EA046966B1 - CONNECTIONS - Google Patents

Description

The present invention relates to new compounds that have activity as positive modulators of the calcium-activated chloride channel (CaCC), TMEM16A. This invention also relates to methods for preparing the compounds and pharmaceutical compositions containing them, as well as the use of these compounds in the treatment of diseases and pathological conditions modulated by TMEM16A, in particular respiratory diseases and pathological conditions.

People can inhale up to 12,000 liters of air every day, and with this comes the possibility of pathogenic microorganisms (such as bacteria, viruses and fungal spores) entering the respiratory tract. To protect against these airborne pathogens, the lungs have developed innate defense mechanisms to minimize the likelihood of infection and colonization of the airways. One such mechanism is the mucus clearance system, whereby secreted mucus is moved up and out of the airways by the coordinated beating of cilia along with cough clearance. This ongoing cleansing of the lungs continually removes inhaled particles and germs, thereby reducing the risk of infection.

In recent years, it has become clear that hydration of the mucus gel is critical for mucus clearance (Boucher 2007; Matsui et al. 1998). In normal, healthy airways, mucus gel typically contains 97% water and 3% w/v. solids, under which mucus is cleared through mucociliary action. Hydration of the mucous membrane of the respiratory tract is regulated by the coordinated activity of a number of ion channels and transporters. The balance of anion secretion (Cl ^- /HCO ₃ ^- ) mediated by the cystic fibrosis transmembrane conductance regulator (CFTR) and calcium-activated chloride conductance (CaCC; TMEM16A) and Na ⁺ absorption through the epithelial Na ⁺ channel (ENaC) determine the hydration state of the respiratory mucosa . As ions are transported across the epithelium, water is required to follow osmotically, and thus fluid is either released or absorbed.

In respiratory diseases such as chronic bronchitis and cystic fibrosis, the % solids in mucus gel increases as hydration decreases and mucus clearance decreases (Boucher, 2007). In cystic fibrosis, where loss of functional mutations in CFTR impair the ability of the airways to clear fluid, % solids may be increased to 15%, which is thought to contribute to small airway obstruction and impaired mucus clearance. Strategies to increase hydration of airway mucus include both anion stimulation and consequently fluid secretion or inhibition of Na ⁺ absorption. To this end, stimulating the activity of TMEM16A channels will increase the secretion of anions and, therefore, increase the accumulation of fluid in the mucous membrane of the respiratory tract, hydrate mucus and enhance mucus clearance mechanisms.

TMEM16A, also called Anoctamin-1 (Ano1), is the molecular identity of calcium-activated chloride channels (Caputo et al., 2008; Yang et al., 2008). TMEM16A channels open in response to increased intracellular calcium levels and allow bidirectional flow of chloride, bicarbonate and other anions across the cell membrane. Functionally, TMEM16A channels have been proposed to modulate transepithelial ion transport, gastrointestinal motility, nociception, and cell migration/proliferation (Pedemonte & Galietta, 2014).

TMEM16A channels are expressed by epithelial cells of various organs, including lung, liver, kidney, pancreas and salivary glands. In the airway epithelium, TMEM16A is expressed at high levels in mucosal cells, cuboid cells, ciliated cells, and submucosal glands. Physiologically, TMEM16A is activated by stimuli that mobilize intracellular calcium, especially purinergic agonists (ATP, UTP), which are released by the respiratory epithelium in response to cyclic shear stress caused by respiration and other mechanical stimuli such as coughing. In addition to increasing the secretion of anions, leading to increased hydration of the airways, activation of TMEM16A plays an important role in the secretion of bicarbonate. Bicarbonate secretion has been reported to be an important regulator of mucus properties and control of airway luminal pH and, consequently, the activity of native antimicrobials such as defensins (Pezzulo et al., 2012).

Indirect modulation of TMEM16A, through an increase in intracellular calcium, has been clinically studied, for example, Denufosol (Kunzelmann & Mall, 2003). Although encouraging initial results were observed in small groups of patients, this approach did not provide clinical benefit in larger groups of patients (Accurso et al 2011; Kellerman et al 2008). This lack of clinical effect has been explained only by a transient increase in anion secretion, a result of denufozole's short half-life at the epithelial surface and receptor/pathway desensitization, as well as the undesirable effects of increased intracellular calcium, such as increased mucus release from goblet cells (Moss, 2013). Compounds that act directly on TMEM16A to enhance channel opening at low levels of calcium elevation are expected to long-term improve anion secretion and mucociliary clearance in patients and improve innate protection. Because TMEM16A activity is independent of CFTR function, positive TMEM16A modulators have the potential to provide clinical benefit to all patients with CF and res.

- 1 046966 piratory diseases without CF, characterized by mucus stagnation, including chronic bronchitis and severe asthma.

Modulation of TMEM16A has been implicated as a therapy for dry mouth (xerostomia) resulting from salivary gland dysfunction in Sjögren's syndrome and radiation therapy, dry eyes, cholestasis and gastrointestinal motility disorders.

The inventors of the present invention have developed new compounds that are positive modulators of TMEM16A and, therefore, which are useful for the treatment of diseases and pathological conditions in which modulation of TMEM16A plays a role, in particular respiratory diseases and pathological conditions.

In a first aspect of the present invention there is provided a compound of general formula (I) and a salt thereof:

R ¹ O R ^5b

R ^5a (I) where R ¹ represents H, CN, C(O)OR ¹² , ^alkyl, ^alkenyl or C _2-3 alkynyl, any of the alkyl, alkenyl or alkynyl groups being optionally substituted with one or more substituents, selected from fluorine, OR ¹² , N(R ¹² )2, C(O)OR ¹² , C(O)N(R ¹² )2, C(O)R ¹² and N(R ¹³ )C(O)R ¹² ;

where each R ¹² and R ¹³ are independently selected from H, ^^alkyl and ^^fluoroalkyl.

R ² represents H or O^alkyl, optionally substituted with OR ¹² ;

R ³ represents:

_C1-10 alkyl, _C2-10 alkenyl or _C2-10 alkynyl, any of which is optionally substituted with one or more substituents selected from fluorine, CN, ^R14 , ^OR14 , ^OR15 , N( ^R15 )2, C(O)OR ¹⁵ , C(O)N(R ¹⁵ )2, N(R ¹⁶ )C(O)R ¹⁵ , N(R ¹⁵ )S(O)2R ¹⁴ , N(R ¹⁵ )S(O )2R ¹⁶ and N(R ¹⁵ )C(O)OR ¹⁶ ; or

a 3-7 membered carbocyclic or heterocyclic ring system or a 6-10 membered aryl or 5-10 membered heteroaryl ring system, any of which is optionally substituted with one or more substituents independently selected from halogen, CN, C _1-4 alkyl, C _1-4 haloalkyl, OR ¹⁷ and N(R ¹⁷ ) ₂ ;

where R ¹⁴ represents a 6-10 membered aryl or 5-10 membered heteroaryl ring system, or a 3-7 membered carbocyclic or heterocyclic ring system, any of which is optionally substituted with one or more substituents selected from halogen, C1-4alkyl , C1-4haloalkyl, OR ¹⁷ and N(R ¹⁷ )2; wherein each R ¹⁷ independently represents H, C _1-4 alkyl or C _1-4 haloalkyl;

each R ¹⁵ and R ¹⁶ independently represents H, C _1-6 alkyl or C _1-6 haloalkyl; or

^R2 and ^R3 , together with the carbon atom to which they are attached, combine to form a 310-membered carbocyclic or heterocyclic ring system, optionally substituted with one or more substituents independently selected from halogen, CN, ^OR9 , N( ^R9 )2 , C(O)OR ⁹ , C(O)N(R ⁹ )2, C(O)R ⁹ , N(R ⁹ )C(O)R ⁹ and C1-4alkyl, optionally substituted with halogen, OR ⁹ or N (R ⁹ )2; or

R ¹ , R ² and R ³ together with the carbon atom to which they are attached combine to form a bridged 5-10 membered carbocyclic or heterocyclic ring system or phenyl, any of which is optionally substituted with one or more substituents selected from halogen, CN , OR ⁹ , N(R ⁹ )2, C(O)OR ⁹ , C(O)N(R ⁹ )2, C(O)R ⁹ , N(R ⁹ )C(O)R ⁹ and C _{1 -4} alkyl, optionally substituted with halogen, OR ⁹ or N(R ⁹ )2;

each R ⁹ is independently selected from H, ^alkyl or ^^haloalkyl;

X ¹ represents N;

X ² represents CR ⁸ ;

R ⁸ represents H, halogen, OH, O(C _1-4 alkyl), CN or NH ₂ ;

Y is a straight chain bond or alkylene which is optionally substituted with one or more R ¹⁸ substituents, the two R ¹⁸ substituents being attached to the same or different carbon atoms;

wherein each R ¹⁸ independently represents ^^alkyl or ^^haloalkyl, in which -CH ₂ - is optionally replaced by -NH- or -O- and where two R ¹⁸ groups can be combined with the atom or atoms to which they are attached with the formation of a 3-6-membered carbocyclic or heterocyclic ring system;

Z represents -C(O)- or -C(O)NH-;

R ⁴ is a 6-14 membered aryl, 5-14 membered heteroaryl or 5-10 membered carbocyclic ring system, any of which is optionally substituted with one or more

- 2,046,966 by placeholders selected from:

halogen, CN, nitro, R ¹⁹ , OR ¹⁹ , OR ⁶ , SR ⁶ , NR ⁶ R ⁷ , C(O)R ⁶ , C(O)R ¹⁹ , C(O)OR ⁶ , C(O)N( R ⁶ )(R ⁷ ), N(R ⁷ )C(O)R ⁶ ;

C _1-6 alkyl or O(C _1-6 αlkyl), any of which is optionally substituted with one or more substituents independently selected from halogen, CN, nitro, R ¹⁹ , OR ⁶ , SR ⁶ , NR ⁶ R ⁷ , C( O)R ⁶ , C(O)OR ⁶ , C(O)N(R ⁶ )(R ⁷ ) and N(R ⁷ )C(O)R ⁶ ; and when R ⁴ is not entirely aromatic, is oxo;

where R ¹⁹ represents a 5- or 6-membered aryl or heteroaryl ring system or a 3-7 membered carbocyclic or heterocyclic ring system, any of which is optionally substituted with one or more substituents selected from halogen, ^^alkyl, C _1-4 haloalkyl, OH, O^^alkyl), O(C _1-4 haloalkyl);

R ⁶ represents H, C1 _-6 alkyl, C1 _-6 haloalkyl, benzyl, 3-7 membered carbocyclyl or 3-7 membered heterocyclyl;

R ⁷ represents H, C _1-6 alkyl or C _1-6 haloalkyl; or

R ⁶ and R ⁷ together with the nitrogen atom to which they are attached may form a 4-7 membered heterocyclic ring, optionally containing one or more heteroatoms selected from N, O and S, and optionally substituted with one or more substituents, selected from oxo and halogen; and each of R ^5a and R ^5b independently represents H, C _1-4 alkyl or halogen;

wherein a heteroaromatic ring or heteroaryl is an aromatic ring system containing from 5 to 14 ring atoms, at least one of which is a heteroatom selected from N, O and S; and wherein the heterocyclic ring or heterocyclyl is a non-aromatic ring system containing from 3 to 10 ring atoms, at least one of which is a heteroatom selected from N, O and S;

provided that:

when X ² represents CH, Z represents -C(O)-, and Y represents a bond, R ⁴ is not a 5-10 membered heteroaryl ring attached to Y via a nitrogen atom, and where compounds of formula (A) :

A, or a salt thereof, wherein R ^1a represents ethyl;

R ^2a represents tert-butyl;

T, U and Y represent CH, and

Z represents N; And

R ⁵ represents C(O)NHEt, C(O)NH(CH2)2CH3, C(O)NH(CH2)2CH2F, C(O)NH(CH2hCH3, C(O)NH(CH ₂ ) ₃ CH ₂ F, C(O)NHCH ₂ C=CH or C(O)NHCH ₂ CH=CH ₂ are excluded;

for use in medicine.

As used herein, unless the context otherwise requires due to language or intended meaning, the word contains or variants such as contains or containing is used in an inclusive sense, that is, to indicate the presence of the claimed features, but not to to eliminate the presence or addition of additional features in various embodiments of the invention.

As used herein, references to pharmaceutical use refer to use for administration to a human or animal, particularly a human or mammal, such as a pet or companion animal, for the treatment or prevention of a disease or medical condition. The term pharmaceutical composition refers to a composition that is suitable for pharmaceutical use, and pharmaceutically acceptable refers to an agent that is suitable for use in a pharmaceutical composition. Other similar terms shall be construed accordingly.

As used herein, the term C _1-6 alkyl refers to a linear or branched fully saturated hydrocarbon group having from 1 to 6 carbon atoms. The term covers methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl. Other alkyl groups, such as ^^alkyl, are as defined above but contain different numbers of carbon atoms.

The term C _2-6 alkenyl refers to a straight or branched hydrocarbon group having from 1 to 6 carbon atoms and at least one carbon-carbon double bond. The term covers ethenyl, propen-1-yl, propen-2-yl, buten-1-yl and buten-2-yl. Other alkenyl groups, e.g.

- 3 046966

C _2-10 alkenyl are as defined above, but contain different numbers of carbon atoms.

The term C _2-6 alkynyl refers to a straight or branched hydrocarbon group having from 1 to 6 carbon atoms and at least one carbon-carbon triple bond. The term covers ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl and butyn-2-yl. Other alkynyl groups, for example C _2-10 alkynyl, are as defined above but contain different numbers of carbon atoms.

The term alkylene refers to a straight or branched fully saturated hydrocarbon chain having from 1 to 6 carbon atoms. Examples of alkylene groups include -CH2-, -CH2CH2-, CH( _CH3 ) _-CH2- , _CH2CH ( _CH3 )-, -CH2CH2CH2-, _{-CH2CH ( CH2CH3} )- and - CH ₂ CH (CH ₂ CH ₃ )CH ₂ -. Other alkylene groups, for example C _1-3 alkylene, are as defined above except that they contain the specified number (eg, 1 to 3) carbon atoms.

The terms carbocyclic and carbocyclyl refer to a non-aromatic hydrocarbon ring system containing from 3 to 10 ring carbon atoms, unless otherwise noted, and optionally one or more double bonds. The carbocyclic group may be a single ring or may contain two or three rings, which may be fused or bridged, wherein the carbon atoms in the bridge are included in the number of carbon atoms in the ring. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl, as well as bridging systems such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl and adamantyl.

As used herein, the terms heterocyclic and heterocyclyl refer to a non-aromatic ring system containing from 3 to 10 ring atoms, including at least one heteroatom selected from N, O and S. A heterocyclic group may be one ring or may contain two or three rings that may be fused or bridged, where the bridge atoms are included among the ring atoms. Examples include tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and thiomorpholinyl, as well as fused systems such as cyclopropyl-fused pyrrolidine.

The terms aryl and aromatic as used herein refer to a ring system with aromatic character having from 5 to 14 ring carbon atoms and containing up to three rings. If an aryl group contains more than one ring, not all rings need to be completely aromatic in character. Examples of aromatic groups are benzene, naphthalene, fluorene, tetrahydronaphthalene, indane and indene.

The terms heteroaryl and heteroaromatic as used herein refer to a ring system with aromatic character having from 5 to 14 ring atoms, at least one of which is a heteroatom selected from N, O and S, and containing up to three rings. If a heteroaryl group contains more than one ring, not all rings need to be aromatic in character. Examples of heteroaryl groups include pyridine, pyrimidine, indole, indazole, thiophene, benzothiophene, benzoxazole, benzofuran, dihydrobenzofuran, tetrahydrobenzofuran, benzimidazole, benzimidazoline, quinoline and indoline.

The term oxo refers to a C=O substituent where the carbon atom is a ring atom of a carbocyclyl, heterocyclyl group or ring of an aryl or heteroaryl group that is non-aromatic in nature.

The term halogen refers to fluorine, chlorine, bromine or iodine, and the term halogen refers to fluorine, chlorine, bromine or iodine groups. Likewise, halide refers to fluoride, chloride, bromide or iodide.

The term Cl _-6 haloalkyl as used herein, the term refers to a C1-6 alkyl group as defined above in which one or more hydrogen atoms are replaced by a halogen group. Any number of hydrogen atoms can be replaced, up to perhalogen substitution. Examples include trifluoromethyl, chloroethyl and 1,1-difluoroethyl. A fluoroalkyl group is a haloalkyl group in which the halogen is fluorine.

The compounds of general formula (I) are TMEM16A modulators and, therefore, a further aspect of the invention provides the use of a compound of general formula (I) as defined above in the treatment or prevention of diseases and pathological conditions affected by modulation of TMEM16A.

The use of compounds of general formula (I) in the production of a medicinal product for the treatment or prevention of diseases and pathological conditions affected by TMEM16A modulation is also envisaged.

Also provided is a method for treating or preventing diseases and pathological conditions affected by modulation of TMEM16A, the method comprising administering to a patient in need of such treatment an effective amount of a compound of general formula (I).

Diseases and conditions affected by TMEM16A modulation include respiratory diseases and conditions, dry mouth (xerostomia), intestinal hypermobility, cholestasis and eye diseases.

In this case, respiratory diseases and pathological conditions can be selected from cystic fibrosis, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema,

- 4 046966 bronchiectasis, including non-cystic fibrosis, asthma and primary ciliary dyskinesia;

dry mouth may result from Sjögren's syndrome, radiation therapy and xerogenic drugs;

bowel hypermobility may be associated with gastric dyspepsia, gastroparesis, chronic constipation and irritable bowel syndrome;

the eye disease may be dry eye disease.

In some cases, in a compound of general formula (I), Z is -C(O)- and R ^5b is H, such that the compound has formula (Iz):

R ¹ O

Γβ' ΥΎ γ

Xk^ ^{x 0}

R ^5a

2 3 4 _5a (b) where R1, ^R2 , ^R3 , ^R4 , ^R5a and Y are as defined for general formula (I).

In some cases, in a compound of general formula (I), Z is -C(O)NH-, and R ^5b is H, so that the compound is a compound of general formula (Iy):

(iy) where R1, ^R2 , ^R3 , ^R4 , ^R5a and Y are as defined for general formula (I).

In some compounds of the general formula (Iz), Y does not represent a bond.

In some useful compounds of this invention, R ¹ is H, CN, ethynyl, methyl, any of which is unsubstituted or substituted with OH.

In some useful compounds of this invention:

R ² represents methyl or ethyl, in particular methyl; And

R ³ represents C1 _-4 alkyl, or more suitably C1 _-3 alkyl, for example methyl, ethyl or isopropyl; any of which is optionally substituted with one or more substituents selected from hydroxyl, methoxy, ethoxy, -C(O)O-( _C1-4 alkyl) and -^H)C(O)O-( _C1-4 alkyl).

More suitably in this case, R ³ is unsubstituted or substituted with one substituent selected from methoxy, ethoxy and -^H)C(O)O-(C _1-4 alkyl), particularly methoxy or and ^(H)C(O) O-(C _1-4 alkyl).

In these compounds, R1 is suitably methyl.

In other useful compounds of this invention, R ² is H or C1 _-4 alkyl, more suitably H, methyl or ethyl, especially H or methyl.

In some useful compounds of this invention, R ³ is C1 _-10 alkyl, more suitably C1 _-6 alkyl or C _2-3 alkynyl, any of which is optionally substituted with one substituent selected from fluorine, R1 ⁴ , OR ¹⁴ , OR ¹⁵ , C(O)OR1 ⁵ , N(R1 ⁵ )S(O)2R16 and N(R1 ⁵ )C(O)OR1 ⁶ ; Where

R1 ⁴ is selected from phenyl, pyridyl and a 5- or 6-membered heterocyclic ring;

R ¹⁵ is selected from H or C _1-4 alkyl; And

R ¹⁶ represents H.

More suitably, R ³ is C _1-10 alkyl, more suitably C _1-6 alkyl, or C _2-3 alkynyl.

In these compounds it is even more suitable that R ¹⁴ be selected from a phenyl, pyridyl and 5 or 6 membered heterocyclic ring, especially a nitrogen ring and more particularly a 6 membered nitrogen ring such as morpholine, piperidine or piperazine. More suitably, R ¹⁵ is selected from H, or C _1-4 alkyl. R ¹⁶ is suitably H.

Examples of such ^R3 groups include:

methyl or ethyl, optionally substituted with OH, F, phenyl, O-phenyl, morpholine, NHS(O) ₂ C _1-4 alkyl or NHC(O)C _1-4 alkyl;

propynyl, for example prop-1-ynyl and ethynyl.

In other suitable compounds, R ³ represents a 3-7 membered carbocyclic or heterocyclic ring system, in particular a C _3-7 cycloalkyl group, for example cyclopropyl, which may be substituted as defined above, but is more suitably unsubstituted.

In yet other suitable compounds of general formula (I), R ³ represents a phenyl or pyridyl group, either of which is unsubstituted or substituted with one or more substituents, you

- 5 046966 branes of OR ¹⁷ and N(R ¹⁷ )2, where each R ¹⁷ represents H or methyl.

In some particularly useful compounds of the present invention, R ¹ is methyl or CN and R 2 and R ³ are both methyl.

In some useful compounds of this invention, R2 and ^R3 combine with the carbon atom to which they are attached to form a 3-10 membered carbocyclic or heterocyclic ring system, optionally substituted with one or more substituents independently selected from halogen, CN, OR ⁹ , N(R ⁹ )2, C(O)OR ⁹ , C(O)N(R ⁹ )2, C(O)R ⁹ , N(R ⁹ )C(O)R ⁹ and C _1-4 alkyls , optionally substituted with halogen, OR ⁹ or N(R ⁹ )2.

Suitable carbocyclic rings formed by R2 and ^R3 include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; and bridging systems such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo-[2.2.2]octyl and adamantyl (provided that the atom to which R ² and R ³ are attached does not represent is a bridging atom).

More suitable carbocyclic rings formed by R ² and R ³ include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Suitable heterocyclic rings formed by R ² and R ³ include; tetrahydropyranyl, for example tetrahydropyran-4-yl; tetrahydrofuranyl, for example tetrahydrofuran-3-yl; oxetanyl, for example oxetan-3-yl; piperidinyl, for example piperidin-2-yl and piperidin-4-yl; morpholinyl, piperazinyl and cyclopropyl-fused pyrrolidine.

More suitable heterocyclic rings formed by R ² and R ³ include; tetrahydropyran-yl, for example tetrahydropyran-4-yl; tetrahydrofuranyl, for example tetrahydrofuran-3-yl; oxetanyl, for example oxetan-3-yl; piperidinyl, for example piperidin-2-yl and piperidin-4-yl; and cyclopropyl-fused pyrrolidine.

In some compounds where R ² and R ³ form a carbocyclic or heterocyclic ring system, R ¹ represents H;

In other such compounds, R ¹ is methyl.

In other such compounds, R ¹ is methyl substituted with OH.

In still other such compounds, R ¹ is CN.

In yet other such compounds, R ¹ is ethynyl.

In still other such compounds, R ¹ is C(O)OR ¹² , for example C(O)OCH ₃ .

In particularly suitable compounds where R ² and R ³ form a carbocyclic or heterocyclic ring system: R ¹ represents H or cyano and R ² and R ³ form a 5-6 membered carbocyclic or heterocyclic ring system, in particular a 6 membered ring system system, for example cyclohexyl or tetrahydropyranyl, such as tetrahydropyran-4-yl.

In other useful compounds of the present invention, R ¹ , R ² and R ³ in combination with the carbon atom to which they are attached form a bridged 5-10 membered carbocyclic or heterocyclic ring system or phenyl, any of which is optionally substituted with one or more substituents , selected from halogen, CN, OR ⁹ , N(R ⁹ )2, C(O)OR ⁹ , C(O)N(R ⁹ )2, C(O)R ⁹ , N(R ⁹ )C(O )R ⁹ and C1-4alkyl, optionally substituted with halogen, OR ⁹ or N(R ⁹ )2.

In some cases, the carbocyclic system may be selected from 3-bicyclo[1.1.1]pentanyl, bicyclo-[2.2.1]heptanyl, bicyclo[2.2.2]octanyl and 1-adamantyl.

In other cases, the carbocyclic ring system may be selected from bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl and adamantyl, especially 3-bicyclo[1.1.1]pentanyl, 1-bicyclo[2.1.1]hexanyl and 1- adamantyl,

Alternatively, the ring system may be unsubstituted or substituted with one or more substituents, suitably one or two substituents and, more suitably, one substituent selected from fluorine, cyano, alkyl, OR ⁹ and C(O)OR ⁹ , where R ⁹ is as defined above, but suitably is H, methyl or ethyl, especially H or methyl and more especially methyl.

In other useful compounds of the present invention, R ¹ , R ² and R ³ combine with the carbon atom to which they are attached to form a phenyl group, which may be substituted as defined above, but more suitably is unsubstituted.

In certain suitable compounds of general formula (I), X ¹ is N and X ² is CR ⁸ , where R ⁸ is as defined above. In particular, X ¹ represents N and X ² represents CH.

Suitably, in such compounds, when -Z is -C(O)- and Y is a bond, then R ⁴ is not a 5-10 membered heteroaryl ring system that is attached to the linker Y via a ring nitrogen atom.

In such compounds, R ⁴ suitably represents phenyl having an OH substituent at the 2 or 3 position and, optionally, one or more additional substituents as defined above.

More suitably, R ⁴ is phenyl having an OH substituent at the 2-position and, optionally, one or more additional substituents as defined above.

In some useful compounds of this type, Z is -C(O)- and Y is not

- 6 046966 is a connection. Therefore, Y may be a straight chain C _1-6 alkylene, optionally substituted with one or more R ¹⁸ substituents as defined above.

In other suitable compounds of general formula (I), in which X ¹ represents CR ⁸ , where R ⁸ is as defined above, and X ² represents N:

when R ¹ and R ² are both H, R ³ is not a 5- or 6-membered aryl or heteroaryl ring system, optionally substituted as described above; and when R ¹ is H, R ² and R ³ do not combine to form a cyclohexyl ring.

In the compounds of the present invention, R ⁸ suitably represents H or a halogen, for example H or fluorine. In alternative suitable compounds, R ⁸ is H, halogen, OH, methoxy or ethoxy, especially H, fluorine, chlorine, OH or methoxy.

As described above, in more suitable compounds of the present invention, Z is -C(O)- or C(O)NH and such that the compound is a compound of general formula (Iz).

In some more useful compounds of the present invention, Y is a C _1-3 alkylene, even more suitably -CH ₂ -, -CH(CH ₃ )CH ₂ - or -CH ₂ CH ₂ -. More suitably, Y is -CH ₂ - or -CH ₂ CH ₂ - and in particularly suitable compounds, Y is -CH ₂ -.

In other useful compounds of this invention, Y represents a bond.

In other useful compounds of this invention, Y is a straight chain alkylene, optionally substituted with one or more R ¹⁸ substituents, wherein R ¹⁸ is as defined above and the two R ¹⁸ substituents may be attached to the same or different atoms carbon.

Suitably, in such compounds, each R ¹⁸ is independently methyl or ethyl, or two R ¹⁸ groups attached to the same carbon atom combine to form a cyclopropyl, cyclobutyl or cyclopentyl ring.

Even more suitably, Y represents a bond or ^^alkplene-.

Examples of Y linkers include the bond, -CH ₂ -, -CH(CH ₃ )-, -CH ₂ CH ₂ - and

In other suitable compounds of general formula (I), Y is -CH ₂ -, -CH ₂ CH ₂ -, -CH(CH ₃ )CH ₂ -, -CH ₂ CH(CH ₃ )- or -CH ₂ CH ₂ CH ₂ -, especially -CH ₂ - or -CH ₂ CH ₂ - and, more especially, -CH ₂ -.

In some suitable compounds of general formula (I), R ^5b is H or a halogen, for example fluorine.

More typically, R ^5b is H so that the compound is a compound of general formula (Iz) above.

In some suitable compounds of general formulas (I) and (Iz), R ^5a is H, C _1-4 alkyl or halogen, for example fluorine.

In some suitable compounds of general formulas (I) and (Iz), R ^5a is methyl or ethyl, especially methyl.

In other suitable compounds of general formula (I) and (Iz), R ^5a is halogen, especially fluorine.

More commonly, in compounds of general formulas (I) and (Iz), R ^5a is H.

In still other useful compounds of the invention, R ⁵ is halogen, especially fluorine.

In typical compounds of general formula (I), both R ^5a and R ^5b are H.

In the compounds of the present invention, R ⁴ is a 6-14 membered aryl, 5-14 membered heteroaryl or 5-10 membered carbocyclic ring system, any of which is optionally substituted as defined above. More suitably, R ⁴ is a 6-10 membered aryl, 5-10 membered heteroaryl, or a 5-10 membered carbocyclic or heterocyclic ring system, any of which is optionally substituted with one or more substituents as described above.

In some more suitable compounds of general formula (I), R ⁴ represents a 6-11 membered aryl group, for example a group selected from phenyl, naphthyl, indanyl, 1,2,3,4tetrahydronaphthyl and benzocycloheptanyl, any of which is optionally substituted as described higher.

In other more suitable compounds of general formula (I), R ⁴ represents a 5-10 membered heteroaryl group, for example a group selected from pyridyl, quinolinyl, quinoxalinyl, indazolyl, indolyl, benzoxazolyl, dihydrobenzofuranyl, furyl and thienyl, any of which is optional substituted as described above.

In other more suitable compounds of general formula (I), R ⁴ represents a carbocyclyl group, for example a group selected from cyclohexyl and adamantyl, either of which is unsubstituted or substituted, as described above.

In some useful compounds of this invention, R ⁴ is phenyl, optionally substituted with one or more substituents as described above.

Alternatively, R ⁴ is a 5-10 membered heteroaryl, optionally substituted with one

- 7 046966 or more substituents as described above. More suitably, in this case, R ⁴ is pyridyl, pyrrolyl, thienyl, furyl, benzoxazolyl, imidazolyl, indolyl or indazolyl.

In some suitable compounds, R ⁴ is substituted with one or more substituents selected from: halogen, CN;

OR ⁶ , NR ⁶ R ⁷ , C(O)OR ⁶ , C(O)N(R ⁶ )(R ⁷ );

C _1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, CN, OR ⁶ , NR ⁶ R ⁷ , C(O)OR ⁶ and C(O)N(R ⁶ )(R ⁷ );

where R ⁶ represents H, C _1-6 alkyl, C _1-6 haloalkyl, 3-7 membered carbocyclyl or 3-7 membered heterocyclyl;

R ⁷ represents H, C _1-6 alkyl or C _1-6 haloalkyl; or

R ⁶ and R ⁷ together with the nitrogen atom to which they are attached may form a 5- or 6-membered heterocyclic ring, optionally containing one or more heteroatoms selected from N, O and S, and optionally substituted with one or more oxo substituents .

In other suitable compounds where R ⁴ represents an aryl group, it is more suitable when it is unsubstituted or substituted with one or more substituents selected from:

halogen, CN, R ¹⁹ , OR ¹⁹ ;

OR ⁶ , C(O)OR ⁶ ;

C _1-4 alkyl or O(C _1-4 alkyl), optionally substituted with one or more substituents independently selected from halogen, CN, R ¹⁹ , OR ⁶ and NR ⁶ R ⁷ ;

where R ⁶ , R ⁷ and R ¹⁹ are as defined above.

More suitably, although R ⁶ is H, C1. ₄ alkyl or C _1-4 haloalkyl or, for the NR ⁶ R ⁷ fragment, R ⁶ and R ⁷ together with the nitrogen atom to which they are attached, can form a 4-7 membered heterocyclic ring, optionally containing one or more heteroatoms selected of N, O and S, and optionally substituted with one or more halogen substituents.

R ¹⁹ is more suitably a 3-6 membered carbocyclyl group or phenyl, or which is optionally substituted with one or more substituents independently selected from halogen, methyl and methoxy.

In particularly useful compounds, R ⁴ is phenyl substituted with an OH group at the 2- or 3-position and optionally with one or more additional substituents as defined for general formula (I), more suitably with one or more additional substituents, e.g. an additional substituent selected from those defined immediately above.

When R ⁴ represents a bicyclic aryl group, it is more suitably unsubstituted or substituted with one or two substituents selected from OH and halogen.

When R ⁴ represents a heteroaryl group, it is more suitably unsubstituted or substituted with one or more substituents selected from OH and halogen.

When R ⁴ represents a carbocyclic group, it is more suitably unsubstituted or substituted with one or more substituents selected from OH and halogen. Even more suitably, it is unsubstituted.

In particularly useful compounds of the present invention, Y is -CH ₂ -, R ⁴ is phenyl, and the compound is of general formula (Ia):

(la) where R ¹ , R ² , R ³ , R ^5a , X ¹ and X ² are as defined in claim 1;

R ¹⁰ represents H, OH, halogen, C^alkyl, -O(C1-6alkyl); each R ¹¹ independently represents H, halogen, OH, CN, C1-6alkyl, _{C1-6haloalkyl} , -O( _C1-6alkyl ) or C(O)O-( _C1-6alkyl ); and n is 1 or 2.

In the compounds of general formula (Ia), suitable groups R ¹ , R ² , R ³ , R ⁵ , X ¹ and X ² are as defined above for the compounds of general formula (I). Although even more suitably, X ¹ is N, X ² is CH and R ^5b is H, so that the compounds have the general formula (Id) or (Ie):

- 8 046966

where R ¹ , R ² , R ³ , R ^11a , R ^11b and R ^11c are as defined above for compounds of general formula (I).

Particularly suitable R ^11a groups for compounds of general formulas (Id) and (Ie) are H, halogen, C _1-4 alkyl, C _1-4 haloalkyl or SODStshil).

Particularly suitable R ^11b groups for compounds of general formulas (Id) and (Ie) are H, halogen, C _1-4 alkyl or C _1-4 haloalkyl.

