Z ² , -NZ ⁴ C(=O)Z ² , -NZ ⁴ C(=O)-OZ ² , -NZ ⁴ C(=O)NZ ⁴ Z ⁵ , cyano, -C(=O)Z ³ , -C(=O)OZ ² , -C(=O )NZ ⁴ Z ⁵ , -C(=O)H, C _1-6 alkyl, heteroC _1-6 alkyl, aryl, heterocycle and heterocycle-C _1-6 alkyl; and where said C _1-6 alkyl, heteroC _1-6 alkyl, aryl, heterocycle and heterocycle-C _1-6 alkyl are optionally substituted with one, two or three substituents selected from hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, -OCF ₃ , -OC(O)Me, cyano, nitro, -C(O)0n, -C(O)OC _1-6 alkyl, -NH2, -NHCH ₃ ; -N(CH ₃ )2, -NH-C(=O)O-C _1-4 αkyl; -S(O) ₂ C _{1-4 4} alkyl and -O-C _1-6 alkyl; each Z ² is independently selected from C _1-6 alkyl, aryl, heterocycle, and heterocycle-C _1-6 alkyl; where the specified C _1-6 alkyl, aryl, heterocycle and heterocycle-C _1-6 alkyl are optionally substituted with one, two or three substituents selected from hydroxyl, =O, halogen, -SH, =S, trifluoromethyl, difluoromethyl, -OC _{1 -6} alkyl, -OCF ₃ , -S (= O) ₂ C _1-4 alkyl, cyano, nitro, -C (= O) OH, -C (= O) O-C _1-4 alkyl, -NH ₂ and -N(CH ₃ ) ₂ , pyrrolidinyl, piperidinyl and piperazinyl; each Z ³ is independently selected from hydroxyl, C _1-6 alkyl, aryl and heterocycle, wherein said C _1-6 alkyl, aryl and heterocycle are optionally substituted with one, two or three substituents selected from C _1-6 alkyl and -N(CH ₃ ) ₂ ; each Z ⁴ and Z ⁵ is independently selected from hydrogen, C _1-6 alkyl, aryl, C _3-7 cycloalkyl, and heterocycle; or 1-(indolin-1-yl)-2-((3-methoxyphenyl)amino)-2-phenylethanone; and its stereoisomers or tautomers or pharmaceutically acceptable salts; where the term heteroalkyl as used herein refers to an acyclic alkyl in which one or more carbon atoms are replaced by an oxygen, nitrogen or sulfur atom, provided that said chain cannot contain two adjacent O atoms or two adjacent S atoms; where the term heterocycle means a saturated, unsaturated or aromatic ring system of 3-18 atoms, including at least one N, O, S or P; the term aryl means an aromatic hydrocarbon radical of 6-20 carbon atoms formed by the removal of a hydrogen from a carbon atom of the parent aromatic ring system. 4. The compound according to claim 1, where each Z ^1a is independently selected from the group consisting of halogen, hydroxyl, -OZ ² , -OC(=O)Z ³ , =O, -S(=O)2Z ³ , -S (=O)2NZ ⁴ Z ⁵ , trifluoromethoxy, -NZ ⁴ Z ⁵ , -NZ ⁴ C(=O)Z ² , -NZ ⁴ C(=O)-OZ ² , cyano, -C(=O)Z ³ , -C(=O)OZ ² , -C(=O)NZ ⁴ Z ⁵ , heteroC _1-6 alkyl, aryl, heterocycle and heterocycle-C _1-6 alkyl; and wherein said aryl and heterocycle are optionally substituted with one, two or three substituents selected from hydroxyl, =O, -O-C(O)Me, cyano, -C(O)OH, -C(O)OC _1-6 alkyl , -NH2, -NHCH3; -N(CH ₃ )2, -NH-C(=O)O-C _1-4 alkyl; -S(O) ₂ C _1-4 alkyl and -O-C _1-6 α alkyl; each Z ^1b is independently selected from the group consisting of halogen, hydroxyl, -OZ ² , -OC(=O)Z ³ , =O, -S(=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethyl, trifluoromethoxy, -NZ ⁴ Z ⁵ , cyano, -C(=O)Z ³ , C _1-6 alkyl, heteroC _1-6 alkyl, aryl and heterocycle; and where the specified C _1-6 αlkyl, aryl and heterocycle are optionally substituted with one, two or three substituents selected from hydroxyl, -O-C(O)Me, cyano, -C(O)OH, -C(O)OC _{1 -6} alkyl, -NH2, -NHCH ₃ ; -N(CH ₃ ) ₂ , -NH-C(=O)O-C _1-4 alkyl; -S(O) ₂ C _1-4 alkyl and -O-C _1-6 alkyl; each Z ² is independently selected from C _1-6 alkyl and aryl, wherein said C _1-6 alkyl and aryl are optionally substituted with one, two or three substituents selected from hydroxyl, halogen, difluoromethyl, -OC _1-6 αalkyl, -S( =O) ₂ C _1-4 αalkyl, -C(=O)OH, -C(=O)O-C _1-4 αalkyl, -NH2 and -N(CH ₃ )2, pyrrolidinyl, piperidinyl and piperazinyl; each Z ³ is independently selected from hydroxyl, C _1-6 alkyl and heterocycle, wherein said C _1-6 alkyl and heterocycle are optionally substituted with one, two or three substituents selected from C _1-6 alkyl and —N(CH ₃ ) ₂ ; each Z ⁴ and Z ⁵ is independently selected from hydrogen, C _1-6 alkyl and C _3-7 cycloalkyl; and its stereoisomers or tautomers or pharmaceutically acceptable salts. 5. The compound of claim 2 wherein each Z is independently selected from the group consisting of halogen, hydroxyl, -OZ ² , -OC(=O)Z ³ , =O, -S(=O)2Z ³ , -S( =O)2NZ ⁴ Z ⁵ , trifluoromethyl, trifluoromethoxy, -NZ ⁴ Z ⁵ , -NZ ⁴ C(=O)Z ² , -NZ ⁴ C(=O)-OZ ² , cyano, -C(=O)Z ³ , -C(=O)OZ ² , -C(=O)NZ ⁴ Z ⁵ , C1-6alkyl, heteroC1-6alkyl, aryl, heterocycle and heterocycle- _C1-6alkyl ; and wherein said C _1-6 alkyl, aryl and heterocycle are optionally substituted with one, two or three substituents selected from hydroxyl, =O, -O-C(O)Me, cyano, -C(O)OH, -C(O )OC _1-6 αkyl, -NH2, -NHCH ₃ ; -N(CH ₃ ) ₂ , -NH-C(=O)O-C _1-4 αkyl; -S(O) ₂ C _1-4 alkyl and -O-C _1-6 alkyl; each Z ^1b is independently selected from the group consisting of halogen, hydroxyl, -OZ ² , -OC(=O)Z ³ , =O, -S(=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethyl, trifluoromethoxy, -NZ ⁴ Z ⁵ , cyano, -C(=O)Z ³ , -C(=O)OZ ² , - 174 040588 C _1-6 alkyl, heteroC _1-6 alkyl, aryl and heterocycle; and wherein said C _1-6 alkyl, aryl and heterocycle are optionally substituted with one, two or three substituents selected from hydroxyl, -O-C(O)Me, cyano, -C(O)OH, -C(O)OC _{1 -6} alkylα, -NH2, -NHCH ₃ ; -N(CH ₃ )2, -NH-C(=O)OC _1-4 alkyl; -S(O) ₂ C _1-4 alkyl and -O-C _1-6 alkyl; each Z ² is independently selected from C _1-6 alkyl, aryl and heterocycle-C _1-6 alkyl, wherein said C _1-6 alkyl and aryl are optionally substituted with one, two or three substituents selected from hydroxyl, halogen, difluoromethyl, -OC ₁ . ₆ alkyl, -S(=O) ₂ C ₁ . ₄ alkylα, -C(=O)OH, -C(=O)O-C ₁ . ₄ alkyl, -NH ₂ , -N(CH ₃ ) ₂ , pyrrolidinyl, piperidinyl and piperazinyl; each Z ³ is independently selected from hydroxyl, C1. ₆ alkyl and heterocycle, where the specified C1. ₆ alkyl and heterocycle are optionally substituted with one, two or three substituents selected from C1. ₆ alkyl and -N(CH ₃ )2; each Z ⁴ and Z ⁵ is independently selected from hydrogen, C1. ₆ alkyl and C ₃ .7 cycloalkyl. 6. The compound according to claim 3, where each Z ¹ is independently selected from the group consisting of halogen, hydroxyl, -OZ ² , -OC(=O)Z ³ , =O, -S(=O)2Z ³ , -S (=O)2NZ ⁴ Z ⁵ , trifluoromethyl, trifluoromethoxy, -NZ4Z ⁵ , -NZ4C(=O)Z ² , -NZ4C(=O)-OZ ² , cyano, -C(=O)Z ³ , -C( =O)OZ ² , -C(=O)NZ4Z ⁵ , C _1-6 alkyl, heteroC1. ₆ alkyl, aryl, heterocycle and heterocycle-C ₁ . ₆ alkyl; and where specified C1. ₆ alkyl, aryl and heterocycle are optionally substituted with one, two or three substituents selected from hydroxyl, =O, -O-C(O)Me, cyano, -C(O)OH, -C(O)OC ₁ . ₆ alkyl, -NH2, -NHCH3; -N(CH3)2, -NH-C(=O)O-C1-4alkylα; ^^ malalkyl and -O-C1-6 alkyl; each Z ^1a is independently selected from the group consisting