Particularly suitable R ^11c groups for compounds of general formulas (Id) and (Ie) are H, halogen, CN, C _1-4 alkyl or C _1-4 haloalkyl. Suitable compounds of general formula (I) include: Specific examples of compounds of general formula (I) include the following:

- 9 046966

X-tert-Butyl-4-[[2-(2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 1);

N-(1-Ad amantyl)-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyr idine-2 carboxamide (Compound 1.3);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(3-methoxy-1,1dimethylpropyl)pyridine-2-carboxamide (Compound 1.4);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-G4-(1-methylcyclobutyl)pyridine-2carboxamide (Compound 1.6);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1-methylcyclohexyl)pyridine-2carboxamide (Compound 1.7);

tert-Butyl-M-[3-[[4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2carbonyl]amino]-3-methyl-butyl]carbamate (Compound 1.8);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-cyclohexylpyridine-2carboxamide (Compound 1.10);

X-tert-Butyl-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyr idine-2 carboxamide (Compound 3);

X-(1,1-Dimethylpropyl)-4-[[2-(4-fluoro-2-hydroxyphenyl)acetyl]amino]pyridine-2carboxamide (Compound 3.1a);

X-tert-Butyl-4-[[2-(4-fluoro-2-hydroxyphenyl)acetyl]amino]pyride in-2carboxamide (Compound 3.2a);

X-tert-Butyl-4-[[2-(2-chloro-6-hydroxyphenyl)acetyl] amino]pyr idine-2 carboxamide (Compound 3.3a);

4-[[2-(4-Bromo-5-chloro-2-hydroxyphenyl)acetyl]amino]-X-tert-butylpyridine-2carboxamide (Compound 3.4a);

4-[[2-(5-tert-Butyl-2-hydroxyphenyl)acetyl]amino]-M-(1cyanocyclobutyl)pyridine-2-carboxamide (Compound 3.5a);

4-[[2-(5-tert-Butyl-2-hydroxyphenyl)acetyl]amino]-M-(1methylcyclobutyl)pyridine-2-carboxamide (Compound 3.6a);

X-tert-butyl-4-[2-(2,5-dibromo-3-fluoro-6-hydroxyphenyl)acetamido]pyridine-2-car boxamide (Compound 3.7a);

X-tert-Butyl-4-[[2-[2-hydroxy-5-(trifluoromethyl)phenyl] acetyl] amino] pyrid in-2carboxamide (Compound 3.5b);

- 10 046966 ]H-tert-Butyl-4-[[2-(4-chloro-2-hydroxyphenyl)acetyl] amino]pyr idine-2 carboxamide (Compound 3.6b);

M-tert-Butyl-4-[[2-[2-hydroxy-4-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2carboxamide (Compound 3.7b);

M-tert-Butyl-4-[[2-(2-hydroxy-5-methoxyphenyl)acetyl]amino]pyridine-2carboxamide (Compound 3.8b);

T4-tert-Butyl-4-[(6-hydroxyindan-1-carbonyl)amino]pyridine-2-carboxamide (Compound 3.9b);

M-tert-Butyl-4-[(7-hydroxyindan-1-carbonyl)amino]pyridine-2-carboxamide (Compound 3.10b);

T\G-tert-Butyl-4-[[2-(2,5-dibromo-3-chloro-6-hydroxyphenyl)acetyl]amino]pyridine-2carboxamide (Compound 3.11b);

M-tert-Butyl-4-[[2-(3-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.12b);

T4-tert-Butyl-4-[[2-(2-fluoro-5-hydroxyphenyl)acetyl]amino]pyride in-2carboxamide (Compound 3.13b);

T\G-tert-Butyl-4-[[2-(4-chloro-3-hydroxyphenyl)acetyl] amino]pyr idine-2 carboxamide (Compound 3.14b);

T\G-tert-Butyl-4-[[2-(2-chloro-3-hydroxyphenyl)acetyl] amino]pyr idine-2 carboxamide (Compound 3.15b);

T4-tert-Butyl-4-[[2-(2-chloro-5-hydroxyphenyl)acetyl] amino]pyr idine-2 carboxamide (Compound 3.16b);

T4-tert-Butyl-4-[[2-(3-chloro-5-hydroxyphenyl)acetyl] amino]pyr idine-2 carboxamide (Compound 3.17b);

T\G-tert-Butyl-4-[[2-(2-thienyl)acetyl] amino] pyridine-2-carboxamide (Compound 5);

4-[[2-(2-Adamantyl)acetyl]amino]-M-tert-butylpyridine-2-carboxamide (Compound 5.1);

M-tert-Butyl-4-[[2-(4-fluoro-2-methoxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.2);

T4-tert-Butyl-4-[[2-(5-chloro-2-fluorophenyl)acetyl]amino]pyride in-2-carboxamide (Compound 5.3);

b1-tert-Butyl-4-[[2-(2-furyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.4);

M-tert-Butyl-4-[[2-(3-chlorophenyl)acetyl]amino]pyridine-2-carboxamide

- 11 046966 (Connection 5.5);

]H-tert-Butyl-4-[[2-(1 H-indol-3-yl)acetyl]amino]pyridine-2-carboxamide (Compound 5.6);

T\G-tert-Butyl-4-[[2-(o-tolyl)acetyl]amino]pyr ide in-2-carboxamide (Compound

5.7);

T\G-tert-Butyl-4-[[2-(3,4-dichlorophenyl)acetyl]amino]pyride in-2-carboxamide (Compound 5.8);

T4-tert-Butyl-4-[[2-(3-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.9);

T4-tert-Butyl-4-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.10);

N-tert-Butyl-4-[[2-(p-tolyl)acetyl]amino]pyridine-2-carboxamide (Compound

5.I);

T4-tert-Butyl-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.12);

T\G-tert-Butyl-4-[[2-(4-fluorophenyl)acetyl] amino] pyridine-2-carboxamide (Compound 5.13);

]H-tert-Butyl-4-[[2-(m-tolyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.14);

4-[[2-(1,3-Benzoxazol-6-yl)acetyl]amino]-M-tert-butylpyridine-2-carboxamide (Compound 5.15);

T\G-tert-Butyl-4-[[2-(2-chloro-3-pyridyl)acetyl] amino]pyr ide in-2-carboxamide (Compound 5.16);

T\G-tert-Butyl-4-[[2-(2,6-dichlorophenyl)acetyl]amino]pyride in-2-carboxamide (Compound 5.17);

T\G-tert-Butyl-4-[[2-(4-chloro-3-fluorophenyl)acetyl] amino]pyride in-2-carboxamide (Compound 5.18);

T\G-tert-Butyl-4-[[2-(3,5 - dichlorophenyl)acetyl] amino]pyr ide in-2-carboxamide (Compound 5.19);

M-tert-Butyl-4-[[2-(2-chlorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.20);

T\G-tert-Butyl-4-[[2-(3-chloro-4-hydroxyphenyl)acetyl] amino]pyr idine-2 carboxamide (Compound 5.21);

T\G-tert-Butyl-4-(indan-1-carbonylamino)pyridine-2-carboxamide (Compound

5.22);

- 12 046966

M-tert-Butyl-4-[(2-quinoxalin-6-ylacetyl)amino]pyridine-2-carboxamide (Compound 5.23);

M-tert-Butyl-4-[[2-(2-naphthyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.24);

M-tert-Butyl-4-(2,3-dihydrobenzofuran-3-carbonylamino)pyridine-2-carboxamide (Compound 5.25);

]H-tert-Butyl-4-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-5carbonylamino)pyridine-2-carboxamide (Compound 5.26);

T\G-tert-Butyl-4-(tetrayl in-1-carbonylamino)pyridine-2-carboxamide (Compound 5.27);

M-tert-Butyl-4-[[2-(6-quinolyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.29);

M-tert-butyl-4-[[1 -(3-chlorophenyl)cyclopropanecarbonyl]amino]pyride in-2carboxamide (Compound 5.31);

>4-tert-Butyl-4-[[2-(2,3-dihydro-1,4-benzodioxin-6-yl)acetyl]amino]pyridine-2carboxamide (Compound 5.32);

N-(1,1-Dimethylprop-2-ynyl)-4-[(2-isochroman-1-ylacetyl)amino]pyr idin-2 carboxamide (Compound 5.33);

4-[[2-(4,4-Difluorocyclohexyl)acetyl]amino]-M-(1,1-dimethylprop-2ynyl)pyridine-2-carboxamide (Compound 5.34);

N-(1,1-Dimethylprop-2-ynyl)-4-[[2-[4(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 5.35);

N-(1,1 - Dimethylprop-2-ynyl)-4-[[2-[3-(trifluoromethyl)-1 H-pyrazol-4yl] acetyl] amino] pyrid in-2-carboxamide (Compound 5.36) ;

N-(1,1 - Dimethylprop-2-ynyl)-4-[[2-[3 (trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 5.37);

N-(1,1-Dimethylprop-2-ynyl)-4-[[2-[2(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 5.38);

4-[[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)acetyl]amino]-N-(1,1-d immethylprop-2ynyl)pyridin-2-carboxamide (Compound 5.39);

T\G-tert-Butyl-4-[[2-(5-cyano-2-hydroxyphenyl)acetyl]amino]pyride in-2carboxamide (Compound 6);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1,1-dimethylbutyl)pyridine-2carboxamide (Compound 7.2);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1,1,2-trimethylpropyl)pyridine- 13 046966

2-carboxamide (Compound 7.6);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-isopropylpyridine-2carboxamide (Compound 7.7);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(4-methyltetrahydropyran-4yl)pyridin-2-carboxamide (Compound 7.9);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-tetrahydropyran-4-ylpyridin-2carboxamide (Compound 7.11);

4-[2-(5-Chloro-2-hydroxyphenyl)acetamido]-M-[(18,48)-4-hydroxycyclohexyl]pyridine-2carboxamide (Compound 7.12);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-sec-butylpyridine-2carboxamide (Compound 7.13);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(2-hydroxy-1,1,2trimethylpropyl)pyridine-2-carboxamide (Compound 7.14);

T4-(3-Bicyclo[1.1. 1]pentanyl)-4-[[2-(5-chloro-2hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 7.15);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1-cyanocyclobutyl)pyridine-2carboxamide (Compound 7.16);

tert-Butyl-3-[[4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2carbonyl]amino]piperidine-1-carboxylate (Compound 8.1);

tert-Butyl(1 g, 5 s, 6s)-6-{4-[2-(5-chloro-2-hydroxyphenyl)acetamide o]pyrid in-2-amide o} -3-azabicyclo[3.

1.0]hexane-3-carboxylate (Compound 8.3);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1,1-dimethylpropyl)pyridine-2carboxamide (Compound 9.2);

X-tert-Butyl-4-[[2-(5-tert-butyl-2-hydroxyphenyl)acetyl]amino]pyridine-2carboxamide (Compound 10);

Methyl-3-[2-[[2-(tert-butylcarbamoyl)-4-pyridyl]amino]-2-oxoethyl]-4hydroxybenzoate (Compound 13);

T4-tert-Butyl-4-[[2-(2-hydroxy-5-methylphenyl)acetyl]amino]pyride in-2carboxamide (Compound 15);

T4-tert-Butyl-4-[[2-(3-hydroxy-2-pyridyl)acetyl]amino]pyridin-2-carboxamide (Compound 19);

T4-tert-Butyl-4-[[2-(5-fluoro-2-hydroxyphenyl)acetyl]amino]pyridin-2carboxamide (Compound 20);

- 14 046966

X-tert-Butyl-4-[[(1 R) or (18)-indan-1-carbonyl]amino]pyridine-2-carboxamide (Compound 21a);

X-tert-Butyl-4-[[(1 R) or (18)-indan-1-carbonyl]amino]pyridine-2-carboxamide (Compound 21b);

X-tert-Butyl-4-[(2-phenylacetyl)amino]pyridine-2-carboxamide (Compound 22);

4-(3,3 - D and methylbutanoylam hho)-N-(1,1 -dimethylprop-2-ynyl)pyridine-2carboxamide (Compound 22.1);

4-[(2-Cyclopentylacetyl)amino]-N-(1,1-dimethylprop-2-ynyl)pyride in-2carboxamide (Compound 22.2);

4-[[2-(3-Chloro-4-pyridyl)acetyl]amino]-N-(1,1-d immethylprop-2-ynyl)pyridin-2carboxamide (Compound 22.3);

4-[[2-(4-Chlorophenyl)acetyl]amino]-M-(1-cyanocyclopropyl)pyridine-2carboxamide (Compound 23);

4-[[2-(3-Chlorophenyl)acetyl]amino]-M-(1-cyanocyclopropyl)pyridine-2carboxamide (Compound 23.1);

4-[[2-(2-Chloro-5-fluorophenyl)acetyl]amino]-M-(1-cyanocyclopropyl)pyridine-2carboxamide (Compound 23.2);

X-tert-Butyl-4-(indan-2-carbonylamino)pyridine-2-carboxamide (Compound 23.3);

X-tert-Butyl-4-[[2-[2-(difluoromethoxy)phenyl]acetyl]amino]pyridine-2carboxamide (Compound 23.4);

X-tert-Butyl-4-[[2-[2-(difluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 23.5);

X-tert-Butyl-4-[[2-(3,4-difluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 23.6);

X-tert-Butyl-4-[[2-(3,5-difluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 23.7);

X-tert-Butyl-4-[[2-(2,3-difluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 23.8);

4-[[2-(2-Chlorophenyl)acetyl]amino]-M-tetrahydropyran-4-ylpyridin-2carboxamide (Compound 23.9);

X-(1-Cyanocyclobutyl)-4-[[2-(6-quinolyl)acetyl]amino]pyridine-2-carboxamide (Compound 23.11);

X-tert-Butyl-4-[[2-[2-(trifluoromethyl)phenyl]acetyl]amino]pyride in-2-carboxamide (Compound 23.12);

- 15 046966

4-[[2-(2-Bromophenyl)acetyl]amino]-M-tert-butylpyridine-2-carboxamide (Compound 23.13);

N-tert-Butyl-4-[[2-(2-cyanophenyl)acetyl]amino]pyride in-2-carboxamide (Compound 23.14);

4-[[2-(2-Chlorophenyl)acetyl]amino]-X-(4-cyanotetrahydropyran-4-yl)pyridin-2carboxamide (Compound 23.15);

X-(4-Cyanotetrahydropyran-4-yl)-4-[[2-(6-quinolyl)acetyl]amino]pyridin-2carboxamide (Compound 23.16);

4-[[2-(2-Chloro-5-methoxyphenyl)acetyl]amino]-M-(1-cyanocyclopropyl)pyridine-2carboxamide (Compound 24);

T\G-(3-Bicyclo[1.1.1]pentanyl)-4-[[2-(5-tert-butyl-2-hydroxyphenyl)acetyl] amino] pyridine-2-carboxamide (Compound 25);

4-[[2-(5-tert-Butyl-2-hydroxyphenyl)acetyl]amino]-M-(4-cyanotetrahydropyran4-yl)pyridin-2-carboxamide (Compound 25.1);

X-tert-Butyl-4-[[2-(2-hydroxy-5-phenyl-phenyl)acetyl]amino]pyridine-2carboxamide (Compound 26);

X-tert-Butyl-4-[[2-[5-chloro-2-hydroxy-4-(pyrrolidin-1ylmethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 27);

X-tert-Butyl-4-[[2-[4-[(tert-butyl amine)methyl l]-5-lor-2hydroxyphenyl]acetyl]amino]pyridine-2-carboxamide (Compound 27.1);

M-tert-Butyl-4-[[2-[5-chloro-2-hydroxy-4(morpholinomethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 27.2);

X-tert-Butyl-4-[[2-[5-chloro-4-[(3,3-difluoropyrrolidin-1-yl)methyl]-2hydroxyphenyl]acetyl]amino]pyridine-2-carboxamide (Compound 27.3);

X-tert-butyl-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-5-fluoro-pyridine-2carboxamide (Compound 28);

X-tert-Butyl-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl] amino]-3-fluoro-pyr idine-2carboxamide (Compound 28.1);

4-[[2-(2-Chlorophenyl)acetyl]amino]-X-(1-cyanocyclobutyl)pyridine-2-carboxamide (Compound 30);

4-[[2-(2-Chlorophenyl)acetyl]amino]-X-(1,1-dimethylprop-2-ynyl)pyridine-2carboxamide (Compound 30.1);

4-[[2-(2-Chlorophenyl)acetyl]amino]-M-(4-fluoro-1-bicyclo[2.1.1]hexanyl)pyridine-2carboxamide (Compound 30.2);

4-[[2-(2-Chlorophenyl)acetyl]amino]-M-(1-cyclopropyl-1-methylethyl)pyridine-2-16 046966 carboxamide (Compound 30.3);

4-[[2-(2-Chlorophenyl)acetyl]amino]-X-(1-cyano-1-methylethyl)pyridine-2carboxamide (Compound 30.3a);

4-[[2-(2-Chlorophenyl)acetyl]amino]-M-(1-methyl-3-bicyclo[1.1.1]pentanyl)pyridine2-carboxamide (Compound 30.4);

4-[[2-(2-Chlorophenyl)acetyl]amino]-M-(1-cyano-3-bicyclo[1.1.1]pentanyl)pyridine2-carboxamide (Compound 30.5);

4-[[2-(2-Chlorophenyl)acetyl]amino]-M-(2,2-difluorocyclopropyl)pyridine-2carboxamide (Compound 30.6);

4-[[2-(2-Chlorophenyl)acetyl]amino]-M-(1-cyanocyclopropyl)pyridine-2carboxamide (Compound 30.7);

4-[[2-(2-Chlorophenyl)acetyl]amino]-M-(1-methylcyclopropyl)pyridine-2carboxamide (Compound 30.8);

4-[[2-(2-Chlorophenyl)acetyl]amino]-M-(3-fluoro-1-bicyclo[1.1.1]pentanyl)pyridine2-carboxamide (Compound 30.9);

4-[[2-(2-Chlorophenyl)acetyl]amino]-X-(2-fluoro-1,1-dimethylethyl)pyridine-2carboxamide (Compound 30.10);

4-[[2-(2-Chlorophenyl)acetyl]amino]-M-(4-ethynyltetrahydropyran-4-yl)pyridin-2carboxamide (Compound 30.11);

4-[[2-(2-Chlorophenyl)acetyl]amino]-M-(1-cyanocyclopentyl)pyridine-2carboxamide (Compound 30.12);

4-[[2-(2-Chlorophenyl)acetyl]amino]-M-(2,2-difluoro-1,1-dimethylethyl)pyridine-2carboxamide (Compound 30.13);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(4-cyanotetrahydropyran-4yl)pyridin-2-carboxamide (Compound 31);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1-ethynylcyclopentyl)pyridine2-carboxamide (Compound 31.2);

4-[2-(5-Chloro-2-hydroxyphenyl)acetamido]-N-[(18,23)-2-hydroxycyclohexyl]pyridine-2-carboxamide (Compound 31.3);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-[(18,28)-2hydroxycyclohexyl]pyridine-2-carboxamide or 4-[[2-(5-Chloro-2hydroxyphenyl) acetyl]amino]-M-[(1K,2K)-2-hydroxycyclohexyl]pyridine-2carboxamide (Compound 31.3a);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(4-ethynyltetrahydropyran-4yl)pyridin-2-carboxamide (Compound 31.4);

- 17 046966

N-[(6-Amino-2-pyridyl)methyl]-4-[[2-(5-chloro-2hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 32);

12-[[4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2carbonyl]amino]dodecanoic acid (Compound 32.1);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(3-pyridylmethyl)pyridine-2carboxamide (Compound 32.2);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(2-pyridylmethyl)pyridine-2carboxamide (Compound 32.3);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(4-pyridylmethyl)pyridine-2carboxamide (Compound 32.4);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-T4-[(2hydroxyphenyl)methyl]pyridine-2-carboxamide (Compound 32.5);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1,1-dimethyl-2morpholinoethyl)pyridine-2-carboxamide (Compound 32.6);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-T4-(2-hydroxy-1,1dimethylethyl)pyridine-2-carboxamide (Compound 32.7);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-T4-(3,3-difluoro-4piperidyl)pyridine-2-carboxamide (Compound 32.8);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1H-imidazol-2-yl)pyridin-2carboxamide (Compound 32.9);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-[(1R,2R)-2hydroxycyclopentyl]pyridine-2-carboxamide (Compound 33);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1-cyano-1-methylethyl)pyridine-2carboxamide (Compound 34);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-[3(hydroxymethyl)tetrahydrofuran-3-yl]pyridin-2-carboxamide (Compound 35);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-[(3R)-3(hydroxymethyl)tetrahydrofuran-3-yl]pyridin-2-carboxamide or 4-[[2-( 5-chloro-2hydroxyphenyl)acetyl]amino]-M-[(38)-3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridin2-carboxamide (Compound 35a);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-[(3R)-3(hydroxymethyl)tetrahydrofuran-3-yl]pyridin-2-carboxamide or 4-[[2-( 5-chloro-2hydroxyphenyl)acetyl]amino]-M-[(38)-3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridin2-carboxamide (Compound 35b);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(4-hydroxy-4-methyl- 18 046966 cyclohexyl)pyridine-2-carboxamide in the form of a 6:4 mixture of stereoisomers (Compound 35.1 ); 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-[(18.2g)-2(hydroxymethyl)cyclohexyl]pyridine-2-carboxamide (Compound 35.2);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-[(1 s,3r)-3hydroxycyclopentyl]pyridine-2-carboxamide (Compound 35.3);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-[2-hydroxy-1-(hydroxymethyl)-1methylethyl]pyridine-2-carboxamide (Compound 35.4);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(3hydroxycyclohexyl)pyridine-2-carboxamide as a mixture of stereoisomers (Compound 35.6);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(3-phenoxypropyl)pyridine-2carboxamide (Compound 35.7);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1-methylcyclopropyl)pyridine-2carboxamide (Compound 35.8);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-[1-methyl-1-(2pyridyl)ethyl]pyridine-2-carboxamide (Compound 35.9);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(3-phenylpropyl)pyridine-2carboxamide (Compound 35.10);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-T4-[2-hydroxy-1-(2pyridyl)ethyl]pyridine-2-carboxamide (Compound 35.11);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-[(5-methoxy-2pyridyl)methyl]pyridine-2-carboxamide (Compound 35.12);

Ethyl 3-[[4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyr idin-2carbonyl]amino]-3-methylbutanoate (Compound 35.13);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(3-hydroxy-1,1dimethylpropyl)pyridine-2-carboxamide (Compound 35.14);

X-Benzyl-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 35.15);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-phenylpyridine-2-carboxamide (Compound 35.16);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-[(18,28)-2hydroxycyclopentyl]pyridine-2-carboxamide (Compound 35.17);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-T4-[(1C,28)-2hydroxycyclopentyl]pyridine-2-carboxamide (Compound 35.18);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-T4-[(18.2K)-2-19 046966 hydroxycyclopentyl]pyridine-2-carboxamide (Compound 35.19);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-(1-ethynylcyclohexyl)pyridine2-carboxamide (Compound 35.24);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-[1(hydroxymethyl)cyclobutyl]pyridine-2-carboxamide (Compound 35.25);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-[3-(hydroxymethyl)oxetan-3yl]pyridine-2-carboxamide (Compound 35.26);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1-cyano-2-methoxy-1methylethyl)pyridine-2-carboxamide (Compound 35.27);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-[(1hydroxycyclobutyl)methyl]pyridine-2-carboxamide (Compound 35.28);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-(1,1-dimethylprop-2ynyl)pyridine-2-carboxamide (Compound 36);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1-cyano-1,2dimethylpropyl)pyridine-2-carboxamide (Compound 37);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-(1-methylcyclopentyl)pyridine-2carboxamide (Compound 38);

X-(4-tert-Butylcyclohexyl)-4-[[2-(5-chloro-2hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 39);

T4-tert-Butyl-4-[[2-(2-chloro-3-fluorophenyl)acetyl]amino]pyridin-2-carboxamide (Compound 40);

T4-tert-Butyl-4-[[2-(2-chloro-5-fluorophenyl)acetyl]amino]pyride in-2-carboxamide (Compound 40.1);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-[4-(2hydroxyethyl)tetrahydropyran-4-yl]pyridin-2-carboxamide (Compound 42);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-[1,1-dimethyl-3-(2,2,2trifluoroethylamine)propyl]pyridine-2-carboxamide (Compound 43);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(4-fluoro-1bicyclo[2.1.1]hexanyl)pyridine-2-carboxamide (Compound 44);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-[3-(2,2-dimethylpropanoylamine)1,1-dimethylpropyl]pyridine-2-carboxamide (Compound 45);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1-cyano-2-hydroxy-1methylethyl)pyridine-2-carboxamide (Compound 46);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-[(18)-1-cyano-2-hydroxy-1methylethyl]pyridine-2-carboxamide (Compound 46a);

- 20 046966

4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-M-[(1C)-1-cyano-2-hydroxy-1methylethyl]pyridine-2-carboxamide (Compound 46b);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-(3-cyanotetrahydrofuran-3yl)pyridine-2-carboxamide (Compound 47);

Methyl 2-[4-[[4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyr idin-2carbonyl]amino]tetrahydropyran-4-yl]acetate (Compound 47.1);

Methyl 4-[[4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyrid in-2carbonyl]amino]tetrahydropyran-4-carboxylate (Compound 47.2);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-(3-cyanooxetan-3-yl)pyridin-2carboxamide (Compound 47.3);

4-[[2-(5-Fluoro-2-hydroxyphenyl)acetyl]amino]-N-(1-methylcyclobutyl)pyride in-2carboxamide (Compound 48);

PM-(4-Cyanotetrahydropyran-4-yl)-4-[[2-(5-fluoro-2hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 48.1);

N-[3-(tert-Butylamine)-1,1-dimethyl-3-oxopropyl]-4-[[2-(5-chloro-2hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 49);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-[3-(methanesulfonamido)-1,1dimethylpropyl]pyridine-2-carboxamide (Compound 50);

PM-(3-Acetamido-1,1-dimethylpropyl)-4-[[2-(5-chloro-2hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 51);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-[4(hydroxymethyl)tetrahydropyran-4-yl]pyridin-2-carboxamide (Compound 53);

PM-tert-Butyl-4-[[2-[3-(1-hydroxyethyl)phenyl]acetyl]amino]pyridine-2carboxamide (Compound 54);

M-tert-Butyl-5-chloro-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl] amino] pyrid in-2carboxamide (Compound 55);

M-tert-Butyl-4-[[2-[5-chloro-2-[(4methoxyphenyl)methoxy]phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 56);

PM-tert-butyl-4-[[(18) or (1C)-4-chloro-7-hydroxyindan-1carbonyl]amino]pyridine-2-carboxamide (Compound 57a);

PM-tert-butyl-4-[[(18) or (1C)-4-chloro-7-hydroxyindan-1carbonyl]amino]pyridine-2-carboxamide (Compound 57b);

PM-tert-Butyl-4-[[2-(2-cyclopropylphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 58);

4-[[2-(3-Bromo-5-chloro-2-hydroxyphenyl)acetyl]amino]-N-tert-butylpyride in-2-21 046966 carboxamide (Compound 59);

X-(4-Fluoro-1-bicyclo[2. 1. 1]hexanyl)-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2carboxamide (Compound 60);

X-(1-Cyano-2-hydroxy-1-methylethyl)-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2carboxamide (Compound 60.1);

N-(1,1-Dimethylprop-2-ynyl)-4-[[2-(2-fluorophenyl)acetyl]amino]pyridin-2 carboxamide (Compound 60.2);

T4-tert-Butyl-4-[[2-(5-chloro-2-hydroxy-3-isopropylphenyl)acetyl]amino]pyridine2-carboxamide (Compound 61);

T4-tert-Butyl-4-[[2-[5-chloro-2-hydroxy-3-(1 methoxyethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 62);

4-[[2-(6-Quinolyl)acetyl]amino]-M-tetrahydropyran-4-yl-pyridin-2-carboxamide (Compound 63);

4-(Benzylcarbamoylamine)-M-tert-butylpyridine-2-carboxamide (Compound 64);

T4-tert-Butyl-4-(cyclohexylmethylcarbamoylamine)pyridine-2-carboxamide (Compound 64.1);

M-tert-Butyl-4-(2-phenylethylcarbamoylamine)pyridine-2-carboxamide (Compound 64.2);

M-tert-Butyl-4-[[(1K)-1-phenylethyl]carbamoylamino]pyridine-2-carboxamide (Compound 64.3);

T4-tert-Butyl-4-[[(18)-1-phenylethyl]carbamoylamino]pyridine-2-carboxamide (Compound 64.4);

T4-tert-Butyl-4-[(2-chlorophenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 64.5);

T4-tert-Butyl-4-[(3-chlorophenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 64.7);

T4-tert-butyl-4-[(4-chlorophenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 64.8);

M-tert-Butyl-4-[(2-hydroxyphenyl)carbamoylamino]pyridine-2-carboxamide (Compound 65);

T4-tert-Butyl-4-[(2-methoxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 65.1);

T4-tert-Butyl-4-[(2-hydroxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 65.2);

T4-tert-Butyl-4-[(3-hydroxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide

- 22 046966 (Connection 65.3);

X-tert-Butyl-4-[(4-hydroxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 65.4);

X-tert-Butyl-4-[[2-[2-hydroxy-5-(1-hydroxyethyl)phenyl]acetyl]amino]pyridine2-carboxamide (Compound 66);

T4-tert-Butyl-4-[[2-[2-hydroxy-5 - [1-(2,2,2trifluoroethylamine)ethyl]phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 67);

T\G-tert-Butyl-4-[[2-[3-(cyanomethyl)phenyl] acetyl] amino] pyridine-2-carboxamide (Compound 68);

T\G-tert-Butyl-4-[[2-[3-(methoxymethyl)phenyl]acetyl]amino]pyride in-2-carboxamide (Compound 69);

T\G-tert-Butyl-4-[[2-[2-hydroxy-5-(morpholinomethyl)phenyl]acetyl]amino]pyridine2-carboxamide (Compound 70);

4-[[2-(5-Fluoro-2-hydroxyphenyl)acetyl]amino]-N-[3 (hydroxymethyl)tetrahydrofuran-3-yl]pyridin-2-carboxamide (Compound 72);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-[1-(hydroxymethyl)-2-methoxy-1methylethyl]pyridine-2-carboxamide (Compound 73);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1,1-dimethylbut-2-ynyl)pyridine-2-carboxamide (Compound 73.1);

T4-tert-Butyl-4-[[2-[2-hydroxy-5-(3 hydroxypropyl)phenyl] acetyl] amino] pyrid in-2-carboxamide (Compound 75);

4-[[2-(5-Chloro-4-fluoro-2-hydroxyphenyl)acetyl]amino]-N-(1 methylcyclobutyl)pyridine-2-carboxamide (Compound 76);

4-[[2-(2,5-Difluorophenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2carboxamide (Compound 77);

4-[[2-(2,5 - Difluorophenyl)acetyl]amino]-N-(4-fluoro-1 bicyclo[2.1.1]hexanyl)pyridine-2-carboxamide (Compound 77.1);

4-[[2-(4-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1,1-dimethylprop-2ynyl)pyridine-2-carboxamide (Compound 78);

N-(1,1 - Dimethylprop-2-ynyl)-4-[[2-[2-hydroxy-4(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 78.1);

N-(1,1 - Dimethylprop-2-ynyl)-4-[[2-[2-hydroxy-5(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 78.2);

4-[(2-Chroman-4-ylacetyl)amino]-N-(1,1-dimethylprop-2-ynyl)pyridin-2carboxamide (Compound 79);

- 23 046966

N-(1,1-Dimethylprop-2-ynyl)-4-[[2-(1-isopropyl-3,5-dimethylpyrazol-4yl)acetyl]amino]pyrid in-2-carboxamide (Compound 79.1);

M-(1,1-Dimethylprop-2-ynyl)-4-[[2-(1H-indazol-4-yl)acetyl]amino]pyridine-2carboxamide (Compound 79.2);

M-(1,1-Dimethylprop-2-ynyl)-4-[[2-(1H-indol-7-yl)acetyl]amino]pyridine-2carboxamide (Compound 79.3);

M-(1-Cyano-1-methylethyl)-4-[[2-(5-fluoro-2-hydroxyphenyl)acetyl]amino]pyridine-2carboxamide (Compound 81);

N-(1-Cyano-2-hydroxy-1-methylethyl)-4-[[2-(5-fluoro-2hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 81.1);

4-[[2-(5-Fluoro-2-hydroxyphenyl)acetyl]amino]-N-isopropyl-pyride and n-2carboxamide (Compound 81.2);

N-(1,1 - Dimethylprop-2-ynyl)-4-[[2-(5-fluoro-2hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 81.3);

N-(4-Φτορ-1-bicyclo[2.1.1]hexanyl)-4-[[2-(5-fluoro-2hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 81.4);

4-[[2-(5-Fluoro-2-hydroxyphenyl)acetyl]amino]-Ν-[1 (hydroxymethyl)cyclobutyl]pyridine-2-carboxamide (Compound 81.5);

N-(1-Cyano-1-methylethyl)-4-(thiophene-3-carbonylamino)pyride in-2-carboxamide (Compound 83);

N-(1-Cyano-1-methylethyl)-4-[(2-cyclohexylacetyl)amino]pyridine-2-carboxamide (Compound 83.1);

N-(1-Cyano-1-methylethyl)-4-(cyclohexanecarbonylamino)pyridine-2-carboxamide (Compound 83.2);

N-(1-Cyano-1-methylethyl)-4-[(3,3-difluorocyclopentanecarbonyl)amino]pyrid in-2carboxamide (Compound 83.3);

N-(1-Cyano-1-methylethyl)-4-[(1-methylcyclopentanecarbonyl)amino]pyr idine-2 carboxamide (Compound 83.4);

N-(1-Cyano-1-methylethyl)-4-(3-cyclohexylpropanoylamine)pyridine-2carboxamide (Compound 83.5);

4-(2-{Bicyclo[2.2.1]heptan-2-yl} acetamide ο)-Ν-(1-cyano-1-methylethyl)pyride in-2-carboxamide (Compound 83.6);

N-(1-Cyano-1-methylethyl)-4-[[2-(1-methylcyclohexyl)acetyl]amino]pyrid in-2carboxamide (Compound 83.7);

N-[2-[(l-Cyano-1-methylethyl)carbamoyl]-4-pyridyl]-2-cyclopropyl-pyrimidine-5-24 046966 carboxamide (Compound 83.8);

N-[2-[(l-Cyano-1-methylethyl)carbamoyl]-4-pyridyl]-3-isobutylisoxazole-5carboxamide (Compound 83.9);

X-(1-Cyano-1-methylethyl)-4-[[2-(4,4-difluorocyclohexyl)acetyl]amino]pyridine-2carboxamide (Compound 83.10);

4-[(1-Benzylcyclopropanecarbonyl)amino]-M-(1-cyano-1-methylethyl)pyridine-2carboxamide (Compound 83.11);

N-(1-Cyano-1-methylethyl)-4-[3-(2-methoxy-4-pyridyl)propanoylamino]pyridine-2carboxamide (Compound 83.13);

4-[(5-tert-Butyl-2-methylpyrazole-3-carbonyl)amino]-N-(1-cyano-1 methylethyl)pyridine-2-carboxamide (Compound 83.14);

N-(1-Cyano-1-methylethyl)-4-[(2-pyrazol-1-ylbenzoyl)amino]pyridine-2 carboxamide (Compound 83.15);

X-[2-[(1-Cyano-1-methylethyl)carbamoyl]-4-pyridyl]-6-(trifluoromethyl)pyridine-2carboxamide (Compound 83.16);

N-[2-[(l-Cyano-1-methylethyl)carbamoyl]-4-pyridyl]-3-oxo-4H-1,4-benzoxazine-7carboxamide (Compound 83.17);

N-[2-[(1-Cyano-1-methylethyl)carbamoyl]-4-pyridyl]-1-ethylindole-2-carboxamide (Compound 83.18);

X-(1-Cyano-1-methylethyl)-4-[[2-(2,2,2-trifluoroethyl)pyrazole-3carbonyl]amino]pyridine-2-carboxamide (Compound 83.19);

N-[2-[(l-Cyano-1-methylethyl)carbamoyl]-4-pyridyl]-3-phenylisoxazole-4carboxamide (Compound 83.20);

4-[(1-Benzylpyrazole-4-carbonyl)amino]-N-(1-cyano-1-methylethyl)pyride in-2carboxamide (Compound 83.21);

T4-(1-Cyano-1-methylethyl)-4-[(2-methyl-5-phenylpyrazole-3-carbonyl)amino]pyridine2-carboxamide (Compound 83.22);

N-(1-Cyano-1-methylethyl)-4-[[2-(3-methyl-1,2,4-oxadiazol-5yl)benzoyl]amino]pyride in-2-carboxamide (Compound 83.23);

N-(l-Cyano-1-methylethyl)-4-[(3-methyl-1-phenylpyrazole-4-carbonyl)amino]pyridine2-carboxamide (Compound 83.24);

N-[2-[(l-Cyano-1-methylethyl)carbamoyl]-4-pyridyl]-2-phenoxypyridine-3carboxamide (Compound 83.25);

N-(1-Cyano-1-methylethyl)-4-[[2,5-dimethyl-1-(2-thienylmethyl)pyrrole-3carbonyl]amino]pyridine-2-carboxamide (Compound 83.26);

- 25 046966

X-[2-[(1-Cyano-1-methylethyl)carbamoyl]-4-pyridyl]-5-(2-methoxyphenyl)isoxazole3-carboxamide (Compound 83.27);

X-[2-[(1-Cyano-1-methylethyl)carbamoyl]-4-pyridyl]-4-methyl-2-phenylthiazol-5carboxamide (Compound 83.28);

4-[(4-Acetamidobenzoyl)amino]-M-(1-cyano-1-methylethyl)pyridine-2-carboxamide (Compound 83.29);

N-[2-[(1-Cyano-1-methylethyl)carbamoyl]-4-pyridyl]-1,3-benzothiazol-7carboxamide (Compound 83.30);

N-(1-Cyano-1-methylethyl)-4-[3-(4-fluorophenyl)butanoylamino]pyridine-2carboxamide (Compound 83.31);

N-[2-[(1-Cyano-1-methylethyl)carbamoyl]-4-pyridyl]-1-methyl-2-oxoquinoline-3 carboxamide (Compound 83.32);

N-tert-Butyl-3 - [[2-(2-hydroxycyclohexyl)acetyl]amino]benzamide (Compound 84);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-[1-cyano-2-methoxy-1(methoxymethyl)ethyl]pyridine-2-carboxamide (Compound 86);

4-[[2-(3-Amino-4-tert-butylphenyl)acetyl]amino]-X-tert-butylpyridine-2carboxamide (Compound 87);

4-[[2-(2-Amino-4-tert-butylphenyl)acetyl]amino]-M-tert-butylpyridine-2carboxamide (Compound 88);

X-tert-Butyl-4-[[2-(4-tert-butyl-3-hydroxyphenyl)acetyl]amino]pyridine-2carboxamide (Compound 89);

X-tert-Butyl-4-[[2-(4-tert-butyl-2-hydroxyphenyl)acetyl]amino]pyridine-2carboxamide (Compound 90);

X-tert-Butyl-4-[[2-(4-tert-butyl-2-fluoro-5-hydroxyphenyl)acetyl]amino]pyridine2-carboxamide (Compound 91);

4-[[2-(4-Chloro-3-hydroxyphenyl)acetyl]amino]-M-(4-cyanotetrahydropyran-4yl)pyridin-2-carboxamide (Compound 92);

4-[[2-(4-Chloro-3-hydroxyphenyl)acetyl]amino]-M-(1-cyano-1-methylethyl)pyridine-2carboxamide (Compound 92.1);

4-[[2-(4-Chloro-3-hydroxyphenyl)acetyl]amino]-M-(1,1-dimethylprop-2ynyl)pyridine-2-carboxamide (Compound 92.2);

4-[[2-(4-Chloro-3-hydroxyphenyl)acetyl]amino]-M-[(18,28)-2hydroxycyclopentyl]pyridine-2-carboxamide (Compound 92.3);

4-[[2-(4-tert-Butyl-3-hydroxyphenyl)acetyl]amino]-M-[3(hydroxymethyl)tetrahydrofuran-3-yl]pyridin-2-carboxamide (Compound 93);

4-[[2-(4-tert-Butyl-3-hydroxyphenyl)acetyl]amino]-M-[(28)-2hydroxycyclohexyl]pyridine-2-carboxamide (Compound 93.1);

4-[[2-(4-tert-Butyl-3-hydroxyphenyl)acetyl]amino]-PM-[(28)-2hydroxycyclopentyl]pyridine-2-carboxamide (Compound 93.2);

4-[[2-(4-tert-Butyl-3-hydroxyphenyl)acetyl]amino]-PM-(4-cyanotetrahydropyran4-yl)pyridin-2-carboxamide (Compound 93.3);

4-[[2-(4-tert-Butyl-3-hydroxyphenyl)acetyl]amino]-M-(1-cyano-1methylethyl)pyridine-2-carboxamide (Compound 93.4);

4-[[2-(4-tert-Butyl-3-hydroxyphenyl)acetyl]amino]-M-(1,1-dimethylprop-2ynyl)pyridine-2-carboxamide (Compound 93.5); And

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1-methyl-1-phenylethyl)pyridine2-carboxamide (Compound 94);

and salts of any of the above compounds.

- 26 046966

Some compounds of general formula (I) are new and, therefore, in a further aspect of the present invention there is provided a compound of general formula (I) as defined above, provided that:

when X ¹ is N and X ² is CH, Z is -C(O)- and Y is a bond, R ⁴ is not a 5-10 membered heteroaryl or heterocyclic ring linked to Y through a nitrogen atom; and also when X ¹ represents CH and X ² represents N:

when Z is -C(O)-, Y is not a bond; and when Z is -C(O)NH- and Y is a bond, R ⁴ is not a 12-membered heteroaryl ring system.

In some particularly useful new compounds of the invention, X ¹ is N and X ² is CH.

Examples of new compounds according to this invention are:

X-tert-Butyl-4-[[2-(2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 1);

X-(1,1-Dimethylpropyl)-3-[[2-(2-hydroxyphenyl)acetyl]amino]benzamide (Compound 1.1);

N-( 1 - Ad amantyl)-3 - [[2-(5-chloro-2-hydroxyphenyl)acetyl] amino] benzamide (Compound 1.2);

N-( 1 - Adamantyl)-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl] amino] pyrid in-2carboxamide (Compound 1.3);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(3-methoxy-1,1dimethylpropyl)pyridine-2-carboxamide (Compound 1.4);

3-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1,1-dimethylpropyl)benzamide (Compound 1.5);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-(1-methylcyclobutyl)pyridine-2carboxamide (Compound 1.6);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1-methylcyclohexyl)pyridine-2carboxamide (Compound 1.7);

tert-Butyl-M-[3-[[4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2carbonyl]amino]-3-methyl-butyl]carbamate (Compound 1.8);

3-[[2-(2-Hydroxyphenyl)acetyl]amino]-M-(2-methoxy-1,1-dimethylethyl)benzamide (Compound 1.9);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-cyclohexylpyridine-2carboxamide (Compound 1.10);

N-tert-Butyl-3 - [[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]benzamide (Compound 2);

N-tert-Butyl-3 - [[2-(5-fluoro-2-hydroxyphenyl)acetyl]amino]benzamide (Compound

2.1) ;

N-tert-Butyl-3 - [[2-(3-fluoro-2-hydroxyphenyl)acetyl]amino]benzamide (Compound

2.2) ;

N-tert-Butyl-3 - [[2-(4-fluoro-2-hydroxyphenyl)acetyl]amino]benzamide (Compound

2.3) ;

N-tert-Butyl-3 - [[2-(2,6-dihydroxyphenyl)acetyl]amino]benzamide (Compound

2.4) ;

X-tert-Butyl-3-[3-(2-hydroxyphenyl)propanamido]benzamide (Compound 2.5);

X-tert-Butyl-3-[[2-(2-hydroxy-6-methoxyphenyl)acetyl]amino]benzamide (Compound 2.6);

X-tert-Butyl-3-[2-(2-hydroxyphenyl)propanamido]benzamide (Compound 2.7);

X-tert-Butyl-3-[[2-(2-hydroxy-3-methoxyphenyl)acetyl]amino]benzamide (Compound 2.8);

N-tert-Butyl-3 - [[2-(3,5-difluoro-2-hydroxyphenyl)acetyl]amino]benzamide (Compound 2.9);

3-[[2-(5-Bromo-2-hydroxyphenyl)acetyl]amino]-N-tert-butylbenzamide (Compound

2.Yu);

- 27 046966 No. tert-Butyl-3-[[2-(2,3-difluoro-6-hydroxyphenyl)acetyl]amino]benzamide (Compound 2.11);

N-tert-Butyl-3 - [[2-(4,5-difluoro-2-hydroxyphenyl)acetyl]amino]benzamide (Compound 2.12);

K-(1,1-Dimethylpropyl)-3-[[2-(4-fluoro-2-hydroxyphenyl)acetyl]amino]benzamide (Compound 2.13);

14-tert-Butyl-3-[[2-(2-hydroxy-4-methoxyphenyl)acetyl]amino]benzamide (Compound 2.14);

N-tert-Butyl-3 - [[2-(2-fluoro-6-hydroxyphenyl)acetyl] amino]benzamide (Compound 2.15);

N-tert-Butyl-3 - [[2-(2,3-dihydroxyphenyl)acetyl]amino]benzamide (Compound

2.16);

N-tert-Butyl-3 - [[2-[2-hydroxy-5-(trifluoromethyl)phenyl] acetyl] amino] benzamide (Compound 2.17);

Methyl 3-[2-[3-(tert-butylcarbamoyl)anilino]-2-oxo-ethyl]-4-hydroxybenzoate (Compound 2.18);

N-tert-Butyl-3 - [[2-[2-hydroxy-4-(trifluoromethyl)phenyl] acetyl] amino] benzamide (Compound 2.19);

Ntert-Butyl-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyr idine-2 carboxamide (Compound 3);

N-(l,l-Dimethylpropyl)-4-[[2-(4-fluoro-2-hydroxyphenyl)acetyl]amino]pyridine-2carboxamide (Compound 3.1a);

Ntert-Butyl-4-[[2-(4-fluoro-2-hydroxyphenyl)acetyl]amino]pyride in-2carboxamide (Compound 3.2a);

N tert-Butyl-4-[[2-(2-chloro-6-hydroxyphenyl)acetyl]amino]pyridine-2carboxamide (Compound 3.3a);

4-[[2-(4-Bromo-5-chloro-2-hydroxyphenyl)acetyl]amino]-N-tert-butylpyride in-2carboxamide (Compound 3.4a);

4-[[2-(5-tert-Butyl-2-hydroxyphenyl)acetyl]amino]-M-(1cyanocyclobutyl)pyridine-2-carboxamide (Compound 3.5a);

4-[[2-(5-tert-Butyl-2-hydroxyphenyl)acetyl]amino]-M-(1methylcyclobutyl)pyridine-2-carboxamide (Compound 3.6a);

M-tert-butyl-4-[2-(2,5-dibromo-3-fluoro-6-hydroxyphenyl)acetamido]pyridine-2-car boxamide (Compound 3.7a);

]H-tert-Butyl-4-[[2-[2-hydroxy-5 -(trifluoromethyl)phenyl] acetyl] amino] pyrid in-2carboxamide (Compound 3.5b);

M-tert-Butyl-4-[[2-(4-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2carboxamide (Compound 3.6b);

Ntert-Butyl-4-[[2-[2-hydroxy-4-(trifluoromethyl)phenyl] acetyl] amino] pyrid in-2carboxamide (Compound 3.7b);

Ntert-Butyl-4-[[2-(2-hydroxy-5-methoxyphenyl)acetyl] amino]pyr idine-2 carboxamide (Compound 3.8b);

M-tert-Butyl-4-[(6-hydroxyindan-1-carbonyl)amino]pyridine-2-carboxamide (Compound 3.9b);

]H-tert-Butyl-4-[(7-hydroxyindan-1-carbonyl)amino]pyridine-2-carboxamide (Compound 3.10b);

Ntert-Butyl-4-[[2-(2,5-dibromo-3-chloro-6-hydroxyphenyl)acetyl] amino] pyridine-2 carboxamide (Compound 3.11b);

- 28 046966

T\G-tert-Butyl-4-[[2-(3-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.12b);

T\G-tert-Butyl-4-[[2-(2-fluoro-5-hydroxyphenyl)acetyl] amino] pyrid in-2carboxamide (Compound 3.13b);

T\G-tert-Butyl-4-[[2-(4-chloro-3-hydroxyphenyl)acetyl] amino]pyr idine-2 carboxamide (Compound 3.14b);

T\G-tert-Butyl-4-[[2-(2-chloro-3-hydroxyphenyl)acetyl] amino]pyr idine-2 carboxamide (Compound 3.15b);

T\G-tert-Butyl-4-[[2-(2-chloro-5-hydroxyphenyl)acetyl] amino]pyr idine-2 carboxamide (Compound 3.16b);

T4-tert-Butyl-4-[[2-(3-chloro-5-hydroxyphenyl)acetyl] amino]pyr idine-2 carboxamide (Compound 3.17b);

T4-tert-Butyl-3-[[2-(3-hydroxyphenyl)acetyl]amino]benzamide (Compound 4);

T\G-tert-Butyl-3-[[2-(1H-indazol-3-yl)acetyl]amino]benzamide (Compound 4.1);

N-tert-Butyl-3 - [[2-(5-fluoro-1 N-indol-3-yl)acetyl]amino]benzamide (Compound

4.2) ;

T\G-tert-Butyl-3-[[2-(2-hydroxyphenyl)acetyl]amino]benzamide (Compound 4.3);

T\G-tert-Butyl-4-[[2-(2-thienyl)acetyl] amino] pyridine-2-carboxamide (Compound 5);

4-[[2-(2-Adamantyl)acetyl]amino]-M-tert-butylpyridine-2-carboxamide (Compound 5.1);

T\G-tert-Butyl-4-[[2-(4-fluoro-2-methoxyphenyl)acetyl] amino] pyridine-2-carboxamide (Compound 5.2);

T4-tert-Butyl-4-[[2-(5-chloro-2-fluorophenyl)acetyl]amino]pyride in-2-carboxamide (Compound 5.3);

T\G-tert-Butyl-4-[[2-(2-furyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.4);

T\G-tert-Butyl-4-[[2-(3-chlorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.5);

T\G-tert-Butyl-4-[[2-(1H-indol-3-yl)acetyl]amino]pyridine-2-carboxamide (Compound 5.6);

T4-tert-Butyl-4-[[2-(o-tolyl)acetyl]amino]pyride in-2-carboxamide (Compound

5.7);

T4-tert-Butyl-4-[[2-(3,4-dichlorophenyl)acetyl]amino]pyride in-2-carboxamide (Compound 5.8);

T\G-tert-Butyl-4-[[2-(3-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.9);

T\G-tert-Butyl-4-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.10);

T\G-tert-Butyl-4-[[2-(p-tolyl)acetyl] amino] pyridine-2-carboxamide (Compound

- 29 046966

5.I);

N-tert-Butyl-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.12);

T4-tert-Butyl-4-[[2-(4-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.13);

X-tert-Butyl-4-[[2-(m-tolyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.14);

4-[[2-(1,3-Benzoxazol-6-yl)acetyl]amino]-M-tert-butylpyridine-2-carboxamide (Compound 5.15);

T4-tert-Butyl-4-[[2-(2-chloro-3-pyridyl)acetyl]amino]pyride in-2-carboxamide (Compound 5.16);

T4-tert-Butyl-4-[[2-(2,6-dichlorophenyl)acetyl]amino]pyride in-2-carboxamide (Compound 5.17);

T\G-tert-Butyl-4-[[2-(4-chloro-3-fluorophenyl)acetyl] amino]pyride in-2-carboxamide (Compound 5.18);

T4-tert-Butyl-4-[[2-(3,5-dichlorophenyl)acetyl]amino]pyride in-2-carboxamide (Compound 5.19);

T\G-tert-Butyl-4-[[2-(2-chlorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.20);

T4-tert-Butyl-4-[[2-(3-chloro-4-hydroxyphenyl)acetyl] amino]pyr idine-2 carboxamide (Compound 5.21);

T4-tert-Butyl-4-(indan-1-carbonylamino)pyridine-2-carboxamide (Compound

5.22);

T\G-tert-Butyl-4-[(2-quinoxalin-6-ylacetyl)amino]pyridine-2-carboxamide (Compound 5.23);

T4-tert-Butyl-4-[[2-(2-naphthyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.24);

T4-tert-Butyl-4-(2,3-dihydrobenzofuran-3-carbonylamino)pyridine-2-carboxamide (Compound 5.25);

T\G-tert-Butyl-4-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-5carbonylamino)pyridine-2-carboxamide (Compound 5.26);

T4-tert-Butyl-4-(tetralin-1-carbonylamino)pyridine-2-carboxamide (Compound 5.27);

T\G-tert-Butyl-4-[[2-(6-quinolyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.29);

T\G-tert-butyl-4-[[1-(3-chlorophenyl)cyclopropanecarbonyl]amino]pyridine-2carboxamide (Compound 5.31);

T\G-tert-Butyl-4-[[2-(2,3-dihydro-1,4-benzodioxin-6-yl)acetyl]amino]pyridine-2carboxamide (Compound 5.32);

N-(1,1 - Dimethylprop-2-ynyl)-4-[(2-isochroman-1 -ylacetyl)amino]pyr idin-2 - 30 046966 carboxamide (Compound 5.33);

4-[[2-(4,4-Difluorocyclohexyl)acetyl]amino]-M-(1,1-dimethylprop-2ynyl)pyridine-2-carboxamide (Compound 5.34);

N-(1,1-Dimethylprop-2-ynyl)-4-[[2-[4(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 5.35);

N-(1,1 - Dimethylprop-2-ynyl)-4-[[2-[3-(trifluoromethyl)-1 H-pyrazol-4yl] acetyl] amino] pyrid in-2-carboxamide (Compound 5.36) ;

N-(1,1 - Dimethylprop-2-ynyl)-4-[[2-[3 (trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 5.37);

N-(1,1-Dimethylprop-2-ynyl)-4-[[2-[2(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 5.38);

4-[[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)acetyl]amino]-X-(1,1-dimethylprop-2ynyl)pyridine-2-carboxamide (Compound 5.39);

T4-tert-Butyl-4-[[2-(5-cyano-2-hydroxyphenyl)acetyl]amino]pyridin-2carboxamide (Compound 6);

3-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1,1,2,2tetramethylpropyl)benzamide (Compound 7);

3-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1,1-dimethylbutyl)benzamide (Compound 7.1);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1,1-dimethylbutyl)pyridine-2carboxamide (Compound 7.2);

3-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-cyclohexylbenzamide (Compound 7.3);

3-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-tetrahydropyran-4-ylbenzamide (Compound 7.4);

3-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1,1,2-trimethylpropyl)benzamide (Compound 7.5);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1,1,2-trimethylpropyl)pyridine2-carboxamide (Compound 7.6);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-isopropylpyridine-2carboxamide (Compound 7.7);

3-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(4-methyltetrahydropyran-4yl)benzamide (Compound 7.8);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(4-methyltetrahydropyran-4yl)pyridin-2-carboxamide (Compound 7.9);

3-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1-methylcyclobutyl)benzamide (Compound 7.10);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-tetrahydropyran-4-ylpyridin-2carboxamide (Compound 7.11);

4-[2-(5-Chloro-2-hydroxyphenyl)acetamido]-M-[(18,48)-4-hydroxycyclohexyl]pyri

- 31 046966 din-2carboxamide (Compound 7.12);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-sec-butylpyridine-2carboxamide (Compound 7.13);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(2-hydroxy-1,1,2trimethylpropyl)pyridine-2-carboxamide (Compound 7.14);

T4-(3-Bicyclo[1.1. 1]pentanyl)-4-[[2-(5-chloro-2hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 7.15);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1-cyanocyclobutyl)pyridine-2carboxamide (Compound 7.16);

tert-Butyl-3-[[3-[[2-(5-chloro-2hydroxyphenyl)acetyl]amino]benzoyl]amino]piperidine-1-carboxylate (Compound 8);

tert-Butyl-3-[[4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2carbonyl]amino]piperidine-1-carboxylate (Compound 8.1);

tert-Butyl-4-[[3-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]benzoyl]amino]-4methylpiperidine-1-carboxylate (Compound 8.2);

tert-Butyl(1 g, 5 s, 6s)-6-{4-[2-(5-chloro-2-hydroxyphenyl)acetamide o]pyrid in-2-amide o} -3-azabicyclo[3.

1.0]hexane-3-carboxylate (Compound 8.3);

N-tert-Butyl-3 - [[2-(5-chloro-2-hydroxyphenyl)acetyl] amino]-4-fluorobenzamide (Compound 9);

N-tert-Butyl-3 - [[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-5-methylbenzamide (Compound 9.1);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1,1-dimethylpropyl)pyridine-2carboxamide (Compound 9.2);

T\G-tert-Butyl-4-[[2-(5-tert-butyl-2-hydroxyphenyl)acetyl]amino]pyridine-2carboxamide (Compound 10);

T\G-tert-Butyl-5 - [[2-(5-chloro-2-hydroxyphenyl)acetyl] amino]-2-hydroxy-benzamide (Compound I);

N-tert-Butyl-3 - [[2-(5-cyano-2-hydroxyphenyl)acetyl]amino]benzamide (Compound 12);

Methyl-3-[2-[[2-(tert-butylcarbamoyl)-4-pyridyl]amino]-2-oxoethyl]-4hydroxybenzoate (Compound 13);

N-tert-Butyl-3 - [[2-(5-chloro-2-hydroxyphenyl)acetyl] amino]-4-hydroxy-benzamide (Compound 14);

X-tert-Butyl-4-[[2-(2-hydroxy-5-methylphenyl)acetyl]amino]pyride in-2carboxamide (Compound 15);

N-tert-Butyl-3 - [[2-(5-chloro-2-hydroxyphenyl)acetyl] amino]-4-methoxybenzamide (Compound 16);

No. tert-Butyl-5-[[2-(5-chloro-2-hydroxyphenyl)acetyl] amino]-2-fluorobenzamide

- 32 046966 (Connection 17);

N-tert-Butyl-3 - [[2-(5-chloro-2-hydroxyphenyl)acetyl] amino]-5-fluorobenzamide (Compound 18);

T\G-tert-Butyl-4-[[2-(3-hydroxy-2-pyridyl)acetyl]amino]pyride in-2-carboxamide (Compound 19);

T4-tert-Butyl-4-[[2-(5-fluoro-2-hydroxyphenyl)acetyl]amino]pyridin-2carboxamide (Compound 20);

X-tert-Butyl-4-[[(1 R) or (18)-indan-1-carbonyl]amino]pyridine-2-carboxamide (Compound 21a);

X-tert-Butyl-4-[[(1 R) or (18)-indan-1-carbonyl]amino]pyridine-2-carboxamide (Compound 21b);

L'G-tert-Butyl-4-[(2-phenylacetyl)amino]pyridine-2-carboxamide (Compound 22);

4-(3,3 - D and methylbutanoylam hho)-N-(1,1 -dimethylprop-2-ynyl)pyridine-2carboxamide (Compound 22.1);

4-[(2-Cyclopentylacetyl)amino]-N-(1,1-dimethylprop-2-ynyl)pyride in-2carboxamide (Compound 22.2);

4-[[2-(3-Chloro-4-pyridyl)acetyl]amino]-N-(1,1-d immethylprop-2-ynyl)pyridin-2 carboxamide (Compound 22.3);

4-[[2-(4-Chlorophenyl)acetyl]amino]-M-(1-cyanocyclopropyl)pyridine-2carboxamide (Compound 23);

4-[[2-(3-Chlorophenyl)acetyl]amino]-M-(1-cyanocyclopropyl)pyridine-2carboxamide (Compound 23.1);

4-[[2-(2-Chloro-5-fluorophenyl)acetyl]amino]-M-(1-cyanocyclopropyl)pyridine-2carboxamide (Compound 23.2);

X-tert-Butyl-4-(indan-2-carbonylamino)pyridine-2-carboxamide (Compound 23.3);

X-tert-Butyl-4-[[2-[2-(difluoromethoxy)phenyl]acetyl]amino]pyridine-2carboxamide (Compound 23.4);

X-tert-Butyl-4-[[2-[2-(difluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 23.5);

X-tert-Butyl-4-[[2-(3,4-difluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 23.6);

X-tert-Butyl-4-[[2-(3,5-difluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 23.7);

X-tert-Butyl-4-[[2-(2,3-difluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 23.8);

4-[[2-(2-Chlorophenyl)acetyl]amino]-X-tetrahydropyran-4-ylpyridin-2carboxamide (Compound 23.9);

X-(1-Cyanocyclobutyl)-4-[[2-(6-quinolyl)acetyl]amino]pyridine-2-carboxamide (Compound 23.11);

- 33 046966

X-tert-Butyl-4-[[2-[2-(trifluoromethyl)phenyl]acetyl]amino]pyride in-2-carboxamide (Compound 23.12);

4-[[2-(2-Bromophenyl)acetyl]amino]-M-tert-butylpyridine-2-carboxamide (Compound 23.13);

T\G-tert-Butyl-4-[[2-(2-cyanophenyl)acetyl]amino]pyride in-2-carboxamide (Compound 23.14);

4-[[2-(2-Chlorophenyl)acetyl]amino]-M-(4-cyanotetrahydropyran-4-yl)pyridin-2carboxamide (Compound 23.15);

X-(4-Cyanotetrahydropyran-4-yl)-4-[[2-(6-quinolyl)acetyl]amino]pyridin-2carboxamide (Compound 23.16);

4-[[2-(2-Chloro-5-methoxyphenyl)acetyl]amino]-M-(1-cyanocyclopropyl)pyridine-2carboxamide (Compound 24);

T4-(3-Bicyclo[1.1.1]pentanyl)-4-[[2-(5-tert-butyl-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 25);

-[[2-(5-tert-Butyl-2-hydroxyphenyl)acetyl]amino]-M-(4-cyanotetrahydropyran-4yl)pyridin-2-carboxamide (Compound 25.1);

M-tert-Butyl-4-[[2-(2-hydroxy-5-phenyl-phenyl)acetyl]amino]pyridine-2carboxamide (Compound 26);

T4-tert-Butyl-4-[[2-[5-chloro-2-hydroxy-4-(pyrrolidin-1ylmethyl)phenyl] acetyl] amino] pyridin-2-carboxamide (Compound 27);

T4-tert-Butyl-4-[[2-[4-[(tert-butylamine)methyl]-5-chloro-2hydroxyphenyl]acetyl]amino]pyridine-2-carboxamide (Compound 27.1);

X-tert-Butyl-4-[[2-[5-chloro-2-hydroxy-4(morpholinomethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 27.2);

M-tert-Butyl-4-[[2-[5-chloro-4-[(3,3-difluoropyrrolidin-1-yl)methyl]-2hydroxyphenyl]acetyl]amino]pyridine-2-carboxamide (Compound 27.3);

X-tert-butyl-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-5-fluoro-pyridine-2carboxamide (Compound 28);

X-tert-Butyl-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-3-fluoro-pyridine-2carboxamide (Compound 28.1);

4-[[2-(2-Chlorophenyl)acetyl]amino]-M-(1-cyanocyclobutyl)pyridine-2-carboxamide (Compound 30);

4-[[2-(2-Chlorophenyl)acetyl]amino]-M-(1,1-dimethylprop-2-ynyl)pyridine-2carboxamide (Compound 30.1);

4-[[2-(2-Chlorophenyl)acetyl]amino]-M-(4-fluoro-1-bicyclo[2.1.1]hexanyl)pyridine-2carboxamide (Compound 30.2);

4-[[2-(2-Chlorophenyl)acetyl]amino]-M-(1-cyclopropyl-1-methylethyl)pyridine-2carboxamide (Compound 30.3);

4-[[2-(2-Chlorophenyl)acetyl]amino]-M-(1-cyano-1-methylethyl)pyridine-2carboxamide (Compound 30.3a);

- 34 046966

4-[[2-(2-Chlorophenyl)acetyl]amino]-M-(1-methyl-3-bicyclo[1.1.1]pentanyl)pyridine2-carboxamide (Compound 30.4);

4-[[2-(2-Chlorophenyl)acetyl]amino]-M-(1-cyano-3-bicyclo[1.1.1]pentanyl)pyridine2-carboxamide (Compound 30.5);

4-[[2-(2-Chlorophenyl)acetyl]amino]-M-(2,2-difluorocyclopropyl)pyridine-2carboxamide (Compound 30.6);

4-[[2-(2-Chlorophenyl)acetyl]amino]-M-(1-cyanocyclopropyl)pyridine-2carboxamide (Compound 30.7);

4-[[2-(2-Chlorophenyl)acetyl]amino]-M-(1-methylcyclopropyl)pyridine-2carboxamide (Compound 30.8);

4-[[2-(2-Chlorophenyl)acetyl]amino]-M-(3-fluoro-1-bicyclo[1.1.1]pentanyl)pyridine2-carboxamide (Compound 30.9);

4-[[2-(2-Chlorophenyl)acetyl]amino]-X-(2-fluoro-1,1-dimethylethyl)pyridine-2carboxamide (Compound 30.10);

4-[[2-(2-Chlorophenyl)acetyl]amino]-M-(4-ethynyltetrahydropyran-4-yl)pyridin-2carboxamide (Compound 30.11);

4-[[2-(2-Chlorophenyl)acetyl]amino]-M-(1-cyanocyclopentyl)pyridine-2carboxamide (Compound 30.12);

4-[[2-(2-Chlorophenyl)acetyl]amino]-M-(2,2-difluoro-1,1-dimethylethyl)pyridine-2carboxamide (Compound 30.13);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(4-cyanotetrahydropyran-4yl)pyridin-2-carboxamide (Compound 31);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1-ethynylcyclopentyl)pyridine2-carboxamide (Compound 31.2);

4-[2-(5-Chloro-2-hydroxyphenyl)acetamido]-M-[(18,28)-2-hydroxycyclohexyl]pyridine-2-carboxamide (Compound 31.3);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-[(18,28)-2hydroxycyclohexyl]pyridine-2-carboxamide or 4-[[2-(5-Chloro-2hydroxyphenyl) acetyl]amino]-M-[(1K,2K)-2-hydroxycyclohexyl]pyridine-2carboxamide (Compound 31.3a);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(4-ethynyltetrahydropyran-4yl)pyridin-2-carboxamide (Compound 31.4);

N-[(6-Amino-2-pyridyl)methyl]-4-[[2-(5-chloro-2hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 32); 12-[[4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2carbonyl]amino]dodecanoic acid (Compound 32.1);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(3-pyridylmethyl)pyridine-2carboxamide (Compound 32.2);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(2-pyridylmethyl)pyridine-2carboxamide (Compound 32.3);

- 35 046966

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(4-pyridylmethyl)pyridine-2carboxamide (Compound 32.4);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-T4-[(2hydroxyphenyl)methyl]pyridine-2-carboxamide (Compound 32.5);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1,1-dimethyl-2morpholinoethyl)pyridine-2-carboxamide (Compound 32.6);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(2-hydroxy-1,1dimethylethyl)pyridine-2-carboxamide (Compound 32.7);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(3,3-difluoro-4piperidyl)pyridine-2-carboxamide (Compound 32.8);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1H-imidazol-2-yl)pyridin-2carboxamide (Compound 32.9);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-T4-[(1R,2R)-2hydroxycyclopentyl]pyridine-2-carboxamide (Compound 33);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1-cyano-1-methylethyl)pyridine-2carboxamide (Compound 34);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-[3(hydroxymethyl)tetrahydrofuran-3-yl]pyridin-2-carboxamide (Compound 35);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-[(3R)-3(hydroxymethyl)tetrahydrofuran-3-yl]pyridin-2-carboxamide or 4-[ [2 - ( 5-chloro-2hydroxyphenyl)acetyl]amino]-M-[(38)-3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridin2-carboxamide (Compound 35a);