of halogen, hydroxyl, -OZ ² , -OC(=O)Z ³ , =O, -S(=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethoxy, -NZ ⁴ Z ⁵ , -NZ ⁴ C(=O)-OZ ² , cyano, -C(=O)Z ³ , -C(=O)OZ ² , C1. ₆ alkyl, heteroCl. ₆ alkyl, aryl, heterocycle and heterocycle-C ₁ . ₆ alkyl; and where specified C1. ₆ alkyl, aryl and heterocycle are optionally substituted with one, two or three substituents selected from hydroxyl, -O-C(O)Me, cyano, -C(O)OH, -C(O)OC ₁ . ₆ alkylα, -NH2, -NHCH ₃ ; -N(CH ₃ )2, -NH-C(=O)O-C ₁ . ₄ alkyl; -S(O) ₂ C _1-4 alkylα and -O-C ₁ . ₆ alkyl; each Z ² is independently selected from C1. ₆ alkyl, aryl and heterocycle-C ₁ . ₆ alkyl, where the specified C1. ₆ alkyl and aryl are optionally substituted with one, two or three substituents selected from hydroxyl, halogen, difluoromethyl, -O-C ₁ . ₆ alkyl, -S (= O) ₂ C ₁ . ₄ alkyla, -C(=O)OH, -C(=O)O-C ₁ . ₄ alkyl, -NH2, -N(CH ₃ )2, pyrrolidinyl, piperidinyl and piperazinyl; each Z ³ is independently selected from hydroxyl, C1. ₆ alkyl and heterocycle, where the specified C1. ₆ alkyl and heterocycle are optionally substituted with one, two or three substituents selected from C1. ₆ alkyl and -N(CH ₃ )2; each Z ⁴ and Z ⁵ is independently selected from hydrogen, C ₁ . ₆ alkyl and C ₃ .7 cycloalkyl. 7. The compound of formula (B) according to claim 1, in which the fragment is selected from where the specified fragment is unsubstituted; cycle B is selected from - 175 040588 where the wavy line (—) denotes the point of attachment to the carbon atom of the basic formula (B) and where the depicted cycles may be optionally substituted by one, two or three Z ^1a ; R ¹ is a fragment selected from moreover, the fragment is optionally substituted with one, two or three Z ^1b ; Z ^1b is selected from the group consisting of halogen, hydroxyl, -OZ ² , =O, -S(=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethyl, trifluoromethoxy, -NZ4Z ⁵ , cyano, - C(=O)Z ³ , C _1-6 alkyl, aryl and heterocycle; and where said C _1-6 alkyl, aryl and heterocycle are optionally substituted with one, two or three substituents selected from hydroxyl, -O-C(O)Me, cyano, -C(O)OH, -NHCH ₃ ; -N(CH ₃ ) ₂ , -8(O) ₂ C ₁ . ₄ alkyl and -O-C _1-6 alkyl; R ² is hydrogen; each Z ^1a is independently selected from the group consisting of halogen, hydroxyl, -OZ ² , -OC(=O)Z ³ , =O, -S(=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethoxy, -NZ ⁴ Z ⁵ , -NZ ⁴ C(=O)Z ² , cyano, -C(=O)Z ³ , -C(=O)OZ ² , -C(=O)NZ4Z ⁵ , heteroC _{1 -6} alkyl, aryl, heterocycle and heterocycle-C _1-6 alkyl; where the specified aryl and heterocycle are optionally substituted with one, two or three substituents selected from hydroxyl, =O, -O-C(O)Me, cyano, -C(O)OH, -C(O)OC _1-6 alkyl, -NH ₂ , -NHCH ₃ ; -N(CH ₃ ) ₂ , -NH-C(=O)O-C _1-4 alkyl, morpholinyl, -8(O) ₂ C _1-4 alkyl and -O-C _1-6 alkyl; Z ² is independently selected from C _1-6 alkyl and aryl; where the specified C _1-6 alkyl and aryl are optionally substituted with one, two or three substituents selected from hydroxyl, halogen, difluoromethyl, -O-C _1-6 alkyl, -S (=O) ₂ C _1-4 alkyl, -C (=O)OH, -C(=O)O-C _1-4 αkyl, -NH ₂ and -N(CH ₃ ) ₂ , pyrrolidinyl, piperidinyl and piperazinyl; Z ³ is independently selected from hydroxyl, C _1-6 alkyl and heterocycle; where the specified C _1-6 alkyl and heterocycle optionally substituted with one, two or three substituents selected from C _1-6 alkyl and-N(CH ₃ ) ₂ ; each Z ⁴ and Z ⁵ is independently selected from hydrogen, C _1-6 αkyl, and C _3-7 cycloalkyl. 