-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-[(3R)-3(hydroxymethyl)tetrahydrofuran-3-yl]pyridin-2-carboxamide or 4-[ [2 - (5 -chloro-2hydroxyphenyl)acetyl]amino]-M-[(38)-3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridin2-carboxamide (Compound 35b);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(4-hydroxy-4-methylcyclohexyl)pyridine-2-carboxamide as a 6:4 mixture of stereoisomers (Compound 35.1); 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-[(18.2g)-2(hydroxymethyl)cyclohexyl]pyridine-2-carboxamide (Compound 35.2);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-[(18,3r)-3hydroxycyclopentyl]pyridine-2-carboxamide (Compound 35.3);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-[2-hydroxy-1-(hydroxymethyl)-1methylethyl]pyridine-2-carboxamide (Compound 35.4);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-T4-(3hydroxycyclohexyl)pyridine-2-carboxamide as a mixture of stereoisomers (Compound 35.6);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(3-phenoxypropyl)pyridine-2carboxamide (Compound 35.7);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1-methylcyclopropyl)pyridine-2-36 046966 carboxamide (Compound 35.8);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-[1-methyl-1-(2pyridyl)ethyl]pyridine-2-carboxamide (Compound 35.9);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-(3-phenylpropyl)pyridine-2carboxamide (Compound 35.10);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-[2-hydroxy-1-(2pyridyl)ethyl]pyridine-2-carboxamide (Compound 35.11);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-[(5-methoxy-2pyridyl)methyl]pyridine-2-carboxamide (Compound 35.12);

Ethyl 3-[[4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyr idin-2carbonyl]amino]-3-methylbutanoate (Compound 35.13);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-(3-hydroxy-1,1dimethylpropyl)pyridine-2-carboxamide (Compound 35.14);

X-Benzyl-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 35.15);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-phenylpyridine-2-carboxamide (Compound 35.16);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-[(1S,2S)-2hydroxycyclopentyl]pyridine-2-carboxamide (Compound 35.17);

4-[[2-(5-Chloro-2-hydroxifenyl(acetyl]ami ho]-N-[(1R,2S)-2hydroxycyclopentyl]pyridine-2-carboxamide (Compound 35.18);

4-[[2-(5-Chloro-2-hydroxyphenyl(acetyl]amino]-X-[(1S,2R)-2hydroxycyclopentyl]pyridine-2-carboxamide (Compound 35.19);

- [[2-(5-Fluoro-2-hydroxyphenyl)acetyl]amino]-N-(1-methylcyclohexyl)benzamide (Compound 35.20);

N-(1,1 - Dimethylprop-2-ynyl)-3 - [[2-(5-fluoro-2hydroxyphenyl)acetyl]amino]benzamide (Compound 35.21);

N-Cyclohexyl-3 -[[2-(5-fluoro-2-hydroxyphenyl)acetyl]amino]benzamide (Compound 35.22);

- [[2-(5-Fluoro-2-hydroxyphenyl)acetyl]amino]-N-[3 (hydroxymethyl)tetrahydrofuran-3-yl]benzamide (Compound 35.23);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1-ethynylcyclohexyl)pyridine2-carboxamide (Compound 35.24);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-[1(hydroxymethyl)cyclobutyl]pyridine-2-carboxamide (Compound 35.25);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-[3-(hydroxymethyl)oxetan-3yl]pyridine-2-carboxamide (Compound 35.26);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1-cyano-2-methoxy-1methylethyl)pyridine-2-carboxamide (Compound 35.27);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-[(1-37 046966 hydroxycyclobutyl)methyl]pyridine-2-carboxamide (Compound 35.28);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1,1-dimethylprop-2ynyl)pyridine-2-carboxamide (Compound 36);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-(1-cyano-1,2dimethylpropyl)pyridine-2-carboxamide (Compound 37);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1-methylcyclopentyl)pyridine-2carboxamide (Compound 38);

X-(4-tert-Butylcyclohexyl)-4-[[2-(5-chloro-2hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 39);

X-tert-Butyl-4-[[2-(2-chloro-3-fluorophenyl)acetyl]amino]pyride in-2-carboxamide (Compound 40);

X-tert-Butyl-4-[[2-(2-chloro-5-fluorophenyl)acetyl]amino]pyride in-2-carboxamide (Compound 40.1);

X-(4-Cyanotetrahydropyran-4-yl)-3-[[2-(5-fluoro-2hydroxyphenyl)acetyl]amino]benzamide (Compound 41);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-[4-(2hydroxyethyl)tetrahydropyran-4-yl]pyridin-2-carboxamide (Compound 42);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-[1,1-dimethyl-3-(2,2,2trifluoroethylamine)propyl]pyridine-2-carboxamide (Compound 43);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-(4-fluoro-1bicyclo[2.1.1]hexanyl)pyridine-2-carboxamide (Compound 44);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-[3-(2,2-dimethylpropanoylamine)1,1-dimethylpropyl]pyridine-2-carboxamide (Compound 45);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1-cyano-2-hydroxy-1methylethyl)pyridine-2-carboxamide (Compound 46);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-[(18)-1-cyano-2-hydroxy-1methylethyl]pyridine-2-carboxamide or 4-[[2-( 5-chloro-2-hydroxyphenyl)acetyl]amino]-X[(1R)-1-cyano-2-hydroxy-1-methylethyl]pyridin-2-carboxamide (Compound 46a);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-[(18)-1-cyano-2-hydroxy-1methylethyl]pyridine-2-carboxamide or 4-[[2-( 5-chloro-2-hydroxyphenyl)acetyl]amino]-X[(1R)-1-cyano-2-hydroxy-1-methylethyl]pyridin-2-carboxamide (Compound 46b);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-(3-cyanotetrahydrofuran-3yl)pyridine-2-carboxamide (Compound 47);

Methyl 2-[4-[[4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyr idin-2carbonyl]amino]tetrahydropyran-4-yl]acetate (Compound 47.1);

Methyl 4-[[4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyrid in-2carbonyl]amino]tetrahydropyran-4-carboxylate (Compound 47.2);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(3-cyanooxetan-3-yl)pyridin-2carboxamide (Compound 47.3);

4-[[2-(5-Fluoro-2-hydroxyphenyl)acetyl]amino]-X-(1-methylcyclobutyl)pyridine-2-38 046966 carboxamide (Compound 48);

X-(4-Cyanotetrahydropyran-4-yl)-4-[[2-(5-fluoro-2hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 48.1);

N-[3-(tert-Butylamine)-1,1-dimethyl-3-oxopropyl]-4-[[2-(5-chloro-2hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 49);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-[3-(methanesulfonamido)-1,1dimethylpropyl]pyridine-2-carboxamide (Compound 50);

N-(3-Acetamido-1,1-dimethylpropyl)-4-[[2-(5-chloro-2hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 51);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-[4(hydroxymethyl)tetrahydropyran-4-yl]pyridin-2-carboxamide (Compound 53);

X-tert-Butyl-4-[[2-[3-(1-hydroxyethyl)phenyl]acetyl]amino]pyridine-2carboxamide (Compound 54);

X-tert-Butyl-5-chloro-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl] amino] pyrid in-2carboxamide (Compound 55);

X-tert-Butyl-4-[[2-[5-chloro-2-[(4methoxyphenyl)methoxy]phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 56);

X-tert-butyl-4-[[(18) or (1C)-4-chloro-7-hydroxyindan-1carbonyl]amino]pyridine-2-carboxamide and Example 57b: X-tert-butyl-4-[[( 18) or (lR)-4chloro-7-hydroxyindan-1-carbonyl]amino]pyridine-2-carboxamide (Compound 57a);

X-tert-butyl-4-[[(18) or (1C)-4-chloro-7-hydroxyindan-1carbonyl]amino]pyridine-2-carboxamide and Example 57b: X-tert-butyl-4-[[( 18) or (lR)-4chloro-7-hydroxyindan-1-carbonyl]amino]pyridine-2-carboxamide (Compound 57b);

X-tert-Butyl-4-[[2-(2-cyclopropylphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 58);

4-[[2-(3-Bromo-5-chloro-2-hydroxyphenyl)acetyl]amino]-N-tert-butylpyride in-2carboxamide (Compound 59);

X-(4-Fluoro-1-bicyclo[2.1.1]hexanyl)-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2carboxamide (Compound 60);

N-(1-Cyano-2-hydroxy-1-methylethyl)-4-[[2-(2-fluorophenyl)acetyl] amino]pyr idine-2 carboxamide (Compound 60.1);

N-(1,1-Dimethylprop-2-ynyl)-4-[[2-(2-fluorophenyl)acetyl]amino]pyridin-2 carboxamide (Compound 60.2);

X-tert-Butyl-4-[[2-(5-chloro-2-hydroxy-3-isopropylphenyl)acetyl]amino]pyridine2-carboxamide (Compound 61);

X-tert-Butyl-4-[[2-[5-chloro-2-hydroxy-3-(1 methoxyethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 62);

4-[[2-(6-Quinolyl)acetyl]amino]-M-tetrahydropyran-4-yl-pyridin-2-carboxamide (Compound 63);

4-(Benzylcarbamoylamine)-M-tert-butylpyridine-2-carboxamide (Compound 64);

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X-tert-Butyl-4-(cyclohexylmethylcarbamoylamine)pyridine-2-carboxamide (Compound 64.1);

T\G-tert-Butyl-4-(2-phenylethylcarbamoylamine)pyridine-2-carboxamide (Compound 64.2);

T\G-tert-Butyl-4-[[(1K)-1-phenylethyl]carbamoylamino]pyridine-2-carboxamide (Compound 64.3);

T4-tert-Butyl-4-[[(18)-1-phenylethyl]carbamoylamino]pyridine-2-carboxamide (Compound 64.4);

T\G-tert-Butyl-4-[(2-chlorophenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 64.5);

X-tert-butyl-4-(1H-indol-3-ylcarbamoylamine)pyridine-2-carboxamide (Compound 64.6);

X-tert-Butyl-4-[(3-chlorophenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 64.7);

X-tert-butyl-4-[(4-chlorophenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 64.8);

X-tert-Butyl-4-[(2-hydroxyphenyl)carbamoylamino]pyridine-2-carboxamide (Compound 65);

X-tert-Butyl-4-[(2-methoxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 65.1);

X-tert-Butyl-4-[(2-hydroxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 65.2);

X-tert-Butyl-4-[(3-hydroxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 65.3);

X-tert-Butyl-4-[(4-hydroxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 65.4);

N-tert-Butyl-4-[[2-[2-hydroxy-5-(1-hydroxyethyl)phenyl]acetyl]amino]pyridine2-carboxamide (Compound 66);

T\G-tert-Butyl-4-[[2-[2-hydroxy-5 - [1-(2,2,2trifluoroethylamine)ethyl]phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 67);

T\G-tert-Butyl-4-[[2-[3-(cyanomethyl)phenyl] acetyl] amino] pyridine-2-carboxamide (Compound 68);

T\G-tert-Butyl-4-[[2-[3-(methoxymethyl)phenyl]acetyl]amino]pyride in-2-carboxamide (Compound 69);

T\G-tert-Butyl-4-[[2-[2-hydroxy-5-(morpholinomethyl)phenyl]acetyl]amino]pyridine2-carboxamide (Compound 70);

3-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(3-cyanotetrahydrofuran-3yl)benzamide (Compound 71);

3-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1-methylcyclohexyl)benzamide (Compound 71.1);

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4-[[2-(5-Fluoro-2-hydroxyphenyl)acetyl]amino]-N-[3 (hydroxymethyl)tetrahydrofuran-3-yl]pyridin-2-carboxamide (Compound 72);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-[1-(hydroxymethyl)-2-methoxy-1methylethyl]pyridine-2-carboxamide (Compound 73);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1,1-dimethylbut-2-ynyl)pyridine-2-carboxamide (Compound 73.1);

3-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1,1-dimethylprop-2ynyl)benzamide (Compound 74);

3-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-[3(hydroxymethyl)tetrahydrofuran-3-yl]benzamide (Compound 74.1);

T4-tert-Butyl-4-[[2-[2-hydroxy-5-(3 hydroxypropyl)phenyl] acetyl] amino] pyrid in-2-carboxamide (Compound 75);

4-[[2-(5-Chloro-4-fluoro-2-hydroxyphenyl)acetyl]amino]-N-(1 methylcyclobutyl)pyridine-2-carboxamide (Compound 76);

4-[[2-(2,5-Difluorophenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2carboxamide (Compound 77);

4-[[2-(2,5-Difluorophenyl)acetyl]amino]-N-(4-fluoro-1 bicyclo[2.1.1]hexanyl)pyridine-2-carboxamide (Compound 77.1);

4-[[2-(4-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1,1-dimethylprop-2ynyl)pyridine-2-carboxamide (Compound 78);

N-(1,1 - Dimethylprop-2-ynyl)-4-[[2-[2-hydroxy-4(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 78.1);

N-(1,1 - Dimethylprop-2-ynyl)-4-[[2-[2-hydroxy-5(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 78.2);

4-[(2-Chroman-4-ylacetyl)amino]-N-(1,1-dimethylprop-2-ynyl)pyridin-2carboxamide (Compound 79);

N-(1,1-Dimethylprop-2-ynyl)-4-[[2-(1-isopropyl-3,5-dimethylpyrazol-4yl)acetyl]amino]pyride in-2-carboxamide (Compound 79.1);

M-(1,1-Dimethylprop-2-ynyl)-4-[[2-(1H-indazol-4-yl)acetyl]amino]pyridine-2carboxamide (Compound 79.2);

M-(1,1-Dimethylprop-2-ynyl)-4-[[2-(1H-indol-7-yl)acetyl]amino]pyridine-2carboxamide (Compound 79.3);

3-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(4-cyanotetrahydropyran-4yl)benzamide (Compound 80);

X-(1-Cyano-1-methylethyl)-4-[[2-(5-fluoro-2-hydroxyphenyl)acetyl]amino]pyridine-2·carboxamide (Compound 81);

N-(1-Cyano-2-hydroxy-1-methylethyl)-4-[[2-(5-fluoro-2hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 81.1);

4-[[2-(5-Fluoro-2-hydroxyphenyl)acetyl]amino]-N-isopropyl-pyridin-2 carboxamide (Compound 81.2);

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N-(1,1 - Dimethylprop-2-ynyl)-4-[[2-(5-fluoro-2hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 81.3);

Ν-(4-Φτορ-1-bicyclo[2.1.1]hexanyl)-4-[[2-(5-fluoro-2hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 81.4);

4-[[2-(5-Fluoro-2-hydroxyphenyl)acetyl]amino]-Ν-[1 (hydroxymethyl)cyclobutyl]pyridine-2-carboxamide (Compound 81.5);

N-tert-Butyl-b-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]pyrimide in-4carboxamide (Compound 82);

N-(1-Cyano-1-methylethyl)-4-(thiophene-3-carbonylamino)pyride in-2-carboxamide (Compound 83);

N-(1-Cyano-1-methylethyl)-4-[(2-cyclohexylacetyl)amino]pyridine-2-carboxamide (Compound 83.1);

N-(1-Cyano-1-methylethyl)-4-(cyclohexanecarbonylamino)pyridine-2-carboxamide (Compound 83.2);

N-(1-Cyano-1-methylethyl)-4-[(3,3-difluorocyclopentanecarbonyl)amino]pyrid in-2carboxamide (Compound 83.3);

N-(1-Cyano-1-methylethyl)-4-[(1-methylcyclopentanecarbonyl)amino]pyr idine-2 carboxamide (Compound 83.4);

N-(1-Cyano-1-methylethyl)-4-(3-cyclohexylpropanoylamine)pyridine-2carboxamide (Compound 83.5);

4-(2-{Bicyclo[2.2.1]heptan-2-yl} acetamide ο)-Ν-(1-cyano-1-methylethyl)pyride in-2-carboxamide (Compound 83.6);

N-(1-Cyano-1-methylethyl)-4-[[2-(1-methylcyclohexyl)acetyl]amino]pyrid in-2carboxamide (Compound 83.7);

N-[2-[(l-Cyano-1-methylethyl)carbamoyl]-4-pyridyl]-2-cyclopropyl-pyrimidine-5carboxamide (Compound 83.8);

N-[2-[(l-Cyano-1-methylethyl)carbamoyl]-4-pyridyl]-3-isobutylisoxazole-5carboxamide (Compound 83.9);

N-(l-Cyano-1-methylethyl)-4-[[2-(4,4-difluorocyclohexyl)acetyl]amino]pyridine-2carboxamide (Compound 83.10);

4-[(1-Benzylcyclopropanecarbonyl)amino]-M-(1-cyano-1-methylethyl)pyridine-2carboxamide (Compound 83.11);

N-(1-Cyano-1-methylethyl)-4-[3-(2-methoxy-4-pyridyl)propanoylamino]pyridin-2carboxamide (Compound 83.13);

4-[(5-tert-Butyl-2-methylpyrazole-3-carbonyl)amino]-N-(1-cyano-1 methylethyl)pyridine-2-carboxamide (Compound 83.14);

N-(1-Cyano-1-methylethyl)-4-[(2-pyrazol-1-ylbenzoyl)amino]pyr idin-2 carboxamide (Compound 83.15);

M-[2-[(1-Cyano-1-methylethyl)carbamoyl]-4-pyridyl]-6-(trifluoromethyl)pyridine-2carboxamide (Compound 83.16);

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X-[2-[(1-Cyano-1-methylethyl)carbamoyl]-4-pyridyl]-3-oxo-4H-1,4-benzoxazine-7carboxamide (Compound 83.17);

N-[2-[(1-Cyano-1-methylethyl)carbamoyl]-4-pyridyl]-1-ethylindole-2-carboxamide (Compound 83.18);

X-(1-Cyano-1-methylethyl)-4-[[2-(2,2,2-trifluoroethyl)pyrazole-3carbonyl]amino]pyridine-2-carboxamide (Compound 83.19);

X-[2-[(1-Cyano-1-methylethyl)carbamoyl]-4-pyridyl]-3-phenylisoxazole-4carboxamide (Compound 83.20);

4-[(1-Benzylpyrazole-4-carbonyl)amino]-N-(1-cyano-1-methylethyl)pyride in-2carboxamide (Compound 83.21);

X-(1-Cyano-1-methylethyl)-4-[(2-methyl-5-phenylpyrazole-3-carbonyl)amino]pyridine2-carboxamide (Compound 83.22);

N-(1-Cyano-1-methylethyl)-4-[[2-(3-methyl-1,2,4-oxadiazol-5yl)benzoyl]amino]pyride in-2-carboxamide (Compound 83.23);

N-(l-Cyano-1-methylethyl)-4-[(3-methyl-1-phenylpyrazole-4-carbonyl)amino]pyridine2-carboxamide (Compound 83.24);

X-[2-[(1-Cyano-1-methylethyl)carbamoyl]-4-pyridyl]-2-phenoxypyridine-3carboxamide (Compound 83.25);

N-(1-Cyano-1-methylethyl)-4-[[2,5-dimethyl-1-(2-thienylmethyl)pyrrole-3carbonyl]amino]pyridine-2-carboxamide (Compound 83.26);

X-[2-[(1-Cyano-1-methylethyl)carbamoyl]-4-pyridyl]-5-(2-methoxyphenyl)isoxazole3-carboxamide (Compound 83.27);

X-[2-[(1-Cyano-1-methylethyl)carbamoyl]-4-pyridyl]-4-methyl-2-phenylthiazol-5carboxamide (Compound 83.28);

4-[(4-Acetamidobenzoyl)amino]-M-(1-cyano-1-methylethyl)pyridine-2-carboxamide (Compound 83.29);

X-[2-[(1-Cyano-1-methylethyl)carbamoyl]-4-pyridyl]-1,3-benzothiazol-7carboxamide (Compound 83.30);

N-(1-Cyano-1-methylethyl)-4-[3-(4-fluorophenyl)butanoylamino]pyridine-2carboxamide (Compound 83.31);

N-[2-[(1-Cyano-1-methylethyl)carbamoyl]-4-pyridyl]-1-methyl-2-oxoquinoline-3 carboxamide (Compound 83.32);

N-tert-Butyl-3 - [[2-(2-hydroxycyclohexyl)acetyl]amino]benzamide (Compound 84);

N-tert-Butyl-b-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyrimide in-4carboxamide (Compound 85);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-[1-cyano-2-methoxy-1(methoxymethyl)ethyl]pyridine-2-carboxamide (Compound 86);

4-[[2-(3-Amino-4-tert-butylphenyl)acetyl]amino]-M-tert-butylpyridine-2carboxamide (Compound 87);

- 43 046966

4-[[2-(2-Amino-4-tert-butylphenyl)acetyl]amino]-X-tert-butylpyridine-2carboxamide (Compound 88);

X-tert-Butyl-4-[[2-(4-tert-butyl-3-hydroxyphenyl)acetyl]amino]pyridine-2carboxamide (Compound 89);

M-tert-Butyl-4-[[2-(4-tert-butyl-2-hydroxyphenyl)acetyl]amino]pyridine-2carboxamide (Compound 90);

T4-tert-Butyl-4-[[2-(4-tert-butyl-2-fluoro-5-hydroxyphenyl)acetyl]amino]pyridine2-carboxamide (Compound 91);

4-[[2-(4-Chloro-3-hydroxyphenyl)acetyl]amino]-M-(4-cyanotetrahydropyran-4yl)pyridin-2-carboxamide (Compound 92);

4-[[2-(4-Chloro-3-hydroxyphenyl)acetyl]amino]-M-(1-cyano-1-methylethyl)pyridine-2carboxamide (Compound 92.1);

4-[[2-(4-Chloro-3-hydroxyphenyl)acetyl]amino]-M-(1,1-dimethylprop-2ynyl)pyridine-2-carboxamide (Compound 92.2);

4-[[2-(4-Chloro-3-hydroxyphenyl)acetyl]amino]-X-[(18,28)-2hydroxycyclopentyl]pyridine-2-carboxamide (Compound 92.3);

4-[[2-(4-tert-Butyl-3-hydroxyphenyl)acetyl]amino]-X-[3(hydroxymethyl)tetrahydrofuran-3-yl]pyridin-2-carboxamide (Compound 93);

4-[[2-(4-tert-Butyl-3-hydroxyphenyl)acetyl]amino]-X-[(28)-2hydroxycyclohexyl]pyridine-2-carboxamide (Compound 93.1);

4-[[2-(4-tert-Butyl-3-hydroxyphenyl)acetyl]amino]-X-[(28)-2hydroxycyclopentyl]pyridine-2-carboxamide (Compound 93.2);

4-[[2-(4-tert-Butyl-3-hydroxyphenyl)acetyl]amino]-X-(4-cyanotetrahydropyran4-yl)pyridin-2-carboxamide (Compound 93.3);

4-[[2-(4-tert-Butyl-3-hydroxyphenyl)acetyl]amino]-X-(1-cyano-1methylethyl)pyridine-2-carboxamide (Compound 93.4);

4-[[2-(4-tert-Butyl-3-hydroxyphenyl)acetyl]amino]-M-(1,1-dimethylprop-2ynyl)pyridine-2-carboxamide (Compound 93.5);

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1-methyl-1-phenylethyl)pyridine2-carboxamide (Compound 94); and salts and solvates of any of the above.

The compound of general formula (I) can be prepared as described below, and methods for its preparation constitute a further aspect of the present invention.

A compound of general formula (I) in which Z represents -C(O)- can be prepared from a compound of general formula (II):

R ²

R ¹ O R ^5b

R ^5a

NH ₂ (P) where R ¹ , R ² , R ³ , R ^5a and R ^5b , X ¹ and X ² as defined for general formula (I); by reaction with a compound of general formula (III):

where R ⁴ and Y are as defined for general formula (I)

The reaction is suitably carried out in the presence of a condensation reagent.

One example of a suitable condensation reagent is a carbodiimide such as 1-ethyl-3(3-dimethylaminepropyl)carbodiimide (EDCI) and a triazole such as 1-hydroxy-7-azabenzotriazole (HOAt) or hydroxybenzotriazole (HOBt). Suitably, the reaction is carried out under basic conditions, for example in the presence of an amine such as diisopropylethylamine (DIPEA) and in an organic solvent such as DMF.

- 44 046966

Alternatively, the condensing reagent may be propylphosphonic anhydride (T3P). When T3P is used as the condensing reagent, the reaction can be carried out under basic conditions, for example in the presence of an amine such as diisopropylethylamine (DIPEA) or triethylamine (TEA) and in an organic solvent such as dioxane.

Other known peptide condensing agents such as O-(Benzotriazol-1-yl)-'H.'H.'H'.'H'tetramethyluronium hexafluorophosphate (HBTU), O-(Benzotriazol-1-yl)-H,H N,N-tetramethyluronium tetrafluoroborate (TBTU), O-(7-Azabenzotriazol-1-yl)-H^,^,^-tetramethyluronium hexafluorophosphate (HATU), O-(7-Azabenzotriazol-1-yl)-H,H ^,^-tetramethyluronium tetrafluoroborate (TATU), (Benzotriazol-1-yloxy)tris(dimethylamine)phosphonium hexafluorophosphate (BOP), (Benzotriazol-1yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), etc. can also be used.

The compounds of general formula (III) are commercially available or can be prepared by methods known to those skilled in the art. For example, compounds of general formula (III) in which Y is -CH2- can be synthesized from nitriles of general formula (XXIII):

.. _; y' R ⁴

Ν' (XXIII) where R ⁴ is as defined for the general formula (I);

reaction with an aqueous base, for example a metal hydroxide such as lithium hydroxide, followed by acidification, for example with hydrochloric acid.

The reaction is suitably carried out in an aqueous solution and heated to reflux.

A nitrile of general formula (XXIII) can be prepared from a compound of general formula (XXIV):

r ²⁷ 'r ⁴ (XXIV) where R ⁴ is as defined for general formula (I) and R ²⁷ represents a halogen, for example fluorine, chlorine or bromine, especially chlorine;

by reaction with cyanide such as sodium cyanide.

The reaction can be carried out at a temperature of from about 15 to 25°C, usually at room temperature, in an organic solvent such as N,N-dimethylformamide.

A compound of general formula (XXIV) can be prepared by halogenation of a compound of general formula (XXV):

but v. ⁴ (XXV) where R ⁴ is as defined for the general formula (I).

by reaction with a halogenating agent.

Suitable halogenating agents to use in the reaction will depend on which R ²⁷ halogen group is required. For example, when R ²⁷ is chlorine, the halogenating agent may be thionyl chloride. The reaction can be carried out at a temperature of from about 15 to 25°C, usually at room temperature, in an organic solvent such as dichloromethane.

A compound of general formula (XXV) can be prepared by reducing a compound of general formula (III) in which Y represents a bond, i.e. one that has the formula:

O

HO'^R ⁴ (XXVI) where R ⁴ is as defined for the general formula (I).

The reduction can be carried out using any suitable reducing agent, for example borane-THF, and is suitably carried out at an elevated temperature, for example 30-60°C, usually about 50°C.

In an alternative method for preparing a compound of general formula (I), a compound of general formula (II) as defined above can be reacted with an acid chloride of general formula (IV):

(IV) where R ⁴ and Y are as defined for general formula (I).

The reaction is suitably carried out under basic conditions, for example in the presence of an amine, and

- 45 046966 whom as DIPEA.

This method is especially suitable for compounds in which Y represents a bond or an alkylene.

The acid chloride of the acid of general formula (IV) may be commercially available or can be prepared from the carboxylic acid of general formula (III) by reaction with a chlorinating agent, for example thionyl chloride.

Compounds of general formula (III) are known and are either commercially available or can be prepared by methods known to those skilled in the art.

Alternatively, for compounds of general formula (I) in which Z is -C(O)NH-, a compound of general formula (II) may be reacted with a compound of general formula (XIV):

O=C=NYR ⁴ (XIV) where R ⁴ and Y are as defined for general formula (I).

Suitably, the reaction is carried out in an anhydrous organic solvent such as N,Ndimethylformamide at an elevated temperature, for example about 70-85°C.

An alternative method for preparing a compound of general formula (Ia) is to react a compound of general formula (II) with a compound of general formula (XIII):

(ХШ) where R ¹⁰ , R ¹¹ and n are as defined for the compound of general formula (Ia).

The reaction can be carried out in an organic solvent such as toluene, typically at elevated temperature, eg about 90 to 120°C, eg about 100 to 110°C, and under elevated pressure conditions, eg in a sealed test tube.

Compounds of general formulas (XIII) and (XIV) are known and are either commercially available or can be prepared by methods known to those skilled in the art.

A compound of general formula (II) can be prepared by the reaction of a compound of general formula (VIII):

O R ^5b

R ^5a (VIII) where R ^5a , R ^5b , X ¹ and X ² are as defined for general formula (I); with a compound of general formula (VII):

R ¹

(VII) where R ¹ , R ² and R ³ are as defined for general formula (I).

Accordingly, the reaction is carried out in the presence of a condensing agent as described above for the reaction between compounds of general formula (II) and (III). TBTU is a particularly suitable condensing agent for this reaction, although EDCI and HOAt or HOBt can also be used.

In some cases, a compound of general formula (VIII) may be protected as a carbamate ester of general formula (VI):

O R ^5b

R ^5a (VI) where R ^5a , R ^5b , X ¹ and X ² as defined for general formula (I); and R ²⁰ is C _1-8 alkyl or benzyl.

In this case, reaction with a compound of general formula (VII) results in a carbamate ester of general formula (V):

- 46 046966

(V) where R ¹ , R ² , R ³ , R ^5a , R ^5b , X ¹ and X ² as defined for general formula (I); and R ²⁰ is as defined for the general formula (VI).

The carbamate protecting group can be removed by hydrolysis, suitable acid hydrolysis, for example using hydrochloric acid, and can be carried out in an organic solvent such as dichloromethane.

Compounds of general formulas (VI), (VII) and (VIII) are known and are commercially available or can be prepared by methods known to those skilled in the art.

For example, a compound of general formula (VIII) in which X ² represents C-Cl can be prepared from a compound of general formula (VIII) in which X ² represents CH by reaction with a chlorinating agent such as N-chlorosuccinimide. Suitably, the reaction occurs in an organic solvent, such as N-dimethylformamide, at an elevated temperature, for example about 50 to 70°C.

Also, a compound of general formula (VII) in which R ¹ is ethynyl and R ² and R ² together form a carbocyclic or heterocyclic ring can be prepared by reacting a compound of general formula (XVII):

R ² R ³

II

O (XVII) where R ² and R ³ form a carbocyclic or heterocyclic ring and R ²¹ represents C _3-8 alkyl, for example t-butyl; with a compound of general formula (XVIII):

р23 si ^R2a

Έ ²³ (XVIII) where each R ²³ independently represents C _1-3 alkyl, suitably in the presence of an aluminum catalyst and a base; followed by deprotection using acid.

Suitable bases include strong bases such as n-butyllithium, and a suitable acid for the deprotection step is hydrochloric acid, suitably in an organic solvent such as dioxane.

A compound of general formula (XVII) can be prepared by reacting a compound of general formula (XIX):

h ₂ n. _s ,r ²¹ o (XIX) where R ²¹ is as defined for the general formula (XVII); with a compound of general formula (XX):

(XX) where R ² and R ³ form a carbocyclic or heterocyclic ring.

Suitably, the reaction is catalyzed using a titanium (IV) catalyst, for example titanium (IV) ethoxide.

Compounds of general formulas (XIX) and (XX) are known and readily available.

An alternative method for preparing a compound of general formula (II) is to reduce a compound of general formula (IX):

- 47 046966

R ¹ 0 R ^5t}

R ^5a (IX) where R ¹ , R ² , R ³ , R ^5a , R ^5b , X ¹ and X ² as defined for general formula (I);

for example, hydrogenation over a palladium catalyst.

Hydrogenation is usually carried out in an alcohol solvent such as ethanol at a temperature of about 15 to 25°C, for example at room temperature.

Compounds of general formula (IX) can be prepared by the reaction of compounds of general formula (VIIIa):

_R 5b

It

no ₂

R ⁵³ (Villa) where R ^5a , R ^5b , X ¹ and X ² as defined for general formula (I);

with an amine of general formula (VII).

The reaction can be carried out in the presence of a condensing agent, for example one of the condensing agents described above for the reaction between compounds of general formula (II) and (III).

An alternative method for preparing a compound of general formula (I) is to react a compound of general formula (X):

O R ^5b

II I n

A A.

“ (' Г '( ^x k^ ^{x 0}

R53 (X) where X ¹ , X ² , Y, R ⁴ , R ^5a and R ^5b as defined for general formula (I);

with a compound of general formula (VII) as defined above.

Suitably, the reaction is carried out under basic conditions, for example in the presence of an amine such as DIPEA or TEA, and in the presence of a condensing agent, as described above for the reaction between compounds of general formula (II) and (III). EDCI and HOAt or HOBt is a suitable condensing agent for this reaction, such as HATU TBTU and HBTU.

A compound of general formula (X) can be prepared by deprotecting a compound of general formula (XI):

O R ^5b

XL N. Ж Ί Ύ T ХА>Х ⁰

R ⁵³ (XI) where X ¹ , X ² , Y, R ⁴ , R ^5a and R ^5b as defined for general formula (I); and R ²⁵ is C _1-8 alkyl or benzyl.

One example of a suitable deprotectant is boron tribromide, although other methods for deprotecting a carboxylic acid are known in the art and/or are discussed below.

This method using boron tribromide for deprotection is particularly suitable when the target compound is a compound of general formula (I) in which R ⁴ is replaced by OH, for example a compound of general formula (Id) or (Ie), or a compound of general formula (Ia), in which R ¹⁰ and/or one or more R ¹¹ groups is/are OH. In such compounds, the OH group in the R ⁴ moiety in a compound of general formula (XI) may be protected as OR ²⁶ , where R ²⁶ is C _1-8 alkyl or benzyl. This protecting group can also be removed using boron tribromide. Similarly, deprotection of boron tribromide is also suitable for the preparation of general compounds

- 48 046966 formula (X), in which X ¹ and/or X ² represents CR ⁸ , where R ⁸ represents OH.

On the other hand, if the desired compound of general formula (I) contains a compound containing an alkoxy group, for example a compound in which R ⁴ is replaced by a group such as O^^alkyl) or in which X ¹ and/or X ² represents C (OC _1-4 alkyl), it is preferred that the deprotection is carried out by hydrolysis, in particular alkaline hydrolysis, for example using an alkali metal hydroxide such as lithium hydroxide. This ensures that the C(O)OR ²⁵ group hydrolyzes to C(O)OH without affecting the alkoxy substituents elsewhere in the molecule.

A compound of general formula (XI) can be prepared from a compound of general formula (XII):

where X ¹ and X ² , R ^5a and R ^5b as defined for general formula (I); and R ²⁵ is as defined for the general formula (XI);

by reaction with a compound of general formula (III) as defined above, or by reaction with a compound of general formula (IV) as defined above, or by reaction with a compound of general formula (XIII).

The reaction with a compound of general formula (III) is suitably carried out under basic conditions, for example in the presence of an amine such as DIPEA or TEA, and a condensing agent is used as described above for the reaction between compounds of general formulas (II) and (III). EDCI with HOAt or HOBt is a particularly suitable condensing agent.

The reaction with the compound of general formula (IV) is usually carried out in an organic solvent such as dichloromethane. A compound of general formula (IV) can be generated in situ by reacting a compound of general formula (III) with thionyl chloride.

The reaction with a compound of general formula (XIII) can be carried out in an organic solvent such as toluene, typically at elevated temperature, for example about 90 to 120°C, for example about 100 to 110°C, and under elevated pressure conditions, for example, in a hermetically sealed test tube.

Compounds of general formula (XII) are known and are either commercially available or can be prepared by methods known to those skilled in the art.

In another alternative method, a compound of general formula (I) can be prepared by reacting a compound of general formula (XV):

where X ¹ , X ² , Y, R ⁴ , R ^5a and R ^5b as defined for general formula (I) and R ²² represents halogen, preferably chlorine or bromine;

with an amine of general formula (VII) as defined above and carbon monoxide in the presence of a phosphorus ligand such as XantPhos and a palladium catalyst.

A compound of general formula (XV) can be prepared by reacting a compound of general formula (XVI):

where X ¹ , X ² , R ^5a and R ^5b are as defined for the general formula (I) and R ²² is as defined for the general formula (XV);

with a compound of general formula (IV) as defined above, or with a compound of general formula (III) as defined above, in the presence of a condensing agent such as HATU.

The reaction can be carried out under an inert atmosphere in an organic solvent such as N,Ndimethylformamide, at a temperature of about 15 to 25°C, suitably at room temperature.

- 49 046966

When a compound of general formula (IV) is used, it can be prepared in situ by reacting a compound of general formula (III) with thionyl chloride.

Alternatively, a compound of general formula (XVI) may react with a lactone of general formula (XIII).

The compounds of general formula (XVI) are well known and are either commercially available or can be prepared by methods known to those skilled in the art.

Compounds of general formula (I) can be obtained in the form of protected derivatives. For example, a compound of general formula (I) in which R ⁴ has an OH substituent can be prepared from an equivalent of a compound of general formula (I) in which OH is protected, for example, as a C _1-6 alkoxy, benzyloxy or substituted benzyloxy group, wherein the benzyloxy group may be substituted with C _1-6 alkoxy or halogen. The protecting group may be present in the precursors of general formula (III), (IV), (X), (XI), (XIII), (XIV) and (XV) and can be removed using aqueous acid, for example aqueous hydrochloric acid or hydrogenation for example, under a hydrogen atmosphere in the presence of a metal catalyst such as palladium on carbon.

Compounds of general formula (I) can also be converted into compounds of general formula (I).

A compound of general formula (I) or (Ia) in which R ⁴ is an aryl or heteroaryl ring system substituted with one or more -O(C _1-6 alkyl) substituents can be converted to a compound of general formula (I) or ( Ia), in which the -O(C _1-6 alkyl) substituents are replaced by OH substituents by reaction with boron tribromide. This method is suitable for the preparation of compounds of general formulas (Id) and (Ie).

A compound of general formula (I) or (Ia) in which R ⁴ is an aryl or heteroaryl ring system substituted with OH may also be prepared by reacting an equivalent of a compound of general formula (I) in which R ⁴ is an aryl or heteroaryl ring system an NH2-substituted system by diazotization reaction with nitrous acid formed in situ from sodium nitrite and a strong acid such as sulfuric acid. The resulting diazonium salt reacts with water to form an OH substituent on the R ⁴ group in a reaction that is suitably catalyzed by copper(I), for example in the form of copper(I) oxide.

A compound of general formula (I) or (Ia) in which R ⁴ is an aryl or heteroaryl ring system substituted by NH ₂ can be prepared by reducing an equivalent of a compound of general formula (I) in which R ⁴ is an aryl or heteroaryl ring system , substituted with nitro. Typically reduction is achieved by hydrogenation, suitably catalyzed by palladium.

A compound of general formula (I) or (Ia) in which R ⁴ is an aryl or heteroaryl ring system substituted with nitro can be prepared by nitration of an equivalent of the compound of general formula (I), for example using concentrated nitric acid mixed with sulfuric acid. Alternatively, nitration can be carried out at an earlier stage of the process. For example, nitration can be carried out on a compound of general formula (III) or general formula (IV), and these nitrated derivatives can then be converted into compounds of general formula (I).

A compound of general formula (I) in which R ⁴ represents an aryl or heteroaryl group with a halide substituent can be converted into a compound of general formula (I) in which the halide substituent is replaced by CN, C(O)R ⁶ , C(O)OR ⁶ , C(O)N(R ⁶ )(R ⁷ ), N(R ⁷ )C(O)R ⁶ , R ¹⁹ or C _1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, CN , nitro, cycloalkyl, OR ⁶ , SR ⁶ , NR ⁶ R ⁷ , C(O)R ⁶ C(O)OR ⁶ , C(O)N(R ⁶ )(R ⁷ ) and N(R ⁷ )C( O)R ⁶ wherein R ⁶ and R ⁷ are as defined above for general formula (I), using a palladium-catalyzed carbon-carbon cross-coupling reaction such as the Heck, Suzuki-Miyaura, Stille, Hiyama or Sonogashira reaction. This may be accompanied, if required, by an additional process, for example hydrogenation to reduce alkenyl-alkyl groups.

For example, a compound of general formula (I) in which R ⁴ has a halogen substituent can be converted into an analogue in which R ⁴ has a cyano substituent by reaction with a metal cyanide salt, for example zinc cyanide. The reaction is suitably catalyzed by a palladium/phosphine complex such as tetrakis(triphenylphosphine)palladium(0).

A compound of general formula (I) in which R ⁴ has a C(O)R ⁶ substituent can be prepared from the equivalent of a halogenated compound by a palladium/phosphine catalyzed reaction with 1-vinyloxyalkane or vinyloxysilane. Accordingly, the reaction with the vinyloxyalkane is carried out in the presence of a base, such as triethylamine, and is carried out at an elevated temperature, for example about 90 to 120° C., under pressurized conditions, for example, in a sealed test tube. The reaction with vinyloxysilane can be carried out in the presence of zinc fluoride and in an anhydrous solvent such as NN-dimethylformamide. at elevated temperatures, for example about 60-80°C, under conditions of increased pressure, for example in a hermetically sealed test tube. If desired, the carbonyl group can be reduced to an OH group, for example, using a hydride reducing agent such as sodium borohydride.

Suitably, compounds of general formula (I) in which R ⁴ has a halogen substituent may

- 50 046966 be converted into compounds in which R ⁴ is replaced by CH ₂ CH ₂ -C(O)OR ⁶ by a palladium/phosphine catalyzed reaction with a compound of general formula (XXII):

O (XXII) wherein R ⁶ is as defined for general formula (I), but more preferably is not hydrogen;

followed by catalytic hydrogenation.

The reaction with the compound of general formula (XXII) can be carried out under a nitrogen atmosphere in the presence of a base such as triethylamine and at an elevated temperature, for example about 60 to 80°C.

Hydrogenation can be catalyzed by palladium or palladium/carbon.

The resulting compounds in which R ⁶ is other than hydrogen can be converted to compounds in which R ⁶ is hydrogen by hydrolysis, typically alkaline hydrolysis, for example using an aqueous alkali metal hydroxide such as lithium hydroxide.

The product of general formula (I), in which R ⁴ is substituted by CH2CH2-C(O)OH, can be reduced to obtain compounds of general formula (I), in which R ⁴ is substituted by CH2CH2-CH2OH. Suitably, the acid can be first converted to a mixed anhydride with a suitable alkyl chloroformate reagent, such as methyl chloroformate, followed by in situ reduction to the desired alcohol with a suitable reducing agent, such as sodium borohydride. The reaction can be carried out in the presence of a base such as triethylamine.

Compounds of general formula (I) in which R ⁴ has a C(O)OR ⁶ substituent wherein R ⁶ is not H can be prepared from compounds of general formula (I) in which R ⁴ is substituted with a halogen in a palladium-catalyzed reaction /phosphine, with carbon monoxide and the corresponding alcohol. The catalyst may be derived from a precatalyst, preferably a third generation Buchwald precatalyst such as XantPhos. Carbon monoxide can be produced by reacting formic acid with an agent such as methanesulfonyl chloride and a base such as triethylamine. The C(O)OR ⁶ group can be converted to C(O)OH by hydrolysis, for example alkaline hydrolysis using an alkali metal hydroxide such as lithium hydroxide.

Compounds of general formula (I) in which R ⁴ has a halogen substituent can be converted into compounds of general formula (I) in which R ⁴ is substituted with C _1-6 alkyl, substituted with OR ⁶ or NR ⁶ R ⁷ , where R ⁶ and R ⁷ are as defined for general formula (I), via a palladium-catalyzed reaction with a compound of formula (XXa) or (XXb):

m ⁺

M

R-F

I I,F

R ⁷ % ^B; F (XXa) (XXL) where R ⁶ and R ⁷ are as defined for general formula (I), M ⁺ is a metal ion, suitably potassium ion, and Q is C _1-6 alkylene, suitably -CH2 -.

Suitably, the reaction is carried out under mild basic conditions, for example in the presence of sodium carbonate at an elevated temperature, for example about 70 to 90°C.

Compounds of general formula (I) wherein R ⁴ is aryl substituted with halogen can be converted to compounds of general formula (I) wherein R ⁴ is aryl substituted with aryl by reaction with a suitable arylboronic acid. The reaction is suitably catalyzed by a palladium/phosphine catalyst such as 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II). Suitably, the reaction is carried out in an organic solvent, such as 1,4-dioxane, and is carried out at an elevated temperature, for example about 90 to 120°C under pressurized conditions, for example in a sealed test tube.

Compounds of general formula (I) wherein R ⁴ is phenyl can be alkylated using Friedel-Crafts type alkylation by reaction with an appropriate alcohol or alkyl halide in the presence of a strong acid Lewis catalyst, such as sulfuric acid. The position of the alkylation will depend on the position of other substituents on the ring. For example, when R ⁴ is 2-fluoro-5-hydroxyphenyl, alkylation will occur at the 4 position, as illustrated in Example 91.

In compounds of general formula (I), replacement of a halogen with a methyl group can be achieved using a Suzuki-Miyaura cross-coupling (Grey, et al., Tetrahedron Letters, 41(32), 6237-6240; 2000); introduction of nitrile can be achieved as described by Willardsen et al in Journal of Medicinal Chemistry, 47(16), 4089-4099; 2004. Installation of ester and amides can be accomplished by carbonylation as described by Veryser et al in React. Chem. Eng., 2016, 1, 142-146.

Group R ⁴ of compounds of general formula (I), in which R ⁴ represents aryl or heteroa

- 51 046966 the ryl ring system substituted with an OR ⁶ group can be halogenated by reaction with a halogenating agent, for example N-halosuccinimide or bromine.

The reaction with N-halosuccinimide can be carried out in a polar organic solvent such as acetonitrile and at an elevated temperature, for example about 50 to 70°C. The reaction with bromine can take place in solution in a solvent such as acetic acid and at a reduced temperature, for example about -5 to 5°C.

Reactions of interconversion of groups of substituents on R ⁴ can also be carried out at an earlier stage of the process. For example, compounds of general formula (III), (IV), (VI), (X), (XI) or (XV) can also be interconverted in the same way as compounds of general formula (I).

In compounds in which R ¹ represents C(O)OH, or R ¹ or R ³ is substituted with C(O)OH, or in which R ⁴ has a substituent containing a C(O)OH group, a C(O)OH group, can be reduced to the OH group using any suitable method. Hydride reducing agents such as lithium aluminum hydride are particularly suitable.

In compounds of general formula (I) containing an alkyl group substituted by a primary or secondary amino group N(R)2, the amino group can be converted to an -NiSch)-C(O)-alkyl group (where R represents the group R ⁶ , R ¹² or R ¹⁵ depending on the position of the amino group in the molecule) by reaction with a carboxylic acid in the presence of a condensing agent or with a base followed by treatment with an anhydride.

The primary and secondary amino groups in these compounds can be converted to a -N(R)C(O)O-alkyl group by reaction with a carboxylic acid anhydride. The process can be reversed by treating a compound containing an alkyloxycarbonylamine substituent with an acid or boron tribromide to produce a primary or secondary amine.

Compounds of general formula (I) in which R ³ is N(R ¹⁵ )S(O)2R ¹⁴ or N(R ¹⁵ )S(O)2R ¹⁶ can be prepared from compounds of general formula (I) in which R ³ N(R ¹⁵ ) ₂ , by reaction with a sulfonyl halide WS(O)2R ¹⁴ or WS(O)2R ¹⁶ where W is a halide, especially a chloride, and R ¹⁴ , R ¹⁵ and R ¹⁶ are as defined above .

Other interconversions of various substituent groups can be accomplished by methods known to those skilled in the art.

The compounds of the present invention are generally administered as part of a pharmaceutical composition, and, therefore, the present invention further relates to a pharmaceutical composition containing a compound of the general formula ((I), (Iz), (Ia), (Id) or (Ie) together with pharmaceutical acceptable excipient.

The pharmaceutical composition may be formulated for oral, rectal, nasal, bronchial (inhaled), topical (including dermal, transdermal, eye drops, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration and may be prepared by any methods well known in the field of pharmacy.

The composition can be prepared by combining the above active agent with an excipient. Typically, the formulations are prepared by uniformly and thoroughly combining the active agent with liquid carriers or finely divided solid carriers, or both, and then, if necessary, molding the product. The invention extends to methods for preparing a pharmaceutical composition, comprising bringing a compound of general formula (I) into contact or association with a pharmaceutically acceptable carrier or carrier medium.

The oral compositions of the present invention may be presented in the form of: individual units such as capsules, sachets or tablets, each containing a predetermined amount of the active agent; in the form of powder or granules; in the form of a solution or suspension of the active agent in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; or in the form of a bolus, etc.

For formulations for oral administration (eg, tablets and capsules), the term acceptable carrier includes carriers such as conventional excipients, for example, binders such as syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers, for example corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate, sodium stearate and other metal stearates, glyceryl stearate, stearic acid, silicone fluid, talc waxes, oils and colloidal silica. You can also use flavorings such as peppermint, oil of wintergreen, cherry flavor and the like. It may be desirable to add a coloring agent to make the dosage form easily identifiable. Tablets can also be coated by methods well known in the art.

Tablets may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by pressing

- 52 046966 in a suitable apparatus the active agent in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersant. Molded tablets can be prepared by molding in a suitable apparatus a mixture of a powdered compound moistened with an inert liquid diluent. Tablets may optionally be coated or scored and may be formulated to provide slow or controlled release of the active agent.

Other formulations suitable for oral administration include lozenges containing the active agent in a flavored base, typically sucrose and acacia or tragacanth; lozenges containing the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes containing the active agent in a suitable liquid carrier.

For topical application to the skin, the compounds of general formula (I) may be prepared as a cream, ointment, jelly, solution or suspension, etc. The cream or ointment formulations that may be used for the medicament are conventional formulations well known in the art, for example as described in standard pharmaceutical textbooks such as the British Pharmacopoeia.

Local administration to the lungs can be achieved by using an aerosol composition. Aerosol formulations typically contain the active ingredient suspended or dissolved in a suitable aerosol propellant such as a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC). Suitable CFC propellants include trichloromonoformethane (Propellant 11), dichlorotetrafluoromethane (Propellant 114) and dichlorodifluoromethane (Propellant 12). Suitable HFC propellants include tetrafluoroethane (HFC-134a) and heptafluoropropane (HFC-227). The propellant typically makes up 40-99.5%, for example 40-90%, by weight of the total inhalable composition. The composition may contain excipients, including cosolvents (eg, ethanol) and surfactants (eg, lecithin, sorbitan trioleate and the like). Other possible excipients include polyethylene glycol, polyvinylpyrrolidone, glycerin and the like. Aerosol formulations are packaged in canisters and the appropriate dose is delivered using a metering valve (for example, supplied by Bespak, Valois or 3M or, alternatively, Aptar, Coster or Vari).

Local administration to the lungs can also be achieved by using a non-pressurized formulation such as an aqueous solution or suspension. They can be administered using a nebulizer, such as one that may be hand-held and portable or for home or hospital use (ie, non-portable). The composition may contain excipients such as water, buffers, tonicity adjusting agents, pH adjusting agents, surfactants and co-solvents. Suspension liquid and aerosol formulations (pressurized or unpressurized) typically contain the compound of this invention in finely divided form, for example with a D ₅₀ of 0.510 µm, for example about 1-5 µm. Particle size distribution can be represented using D values ₁₀ , D ₅₀ and D ₉₀ . The median D ₅₀ value of a particle size distribution is defined as the particle size in microns that bisects the distribution. The measurement obtained from laser diffraction is more accurately described as a volume distribution, and therefore the D ₅₀ value obtained using this procedure is more meaningfully referred to as the Dv ₅₀ value (median of the volume distribution). In the context of this document, Dv values refer to particle size dimensions measured by laser diffraction. Similarly, D ₁₀ and D ₉₀ values used in the context of laser diffraction mean Dv ₁₀ and Dv ₉₀ values and refer to the particle size at which 10% of the distribution lies below the D ₁₀ value and 90% of the distribution lies below the D ₉₀ value, respectively .

Local administration to the lungs can also be achieved by using a dry powder formulation. The dry powder formulation will contain the compound of this invention in finely divided form, typically with a mass mean diameter (MMAD) of 1-10 microns, or a D ₅₀ of 0.5-10 microns, for example about 1-5 microns. Powders of the compound of this invention in finely divided form can be obtained using a micronization process or a similar size reduction process. Micronization can be accomplished using a jet mill such as those manufactured by Hosokawa Alpine. The resulting particle size distribution can be measured using laser diffraction (eg a Malvern Mastersizer 2000S). The formulation typically contains a locally acceptable diluent such as lactose, glucose or mannitol (preferably lactose), typically having a relatively large particle size, for example a mass mean diameter (MMAD) of 50 µm or more, for example 100 µm or more, or D ₅₀ , equal to 40-150 microns. As used herein, the term lactose refers to the lactose-containing component, including α-lactose monohydrate, β-lactose monohydrate, α-lactose anhydrous, β-lactose anhydrous and amorphous lactose. Lactose components can be processed by micronization, sieving, milling, pressing, agglomeration or spray drying. Commercially available forms of lactose in various forms are also covered, e.g. products Lactohale® (inhaled lactose; DFE Pharma), InhaLac®70 (sifted

- 53 046966 lactose for dry powder inhaler; Meggle), Pharmatose® (DFE Pharma) and Respitose® (sieved inhalation lactose; DFE Pharma). In one embodiment, the lactose component is selected from the group consisting of α-lactose monohydrate, α-lactose anhydrous, and amorphous lactose. Preferably, the lactose is α-lactose monohydrate.

Dry powder formulations may also contain other excipients. Thus, in one embodiment, the dry powder composition of the present invention contains magnesium or calcium stearate. Such formulations may have excellent chemical and/or physical stability, especially when such formulations also contain lactose.

The dry powder formulation is typically delivered using a dry powder inhalation (DPI) device. Example dry powder delivery systems include SPINHALER®, DISKHALER®, TURBOHALER®, DISKUS®, SKYEHALER®, ACCUHALER® and CLICKHALER®. Additional examples of dry powder delivery systems include ECLIPSE, NEXT, ROTAHALER, HANDIHALER, AEROLISER, CYCLOHALER, BREEZHALER/NEOHALER, MONODOSE, FLOWCAPS, TWINCAPS, X-CAPS, TURBOSPIN, ELPENHALER, MIATHALER, TWISTHALER, NOVOLIZER, PRESSAIR, ELLIPTA, lator dry powder ORIEL, MICRODOSE, PULVINAL, EASYHALER, ULTRAHALER, TAIFUN, PULMOJET, OMNIHALER, GYROHALER, TAPER, CONIX, XCELOVAIR and PROHALER.

In one embodiment, the compound of general formula (I) is provided in the form of a micronized dry powder preparation, for example containing lactose of a suitable quality.

Thus, as an aspect of the invention, there is provided a pharmaceutical composition containing a compound of general formula (I) in particulate form in combination with particulate lactose, said composition optionally containing magnesium stearate.

In one embodiment, the compound of general formula (I) is provided as a micronized dry powder formulation containing suitable quality lactose and magnesium stearate, filled in a device such as a DISKUS. Accordingly, such a device is a multi-dose device, for example, the composition is filled into blisters for use in a multi-dose device such as DISKUS.

In another embodiment, the compound of general formula (I) is provided as a micronized dry powder formulation, eg containing lactose of suitable quality, filled into hard shell capsules for use in a single administration device such as an AEROLISER.

In another embodiment, the compound of general formula (I) is provided as a micronized dry powder formulation containing suitable quality lactose and magnesium stearate, placed in hard shell capsules for use in a single administration device such as an AEROLISER.

In another embodiment, the compound of general formula (I) is provided in the form of a fine powder for use in an inhalation dosage form, the powder being in the form of fine particles with a D50 of 0.5-10 μm, for example about 1-5 μm, which were obtained by a size reduction method other than jet mill micronization, such as spray drying, spray freezing, microfluidization, high pressure homogenization, supercritical fluid crystallization, ultrasonic crystallization, or a combination of these methods, or other suitable particle generation methods known in the art, which are used to produce fine particles with an aerodynamic particle distribution of 0.5-10 microns. The resulting particle size distribution can be measured using laser diffraction (eg a Malvern Mastersizer 2000S). The particles may contain the compound alone or in combination with suitable other excipients that may aid processing. The resulting fine particles may form a final formulation for delivery to humans or may be further formulated with other suitable excipients to facilitate delivery in an acceptable dosage form.

The compound of this invention can also be administered rectally, for example, in the form of suppositories or enemas, which include aqueous or oily solutions, as well as suspensions, emulsions and foams. Such compositions are prepared in accordance with standard procedures well known to those skilled in the art. For example, suppositories can be prepared by mixing the active ingredient with a conventional suppository base such as cocoa butter or other glycerides. In this case, the drug is mixed with a suitable non-irritating excipient that is solid at normal temperatures but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

Typically, for compositions proposed for topical administration to the eye in the form of eye drops or ophthalmic ointments, the total amount of the compound of general formula (I) will be from about 0.0001 to less than 4.0% (w/w).

- 54 046966

Preferably, for topical administration to the eye, the injectable compositions of general formula (I) will be formulated as solutions, suspensions, emulsions and other dosage forms. Aqueous solutions are generally preferred based on the ease of formulation as well as the patient's ability to easily administer such compositions by dropping one or two drops of the solutions into the affected eyes. However, the compositions may also be suspensions, viscous or semi-viscous gels, or other types of solid or semi-solid compositions. Suspensions may be preferred for compounds that are not readily soluble in water.

An alternative for ocular administration is intravitreal injection of a solution or suspension of a compound of general formula (I). In addition, the compound of general formula (I) can also be administered via ocular implants or inserts.

Administered compositions of general formula (I) may also include various other ingredients, including, but not limited to, tonicity agents, buffers, surfactants, stabilizing polymer, preservatives, cosolvents, and viscosity enhancing agents. Suitable pharmaceutical compositions of general formula (I) contain a compound of this invention formulated with a tonic agent and a buffer. Pharmaceutical compositions of general formula (I) may further optionally contain a surfactant and/or a palliative agent and/or a stabilizing polymer.

A variety of tonicity agents can be used to adjust the tonicity of the composition, preferably the same as that of natural tears for ophthalmic compositions. For example, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, simple sugars such as dextrose, fructose, galactose and/or simple polyols such as sugar alcohols, mannitol, sorbitol, xylitol, lactitol, isomaltitol, maltitol and hydrogenated starch hydrolysates may be added to the composition for approximate physiological tonicity. This amount of tonicity agent will vary depending on the particular agent added. In general, however, the compositions will have a tonicity agent in an amount sufficient to ensure that the final composition has an ophthalmologically acceptable osmolality (typically about 150-450 mOsm, preferably 250-350 mOsm, and most preferably about 290 mOsm). Typically, the tonicity agents of this invention will be present in the range of 2 to 4% w/w. Preferred tonicity agents of this invention include simple sugars or sugar alcohols such as D-mannitol.

A suitable buffer system (eg, sodium phosphate, sodium acetate, sodium citrate, sodium borate or boric acid) can be added to the compositions to prevent pH shifts under storage conditions. The specific concentration will vary depending on the agent used. However, it is preferable that the buffer is selected to maintain the target pH in the range of 5 to 8, and more preferably to the target pH of 5 to 7.

Surfactants may optionally be used to deliver higher concentrations of the compound of general formula (I). Surfactants function to dissolve a compound and stabilize a colloidal dispersion such as micellar solution, microemulsion, emulsion and suspension. Examples of surfactants that may optionally be used include polysorbate, poloxamer, polyosyl 40-stearate, polyoxyl castor oil, tyloxapol, Triton and sorbitan monolaurate. Preferred surfactants used in this invention have a hydrophilic/lipophilic/HLB balance ranging from 12.4 to 13.2 and are acceptable for ophthalmic use, such as TritonX114 and tyloxapol.

Additional agents that may be added to the ophthalmic compositions of the compounds of general formula (I) are anti-irritants that function as a stabilizing polymer. The stabilizing polymer should be an ionic/charged example with the benefit of topical application to the eye, more specifically, a polymer that carries a negative charge on its surface that can exhibit a zeta potential of (-) 10-50 mV for physical stability and is capable of forming a dispersion in water (i.e. soluble in water). The preferred stabilizing polymer of this invention may be a polyelectrolyte or polyelectrolytes, if more than one, from the family of cross-linked polyacrylates such as carbomers and Pemulen(R), especially Carbomer 974p (polyacrylic acid), at 0.10.5% w/w .

Other compounds may also be added to ophthalmic compositions of the compound of general formula (I) to increase the viscosity of the carrier. Examples of viscosity enhancing agents include, but are not limited to: polysaccharides such as hyaluronic acid and its salts, chondroitin sulfate and its salts, dextrans, various polymers of the cellulose family; vinyl polymers; and polymers of acrylic acid.

Ophthalmic products for topical administration are typically packaged in multi-dose form. Thus, preservatives are necessary to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, chlorobutanol, benzododecinium bromide, methylparaben, propylparaben, phenylethyl alcohol, disodium edentate, sorbic acid, polyqua

- 55 046966 ternium-1 or other agents known to specialists in the field. Such preservatives are typically used in an amount of 0.001 to 1.0% w/v. Unit dose compositions of general formula (I) will be sterile, but usually not preserved. Consequently, such compositions generally do not contain preservatives.

Parenteral preparations will generally be sterile.

The physician or other skilled person will be able to determine the appropriate dosage for a compound of general formula (I) or (Ia) and, therefore, the amount of a compound of this invention to be included in any particular pharmaceutical composition (in unit dosage form or otherwise).

The compounds of general formula (I) may be used in combination with one or more other active agents which are useful in the treatment or prevention of respiratory diseases and conditions

An additional active agent of this type may be included in the pharmaceutical composition described above, but alternatively it may be administered separately, simultaneously with the compound of general formula (I) or at an earlier or later time.

Therefore, in an additional aspect of the present invention, there is provided a product containing a compound of general formula (I) and an additional agent useful for the treatment or prevention of respiratory diseases, as a combination preparation for simultaneous, sequential or separate use in the treatment of a disease or pathological condition affected by the influence of modulation of TMEM16A, and especially of a respiratory disease or condition, for example one of the diseases and conditions mentioned above.

Also proposed is a compound of general formula (I) in combination with an additional agent suitable for the treatment or prevention of respiratory diseases, as a combination drug for simultaneous, sequential or separate use in the treatment of a disease or pathological condition affected by modulation of TMEM16A, and especially respiratory a disease or condition, such as one of the diseases and conditions mentioned above.

Suitable additional active agents which may be included in the pharmaceutical composition or combination preparation with the compounds of general formula (I) include:

β2-adrenergic agonists such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, indacaterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol, olodaterol, vilanterol and abediter;

antihistamines, for example histamine H1 receptor antagonists such as loratadine, cetirizine, desloratadine, levocetirizine, fexofenadine, astemizole, azelastine and chlorpheniramine or _H4 receptor antagonists;

dornase alfa;

corticosteroids such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, mometasone furoate and fluticasone furoate;

leukotriene antagonists such as montelukast and zafirlukast;

anticholinergic compounds, in particular muscarinic antagonists such as ipratropium, tiotropium, glycopyrrolate, aclidinium and umeclidinium;

CFTR correction therapy (for example, potatoes, correctors or amplifiers of CFTR), such as Ivakaftor, QBW251, VX659, VX445, VX561/CPT-656, VX152, VX440, GLP2737, GLP2222, GLP2451, PTI438, PTI801, PTI80 8, FDL-169 and FDL-176 and CFTR correctors such as lumacaftor and tezacaftor;

ENaC modulators, especially ENaC inhibitors;

antibiotics;

Airway humectants (osmolytes) such as hypertonic saline and mannitol (Bronchitol®); as well as mucolytic agents such as N-acetylcysteine.

When the additional active agent is an ENaC modulator, it may be an ENaC inhibitor such as amiloride, VX-371, AZD5634, QBW276, SPX-101, BI443651 and ETD001. Other suitable ENaC blockers are disclosed in our applications WO 2017/221008, WO 2018/096325, PCT/GB2018/052982 and GB 1808093.7 and any of the example compounds of these applications can be used in combination with compounds of general formula (I). Specific suitable compounds for use in combination with compounds of general formula (I) include those having a cation selected from:

- 56 046966

2-[({3-amino-577-pyrrolo[2,3-b]pyrazin-2-yl} formamide )ethyl]-6-(4{bis [(25.37?,47?, 5/?) -2,3,4,5,6-pentahydroxyhexyl]amine } piperidin-1-carbonyl)-1,3d ethyl-1H-1,3-benzodiazol-3-ium;

2-[({3-amino-577-pyrrolo[2,3-0]pyrazin-2-yl}formamido)methyl]-6-{[2-(4{ bis [(25.3R, 4R, 57? )-2,3,4,5,6-pentahydroxyhexyl]amine } piperidin-1 yl)ethyl]carbamoyl } -1,3-diethyl-177-1,3-benzodiazol-3-ium;

2-[({3-amino-577-pyrrolo[2,3-0]pyrazin-2-yl}formamido)methyl]-5-[4( { bis[(25.37?,47?, 57?) -2,3,4,5,6-pentahydroxyhexyl]amine } methyl)piperide in-1-carbonyl]1,3-diethyl-177-1,3-benzodiazol-3-ium;

2-[({3-amino-577-pyrrolo[2,3-0]pyrazin-2-yl}formamido)methyl]-6-[(37?)-3{ bis [(25.37?,47? , 57?)-2,3,4,5,6-pentahydroxyhexyl]amine }pyrrolidin-1-carbonyl]-1,3d ethyl-177-1,3-benzodiazol-3-ium;

2-[({3-amino-577-pyrrolo[2,3-0]pyrazin-2-yl}formamido)methyl]-6-[(35)-3{ bis [(25.37?,47?, 57?)-2,3,4,5,6-pentahydroxyhexyl]amine }pyrrolidin-1-carbonyl]-1,3d ethyl-177-1,3-benzodiazol-3-ium;

2-[({3-amino-577-pyrrolo[2,3-0]pyrazin-2-yl}formamido)methyl]-1,3-diethyl-6{[(1 g,4 g)-4-{ bis [(25.37?,47?, 57?)-2,3,4,5,6pentahydroxyhexyl]amine } cyclohexyl]carbamoyl } -177-1,3-benzodiazol-3-ium;

2-[({3-amino-577-pyrrolo[2,3-0]pyrazin-2-yl}formamido)methyl]-1,3-diethyl-6{[(15.45)-4-{bis[ (25,37?,47?,57?)-2,3,4,5,6pentahydroxyhexyl]amine}cyclohexyl]carbamoyl}-177-1,3-benzodiazol-3-ium;

and a suitable anion, for example halide, sulfate, nitrate, phosphate, formate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate or p-toluenesulfonate.

The invention is illustrated by the following non-limiting examples and drawings in which: The figure is an example of a TMEM16A Qpatch as used in Biological Example 95 and illustrates the methodology used in this assay. In the figure: S represents saline; V represents the carrier medium; #1 represents the concentration of test compound #1; #2 represents the concentration of test compound 2; #3 represents the concentration of test compound 3; #4 represents the concentration of test compound 4; #5 is the concentration of test compound #5; and R represents the comparison sample. The arrow in column V represents the base current, IBL. The arrows in each of columns #1, #2, #3, #4, #5 and R represent I[#i], I[# ₂ ], I[# ₃ ], I[#4], I[# ₅ ] and I[ _Ref ], which represent the peak current values during the incubation periods for the concentrations of test compounds #1 to #5 and the comparison sample.

Examples

The invention is illustrated by the following examples.

General terms and Conditions.

Mass spectra were performed on LC-MS systems using electrospray ionization. These were performed using either a Waters Acquity uPLC system with Waters PDA and ELS detectors, or Shimadzu LCMS-2010EV systems. [M+H]+ refers to mono-isotopic molecular weights.

NMR spectra were recorded on a Bruker Avance III HD 500 MHz with a 5 mm wideband return probe, a Bruker Avance III HD 250 MHz, or a 400 MHz Avance III HD Nanobay equipped with a 5 mm wideband observable SmartProbe, using solvent as the internal deuterium lock. . Spectra were recorded at room temperature unless otherwise stated and reported relative to the solvent peak.