8. The compound of formula (B) according to claim 2, where the fragment - 176 040588 moreover, the specified fragment is optionally substituted with one or two Z ¹ ; cycle B selected from selected from where the wavy line (—) denotes the point of attachment to the carbon atom of the basic formula (B) and where the depicted cycles are unsubstituted; R ¹ is a fragment selected from - 177 040588 moreover, the fragment is optionally substituted with one, two or three Z ^1b ; R ² is hydrogen; each Z ¹ is independently selected from the group consisting of halogen, hydroxyl, -OZ ² , -OC(=O)Z ³ , =O, -S(=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethyl, trifluoromethoxy, -NZ4Z ⁵ , -NZ4C(=O)Z ² , -NZ4C(=O)-OZ ² , cyano, -C(=O)Z ³ , -C(=O)OZ ² , -C( =O)NZ4Z ⁵ , C _1-6 alkyl, heteroC _1-6 alkyl, aryl, heterocycle and heterocycle-C ₁ - ₆ alkyl; where the specified C ₁ _ ₆ alkyl, aryl and heterocycle are optionally substituted with one, two or three substituents selected from hydroxyl, =O, -O-C(O)Me, cyano, -C(O)OH, -C(O) OC ₁ _ ₆ alkyl, -NH ₂ , -NHCH ₃ ; -N(CH ₃ ) ₂ , -NH-C(=O)O-C ₁ _ ₄ alkyl, morpholinyl, -S(O) ₂ C ₁ _ ₄ alkyl and -OC ₁ _ ₆ alkyl; each Z ^1b is independently selected from the group consisting of halogen, hydroxyl, -OZ ² , -OC(=O)Z ³ , =O, -S(=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethyl, trifluoromethoxy, -NZ4Z ⁵ , cyano, -C(=O)Z ³ _, -C(=O)OZ ² , C _{1_6} alkyl, heteroC1_ ₆ alkyl, aryl and heterocycle; and wherein said _{C1_6} alkyl, aryl and heterocycle are optionally substituted with one, two or three substituents selected from hydroxyl, -O-C(O)Me, cyano, -C(O)OH, -C(O)OC ₁ _ ₆ alkyl, -NH ₂ , -NHCH ₃ ; -N(CH ₃ ) ₂ , -NH-C(=O)OC ₁ _ ₄ alkyl; morpholinyl, -S(O) ₂ C ₁ _ ₄ alkyl and -OC ₁ _ ₆ alkyl; Z ² is independently selected from C ₁ _ ₆ alkyl, aryl and heterocycle-C ₁ - ₆ alkyl, wherein said C ₁ _ ₆ alkyl and aryl are optionally substituted with one, two or three substituents selected from hydroxyl, halogen, difluoromethyl, -OC ₁ _ ₆ alkyl, -S (= O) ₂ C ₁ _ ₄ alkyl, -C (= O) OH, -C (= O) O-C ₁ _ ₄ alkyl, -NH ₂ and -N (CH ₃ ) ₂ , pyrrolidinyl, piperidinyl and piperazinyl; Z ³ is independently selected from hydroxyl, C ₁ _ ₆ alkyl and heterocycle, wherein said C ₁ _ ₆ alkyl and heterocycle are optionally substituted with one, two or three substituents selected from C 1_ ₆ alkyl and -N(CH ₃ ) ₂ ; each Z ⁴ and Z ⁵ is independently selected from hydrogen, C ₁ _ ₆ alkyl and C ₃ - ₇ cycloalkyl. 9. The compound of formula (B) according to claim 3, where the fragment - 178 040588 where the wavy line (—) denotes the point of attachment to the carbon atom of the basic formula (B) and where the depicted cycles are replaced by one, two or three Z ^1a ; R ¹ is a fragment selected from wherein the fragment is unsubstituted; R ² is hydrogen; each Z ¹ is independently selected from the group consisting of halogen, hydroxyl, -OZ ² , -OC(=O)Z ³ , =O, -S(=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethyl, trifluoromethoxy, -NZ ⁴ Z ⁵ , -NZ ⁴ C(=O)Z ² , -NZ ⁴ C(=O)-OZ ² , cyano, -C(=O)Z ³ , -C(=O) OZ ² , -C(=O)NZ ⁴ Z ⁵ , C _1-6 alkyl, heteroC _1-6 alkyl, aryl, heterocycle and heterocycle-C _1-6 alkyl, wherein said C _1-6 alkyl, aryl and heterocycle are optional substituted with one, two or