Referring to the following examples, compounds of preferred embodiments were synthesized using the methods described herein or other methods that are known in the art.

The various starting materials, intermediates and compounds of preferred embodiments can be isolated and purified, where appropriate, using conventional methods such as precipitation, filtration, crystallization, evaporation, distillation and chromatography. Unless otherwise noted, all starting materials are obtained from commercial suppliers and used without further purification. Salts can be prepared from the compounds by known salt formation methods.

Compounds were purified by normal phase silica gel flash column chromatography on Biotage® Isolera systems using an appropriate SNAP cartridge and gradient. Alternatively, compounds were purified on reverse phase silica gel using Biotage® Isolera systems with appropriate

- 57 046966 existing SNAP C18 cartridges and reverse phase or preparative HPLC eluent (if otherwise specified).

Preparative HPLC using acidic pH, early elution method.

Purifications were carried out on a Gilson LC system using Waters Sunfire C18 columns (30 mm x 100 mm, 10 µM; temperature: room temp.) and a gradient of 10-95% B (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) for 14.44 min, then 95% B for 2.11 min at an injection volume of 1500 μl and a flow rate of 40 ml/min. UV spectra were recorded at 215 nm using a Gilson detector.

Preparative HPLC using acidic pH, standard elution method.

Preparative HPLC purifications (acid pH, standard elution method) were performed on a Gilson LC system using Waters Sunfire C18 columns (30 mm x 100 mm, 10 μM; temperature: room temp.) and a gradient of 30-95% B (A = 0 .1% formic acid in water; B = 0.1% formic acid in acetonitrile) for 11 min, then 95% B for 2.11 min at an injection volume of 1500 μl and a flow rate of 40 ml/min. UV spectra were recorded at 215 nm using a Gilson detector.

Preparative HPLC using alkaline pH, early elution method.

Preparative HPLC purifications (alkaline pH, early elution method) were carried out on a Gilson LC system using Waters Xbridge C18 columns (30 mm x 100 mm, 10 μM; temperature: room temp.) and a gradient of 10-95% (A = 0, 2% ammonium hydroxide in water; B = 0.2% ammonium hydroxide in acetonitrile) for 14.44 min, then 95% B for 2.11 min at an injection volume of 1500 μl and a flow rate of 40 ml/min. UV spectra were recorded at 215 nm using a Gilson detector.

Preparative HPLC using alkaline pH, standard elution method.

Preparative HPLC purifications (alkaline pH, standard elution method) were carried out on a Gilson LC system using Waters Xbridge C18 columns (30 mm x 100 mm, 10 μM; temperature: room temp.) and a gradient of 30-95% (A = 0, 2% ammonium hydroxide in water; B = 0.2% ammonium hydroxide in acetonitrile) for 11 min, then 95% B for 2.11 min at an injection volume of 1500 μl and a flow rate of 40 ml/min. UV spectra were recorded at 215 nm using a Gilson detector.

Unless otherwise stated, analytical HPLC conditions are as follows.

Method A.

Column: Phenomenex Kinetix-XB C18 2.1x100 mm, 1.7 µm

Column temperature 40°C

Eluents: A: H20 0.1% formic acid, B: acetonitrile, 0.1% formic acid

Flow rate: 0.6ml/min

Gradient: 0-5.3 min 5-100% B, 5.3-5.8 min 100% B, 5.8-5.82 min 100-5% B, 5.82-7.00 min 5% B Method B.

Column: Waters UPLC ® CSH™ C18 2.1x100 mm 1.7 µm

Column temperature 40°C

Eluents: A: 2 mM agag. Bicarbonate, buffered to pH 10, B: acetonitrile

Flow rate: 0.6ml/min

Gradient: 0-5.3 min 5-100% B, 5.3-5.8 min 100% B, 5.8-5.82 min 100-5% B, 5.82-7.00 min 5% B Method C.

Column: Waters UPLC ® VEN™ C18 2.1x100 mm 1.7 µm

Column temperature 40°C

Eluents: A: 2 mM ammonium bicarbonate, buffered to pH 10, B: acetonitrile

Flow rate: 0.6ml/min

Gradient: 0-5.3 min 5-100% B, 5.3-5.8 min 100% B, 5.8-5.82 min 100-5% B, 5.82-7.00 min 5% B Method D.

Column: Waters Atlantis dC18 2.1x100 mm 3 µm

Column temperature 40°C

Eluents: A: H20 + 0.1% formic acid, B: acetonitrile + 0.1% formic acid

Flow rate: 0.6ml/min

Gradient: 0-5 min 5-100% B, 5-5.4 min 100% B, 5.4-5.42 min 100-5% B, 5.42-7.00 min 5% B Method E.

Column: Kinetex Core-Shell C18 2.1x50 mm 5 µm

Column temperature 40°C

Eluents: A: H20 + 0.1% formic acid, B: acetonitrile + 0.1% formic acid

Flow rate: 1.2ml/min

Gradient: 0-1.20 min 5-100% B, 1.20-1.30 min 100% B, 1.30-1.31 min 100-5% B Method F.

Column: Phenomenex Gemini-NX C18 2x50 mm 3 µm

Column temperature 40°C

Eluents: A: 2 mM ammonium bicarbonate, buffered to pH 10, B: acetonitrile

- 58 046966

Flow rate: 1ml/min

Gradient: 0-1.80 min 1-100% B, 1.80-2.10 min 100% B, 2.10-2.30 min 100-1% B.

The following examples are intended to illustrate the invention and should not be construed as limiting it. Temperatures are shown in degrees Celsius. Unless otherwise specified, all evaporations are performed in a vacuum, preferably from 15 to 100 mmHg. Art. (= 20-133 mbar). The structures of the final products, intermediates and starting materials are confirmed by standard analytical techniques such as microanalysis and spectroscopic characterizations such as MS, IR and NMR. The abbreviations used are those generally accepted in the art. Unless defined, terms have generally accepted meanings.

Abbreviation:

aq.: aquatic;

ears: widened;

d: doublet;

dd: doublet of doublets;

DCM: dichloromethane;

DIPEA: diisopropylethylamine;

DMF: \,\-dimethyl.lformamide;

EDCl: 1-ethyl-3-(3-dimethylaminepropyl)carbodiimide;

EtOAc: ethyl acetate;

HOAt: 1-hydroxy-7-azabenzotriazole;

HATU: 2-(7-aza-III-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate;

HPLC: high performance liquid chromatography;

MeCN: acetonitrile;

MeOH: methanol;

MS: mass spectrometry;

m: multiplet;

min: minute(s);

ml: milliliter(s);

m/z: mass to charge ratio;

NCS: N-chlorosuccinimide;

NMR: nuclear magnetic resonance;

PTFE: polytetrafluoroethylene;

Rt: retention time;

s: singlet;

t: triplet;

TBME: tert-butyl methyl ether;

TBTU: HHNO,NO-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate;

TEA: triethylamine;

TFA: trifluoroacetic acid;

THF: tetrahydrofuran

T3P®: 1,2-propylphosphonium anhydride.

Getting examples

Example 1.

No. tert-Butyl-4-[[2-(2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide

Step 1: Methyl 4-[[2-(2-methoxyphenyl)acetyl]amino]pyridine-2-carboxylate

I

CH ₃

To a solution of 2-(2-methoxyphenyl)acetic acid (218 mg, 1.31 mmol) in DMF (4 ml) was added HOAt (179 mg, 1.31 mmol), EDCI (328 mg, 1.71 mmol), DIPEA (574 μl, 3.29 mmol) and methyl 4aminopyridine-2-carboxylate (200 mg, 1.31 mmol), and the mixture was stirred at room temperature for 6 hours 15 minutes. The resulting mixture was partitioned between H ₂ O (30 ml) and DCM (30 ml) and the two phases were separated. The aqueous phase was further extracted with DCM (30 ml), and the combined organic

- 59 046966 The extracts were washed with a saturated aqueous solution of sodium chloride, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography eluting with EtOAc in heptane to give the title compound as a pale yellow gum.

1H NMR (500 MHz, Chloroform-d) δ 8.58 (d, J=5.5 Hz, 1H), 8.10 (s, 1H), 7.92 (dd, J=5.5, 2, 2 Hz, 1H), 7.84 (d, J=2.1 Hz, 1H), 7.37-7.32 (m, 1H), 7.29 (dd, J=7.4, 1.5 Hz, 1H), 7.04-6.97 (m, 2H), 3.98 (s, 3H), 3.97 (s, 3H), 3.75 (s, 2H).

LC-MS (Method E): Rt 0.96 min; MS m/z 301.1 = [M+H]+ (99% @ 215 nm).

Step 2: 4-[[2-(2-Hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid

A solution of methyl 4-[[2-(2-methoxyphenyl)acetyl]amino]pyridine-2-carboxylate (step 1) (119 mg, 0.4 mmol) in DCM (1.2 ml) was cooled to 0°C and treated with 1 M BBr ₃ in DCM (2.38 mL, 2.38 mmol) for 15 min and stirred at 0°C for 1 h. Once warmed to room temperature, the reaction mixture was stirred for an additional 19 h. An additional portion was added 1 M BBr ₃ in DCM (1.19 ml, 1.19 mmol) at room temperature, and stirring was continued for an additional 72 hours. Water (25 ml) was slowly added to the reaction mixture, and then the two-phase solution was concentrated in vacuo to yield the title compound as a brown solid.

1H NMR (500 MHz, Methanol-BD) δ 8.68-8.60 (m, 2H), 8.39 (dd, J=6.7, 2.4 Hz, 1H), 7.18 (dd, J=7.7, 1.6 Hz, 1H), 7.15-7.10 (m, 1H), 6.85-6.79 (m, 2H), 3.84 (s, 2H). (Compound purity 85%).

LC-MS (Method E): Rt 0.74 min; MS m/z 273.0 = [M+H]+ (92% @ 215 nm).

Step 3: ^tert-Butyl-4-[[2-(2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide

A solution of 4-[[2-(2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (step 2) (138 mg, 0.43 mmol) in DMF (1.5 ml) was treated with EDCI (107 mg, 0 .56 mmol), HOAt (59 mg, 0.43 mmol), DIPEA (113 µl, 0.65 mmol) and 2-methylpropan-2-amine (45 µl, 0.43 mmol). The reaction mixture was stirred for 21 hours at room temperature and then concentrated in vacuo. The crude residue was purified by preparative HPLC (acidic pH early elution method) and the product containing fractions was freeze-dried to obtain the title compound as a white solid.

1H NMR (500 MHz, DMSO-d6) δ 10.65 (s, 1H), 9.49 (s, 1H), 8.43 (d, J=5.5 Hz, 1H), 8.18 (d , J=2.0 Hz, 1H), 8.03 (s, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.13 (dd, J=7, 5, 1.5 Hz, 1H), 7.07 (td, J=7.8, 1.7 Hz, 1H), 6.79 (dd, J=8.0, 0.9 Hz, 1H), 6.75 (td, J=7.4, 1.1 Hz, 1H), 3.65 (s, 2H), 1.39 (s, 9H).

LC-MS (Method A): Rt 2.86 min; MS m/z 328.2 = [M+H]+ (100% @ 215 nm).

Example 1.1.

No.(1,1-Dimethylpropyl)-3-[[2-(2-hydroxyphenyl)acetyl]amino]benzamide

Step 1: Methyl 3-[[2-(2-methoxyphenyl)acetyl]amino]benzoate

2-(2-Methoxyphenyl)acetic acid (1.09 g, 6.62 mmol) in DMF (1.5 ml) was treated with HOAt (900 mg, 6.62 mmol), EDCI (1.65 g, 8.6 mmol), DIPEA (2.89 mL, 16.54 mmol) and methyl 3-amine benzoate (1.0 g, 6.62 mmol), and the mixture was stirred at room temperature for 3.5 hours. The resulting mixture was separated between H2O (30 ml) and DCM (30 ml), and the two phases were separated. The aqueous phase was further extracted with DCM (30 ml) and the combined organic extracts were washed with saturated aqueous sodium chloride, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography eluting with EtOAc in heptane to give the title compound as a beige crystalline solid.

1H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.30 (t, J=1.8 Hz, 1H), 7.86-7.80 (m, 1H), 7 .62 (dt, J=7.7, 1.2 Hz, 1H), 7.44 (t, J=7.9 Hz, 1H), 7.28-7.19 (m, 2H), 6, 98 (d, J=7.9 Hz, 1H), 6.90 (td, J=7.4, 0.9 Hz, 1H), 3.84 (s, 3H), 3.76 (s, 3H ), 3.64 (s, 2H).

LC-MS (Method E): Rt 1.10 min; MS m/z 300.0 = [M+H]+ (100% @ 215 nm).

- 60 046966

Step 2: 3-[[2-(2-Hydroxyphenyl)acetyl]amino]benzoic acid

A solution of methyl 3-[[2-(2-methoxyphenyl)acetyl]amino]benzoate (step 1) (1.21 g, 4.04 mmol) in DCM (15 ml) was cooled to 0°C and treated with 1 M BBr ₃ in DCM (16.17 ml, 16.17 mmol) for 15 min. After addition was complete, the mixture was stirred at 0°C for 1 hour and then stirred at room temperature for 19 hours. Water (50 ml) was slowly added to the mixture and the DCM was concentrated in vacuo. The aqueous residue was extracted with EtOAc (2x50 ml) and the combined organic extracts were washed with saturated aqueous sodium chloride (15 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The recovered material was suspended in DCM (7.5 ml), cooled to 0°C and treated with 1 M BBr ₃ in DCM (7.0 ml, 7.0 mmol) for 10 min. The reaction mixture was stirred at 0°C for 1 hour and then at room temperature for 4 hours. Water (100 ml) was slowly added to the reaction mixture and the DCM was concentrated in vacuo. The resulting mixture was extracted with EtOAc (2x100 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (15 ml), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as a straw-colored solid.

¹ H NMR (500 MHz, DMSO-06) δ 12.89 (s, 1H), 10.22 (s, 1H), 9.47 (s, 1H), 8.24 (t, J=1.7 Hz, 1H), 7.867.80 (m, 1H), 7.60 (dt, J=7.7, 1.2 Hz, 1H), 7.41 (t, J=7.9 Hz, 1H), 7.14 (dd, J=7.5, 1.4 Hz, 1H), 7.07 (td, J=7.8, 1.7 Hz, 1H), 6.80 (dd, J=8, 0, 0.9 Hz, 1H), 6.75 (td, J=7.4, 1.1 Hz, 1H), 3.61 (s, 2H).

LC-MS (Method E): Rt 0.93 min; MS m/z 272.1 = [M+H]+ (92% @ 215 nm).

Step 3: N-(1,1-Dimethylpropyl)-3-[[2-(2-hydroxyphenyl)acetyl]amino]benzamide

To a solution of 3-[[2-(2-hydroxyphenyl)acetyl]amino]benzoic acid (step 2) (70 mg, 0.24 mmol) in DMF (1 ml) was added EDCI (59 mg, 0.31 mmol), HOAt (32 mg, 0.24 mmol), DIPEA (62.2 µl, 0.36 mmol) and 2-methylbutan-2-amine (36.1 µl, 0.31 mmol), and the mixture was stirred at room temperature for 17 hours. The resulting mixture was partitioned between water (5 ml) and DCM (5 ml). The organic layer was collected using a hydrophobic frit and concentrated in vacuo. The residue was purified by preparative HPLC (acidic pH, early elution method) and product fractions were lyophilized overnight to give the title compound as a white, metallic powder.

1H NMR (500 MHz, DMSOC,) δ 10.15 (s, 1H), 9.49 (s, 1H), 7.89 (t, J=1.8 Hz, 1H), 7.80-7, 74 (m, 1H), 7.54 (s, 1H), 7.40 (dt, J=7.7, 1.2 Hz, 1H), 7.33 (t, J=7.9 Hz, 1H ), 7.14 (dd, J=7.5, 1.6 Hz, 1H), 7.06 (td, J=7.8, 1.7 Hz, 1H), 6.80 (dd, J= 8.0, 1.0 Hz, 1H), 6.75 (td, J=7.4, 1.1 Hz, 1H), 3.60 (s, 2H), 1.77 (k, J=7 .5 Hz, 2H), 1.30 (s, 6H), 0.80 (t, J=7.5 Hz, 3H).

LC-MS (Method A): Rt 2.96 min; MS m/z 341.2 = [M+H]+ (99% @ 215 nm).

The compounds of the following tabular examples (Table 1) were prepared analogously to Example 1, replacing 2(2-methoxyphenyl)acetic acid (step 1) and methyl 4-aminopyridine-2-carboxylate (step 1) with the appropriate commercially available acid and amine and replacing 2 -methylpropan-2-amine (step 3) with the appropriate amine.

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Table 1

Example Structure and name 1H NMR, LC-MS retention time, [M+H]+, A Ζ ΞΕ ° =\ O\ y o 1HNMR (500 MHz, DMSO-bb) δ 10.20 (br.s, 1H), 9.81 (br.s, 1H), 7.87 (t, J=l.8 Hz, 1H), 7, 78-7.72 (m, 1H), 7.55 (s, 1H), 7.44-7.37 (m, 1H), 7.32 (t, J=7.9 Hz, 1H), 7 .20 (d, J=2.7 Hz, 1H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.61 (s, 2H), 2.05 (s, 9H), 1.2 N-( 1 - Ad amantyl)-3 - [[2-(5 -chloro-2- 1.65 (s, 6H). LC-MS (Method A): Rt 3.86 min; MS m/z hydroxyphenyl)acetyl]amino]benzamide 439.3/441.3 = [M+H]+ (100% @ 215 nm) X X /° Ζ ΞΕ O =\δ__\ ABOUT 1HNMR (500 MHz, DMSO-bb) δ 10.70 (br.s, 1H), 9.83 (br.s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8, 15 (d, J=2.0 Hz, 1H), 7.91 (s, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.21 (d, J =2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.67 (s , 2H), Ν-( 1 - Ad amantyl)-4- [[2-(5 -chloro-2- 2.06 (s, 9H), 1.67 (s, 6H). LC-MS (Method A): Rt 4.12 min; 1.3 hydroxyphenyl)acetyl]amino]pyr ide in-2-carboxamide MS m/z 440.3/442.3 = [M+H]+ (100% @ 215 nm) 1HNMR (500 MHz, DMSO-bb) δ 10.63 (br.s, 1H), 9.82 (br.s. | ^Nz I n s, 1H), 8.47-8.41 (m, 2H), 8.18-8.13 (m, 1H), 7.80 (dd, J=5.5, 2.0 Hz, 1H), 7.24-7.18 (m, 1H), 7.14-7.08 (m, 1H), 6.82-6.77 ^cbS kJ 5 XJ (m, 1H), 3.66 (s, 2H), 3.44 (t, J=6.3 Hz, 2H), 3.23 (s, ZN), 1.95 (t, J=6.3 Hz, 1.4 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-(3-methoxy-1,1- 2H), 1.40 (s, 6H). LC-MS (Method A): Rt 3.15 min; MS m/z dimethylpropyl)pyridine-2-carboxamide 406.3/408.3 = [M+H]+ (100% @ 215 nm) 1H NMR (500 MHz, DMSO-bb) δ 10.19 (s, 1H), 9.78 (br. s, Н3С СН зс Н 1H), 7.88 (t, J=l.8 Hz, 1H), 7.82-7.70 (m, 1H), 7.54 (s, 1H), 7.43-7.39 (m, 1H), 7.33 (t, J=7.9 Hz, 1H), 7.20 (d, J=2.7 Hz, ^th XY I XY 1H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.61 (s, 2H), 1.77 (k, J=7.5 Hz, 2H), 1.30 (s, 6H), 0.80 (t, J=7.5 Hz, 1.5 3 - [[2-(5 -Chloro-2-hydroxyphenyl)acetyl] amino] -N-( 1,1 - ZN). LC-MS (Method A): Rt 3.31 min; MS m/z 375.2/377.2 dimethylpropyl)benzamide = [M+H]+ (100% @ 215 nm) 1.6 Synthesis details are given at the end of the table. 1HNMR (500 MHz, DMSO-bb) δ 10.74 (s, 1H), 9.84 (s, 1H), f? n 8.45 (d, J=5.5 Hz, 1H), 8.17 (d, J=2.l Hz, 1H), 7.97 (s, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.21 (d, J=2.6 Hz, 1H), 7.12 (dd, сн Η Т Т Ύ J J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.67 (s, 2H), 2.18- But 2.08 (m, 2H), 1.55-1.32 (m, JN), 1.32-1.20 (m, 1H). 1.7 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-( 1 - LC-MS (Method A): Rt 3.78 min; MS m/z 402.3/404.3= methylcyclohexyl)pyridine-2-carboxamide [M+H]+ (100% @ 215 nm) CH, O CH, O hXWAvyW ¹ 1H NMR (500 MHz, Methanol-b4) δ 8.43 (d, J=5.5 Hz, 1H), ^{3 s} ^HUUHU 8.13-8.11 (m, 1H), 7.90 (dd, J=5.5, 2.2 Hz, 1H), 7.19 (d, J=2.6 °but Hz, 1H), 7.09 (dd, J=8.6, 2.6 Hz, 1H), 6.78 (d, J=8.6 Hz, 1H), tert-Butyl-N- [3 -[ [4-[ [2-(5 -chloro-2- 3.71 (s, 2H), 3.15-3.09 (m, 2H), 2.06-2.01 (m, 2H), 1.46 (s, 1.8 hydroxyphenyl)acetyl]amino]pyridine-2-carbonyl]amino]-3- 6H), 1.37 (s, 9H). LC-MS (Method A): Rt 3.44 min; MS m/z methylbutyl]carbamate 491.3/493.3 = [M+H]+ (100% @ 215 nm) 1HNMR (500 MHz, DMSO-bb) δ 10.15 (s, 1H), 9.48 (s, 1H), 7.90 (t, J=l.8 Hz, 1H), 7.81-7, 73 (m, 1H), 7.56 (s, 1H), 7.43- CH, O 7.38 (m, 1H), 7.33 (t, J=7.9 Hz, 1H), 7.14 (dd, J=7.5, 1.5 Hz, n,s^II n O 1H), 7.06 (td, J=7.8, H ₃ C N |J |] J| ⁿ LJ o JL J 1.7 Hz, 1H), 6.80 (dd, J=8.0, 1.0 Hz, 1H), 6.75 (td, J=7.4, 1.1 BUT Hz, 1H), 3.60 (s, 2H), 3.51 (s, 2H), 3.27 (s, ZN), 1.32 (s, 6H). 1.9 3-[[2-(2-Hydroxyphenyl)acetyl]amino]-X-(2-methoxy-1,1- LC-MS (Method A): Rt 2.70 min; MS m/z 357.2 = [M+H]+ dimethylethyl)benzamide (99% @ 215 nm)

- 62 046966

Example 1.6.

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1-methylcyclobutyl)pyridine-2-carboxamide

To a solution of 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (example 31, step 1) (800 mg, 2.61 mmol), 1-methylcyclobutanamine hydrochloride (381 mg, 3.13 mmol) and TEA (800 μL, 5.74 mmol) in DMF (15 mL), HATU (1.19 g, 3.13 mmol) was added and the mixture was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo and the residue was dissolved in EtOAc and washed successively with aqueous 1 M HCl, sat. aqueous NaHCO ₃ and saturated aqueous sodium chloride solution and 1 M NaOH solution. Organic extracts were dried over Na ₂ SO ₄ and concentrated in vacuo. Purification of the crude product by chromatography on silica gel, eluting with 50-100% ethyl acetate in a mixture of heptanes, gave a pale yellow foam. The isolated material was recrystallized by dissolving in methanol (15 ml) and heating at reflux until all solids dissolved. The mixture was left to cool slowly to room temperature. The resulting crystals were filtered to obtain the title compound as a pale yellow solid.

1H NMR (500 MHz, DMSO-06) δ 10.67 (s, 1H), 9.81 (s, 1H), 8.47 (s, 1H), 8.45 (d, J=5.5 Hz , 1H), 8.15 (d, J=1.9 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J=2, 7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.67 (s, 2H) , 2.42-2.36 (m, 2H), 2.02-1.96 (m, 2H), 1.84-1.77 (m, 2H), 1.47 (s, 3H).

LC-MS (Method A): Rt 3.24 min; MS m/z 374.3/376.3= [M+H]+ (100% @ 215 nm).

Example 1.10.

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-I-cyclohexylpyridine-2-carboxamide

Q O

Step 1: 4-[[2-(5-Chloro-2-methoxyphenyl)acetyl]amino]-M-cyclohexylpyridine-2-carboxamide

Solution of 4-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 8.1 step 2) (3.0 g, 9.07 mmol), cyclohexanamine (1.25 ml , 10.89 mmol), EDCI (2.09 g, 10.89 mmol), HOAt (1.48 g, 10.89 mmol) and DIPEA (3.17 ml, 18.15 mmol) in DMF (30 ml ) was stirred at room temperature for 19.5 hours. The resulting mixture was concentrated in vacuo and the residue was partitioned between EtOAc (200 ml) and water (200 ml). The organic portion was separated and the aqueous layer was re-extracted with EtOAc (2x100 ml). The combined organic extracts were washed with water (2x100 ml), and saturated aqueous sodium chloride (2x100 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound as a red/brown solid.

1H NMR (500 MHz, DMSO-06) δ 10.69 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.38 (d, J=8.6 Hz, 1H ), 8.18 (d, J=2.1 Hz, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.35-7.27 (m, 2H) , 7.05-6.98 (m, 1H), 3.76 (s, 3H), 3.71 (s, 2H), 1.85-1.67 (m, 4H), 1.64-1 .53 (m, 1H), 1.45-1.27 (m, 4H), 1.25-1.03 (m, 2H).

LC-MS (Method E): Rt 1.26 min; MS m/z 402.0/404.1 = [M+H]+ (89% @ 215 nm).

Step 2: 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-cyclohexylpyridine-2-carboxamide

M BBr ₃ in DCM (21.26 ml, 21.26 mmol) was added to a stirred suspension of 4-[[2-(5-chloro-2methoxyphenyl)acetyl]amino]-I-cyclohexylpyridine-2-carboxamide (step 1) ( 3.2 g, 7.09 mmol) in DCM (50 ml) at 0°C. After addition, the ice bath was removed and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched by slowly adding water (~70 ml), and the mixture was partially concentrated in vacuo to remove volatile solvent. EtOAc (200 ml) was added followed by water (100 ml). The organic portion was separated and the aqueous layer was extracted with EtOAc (100 ml). The combined organic phases were washed with sat. NaHCO ₃ (2x150 ml), and saturated aqueous sodium chloride (100 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The crude material was purified by C18 reverse phase chromatography, eluting with 10-100% MeCN in water with 0.1% formic acid to give dark

- 63 046966 brown/orange solid. The solid was dissolved in a minimal volume of boiling MeCN (~100 ml) and left to stand overnight. The resulting crystals were collected by vacuum filtration and dried in a vacuum oven at 40°C for 5 hours to obtain the title compound as pale beige needles.

1H NMR (500 MHz, DMSO-06) δ 10.68 (br.s, 1H), 9.81 (br.s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8 .38 (d, J=8.6 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H) , 7.21 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.83-3.70 (m, 1H), 3.66 (s, 2H), 1.85-1.75 (m, 2H), 1.75-1.65 (m, 2H) , 1.63-1.54 (m, 1H), 1.45-1.25 (m, 4H), 1.21-1.07 (m, 1H).

LC-MS (Method A): Rt 3.46 min; MS m/z 388.2/390.1 = [M+H]+ (100% @ 215 nm).

Example 2.

No. tert-Butyl-3-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]benzamide

Stage 1a: tert-Butyl-SH3-(tert-butylcarbamoyl)phenyl]carbamate

Commercially available 3-(tert-butoxycarbonylamino)benzoic acid (2.5 g, 10.54 mmol) in DMF (40 ml) was treated with HOAt (1.4 g, 10.54 mmol), EDCI (2.63 g, 13 .7 mmol), TEA (1.9 ml, 13.7 mmol) and 2-methylpropan-2-amine (1.44 ml, 13.7 mmol) and stirred at room temperature for 2 hours. The resulting mixture was diluted with water (100 ml) with stirring, and the resulting white suspension was collected by filtration. The filter cake was washed with water (3x15 ml) and oven dried to give the title compound as a white metallic solid.

1H NMR (500 MHz, Methanol^) δ 7.78-7.70 (m, 1H), 7.52-7.46 (m, 1H), 7.38-7.28 (m, 2H), 1 .53 (s, 9H), 1.45 (s, 9H).

LC-MS (Method E): Rt 1.17 min; MS m/z 293.0 = [M+H]+ (100% @ 215 nm).

Step 1b: 3-Amino-N-tert-butylbenzamide hydrochloride

tert-butyl Na[3-(tert-butylcarbamoyl)phenyl]carbamate (step 1a) (5.3 g, 18.13 mmol) was suspended in 1,4-dioxane (20 ml) and then 4 M HCl in dioxane was added ( 9.59 ml, 271.92 mmol). After stirring at room temperature for 24 hours, the resulting mixture was concentrated in vacuo and subjected to azeotropic distillation with methanol. The resulting foam was dried in a vacuum oven at 40°C for an additional 3 hours to obtain the title compound as a light orange foam.

¹ H NMR (500 MHz, DMSO-06) δ 10.25 (br.s, 2H), 7.91 (s, 1H), 7.76 (d, J=7.1 Hz, 1H), 7, 71-7.68 (m, 1H), 7.50 (t, J=7.8 Hz, 1H), 7.47-7.43 (m, 1H), 1.37 (s, 9H).

LC-MS (Method E): Rt 0.73 min; MS m/z 193.1 = [M+H]+ (99% @ 215 nm).

Step 2: 2-(5-Chloro-2-methoxyphenyl)acetic acid

To a cooled (-10°C), stirred solution of 2-(2-methoxyphenyl)acetic acid (2.0 g, 12.04 mmol) in THF (34.8 ml) was added dropwise sulfuryl chloride (1.37 ml, 16 .85 mmol) for 15 minutes and stirring was continued for 1 hour. The reaction mixture was quenched with ice water (34.8 ml) and extracted with EtOAc (3x50 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound as a pink solid.

1H NMR (250 MHz, DMSO-06) δ 12.24 (s, 1H), 7.30 (d, J=2.7 Hz, 2H), 6.99 (d, J=8.8 Hz, 1H ), 3.76 (s, 3H), 3.51 (s, 2H).

LC-MS (Method E): Rt 1.01 min; MS m/z characteristic mass of the ion was not observed.

Step 3: N-tert-Butyl-3-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]benzamide

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To 2-(5-chloro-2-methoxyphenyl)acetic acid (step 2) (114 mg, 0.57 mmol) in DMF (3 ml) was added HOAt (77 mg, 0.57 mmol), EDCI (142 mg, 0.74 mmol), DIPEA (248 μl, 1.42 mmol) and 3-amino-tert-butylbenzamide hydrochloride (step 1b) (130 mg, 0.57 mmol). The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was partitioned between water (8 ml) and (DCM (8 ml) and the phases were separated using a PTFE phase separator frit. The organic layer was concentrated in vacuo and the crude product was purified by chromatography on silica gel, eluting with EtOAc in heptane, product fractions in vacuo to give the title compound as a white solid.

1H NMR (500 MHz, Chloroform-d) δ 7.76-7.64 (m, 3H), 7.41-7.37 (m, 1H), 7.36-7.31 (m, 1H), 7.30-7.26 (m, 2H), 6.88 (d, J=8.6 Hz, 1H), 5.97 (br. s, 1H), 3.92 (s, 3H), 3 .68 (s, 2H), 1.45 (s, 9H).

LC-MS (Method E): Rt 1.20 min; MS m/z 375.0/377.0 = [M+H]+ (94% @ 215 nm).

Step 4: N-tert-Butyl-3-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]benzamide

A solution of N-tert-butyl-3-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]benzamide (step 3) (3.83 g, 10.2 mmol) in DCM (80 ml) was cooled to 0 °C and add 1 M BBr ₃ in DCM (20.4 ml, 20.4 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The resulting mixture was diluted with water (10 ml) and the volatile solvent was removed in vacuo to leave a gummy residue. The residue was dissolved in EtOAc (60 ml) and saturated sodium hydrogen carbonate (60 ml) and stirred for 1 hour to ensure complete dissolution. The biphasic mixture was separated and the organic portion was washed with saturated sodium hydrogen carbonate (80 ml), and saturated aqueous sodium chloride (80 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give a thick beige oil. Purification of the crude product by chromatography on silica gel, eluting with 0-100% EtOAc in heptane, gave a white foam. The material was azeotroped with MeCN (2x80 ml), then dissolved by boiling MeCN (~30 ml) and allowed to cool to room temperature. After 3 hours, the resulting crystalline material was collected by filtration and recrystallized again from boiling MeCN (40 ml) to obtain the title compound as a white crystalline solid.

1H NMR (500 MHz, DMSO) δ 10.22 (s, 1H), 9.81 (s, 1H), 7.90 (t, J=1.7 Hz, 1H), 7.78-7.72 (m, 1H), 7.69 (s, 1H), 7.42 (dt, J=7.8, 1.1 Hz, 1H), 7.33 (t, J=7.9 Hz, 1H) , 7.20 (d, J=2.7 Hz, 1H), 7.10 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.61 (s, 2H), 1.36 (s, 9H).

LC-MS (Method A): Rt 3.19 min; MS m/z 361.1/363.2 = [M+H]+ (100% @ 215 nm)

The compounds of the following tabular examples (Table 2) were prepared analogously to Example 2, replacing 2(5-chloro-2-methoxyphenyl)acetic acid (step 2) with the appropriate commercially available acid.

table 2

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X-tert-Butyl-3-[[2-(2,62.4 dihydroxyphenyl)acetyl]amino]benzamide

N-tert-Butyl-3 - [3 -(22.5 hydroxyphenyl)propanamido] benzamide

I

CH ₃

1H NMR (500 MHz, DMSO-bb) δ 9.98 (s, 1H), 9.29 (br.s, 2H), 7.88 (t, J=l.8 Hz, 1H), 7.77 -7.71 (m, 1H), 7.69 (s, 1H), 7.42-7.36 (m, 1H), 7.31 (t, J=7.9 Hz, 1H), 6, 84 (t, J=8.1 Hz, 1H), 6.30 (d, J=8.1 Hz, 2H), 3.59 (s, 2H), 1.36 (s, 9H).

LC-MS (Method A): Rt 2.36 min; MS m/z 343.2 = [M+H]+ (99% @ 215 nm)

1H NMR (500 MHz, DMSO-bb) δ 9.99 (br.s, 1H), 9.35 (br.s, 1H), 7.92-7.85 (m, 1H), 7.80- 7.73 (m, 1H), 7.70 (s, 1H), 7.44-7.38 (m, 1H), 7.32 (t, J=7.9 Hz, 1H), 7.09 (dd, J=7.4, 1.3 Hz, 1H), 7.00 (td, J=7.8,

1.6 Hz, 1H), 6.81-6.77 (m, 1H), 6.70 (td, J=7.4, 0.9 Hz, 1H), 2.87-2.79 (m , 2H), 2.61-2.55 (m, 2H), 1.37 (s, 9H).

LC-MS (Method A): Rt 2.83 min; MS m/z 341.2 = [M+H]+ (100% @ 215 nm)

1H NMR (500 MHz, DMSO-bb) δ 10.00 (s, 1H), 9.44 (br.s, 1H), 7.89 (t, J=l.8 Hz, 1H), 7.76 -7.70 (m, 1H), 7.68 (s, 1H), 7.43-7.36 (m, 1H), 7.31 (t, J=7.9 Hz, 1H), 7, 02 (t, J=8.2 Hz, 1H), 6.49-6.43 (m, 2H), 3.71 (s, ZN), 3.61 (s, 2H), 1.36 (s , 9H). LC-MS (Method A): Rt 2.76 min; MS m/z 357.2 = [M+H]+ (100% @ 215 nm)

2.6

X-tert-Butyl-3-[[2-(2-hydroxy-6methoxyphenyl)acetyl]amino]benzamide

X-tert-Butyl-3-[2-(2hydroxyphenyl)propanamido]benzamide

H ₃ C

H ₃ C sn„ O

H ₃ C

X-tert-Butyl-3-[[2-(2-hydroxy-3methoxyphenyl)acetyl]amino]benzamide

1HNMR (500 MHz, DMSO-bb) δ 10.03 (s, 1H), 9.67 (br. s, 1H), 7.977.86 (m, 1H), 7.80-7.74 (m, 1H ), 7.69 (s, 1H), 7.43-7.38 (m, 1H), 7.31 (t, J=7.9 Hz, 1H), 7.21 (dd, J=7, 6, 1.3 Hz, 1H), 7.05 (td, J=8.0, 1.4 Hz, 1H), 6.84-6.79 (m, 1H), 6.79-6.72 (m, 1H), 4.10 (k, J=7.0 Hz, 1H), 1.49-1.21 (m, 12H). LC-MS (Method A): Rt 2.96 min; MS m/z 341.2 = [M+H]+ (100% @215 nm)

1HNMR (500 MHz, DMSO-bb) δ 10.15 (s, 1H), 8.72 (br. s, 1H), 7.947.86 (m, 1H), 7.80-7.73 (m, 1H ), 7.70 (s, 1H), 7.44-7.38 (m, 1H), 7.32 (t, J=7.9 Hz, 1H), 6.86 (dd, J=7, 9, 1.5 Hz, 1H), 6.80-6.75 (m, 1H), 6.75-6.68 (m, 1H), 3.78 (s, ZN), 3.61 (s , 2H), 1.36 (s, 9H).

LC-MS (Method A): Rt 2.79 min; MS m/z 357.3 = [M+H]+ (98% @ 215 nm)

N-tert-Butyl-3 - [[2-(3,5-difluoro-2hydroxyphenyl)acetyl] amino]benzamide

1H NMR (500 MHz, DMSO-bb) δ 10.26 (s, 1H), 9.60 (br. s, 1H), 7.90 (t, J=1.8 Hz, 1H), 7.78 -7.73 (m, 1H), 7.71 (s, 1H), 7.45-7.40 (m, 1H), 7.33 (t, >7.9Hz, 1H), 7.14- 7.06 (m, 1H), 6.95-6.88 (m, 1H), 3.70 (s, 2H), 1.36 (s, 9H). LC-MS (Method A): Rt 2.91 min; MS m/z 363.2 = [M+H]+ (98% @ 215 nm)

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2.10 sn ₃ o _u n ₃ s. ι II ⁿ Br n ₃ s n γ ⁿ kJ o but 3-[[2-(5-Bromo-2-hydroxyphenyl)acetyl]amino]-T4-tert-butylbenzamide 1H NMR (500 MHz, DMSO-bb) δ 10.18 (s, 1H), 9.83 (s, 1H), 7.90 (t, J=l.8 Hz, 1H), 7.80-7 .73 (m, 1H), 7.70 (s, 1H), 7.45-7.39 (m, 1H), 7.377.29 (m, 2H), 7.23 (dd, J=8.6 , 2.6 Hz, 1H), 6.76 (d, J=8.6 Hz, 1H), 3.61 (s, 2H), 1.36 (s, 9H). LC-MS (Method A): Rt 3.14 min; MS m/z 405.2/407.2 = [M+H]+ (100% @215 nm) 2.11 CH ₃ 0 „ F ^X:L sgpU N-tert-Butyl-3 -[[2-(2,3-difluoro-6hydroxyphenyl)acetyl] amino] benzamide 1H NMR (500 MHz, DMSO-bb) δ 10.29 (s, 1H), 10.01 (s, 1H), 7.89 (t, J=l.8 Hz, 1H), 7.76-7 .68 (m, 2H), 7.42 (d, J=7.8 Hz, 1H), 7.33 (t, J=7.9 Hz, 1H), 7.12 (k, J=9, 4 Hz, 1H), 6.61 (ddd, J=8.9, 3.9, 1.6 Hz, 1H), 3.69 (s, 2H), 1.36 (s, 9H). LC-MS (Method A): Rt 2.91 min; MS m/z 363.2 = [M+H]+ (100% @ 215 nm) 2.12 CH ₃ 0 ,, Wra HO F X-tert-Butyl-3-[[2-(4,5-difluoro-2hydroxyphenyl)acetyl] amino] benzamide 1H NMR (500 MHz, DMSO-bb) δ 10.20 (s, 1H), 7.89 (t, J=1.7 Hz, 1H), 7.78-7.73 (m, 1H), 7 .70 (s, 1H), 7.44-7.39 (m, 1H), 7.33 (t, >7.9Hz, 1H), 7.22 (dd, J=11.4, 9.5 Hz, 1H), 6.75 (dd, J=12.3, 7.2 Hz, 1H), 3.59 (s, 2H), 1.36 (s, 9H). LC-MS (Method A): Rt 2.99 min; MS m/z 363.2 = [M+H]+ (100% @ 215 nm) 2.13 CH, 0 BUT F N-(1,1-Dimethylpropyl)-3 - [[2-(4-fluoro-2- 1H NMR (500 MHz, Methanol-b4) δ 7.88 (t, J=l,8 Hz, 1H), 7.67 (ddd, J=8.0, 2.1, 1.1 Hz, 1H) , 7.53 (s, 1H), 7.47-7.41 (m, 1H), 7.36 (t, J=7.9 Hz, 1H), 7.16 (dd, J=8,l , 6.9 Hz, 1H), 6.59-6.50 (m, 2H), 3.66 (s, 2H), 1.86 (k, J=7.5 Hz, 2H), 1.38 (s, 6H), 0.90 (t, J=7.5 Hz, ZN). LC-MS (Method A): Rt 3.08 min; MS m/z 359.2 = [M+H]+ (100% @215 nm) hydroxyphenyl)acetyl]amino]benzamide 2.14 CH ₃ 0 ,, H ₃ C^| ³ II n HO 0 cn ₃ X-tert-Butyl-3-[[2-(2-hydroxy-4methoxyphenyl)acetyl] amino] benzamide 1H NMR (500 MHz, DMSO-bb) δ 10.08 (s, 1H), 9.58 (br. s, 1H), 7.90 (t, >1.6Hz, 1H), 7.80-7 .73 (m, 1H), 7.70 (s, 1H), 7.46-7.38 (m, 1H), 7.32 (t, J=7.9 Hz, 1H), 7.04 ( d, J=8.3 Hz, 1H), 6.39 (d, J=2.5 Hz, 1H), 6.35 (dd, J=8.3, 2.5 Hz, 1H), 3.68 (s, ZN), 3.52 (s, 2H), 1.36 (s, 9H). LC-MS (Method A): Rt 2.78 min; MS m/z 357.3= [M+H]+ (100% @ 215 nm) 2.15 CH, O F X-tert-Butyl-3-[[2-(2-fluoro-6hydroxyphenyl)acetyl]amino]benzamide 1H NMR (500 MHz, DMSO-bb) δ 10.25 (s, 1H), 10.15 (br. s, 1H), 7.947.86 (m, 1H), 7.76-7.72 (m, 1H), 7.71 (s, 1H), 7.44-7.38 (m, 1H), 7.33 (t, J=7.9 Hz, 1H), 7.12-7.05 (m , 1H), 6.66 (d, J=8.2 Hz, 1H), 6.60 (t, J=8.8 Hz, 1H), 3.64 (s, 2H), 1.36 (s , 9Н). LC-MS (Method A): Rt 2.82 min; MS m/z 345.2 = [M+H]+ (97% @ 215 nm) 2.16 CH ₃ 0 ,, OH T4-tert-Butyl-3-[[2-(2,3dihydroxyphenyl)acetyl] amino] benzamide 1H NMR (500 MHz, DMSO-bb) δ 10.14 (s, 1H), 9.21 (br.s, 1H), 8.50 (br.s, 1H), 7.89 (t, J= l.8 Hz, 1H), 7.79-7.73 (m, 1H), 7.70 (s, 1H), 7.41 (dt, J=7.6, 1.1 Hz, 1H), 7.33 (t, J=7.9 Hz, 1H), 6.68 (dd, J=7.6, 1.8 Hz, 1H), 6.61 (dd, J=7.6, 1.8 Hz, 1H), 6.57 (t, J=7.6 Hz, 1H), 3.59 (s, 2H), 1.36 (s, 9H). LC-MS (Method A): Rt 2.48 min; MS m/z 343.2 = [M+H]+ (100% @ 215 nm)

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2.17 CH _{3 Osh} F X-tert-Butyl-3-[[2-[2-hydroxy-5(trifluoromethyl)phenyl]acetyl]amino]benzamide 1H NMR (500 MHz, DMSO-bb) δ 11.12-9.35 (m, 2H), 7.90 (t, J=1.8 Hz, 1H), 7.77-7.72 (m, 1H), 7.70 (s, 1H), 7.52 (d, J=2.l Hz, 1H), 7.46-7.38 (m, 2H), 7.33 (t, J=7 .9 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 3.69 (s, 2H), 1.36 (s, 9H). LC-MS (Method A): Rt 3.27 min; MS m/z 395.2 = [M+H]+ (100% @215 nm) 2.18 CH, O O Methyl-3-[2-[3-(tert-butylcarbamoyl)anilino]-2oxoethyl]-4-hydroxybenzoate 1H NMR (500 MHz, DMSO-bb) δ 10.48 (br. s, 1H), 10.22 (s, 1H), 7.90 (t, J=l.8 Hz, 1H), 7.82 (d, J=2.2 Hz, 1H), 7.79-7.74 (m, 1H), 7.73 (dd, J=8.5, 2.2 Hz, 1H), 7.71 ( s, 1H), 7.46-7.39 (m, 1H), 7.33 (t, J=7.9 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 3.78 (s, 3H), 3.66 (s, 2H), 1.36 (s, 9H). LCMS (Method A): Rt 2.78 min; MS m/z 385.2 = [M+H]+ (98% @ 215 nm) 2.19 CH ₃ O F T\G-tert-Butyl-3-[[2-[2-hydroxy-4(trifluoromethyl)phenyl]acetyl]amino]benzamide 1H NMR (500 MHz, DMSO-bb) δ 10.27 (s, 2H), 7.90 (t, J=1.8 Hz, 1H), 7.80-7.73 (m, 1H), 7 .70 (s, 1H), 7.47-7.40 (m, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.33 (t, J=7.9 Hz, 1H), 7.12-7.08 (m, 1H), 7.08-7.05 (m, 1H), 3.69 (s, 2H), 1.36 (s, 9H). LC-MS (Method A): Rt 3.30 min; MS m/z 395.2 = [M+H]+ (100% @ 215 nm)

Example 3.

No. tert-Butyl-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide

Step 1: 4-Amino^-tert-butide11iridine-2-carboxamide

To a mixture of 4-aminopyridine-2-carboxylic acid (8.0 g, 57.92 mmol), TBTU (22.32 g, 69.5 mmol) and TEA (24.22 ml, 173.76 mmol) in DMF ( 100 ml) 2-methylpropan-2-amine (7.30 ml, 69.5 mmol) was added. The resulting mixture was stirred at room temperature for 22 hours and then concentrated in vacuo. The crude material was purified by chromatography on silica gel, eluting with 3.5 M methanolic ammonia in DCM, and the product fractions were combined and concentrated in vacuo to yield the title compound as a light yellow solid.

1H NMR (500 MHz, Methanol-a ₄ ) δ 7.99 (d, J=5.6 Hz, 1H), 7.23 (d, J=2.2 Hz, 1H), 6.62 (dd, J=5.6, 2.4 Hz, 1H), 1.45 (s, 9H).

LC-MS (Method F): Rt 1.47 min; MS m/z 194.3 = [M+H]+ (100% @ 215 nm).

Step 2: N-tert-Butyl-4-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]pyridine-2-carboxamide

A solution of 2-(5-chloro-2-methoxyphenyl)acetic acid (2.26 g, 11.27 mmol) in thionyl chloride (8.13 ml, 92.21 mmol) was heated at 70°C for 30 min. After cooling to room temperature, excess thionyl chloride was removed in vacuo by azeotropic distillation with toluene. The resulting residue was dissolved in DCM (5 ml) and added to a solution of 4-amino-N-tert-butylpyridin-2carboxamide (step 1) (2.0 g, 10.25 mmol) and DIPEA (2.15 ml, 12.29 mmol ) in DXM (25 ml). The mixture was stirred at room temperature for 1 hour and then diluted with water (50 ml) and extracted with DCM. The combined organic extracts were washed with saturated aqueous sodium chloride (50 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The crude residue was purified by chromatography on silica gel, eluting with 0-50% EtOAc in heptane, to give the title compound as a pale orange powder.

1H NMR (500 MHz, Chloroform-d) δ 8.39 (d, J=5.6 Hz, 1H), 8.20 (dd, J=5.6, 2.2 Hz, 1H), 8.10 (br.s, 1H), 7.98 (br.s, 1H), 7.56 (d, J=2.1 Hz, 1H), 7.29-7.26 (m, 2H), 6, 89 (d, J=9.5 Hz, 1H), 3.94 (s, 3H), 3.70 (s, 2H), 1.47 (s, 9H).

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LC-MS (Method E): Rt 1.21 min; MS m/z 376.1/ 378.1 = [M+H]+ (92% @ 215 nm).

Step 3: ^tert-Butyl-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide

To a solution of N-tert-butyl-4-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]pyridine-2-carboxamide (step 2) (2.7 g, 6.82 mmol, 95%) in DCM (10 ml) at 0°C was added dropwise 1 M BBr ₃ in DCM (27.3 ml, 27.3 mmol). When the addition was complete, the mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was quenched by the slow addition of water (10 ml) and the DCM was removed in vacuo. The resulting residue was dissolved in EtOAc and washed with sat. NaHCO ₃ solution (50 ml) and saturated aqueous sodium chloride solution (50 ml). The organic portion was separated, dried with Na ₂ SO ₄ and concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with 0-70% EtOAc in heptane to give the product as an orange powder. It was further purified by reverse phase chromatography, eluting with 0-100% MeCN in water with 0.1% formic acid to give the product as a colorless powder. The product was recrystallized from MeCN to give the title compound. The second part was isolated by adding water dropwise to the MeCN filtrate, followed by heating and cooling the mixture.

1H NMR (500 MHz, DMSO) δ 10.69 (br.s, 1H), 9.82 (br.s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.17 (d, J=1.9 Hz, 1H), 8.03 (s, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J= 2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.67 (s, 2H), 1.40 (s, 9H).

LC-MS (Method A): Rt 3.28 min; MS m/z 362.1/ 364.1 = [M+H]+ (99% @ 215 nm).

The compounds of the following tabular examples (Table 3a) were prepared analogously to Example 3, replacing 2-methylpropan-2-amine (step 1) with the corresponding amine, replacing 2-(5-chloro-2-methoxyphenyl)acetic acid (step 2) with the corresponding commercially available acid.

Table 3 a

Example Structure and name 1H NMR, LC-MS retention time, [M+HJ+, 3.1a sn ₃ O,, n ₃ s. I ³ II Н ³ n |< pud i ' 1 1 । N<S s' O X HO F N-( 1,1 - Dimethylpropyl)-4- [[2-(4-fluoro-2hydroxyphenyl)acetyl] amino] pyrid in-2-carboxamide 1H NMR (500 MHz, DMSO-bb) δ 10.69 (s, 1H), 10.05 (br. s, 1H), 8.49-8.40 (m, 1H), 8.20-8, 14 (m, 1H), 7.94 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.21-7.09 (m, 1H), 6 .65-6.49 (m, 2H), 3.63 (s, 2H), 1.77 (k, J=7.5 Hz, 2H), 1.34 (s, 6H), 0.81 ( t, J=7.5 Hz, ZN). LC-MS (Method A): Rt 3.25 min; MS m/z 360.3 = [M+H]+ (100% @215 nm) 3.2a CH _{3 Osh} NO F N-tert-Butyl-4-[[2-(4-fluoro-2-hydroxyphenyl)acetyl] amino] pyrid in-2-carboxamide 1H NMR (500 MHz, DMSO-bb) δ 12.34-9.82 (m, 2H), 9.28-9.21 (m, 1H), 9.00-8.96 (m, 1H), 8.84 (s, 1H), 8.62 (dd, J=5.5,2.2 Hz, 1H), 8.017.92 (m, 1H), 7.43-7.35 (m, 2H) , 4.44 (s, 2H), 2.20 (s, 9H). LC-MS (Method A): Rt 3.00 min; MS m/z 346.2 = [M+H]+ (100% @215 nm) 3.3a CH ₃ O CI X-tert-Butyl-4-[[2-(2-chloro-6-hydroxyphenyl)acetyl] amino] pyrid in-2-carboxamide 1HNMR (500 MHz, Methanol-b4) δ 8.44-8.39 (m, 1H), 8.11-8.07 (m, 1H), 7.91 (dd, J=5.6, 2, 2 Hz, 1H), 7.09 (t, J=8.l Hz, 1H), 6.91 (dd, J=8.l, 1.0 Hz, 1H), 6.77 (dd, J= 8.2, 1.0 Hz, 1H), 3.96 (s, 2H), 1.47 (s, 9H). LC-MS (Method A): Rt 3.17 min; MS m/z 362.2/364.2 = [M+H]+ (98%@ 215 nm)

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3.4a CH _{3 Osh} HO Br 4-[[2-(4-Bromo-5-chloro-2-hydroxyphenyl)acetyl]amino]-Mtert-butylpyridine-2-carboxamide 1HNMR (500 MHz, DMSO-46) δ 10.70 (s, 1H), 10.27 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.16 (d, 3=2.0Hz, 1H), 8.03 (s, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.43 (s, 1H), 7.12 (s, 1H), 3.67 (s, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 3.59 min; MS m/z 440.0/441.9/443.9 = [M+H]+ (95% @ 215 nm) 3.5a 4-[[2-(5-tert-Butyl-2-hydroxyphenyl)acetyl]amino]-N(1-cyanocyclobutyl)pyridine-2-carboxamide 1H NMR (500 MHz, Methanol-44) δ 8.48 (d, J=5.5 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H), 7.93 (dd, J =5.5, 2.2 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 7.15 (dd, J=8.4,2.5 Hz, 1H), 6 .75 (d, J=8.4 Hz, 1H), 3.72 (s, 2H), 2.842.75 (m, 2H), 2.63-2.53 (m, 2H), 2.28- 2.16 (m, 1H), 2.18-2.06 (m, 1H), 1.28 (s, 9H). LC-MS (Method A): Rt 3.40 min; MS m/z 407.4 = [M+H]+ (98% @ 215 nm) 3.6a /\ o _sh CH, II ⁿ |^bn ₃ >4 /X xX x-X x<\ xX n ₃ s ν Er Dr sn ₃ ⁿ M s jo HO 4- [[2-(5-tert-Butyl- 2-hydroxyphenyl)acetyl]amino]-N(1-methylcyclobutyl)pyride in-2-carboxamide 1H NMR (500 MHz, Methanol-44) δ 8.43 (d, J=5.4 Hz, 1H), 8.09 (d, J=l.7 Hz, 1H), 7.90 (dd, J =5.5, 2.0 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 7.15 (dd, J=8.4,2.5 Hz, 1H), 6 .75 (d, J=8.4 Hz, 1H), 3.72 (s, 2H), 2.502.39 (m, 2H), 2.17-2.07 (m, 2H), 1.97- 1.85 (m, 2H), 1.55 (s, ZN), 1.28 (s, 9H). LC-MS (Method A): Rt 3.77 min; MS m/z 396.4 = [M+H]+ (100% @215 nm) 3.7a CH ₃ O ,, Br ^НзС l Αχ^ίν^Χχ^ ⁿ = ^s k gu tjTj U O χ^-Ο but Ar Br X-tert-butyl-4-[2-(2,5-dibromo-3-fluorine -6-hydroxyphenyl)acetamido]pyridine-2-carboxamide 1HNMR (500 MHz, DMSO-46) δ 10.87 (s, 1H), 9.74 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.15 (d, J=2.0 Hz, 1H), 8.03 (s, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.65 (d, J=8.1 Hz, 1H), 4.03 (s, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 3.61 min; MS m/z 502.1/504.1/506.1 = [M+H]+ (99% @ 215 nm)

Example 3.5b.

No. tert-Butyl-4-[[2-[2-hydroxy-5-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

Step 1: N-tert-butyl-4-[[2-[2-methoxy-5-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2carboxamide

dn ₃

To a solution of 4-amino-^tert-butylpyridin-2-carboxamide (example 3, step 1) (70 mg, 0.36 mmol), TEA (127 μl, 0.72 mmol) and 2-[2-methoxy-5 -(trifluoromethyl)phenyl]acetic acid (102 mg, 0.43 mmol) in 1,4-dioxane (1 ml), T3P® 50% solution in EtOAc (948 μl, 0.8 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was partitioned between water (25 ml) and EtOAc (25 ml). The organic layer was separated, washed with water (20 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with EtOAc in heptane to give the title compound as a yellow solid.

1H NMR (500 MHz, DMSO-06) δ 10.75 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.17 (d, J=2.1 Hz, 1H ), 8.03 (s, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.69-7.61 (m, 2H), 7.18 (d, J=8.5 Hz, 1H), 3.83 (s, 3H), 3.81 (s, 2H), 1.40 (s, 9H).

LC-MS (Method E): Rt 1.23 min; MS m/z 410.0 = [M+H]+ (93% @ 215 nm).

Step 2: N-tert-Butyl-4-[[2-[2-hydroxy-5-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2 carboxamide

The title compound was prepared from N-tert-butyl-4-[[2-[2-methoxy-5(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Step 2) analogously to Example 3, Step 3.

'and NMR (500 MHz, DMSO-SH) δ 11.32-9.82 (m, 2H), 8.44 (d, J=5.5 Hz, 1H), 8.17 (d, J=2 .0 Hz, 1H), 8.03

- 70 046966 (s, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.54 (d, J=2.0 Hz, 1H), 7.45 (dd , J=8.5, 2.1 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 3.76 (s, 2H), 1.40 (s, 9H).

LC-MS (Method A): Rt 3.41 min; MS m/z 396.2 = [M+H]+ (100% @ 215 nm).

The compounds of the following tabular examples (Table 3b) were prepared analogously to Example 3.5b, steps 1 and 2, replacing 2-[2-methoxy-5-(trifluoromethyl)phenyl]acetic acid (step 1) with the appropriate commercially available acid.

Table 3 b

Example Structure and name 1NMR Retention time LC-MS, [M+H]+, 3.6b CH ₃ O HO CI X-tert-Butyl-4-[[2-(4-chloro-2hydroxyphenyl)acetyl] amino] pyridine-2carboxamide 1H NMR (500 MHz, Methanol-b4) δ 8.42 (d, J=5.5 Hz, 1H), 8.12 (d, J=2.0 Hz, 1H), 7.90 (dd, J =5.5, 2.2 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H), 6.84-6.77 (m, 2H), 3.70 (s, 2H) , 1.47 (s, 9H). LC-MS (Method A): Rt 3.33 min; MS m/z 362.1/364.1 = [M+H]+ (98% @ 215 nm) 3.7b сн _{3 Ош} F Х-tert-Butyl-4-[[2-[2-hydroxy-4(trifluoromethyl)phenyl]acetyl]amino]pyridine-2carboxamide 1H NMR (500 MHz, DMSO-bb) δ 10.81 (br.s, 1H), 10.30 (br.s, 1H), 8.44 (d, 1=5.5Hz, 1H), 8, 17 (d, J=2.0 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.38 (d, J =7.8 Hz, 1H), 7.16-7.00 (m, 2H), 3.75 (s, 2H), 1.40 (s, 9H LC-MS (Method A): Rt 3.44 min; MS m/z 396.2 = [M+H]+ (100% @ 215 nm) 3.8b CH ₃ O but X-tert-Butyl-4-[[2-(2-hydroxy-5methoxyphenyl)acetyl] amino] pyridine-2carboxamide 1H NMR (500 MHz, DMSO-ab)b10.64 (s, 1H), 9.06 (s, 1H), 8.43 (d, J=5.5 Hz, 1H), 8.18 (d, J=l.9 Hz, 1H), 8.03 (s, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 6.76 (d, J=3.0 Hz, 1H), 6.71 (d,

- 71 046966

>8.7 Hz, 1H), 6.67 (dd, >8.7, 3.0 Hz, 1H), 3.66 (s, ZN), 3.63 (s, 2H), 1.40 ( s, 9H). LC-MS (Method A): Rt 2.87 min; MS m/z 358.2 = [M+H]+ (99% @ 215 nm) 3.9b CH ₃ 0 _u I---\ ⁿ A Ja ⁿ = ^s y rY ΥΎ J OH X-tert-Butyl-4-[(6-hydroxyindan-1 carbonyl)amino]pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-ab) 510.83 (s, 1H), 9.16 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.23 (d, >2.0 Hz, 1H), 8.05 (s, 1H), 7.90 (dd, J=5.5, 2.2 Hz, 1H), 7.05 (d, J=8.l Hz , 1H), 6.73 (d, J=l.9 Hz, 1H), 6.60 (dd, J=8.l, 2.2 Hz, 1H), 4.07 (t, >7.4 Hz, 1H), 2.98-2.90 (m, 1H), 2.83-2.73 (m, 1H), 2.39-2.23 (m, 2H), 1.41 (s, 9H). LC-MS (Method A): Rt 3.00 min; MS m/z 354.2 = [M+H]+ (100% @ 215 nm) 3.10b HO T\G-tert-Butyl-4-[(7-hydroxyind an-1 carbonyl)amino]pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-ab) 510.64 (s, 1H), 9.49 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.20 (d, J=2.l Hz, 1H), 8.03 (s, 1H), 7.84 (dd, J=5.5, 2.2 Hz, 1H), 7.02 (t, >7.7 Hz , 1H), 6.72 (d, >7.4 Hz, 1H), 6.58 (d, >7.9 Hz, 1H), 4.11 (dd, >8.6, 5.3 Hz, 1H), 3.062.98 (m, 1H), 2.89-2.81 (m, 1H), 2.36-2.29 (m, 1H),

- 72 046966

2.25-2.17 (m, 1H), 1.41 (s, 9H). LC-MS (Method A): Rt 3.26 min; MS m/z 354.2 = [M+H]+ (96% @ 215 nm) 3.11b CH ₃ 0 Br ^H3C >k ^H3C cGUdG Br b4-tert-Butyl-4-[[2-(2,5-dibromo-3-chloro-6hydroxyphenyl)acetyl] amino] pyridine-2carboxamide 1H NMR (500 MHz, DMSO-ab) 510.93 (s, 1H), 10.06 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.14 (d, J=2.l Hz, 1H), 8.03 (s, 1H), 7.81 (s, 1H), 7.79 (dd, J=5.5, 2.2 Hz, 1H), 4, 07 (s, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 3.84 min; MS m/z 518.0/520.0/522.1 = [M+H]+ (98% @ 215 nm) 3.12b ^H3C x ^CH3 n ₃ s nh n / ^{he 0} ιί^Υ n^j ⁰ X-tert-Butyl-4-[[2-(3hydroxyphenyl)acetyl] amino] pyridine-2carboxamide 1H NMR (500 MHz, DMSO-ab) 510.71(s, 1H), 9.35 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 8.02 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.11 (t, J=7.9 Hz, 1H), 6.76-6.72 (m, 2H), 6.68-6.62 (m, 1H), 3.60 (s, 2H), 1.39 (s, 9H). LC-MS (Method A): Rt 2.68 min; MS m/z 328.2 = [M+H]+ (99% @215 nm). 3.13b ,, CH ₃ 0 u F ^H 3 ^C ^L 11 ^H 1 “ kAHSf on X-tert-Butyl-4-[[2-(2-fluoro-5- 1H NMR (500 MHz, DMSO-06) 510.77 (s, 1H), 9.33 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.0 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 6.97 (t,

- 73 046966

hydroxyphenyl)acetyl]amino]pyridine-2carboxamide J=9.2 Hz, 1H), 6.75 (dd, J=6.2, 3.0 Hz, 1H), 6.65 (ddd, J=8.8, 4.0, 3.2 Hz , 1H), 3.70 (s, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 2.74 min; MS m/z 346.2 = [M+H]+ (100% @ 215 nm) 3.14b CH ₃ O _n ^N h ^C \| II ^H he X-tert-Butyl-4-[[2-(4-chloro-3hydroxyphenyl)acetyl] amino] pyridine-2carboxamide 1H NMR (500 MHz, DMSO-ab) 510.74 (s, 1H), 10.14 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.18 (d, 1=2.1Hz, 1H), 8.02 (s, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.26 (d, J=8.l Hz , 1H), 6.95 (d, J=2.0 Hz, 1H), 6.76 (dd, J=8,l, 2.0 Hz, 1H), 3.62 (s, 2H), 1 .40 (s, 9H). LC-MS (Method A): Rt 3.01 min; MS m/z 362.2/364.2 = [M+H]+ (100% @215 nm) 3.15b H ₃ C^| ³ and ⁿ “ ^with VnXQ OH X-tert-Butyl-4-[[2-(2-chloro-3 hydroxyphenyl)acetyl] amino] pyridine-2carboxamide 1H NMR (500 MHz, DMSO-ab) 510.77 (s, 1H), 10.10 (br. s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.17 ( d, J=2.l Hz, 1H), 8.03 (s, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.09 (t, J=7 ,8 Hz, 1H), 6.90 (dd, J=8.2, 1.4 Hz, 1H), 6.84 (dd, J=7.6, 1.4 Hz, 1H), 3.85 (s, 2H), 1.39 (s, 9H). LC-MS (Method A): Rt

- 74 046966

2.97 min; MS m/z 362.2/364.2= [M+H]+ (100% @215 nm) 3.16b ,, CH ₃ O _n CI ^:s EEogPf OH X-tert-Butyl-4-[[2-(2-chloro-5hydroxyphenyl)acetyl] amino] pyridine-2carboxamide 1H NMR (500 MHz, DMSO-ab) 5Iu.78(s, 1H), 9.64 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 8.03 (s, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.21 (d, J=8.7 Hz, 1H), 6.83 (d, J=2.9 Hz, 1H), 6.70 (dd, J=8.7, 2.9 Hz, 1H), 3.79 (s, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 2.98 min; MS m/z 362.2/364.2= [M+H]+ (100% @215 nm) 3.17b „ „ CH ₃ O _n EEUG'fg OH X-tert-Butyl-4-[[2-(3-chloro-5hydroxyphenyl)acetyl] amino] pyridine-2carboxamide 1H NMR (500 MHz, DMSO-ab) 510.75 (s, 1H), 9.96 (br. s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.18 ( d, J=2.1 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 6.83 (t, J= 1 .6 Hz, 1H), 6.73-6.68 (m, 2H), 3.64 (s, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 3.12 min; MS m/z 362.2/364.2= [M+H]+ (100% @215 nm)

Example 4.

N-tert-Butyl-3 -[[2-(3-hydroxyphenyl)acetyl]amino]benzamide

Mixture containing 3-amino-Ntert-butylbenzamide hydrochloride (example 2, step 1b) (50 mg, 0.22 mmol), EDCI (50 mg, 0.26 mmol), HOAt (36 mg, 0.26 mmol) , DIPEA (0.09 ml, 0.52 mmol) in DCM (1.25 ml), treated with 2-(3-hydroxyphenyl)acetic acid (33 mg, 0.22 mmol) and stirred at room temperature for 1 h The resulting mixture was diluted with water (5 ml) and extracted with DCM (3x5 ml). The combined organics were passed through a PTFE phase separator and concentrated in vacuo. The crude product was purified by preparative HPLC (acidic pH early elution method) and product fractions were concentrated and dried in vacuo to give the title compound as a white solid.

1H NMR (500 MHz, Methanol^ ₄ ) δ 7.90 (t, J=1.8 Hz, 1H), 7.72 (s, 1H), 7.69 (ddd, J=8.0, 2, 1, 1.1 Hz, 1H), 7.49-7.45 (m, 1H), 7.39 (t, J=7.9 Hz, 1H), 7.19-7.13 (m, 1H ), 6.87-6.81 (m, 2H), 6.73-6.68 (m, 1H), 3.63 (s, 2H), 1.46 (s, 9H).

LC-MS (Method B): Rt 2.56 min; MS m/z 344.3 = [M+NH ₃ ]+ (99% @ 215 nm).