three substituents selected from hydroxyl, =O, -O-C(O)Me, cyano, -C(O)OH, -C(O)OC _1-6 alkyl, -NH ₂ , -NHCH ₃ ; -N(CH ₃ ) ₂ , -NH-C(=O)O-C _1-4 alkyl, morpholinyl, -S(O) ₂ C _1-4 alkyl and -O-C _1-6 alkyl; each Z ^1a is independently selected from the group consisting of halogen, hydroxyl, -OZ ² , -OC(=O)Z ³ , =O, -S(=O)2Z ³ , -S(=O)2NZ ⁴ Z ⁵ , trifluoromethoxy, -NZ ⁴ Z ⁵ , -NZ ⁴ C(=O)-OZ ² , cyano, -C(=O)Z ³ , -C(=O)OZ ² , -C(=O)NZ ⁴ Z ⁵ , C _1-6 alkyl, heteroC _1-6 alkyl, aryl, heterocycle and heterocycle-C _1-6 alkyl; and where said C _1-6 alkyl, aryl and heterocycle are optionally substituted with one, two or three substituents selected from hydroxyl, =O, -O-C(O)Me, cyano, -C(O)OH, -C(O )OS ₁ . ₆ alkyl, -NH ₂ , -NHCH ₃ ; -N(CH ₃ ) ₂ , -NH-C(=O)O-C ₁ . ₄ alkyl; morpholinyl, -3 (O) ₂ C ₁ . ₄ alkyl and -O-C ₁ . ₆ alkyl; Z ² is independently selected from Aralkyl, aryl and heterocycle-C ₁ . ₆ alkyl, where the specified C ₁ . ₆ alkyl and aryl are optionally substituted with one, two or three substituents selected from hydroxyl, halogen, difluoromethyl, -O-C ₁ . ₆ alkyl, -3 (= O) ₂ C ₁ . ₄ alkyl, -C(=O)OH, -C(=O)O-C ₁ . ₄ alkyl, -NH ₂ and -N(CH ₃ ) ₂ , pyrrolidinyl, piperidinyl and piperazinyl; Z ³ is independently selected from hydroxyl, Aralkyl and heterocycle, wherein said C _1-6 alkyl and heterocycle are optionally substituted with one, two or three substituents selected from C _1-6 alkyl and -N(CH ₃ ) ₂ ; - 179 040588 each Z ⁴ and Z ⁵ independently selected from hydrogen, C _1-6 alkyl and C _3-7 cycloalkyl. 10. A compound according to any one of claims 1 or 4, wherein the compound is characterized by the structure of formula (G) where ring B, R ¹ , R ² , X ¹ and Z ¹ are the same as defined in any of claims 1 or 4, R ⁴ is hydrogen, X ¹ is N or CH and n is 0. 11. A compound according to any one of claims 2 or 5, wherein the compound is characterized by the structure of formula (G) where cycle B, R ¹ , R ² , X ¹ and Z ¹ are defined in any of paragraphs 2 or 5, R ⁴ is hydrogen, X ¹ is N or CH and n is selected from 0; 1; and 2. 12. A compound according to any one of claims 3 or 6, wherein the compound is characterized by the structure of formula (G) where cycle B, R ¹ , R ² , X ¹ and Z ¹ are defined in any of paragraphs 3 or 6, R ⁴ is hydrogen, X ¹ is N or CH and n is selected from 1; and 2. 13. A compound according to any one of claims 1 or 4, wherein the compound is characterized by the structure of formula (H) where cycle In, each Z ¹ independently and each Z ^1b independently are the same as defined in any of claims 1 or 4; m is selected from 0, 1, 2 and 3; n is 0; and where X ² is NH and X ¹ is CH or N, or X ² is S and X ¹ is CH or X ² is O and X ¹ is N. 14. A compound according to any one of claims 2 or 5, wherein the compound is characterized by the structure of formula (H) m is selected from 0, 1, 2 and 3; n is selected from 0, 1 and 2; and where X ² is NH and X ¹ is CH or N, or X ² is S and X ¹ is CH, or X ² is O and X ¹ is N. 15. A compound according to any one of claims 3 or 6, wherein the compound is characterized by the structure of formula (H) - 180 040588 m is 0; n is selected from 1 and 2; and where X ² is NH and X ¹ is CH or N, or X ² is S and X ¹ is CH, or X ² is O and X ¹ is N. 16. The compound according to any one of claims 1 or 4, characterized by the structure of formula (I) cycle B is defined in any one of claims 1 or 4; n is 0; and m is selected from 0, 1, 2 and 3. 17. A compound according to any one of claims 2 or 5, wherein the compound is characterized by the structure of formula (I) where each Z ¹ independently and each Z ^1b independently defined in any of paragraphs.2 or 5; cycle B is defined in any of claims 2 or 5; n is selected from 0, 1 and 2; and m is selected from 0, 1, 2 and 3. 18. A compound according to any one of claims 3 or 6, wherein the compound is characterized by the structure of formula (I) where each Z ¹ independently and each Z ^1b independently defined in any of paragraphs.3 or 6; cycle B is defined in any of claims 3 or 6; n is selected from 1 and 2; and m is 0. 19. The compound according to any one of claims 1-3, and the fragment represents 20. A compound according to any one of claims 1 to 3, wherein the compound is characterized by the structure of formula (F1) - 181 040588 and the bicyclic fragment is chosen from 21. A compound according to any one of claims 1 to 20, wherein the carbon atom substituted with the B ring is in the R configuration. 22. A compound according to any one of claims 1 to 20, wherein the carbon atom substituted with the B ring is in the S configuration. 23. A medicament for the prevention or treatment of a flavivirus infection in an animal, which contains an effective amount of a compound according to any one of claims 1-20. 24. The drug according to claim 23, wherein said animal is a mammal. 25. The drug according to claim 24, wherein said mammal is a human. 26. The medicament according to claim 23, wherein the flavivirus infection is an infection with dengue virus or yellow fever virus. 27. The use of a compound according to any one of claims 1 to 20 for the manufacture of a medicament for the treatment or prevention of a flavivirus infection. 28. The use of a medicinal product according to claim 23 for the treatment or prevention of flavivirus infection. 29. The use of a compound according to any one of claims 1 to 20 for the treatment or prevention of a flavivirus infection. 30. Use according to claim 28, wherein the flavivirus infection is an infection with dengue virus or yellow fever virus. 31. Use according to claim 29, wherein the flavivirus infection is an infection with dengue virus or yellow fever virus. 32. A pharmaceutical composition containing a pharmaceutically acceptable carrier and, as an active ingredient, an effective amount of a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof. 33. A method for preparing a compound according to any one of claims 1 to 20, comprising the steps of reacting a compound of formula (X1) with an amine R1R2NH in a suitable solvent, wherein ring A corresponds to the moiety formula (B), as defined in paragraphs.1-20, cycle B, R ¹ and R ² are characterized by a value according to any one of paragraphs. 1-20 and LG is the leaving group where the leaving group is selected from a halogen atom or a sulfonate. 34. The method of claim 33 wherein the leaving group is selected from chlorine, bromine and iodine. 35. A method for preparing a compound according to any one of claims 1 to 20, wherein the method comprises the steps of reacting an imine of formula (X2) with an aldehyde of formula (X3) in the presence of a catalyst and a suitable solvent to obtain a compound of formula (A1), where the ring A of formula - 182 -