The compounds of the following tabular examples (Table 4) were prepared analogously to Example 4, replacing 2(3-hydroxyphenyl)acetic acid with the corresponding commercially available acid.

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Table 4

Example Structure and name 1NMR LC-MS retention time, [M+H]+, 4.1 N-tert-Butyl-3 -[[2-(1H-ind azol-3 yl)acetyl]amino]benzamide 1H NMR (500 MHz, Chloroform-d) δ 10.12 (s, 1H), 8.93 (s, 1H), 7.83-7.75 (m, ZH), 7.52 (d, J= 8.4 Hz, 1H), 7.477.43 (m, 1H), 7.40 (d, J=7.7 Hz, 1H), 7.34 (t, J=7.8 Hz, 1H), 7.23 (t, J=7.5 Hz, 1H), 5.96 (s, 1H), 4.14 (s, 2H), 1.46 (s, 9H). LC-MS (Method A): Rt 2.64 min; MS m/z 351.2 = [M+H]+ (100% @215 nm) 4.2 F CH, 0 n ₃ cm II ⁿ N \ F xZ ✓'k L 1 n ₃ s Ν γ γ h ⁿ L U o L ' ⁰ ^ΝΗ N-tert-Butyl-Z -[ [2-(5-fluorine -1 H-ind ol-3 yl)acetyl]amino]benzamide 1H NMR (500 MHz, Chloroform-d) δ 8.67 (s, 1H), 7.71 (d, J=8.2 Hz, 1H), 7.61-7.57 (m, 2H), 7 .35 (d, J=7.8 Hz, 1H), 7.34-7.27 (m, 2H), 7.22 (dd, J=9.5, 2.1 Hz, 2H), 6, 98 (td, J=9.0, 2.4 Hz, 1H), 5.97 (s, 1H), 3.82 (s, 2H), 1.44 (s, 9H). LC-MS (Method A): Rt 2.97 min; MS m/z 368.2 = [M+H]+ (100% @215 nm) 4.3 CH _{3 Osh} bT-tert-Butyl-3-[[2-(2-hydroxyphenyl)acetyl] amino] benzamide 1H NMR (500 MHz, Methanol-b4) δ 7.86 (t, J=l,7 Hz, 1H), 7.70-7.63 (m, 1H), 7.44 (d, J=7, 8 Hz, 1H), 7.36 (t, J=7.9 Hz, 1H), 7.19 (d, J=7.5 Hz, 1H), 7.11 (td, J=8.0, 1.6 Hz, 1H), 6.89-6.75 (m, 2H), 3.70 (s, 2H), 1.44 (s, 9H). LC-MS (Method A): Rt 2.72 min; MS m/z 327.3 = [M+H]+ (100% @215 nm)

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4.4 СНз ⁰ U НзС | II Н [ \ НзС NY VW ^H LJ О 1 'f Х>^ ⁰ Z^NH ^r НзС N-tert-Butyl-3 -[ [2-(7-fluoro-2-methyl-1 N-indol-3 yl )acetyl]amino]benzamide 1H NMR (500 MHz, Chloroform-d) δ 8.35 (s, 1H), 7.71 (ddd, J=8.0.2.0, 1.1 Hz, 1H), 7.54 (t, J=l,9 Hz, 1H), 7.40 (s, 1H), 7.35 (dt, J=7.7, 1.3 Hz, 1H), 7.30 (t, J=7.8 Hz, 1H), 7.24 (d, J=7.9 Hz, 1H), 7.04 (td, J=7.9, 4.7 Hz, 1H), 6.90 (ddd, J=11 ,0, 7.9, 0.6 Hz, 1H), 5.93 (s, 1H), 3.81 (s, 2H), 2.47 (s, ZN), 1.43 (s, 9H) . LC-MS (Method A): Rt 3.15 min; MS m/z 382.2 = [M+H]+ (100% @215 nm) 4.5 N-tert-Butyl-3 -[[2-(1 N-indol-3 yl)acetyl]amino]benzamide 1H NMR (500 MHz, DMSO-ab) δ 10.91 (s, 1H), 10.19 (s, 1H), 7.89 (t, J=l.8 Hz, 1H), 7.817.75 (m , 1H), 7.70 (s, 1H), 7.61 (d, J=7.9 Hz, 1H), 7.41 (dt, J=7.9, 1.3 Hz, 1H), 7 .35 (d, J=8.l Hz, 1H), 7.32 (t, J=7.9 Hz, 1H), 7.26 (d, J=2.3 Hz, 1H), 7.07 (td, J=8.0, 7.0, 1.1 Hz, 1H), 6.98 (td, J=7.5, 7.1, 0.9 Hz, 1H), 3.73 (s, 2H), 1.36 (s, 9H). LC-MS (Method A): Rt 2.91 min; MS m/z 350.2 = [M+H]+ (100% @215 nm)

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4.6 CH ₃ 0 _u X-tert-Butyl-3-[(2-phenylacetyl)amino]benzamide 1H NMR (500 MHz, Chloroform-d) δ 7.72 (d, J=7.9 Hz, 1H), 7.65 (d, J=l.8 Hz, 1H), 7.44-7.38 (m, ZN), 7.38-7.31 (m, 4H), 7.13 (s, 1H), 5.95 (s, 1H), 3.76 (s, 2H), 1.45 ( s, 9H). LC-MS (Method A): Rt 2.96 min; MS m/z 311.2 = [M+H]+ (99% @215 nm) 4.7 CH ₃ o ,, F ^: ^ ^ϊΑ σΌό sn ₃ X-tert-Butyl-3-[[2-(2-fluoro-6methoxyphenyl)acetyl ] amino] benzamide 1H NMR (500 MHz, DMSO-ab) δ 10.24 (s, 1H), 7.92-7.87 (m, 1H), 7.75-7.67 (m, 2H), 7.41 ( d, J=7.8 Hz, 1H), 7.357.25 (m, 2H), 6.86 (d, J=8.4 Hz, 1H), 6.80 (t, J=8.7 Hz, 1H), 3.79 (s, 3H), 3.68 (s, 2H), 1.36 (s, 9H). LC-MS (Method A): Rt 3.01 min; MS m/z 359.1 = [M+H]+ (100% @215 nm) 4.8 CH ₃ O F 1 CH ₃ X-tert-Butyl-3-[[2-(2,3-difluoro-6methoxyphenyl)acetyl ] amino] benzamide 1H NMR (500 MHz, Chloroform-d) δ 7.75 (t, J=l.8 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.61 (s, 1H ), 7.40 (d, J=7.8 Hz, 1H), 7.34 (t, J=7.9 Hz, 1H), 7.10 (k, J=9.2 Hz, 1H), 6.65 (ddd, J=9.2, 3.4, 2.0 Hz, 1H), 5.97 (s, 1H),

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3.90 (s, ZN), 3.79 (d, >1.6 Hz, 2H), 1.45 (s, 9H). LC-MS (Method A): Rt 3.19 min; MS m/z 377.3 = [M+H]+ (98% @215 nm) 4.9 CH ₃ O ,, CH ₃ F X-tert-Butyl-3-[[2-[2-methoxy-4(trifluoromethyl)phenyl] acetyl] amino] benzamide 1H NMR (500 MHz, DMSO-bb) 5 10.24 (s, 1H), 7.90 (t, >1.8 Hz, 1H), 7.79-7.68 (m, 2H), 7, 44 (dd, >14.6, 7.8 Hz, 2H), 7.33 (t, >7.9 Hz, 1H), 7.28 (d, >7.8 Hz, 1H), 7.25 (s, 1H), 3.85 (s, 3H), 3.73 (s, 2H), 1.36 (s, 9H). LC-MS (Method A): Rt 3.45 min; MS m/z 409.2 = [M+H]+ (100% @215 nm)

Example 5.

No. tert-Butyl-4-[[2-(2-thienyl)acetyl]amino]pyridine-2-carboxamide

A solution of 4-amino-Ntert-butylpyridin-2-carboxamide (example 3, step 1) (50 mg, 0.26 mmol), 2(2-thienyl)acetic acid (37 mg, 0.26 mmol) and TEA ( 0.09 ml, 0.52 mmol) in 1,4-dioxane (2 ml) was treated with a 50% T3P® solution in EtOAc (617 µl, 0.97 mmol) and stirred at room temperature under an inert atmosphere for 1 hour. The resulting mixture was diluted with EtOAc (10 ml) and washed with water (10 ml). The organic portion was separated and concentrated in vacuo. Preparative HPLC purification (acidic pH, standard elution method) and freeze-drying of product fractions yielded the title compound as a white solid.

¹ H NMR (500 MHz, DMSO-06) δ 10.80 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 8.03 (s, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.41 (dd, J=5.0, 1.4 Hz, 1H ), 7.03-6.94 (m, 2H), 3.95 (s, 2H), 1.40 (s, 9H).

LC-MS (Method A): Rt 3.19 min; MS m/z 318.2 = [M+H]+ (99% @ 215 nm).

Example 5.1.

4-[[2-(2-Adamantyl)acetyl]amino]-Ntert-butylpyridine-2-carboxamide

A solution of 2-(2-adamantyl)acetic acid (40 mg, 0.21 mmol) in thionyl chloride (160 μL, 1.82 mmol) was heated at 70°C for 30 min. Excess thionyl chloride was removed in vacuo (azeotropic drying with DCM) and the residue was treated with a mixture of 4-amino-Nt-butylpyridine-2-carboxamide (Example 3, Step 1) (40 mg, 0.21 mmol) and DIPEA (43 μl, 0.25 mmol) in DCM (1.5 ml) and stirred at room temperature for 1 hour. The resulting mixture was partitioned between water (5 ml) and DCM (5 ml). The phases were separated through a PTFE separator frit and the organic layer was concentrated in vacuo. The crude product was purified by preparative HPLC (acid pH, standard elution method) and product fractions were concentrated in vacuo to give the title compound as a white crystalline solid.

1H NMR (500 MHz, DMSO-06) δ 10.50 (s, 1H), 8.42 (d, J=5.5 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H ), 8.02 (s, 1H), 7.79 (dd, J=5.5, 2.2 Hz, 1H), 2.54-2.51 (m, 2H), 2.27-2, 19 (m, 1H), 1.94-1.87 (m, 2H), 1.87-1.83 (m, 1H), 1.83-1.77 (m, 3H), 1.77- 1.71 (m, 2H), 1.71-1.65 (m, 4H), 1.54-1.49 (m, 2H), 1.39 (s, 9H).

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LC-MS (Method A): Rt 4.29 min; MS m/z 370.3 = [M+H]+ (100% @ 215 nm)

The compounds of the following tabulated examples (Table 5) were prepared analogously to both Example 5 (using T3P®) and Example 5.1 (using thionyl chloride) from 4-aminoA-tert-butylpyridine-2carboxamide (Example 3, Step 1) and the corresponding commercially available acid .

Table 5

Example Structure and name Activating reagent 1NMR LC-MS retention time, [M+HJ+, 5.2 sn ₃ O, , N ₃ S. | II n >k kk n ₃ s n A ^H U o yes o F CH ₃ X-tert-Butyl-4-[[2-(4-fluoro-2methoxyphenyl)acetyl] amino] pyrid in-2-carboxamide Thionilhlo RID 1H NMR (500 MHz, Chloroform-d) δ 8.39 (d, J=5.6 Hz, 1H), 8.21 (dd, J=5.6, 2.2 Hz, 1H), 8.01 -7.93 (m, 2H), 7.55 (d, J=2.l Hz, 1H), 7.23 (dd, J=8.9, 6.5 Hz, 1H), 6.74- 6.67 (m, 2H), 3.93 (s, ZN), 3.69 (s, 2H), 1.47 (s, 9H). LC-MS (Method A): Rt 3.31 min; MS m/z 360.2 = [M+H]+ (97% @ 215 nm) 5.3 dn ₃ o _y n ₃ d || n >k Ak _С1 Н ₃ С N к| Ak Y VY ⁿ A ϋ AJ X-tert-Butyl-4-[[2-(5-chloro-2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide Thionilhlo RID 1HNMR (500 MHz, DMSO-ab) δ 10.84 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.16 (d, J=l.9 Hz, 1H) , 8.03 (s, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.51 (dd, J=6.4, 2.7 Hz, 1H), 7.40 (ddd, J=8.7, 4.4, 2.8 Hz, 1H), 7.26 (t, J=9.l Hz, 1H), 3.83 (s, 2H), 1 .40 (s, 9H). LC-MS (Method A): Rt 3.61 min; MS m/z 364.2/366.2 = [M+H]+ (97% @ 215 nm) 5.4 CH ₃ O ,, X-tert-Butyl-4-[[2-(2-furyl)acetyl]amino]pyridine2-carboxamide TZR® 1H NMR (500 MHz, DMSO16) δ 10.77 (s, 1H), 8.46 (d, 7=5.5 Hz, 1H), 8.18 (d, 7=2.0 Hz, 1H), 8.03 (s, 1H), 7.80 (dd, 7=5.5, 2.2 Hz, 1H), 7.58 (dd, 7=1.8, 0.7 Hz, 1H), 6 .41 (dd, 7=3.1, 1.9 Hz, 1H), 6.36-6.24 (m, 1H), 3.81 (s, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 2.97 min; MS m/z 302.2 = [M+H]+ (100% @215 nm) 5.5 CH ₃ O ,, CI M-tert-Butyl-4-[[2-(3-chlorophenyl)acetyl] amino] pyrid in-2-carboxamide TZR® 1H NMR (500 MHz, DMSO16) δ 10.78 (s, 1H), 8.45 (d, 7=5.5 Hz, 1H), 8.18 (d, 7=2.0 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, 7=5.5, 2.2 Hz, 1H), 7.43-7.41 (m, 1H), 7.39-7.31 ( m, 2H), 7.31-7.27 (m, 1H), 3.75 (s, 2H), 1.39 (s, 9H) LC-MS (Method A): Rt 3.60 min; MS m/z 346.2, 348.2 = [M+H]+ (100% @ 215 nm) 5.6 DUGPR X-tert-Butyl-4-[[2-(1H-indol-3 yl)acetyl]amino]pyridine-2-carboxamide TZR® 1HNMR (500 MHz, DMSO-ab) δ 10.95 (s, 1H), 10.71 (s, 1H), 8.43 (d, J=5.5 Hz, 1H), 8.20 (d, J=2.l Hz, 1H), 8.02 (s, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.58 (d, J=7.9 Hz, 1H), 7.36 (d, J=8.l Hz, 1H), 7.28 (d, J=2.1 Hz, 1H), 7.10-7.05 (m, 1H), 7.01-6.96 (m, 1H), 3.80 (s, 2H), 1.39 (s, 9H). LC-MS (Method A): Rt 3.19 min; MS m/z 351.2 = [M+H]+ (97% @ 215 nm) 5.7 CH ₃ O CH ₃ N-tert-Butyl-4-[[2-(o-tolyl)acetyl] amino] pyridine2-carboxamide TZR® 1HNMR (500 MHz, DMSO-ab) δ 10.76 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H) , 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.27-7.22 (m, 1H), 7.20-7.12 (m, ZN), 3.75 (s, 2H), 2.28 (s, ZN), 1.39 (s, 9H). LC-MS (Method A): Rt 3.46 min; MS m/z 326.2 = [M+H]+ (98% @ 215 nm)

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5.8 CH ₃ O H ₃ C. | II ^H X /X x<\ x-\ x^h. .CI ^НзС й nf ϊΎΎ N<s JJ O CHA _S| X-tert-Butyl-4-[[2-(3,4-dichlorophenyl)acetyl]amino]pyridine-2-carboxamide TZR® 1HNMR (500 MHz, DMSO-bb) δ 11.62 (s, 1H), 9.26 (d, J=5.5 Hz, 1H), 8.98 (d, J=2.0 Hz, 1H) , 8.84 (s, 1H), 8.61 (dd, J=5.5, 2.2 Hz, 1H), 8.42 (d, J=2.0 Hz, 1H), 8.41 ( d, J=8.3 Hz, 1H), 8.13 (dd, J=8.3, 2.0 Hz, 1H), 4.59 (s, 2H), 2.20 (s, 9H). LC-MS (Method A): Rt 3.86 min; MS m/z 380.1/ 382.1/ 384.1 = [M+H]+ (100% @ 215 nm) 5.9 CH ₃ 0 _w “ ^: ' ^l XgTO' X-tert-Butyl-4-[[2-(3fluorophenyl)acetyl]amino]pyridine-2-carboxamide TZR® 1HNMR (500 MHz, DMSO-bb) δ 10.79 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.0 Hz, 1H) , 8.02 (s, 1H), 7.81 (dd, J=5.5, 2.1 Hz, 1H), 7.42-7.33 (m, 1H), 7.21-7.14 (m, 2H), 7.12-7.05 (m, 1H), 3.76 (s, 2H), 1.39 (s, 9H). LC-MS (Method A): Rt 3.39 min; MS m/z 330.2 = [M+H]+ (99% @ 215 nm) 5.10 сн _{3 Ош} Н ₃ С.| II N Xx χΆ x<\ x^\ x-\ x-^ x- ^s| H,C N AG and ' 1 ” 1 \ N<s^ o AG Q XZ CH ₃ M-tert-Butyl-4-[[2-(5-chloro-2methoxyphenyl)acetyl] amino] pyrid in-2- carboxamide Thionilhlo RID 1HNMR (500 MHz, DMSO-bb) δ 10.70 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.17 (d, J=l.9 Hz, 1H) , 8.03 (s, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.33-7.28 (m, 2H), 7.03-6.99 (m, 1H), 3.75 (s, ZN), 3.71 (s, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 3.61 min; MS m/z 376.2/378.2 = [M+H]+ (98% @ 215 nm) 5.11 CH ₃ 0 ,, AVynX ^Пз TZR® 1HNMR (500 MHz, Methanol-sM) δ 8.42 (d, J=5.5 Hz, 1H), 8.13 (d, J=2.0 Hz, 1H), 7.89 (dd, J= 5.5, 2.2 Hz, 1H), 7.22 (d, J=8.0 Hz, 2H), 7.14 (d, J=7.9 Hz, 2H), 3.68 (s, 2H), 2.31 (s, ZN), 1.47 (s, 9H). X-tert-Butyl-4-[[2-(p-tolyl)acetyl]amino]pyridine2-carboxamide LC-MS (Method A): Rt 3.52 min; MS m/z 326.2 = [M+H]+ (98% @ 215 nm) 5.12 сн ₃ О ^НзС Х А^ч^Хх^/^ ^НзС к njTj О AG _F Х-tert-Butyl-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide TZR® 1HNMR (500 MHz, Methanol-sM) δ 8.43 (d, J=5.3 Hz, 1H), 8.13 (d, J=l.8 Hz, 1H), 7.90 (dd, J= 5.5, 2.2 Hz, 1H), 7.36 (tdd, J=7.6, 1.6 Hz, 1H), 7.31 (tdd, J=7.4, 5.3, 1, 8 Hz, 1H), 7.16 (td, J=7.5, 1.1 Hz, 1H), 7.10 (ddd, J=9.5, 8.3, 1.0 Hz, 1H), 3.82 (s, 2H), 1.47 (s, 9H). LC-MS (Method A): Rt 3.30 min; MS m/z 330.2 = [M+H]+ (98% @ 215 nm) 5.13 CH ₃ O ^H3C A ^H3C To that X|fl _F X-tert-Butyl-4-[[2-(4-fluorophenyl)acetyl]amino]pyridine-2-carboxamide TZR® 1HNMR (500 MHz, Methanol-sM) δ 8.43 (d, J=5.5 Hz, 1H), 8.13 (d, J=l.9 Hz, 1H), 7.90 (dd, J= 5.5, 2.2 Hz, 1H), 7.36 (dd, J=8.7, 5.4 Hz, 2H), 7.10-7.01 (m, 2H), 3.72 (s , 2H), 1.47 (s, 9H). LC-MS (Method A): Rt 3.34 min; MS m/z 330.2 = [M+H]+ (98% @ 215 nm) 5.14 sn _{3 Osh} n, s. | II ⁿ x\ x^. .He. n ₃ s n γ' γ γ γ γ ⁿ 1 l X-tert-Butyl-4-[[2-(m-tolyl)acetyl]amino]pyridine2-carboxamide TZR® 1HNMR (500 MHz, DMSO-bb) δ 10.74 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.l Hz, 1H) , 8.02 (s, 1H), 7.81 (dd, J=5.5, 2.1 Hz, 1H), 7.21 (t, J=7.5 Hz, 1H), 7.14 ( s, 1H), 7.12 (d, J=7.6 Hz, 1H), 7.07 (d, J=7.6 Hz, 1H), 3.66 (s, 2H), 2.29 ( s, ZN), 1.39 (s, 9H). LC-MS (Method A): Rt 3.58 min; MS m/z 326.2 = [M+H]+ (98% @ 215 nm)

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5.15 CH ₃ 0 ,, 4-[[2-(1,3-Benzoxazol-6-yl)acetyl]amino]-X-tert-butylpyridine-2-carboxamide TZR® 1H NMR (500 MHz, Methanol-b4) δ 8.46 (s, 1H), 8.42 (d, J=5.5 Hz, 1H), 8.14 (d, J=l.9 Hz, 1H ), 7.90 (dd, J=5.6, 2.2 Hz, 1H), 7.79-7.73 (m, 1H), 7.64 (d, J=8.4 Hz, 1H) , 7.45 (dd, J=8.5, 1.6 Hz, 1H), 3.88 (s, 2H), 1.47 (s, 9H). LC-MS (Method A): Rt 2.82 min; MS m/z 353.1 = [M+H]+ (98% @ 215 nm) 5.16 CH ₃ 0 ,, Cl G1-tert-Butyl-4-[[2-(2-chloro-3-pyridyl)acetyl]amino]pyridine-2-carboxamide TZR® 1HNMR (500 MHz, DMSO-bb) δ 10.89 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.35 (dd, J=4.8, 1.8 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H), 8.03 (s, 1H), 7.90 (dd, J=7.5, 1.8 Hz, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.44 (dd, J=7.5, 4.8 Hz, 1H), 3.95 (s, 2H), 1 .40 (s, 9H). LC-MS (Method A): Rt 2.76 min; MS m/z 347.1, 349.1= [M+H]+ (97% @ 215 nm) 5.17 CH ₃ 0 CI G1-tert-Butyl-4-[[2-(2,6-dichlorophenyl)acetyl]amino]pyridine-2-carboxamide TZR® 1HNMR (500 MHz, DMSO-bb) δ 10.95 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.16 (d, J=2.l Hz, 1H) , 8.03 (s, 1H), 7.78 (dd, J=5.5, 2.2 Hz, 1H), 7.51 (d, J=8.l Hz, 2H), 7.40- 7.32 (m, 1H), 4.11 (s, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 3.66 min; MS m/z 380.1/ 382.1/ 384.1 = [M+H]+ (98% @ 215 nm) 5.18 CH ₃ O ,, “Vrrva: G1-tert-Butyl-4-[[2-(4-chloro-3-fluorophenyl)acetyl]amino]pyridine-2-carboxamide TZR® 1HNMR (500 MHz, DMSO-bb) δ 10.78 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.17 (d, J=2.l Hz, 1H) , 8.03 (s, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.55 (t, J=8.l Hz, 1H), 7.39 ( dd, J=10.5, 1.8 Hz, 1H), 7.20 (dd, J=8.2, 1.6 Hz, 1H), 3.78 (s, 2H), 1.40 (s , 9H). LC-MS (Method A): Rt 3.67 min; MS m/z 364.1/ 366.1 = [M+H]+ (97% @ 215 nm) 5.19 CH ₃ O Cl T4-tert-Butyl-4-[[2-(3,5-dichlorophenyl)acetyl]amino]pyridine-2-carboxamide TZR® 1HNMR (250 MHz, DMSO-bb) δ 10.78 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.16 (d, J=l.9 Hz, 1H) , 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.52 (t, J=l.9 Hz, 1H), 7.41 ( d, J=l.9 Hz, 2H), 3.80 (s, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 3.99 min; MS m/z 380.1 /382.1 /384.1 = [M+H]+ (94% @ 215 nm) 5.20 sn ₃ O ,, H ₃ C. I II n n ₃ s n y π π ί ⁿ nU ¹ o AJ CI b1-tert-Butyl-4-[[2-(2-chlorophenyl)acetyl] amino] pyridine -2-carboxamide TZR® 1HNMR (500 MHz, DMSO-bb) δ 10.84 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H) , 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.1 Hz, 1H), 7.50-7.40 (m, 2H), 7.36-7.28 (m, 2H), 3.92 (s, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 3.44 min; MS m/z 346.1/348.1 = [M+H]+ (100% @ 215 nm)

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5.21 CH ₃ 0 ,, Cl X-tert-Butyl-4-[[2-(3-chloro-4hydroxyphenyl)acetyl] amino] pyrid in-2carboxamide TZR® 1HNMR (500 MHz, Methanol-sM) δ 8.42 (d, J=5.5 Hz, 1H), 8.12 (d, J=2.0 Hz, 1H), 7.90 (dd, J= 5.5, 2.2 Hz, 1H), 7.29 (d, J=2.l Hz, 1H), 7.09 (dd, J=8.3, 2.2 Hz, 1H), 6, 87 (d, J=8.3 Hz, 1H), 3.62 (s, 2H), 1.47 (s, 9H). LC-MS (Method A): Rt 3.03 min; MS m/z 362.1/ 364.1 = [M+H]+ (99% @ 215 nm) 5.22 T4-tert-Butyl-4-(indan-1-carbonylamino)pyridine-2carboxamide Thionilhlo RID 1HNMR (500 MHz, DMSO-bb) δ 10.86 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.23 (d, J=2.l Hz, 1H) , 8.03 (s, 1H), 7.87 (dd, J=5.5, 2.2 Hz, 1H), 7.30 (dd, J=19.3, 7.3 Hz, 2H), 7.20 (t, J=7.0 Hz, 1H), 7.16 (t, J=7.0 Hz, 1H), 4.16 (t, J=7.3 Hz, 1H), 3, 10-3.03 (m, 1H), 2.94-2.86 (m, 1H), 2.39-2.27 (m, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 3.58 min; MS m/z 338.2 = [M+H]+ (100% @215 nm) 5.23 CH, O T4-tert-Butyl-4-[(2-quinoxalin-6ylacetyl)amino]pyridine-2-carboxamide TZR® 1H NMR (500 MHz, DMSO-bb) δ 10.89 (s, 1H), 8.96-8.91 (m, 2H), 8.45 (d, J=5.5 Hz, 1H), 8 .20 (d, J=2.1 Hz, 1H), 8.09-8.06 (m, 2H), 8.02 (s, 1H), 7.87-7.81 (m, 2H), 4.04 (s, 2H), 1.39 (s, 9H). LC-MS (Method A): Rt 2.66 min; MS m/z 364.2 = [M+H]+ (100% @215 nm) 5.24 CH ₃ O X-tert-Butyl-4-[[2-(2naphthyl)acetyl] amino] pyrid in-2-carboxamide TZR® 1HNMR (500 MHz, DMSO-bb) δ 10.86 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.21 (d, J=2.1 Hz, 1H) , 8.02 (s, 1H), 7.92-7.86 (m, ZN), 7.86-7.84 (m, 1H), 7.84-7.81 (m, 1H), 7 .54-7.45 (m, ZN), 3.90 (s, 2H), 1.39 (s, 9H). LC-MS (Method A): Rt 3.74 min; MS m/z 362.2 = [M+H]+ (99% @ 215 nm) 5.25 ALsgA T4-tert-Butyl-4-(2,3-dihydrobenzofuran-3 carbonylamino)pyridine-2-carboxamide TZR® 1HNMR (500 MHz, DMSO-bb) δ 10.99 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.21 (d, J=2.l Hz, 1H) , 8.03 (s, 1H), 7.87 (dd, J=5.5, 2.1 Hz, 1H), 7.38 (d, J=7.4 Hz, 1H), 7.17 ( t, J=7.7 Hz, 1H), 6.85 (t, J=7.5 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 4.85 (dd, J=9.0, 6.0 Hz, 1H), 4.70 (t, J=9.2 Hz, 1H), 4.51 (dd, J=9.3, 6.0 Hz, 1H), 1.40 (s, 9H). LC-MS (Method A): Rt 3.32 min; MS m/z 340.2 = [M+H]+ (98% @ 215 nm) 5.26 СНз О ,, ( ) Н ₃ С. 1 II ⁿ \ / Ж хЖ/N. A. A. N ₃ C Ν ⁿ M and X-tert-Butyl-4-(6,7,8,9-tetrahydro-5Hbenzo[7]annulen-5-carbonylamino)pyridine-2carboxamide TZR® 1HNMR (500 MHz, DMSO-bb) δ 10.62 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.26 (d, J=2.0 Hz, 1H) , 8.03 (s, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.19 (dd, J=7.2, 1.6 Hz, 1H), 7.12 (dtd, J=14.9, 7.3, 1.6 Hz, 2H), 7.00-6.97 (m, 1H), 4.06-4.01 (m, 1H), 2.93-2.80 (m, 2H), 2.06-2.00 (m, 1H), 1.91-1.63 (m, 4H), 1.43-1.32 (m, JN ). LC-MS (Method A): Rt 4.09 min; MS m/z 366.2 = [M+H]+ (96% @ 215 nm)

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X-tert-Butyl-4-(tetral in-1 carbonylamino)pyridine-2-carboxamide

S-tert-Butyl-4-[[2-(6quinolyl)acetyl]amino]pyridine-2-carboxamide

1HNMR (500 MHz, DMSO-bb) δ 10.79 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.23 (d, J=2.0 Hz, 1H) , 8.03 (s, 1H), 7.85 (dd, J=5.5, 2.1 Hz, 1H), 7.17-7.06 (m, 4H), 3.92 (t, J =6.6 Hz, 1H), 2.84-2.69 (m, 2H), 2.11-1.95 (m, ZN), 1.73-1.63 (m, 1H), 1, 40 (s, 9H).

LC-MS (Method A): Rt 3.73 min; MS m/z 352.2 = [M+H]+ (99% @ 215 nm)

1HNMR (500 MHz, DMSO-bb) δ 10.87 (s, 1H), 8.87 (dd, J=4.2, 1.7 Hz, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.37-8.32 (m, 1H), 8.21 (d, J=2.0 Hz, 1H), 8.02 (s, 1H), 7.99 (d, J =8.7 Hz, 1H), 7.90 (d, J= 1.5 Hz, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.74 (dd , J=8.7, 2.0 Hz, 1H), 7.52 (dd, J=8.3, 4.2 Hz, 1H), 3.95 (s, 2H), 1.39 (s, 9H).

LC-MS (Method A): Rt 1.98 min; MS m/z 363.2 = [M+H]+ (97% @ 215 nm)

ci

N-tert-butyl-4-[[ 1 -(3 chlorophenyl)cyclopropanecarbonyl]amino]pyridine-2carboxamide

1HNMR (500 MHz, Methanol-SI) δ 8.41 (d, J=5.5 Hz, 1H), 8.12 (d, J=2.l Hz, 1H), 7.81 (dd, J= 5.6, 2.2 Hz, 1H), 7.52-7.47 (m, 1H), 7.40 (dd, J=5.2, 2.7 Hz, 2H), 7.37 (ddt , J=6.7, 4.4, 2.5 Hz, 1H), 1.66-1.60 (m, 2H), 1.47 (s, 9H), 1.28-1.22 (m , 2H).

LC-MS (Method A): Rt 4.01 min; MS m/z 372.2/374.2 = [M+H]+ (100% @ 215 nm)

X-tert-Butyl-4-[[2-(2,3-dihydro-1,4-benzodioxin-6yl)acetyl]amino]pyridine-2-carboxamide

1HNMR (500 MHz, DMSO-bb) δ 10.67 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.17 (d, J=2.0 Hz, 1H) , 8.02 (s, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 6.83 (d, J=l.8 Hz, 1H), 6.79 ( d, J=8.2 Hz, 1H), 6.77 (dd, J=8.3, 1.9 Hz, 1H), 4.21 (s, 4H), 3.57 (s, 2H), 1.39 (s, 9H). LC-MS (Method A): Rt 3.23 min; MS m/z 370.3/371.3 = [M+H]+ (98% @ 215 nm)

Example 5.33.

N-(1,1-Dimethylprop-2-ynyl)-4-[(2-isochroman-1-ylacetyl)amino]pyridin-2-carboxamide

The title compound was prepared from 4-amino-N(1,1-dimethylprop-2-ynyl)pyridin-2-carboxamide (Example 78, Step 1) and 2-isochroman-1-ylacetic acid analogously to Example 5.1.

1H NMR (500 MHz, DMSO-06) δ 10.60 (s, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.33 (s, 1H), 8.22 (d , J=2.0 Hz, 1H), 7.87 (dd, J=5.5, 2.2 Hz, 1H), 7.19 (tdd, J=12.4, 9.2, 5.5 Hz, 4H), 5.19 (dd, J=10.0, 3.1 Hz, 1H), 4.08-4.01 (m, 1H), 3.72 (ddd, J=11.4, 9.0, 4.1 Hz, 1H), 3.21 (s, 1H), 3.09 (dd, J=14.6, 3.4 Hz, 1H), 2.92-2.84 (m , 1H), 2.752.67 (m, 2H), 1.65 (s, 6H).

LC-MS (Method A): Rt 3.22 min; MS m/z 378.3 = [M+H]+ (100% @ 215 nm).

Example 5.34.

4-[[2-(4,4-Difluorocyclohexyl)acetyl]amino]-^(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide

The title compound was prepared from 4-amino-N(1,1-dimethylprop-2-ynyl)pyridin-2-carboxamide (Example 78, Step 1) and 2-(4,4-difluorocyclohexyl)acetic acid analogously to Example 5.1.

1H NMR (500 MHz, DMSO-06) δ 10.52 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.30 (s, 1H), 8.20 (d , J=2.0 Hz, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 3.21 (s, 1H), 2.34 (d, J=7, 1 Hz, 2H), 2.05-1.90 (m, 3H), 1.90-1.82 (m, 1H), 1.82-1.75 (m, 3H), 1.64 (s , 6H), 1.32-1.18 (m, 2H).

LC-MS (Method A): Rt 3.26 min; MS m/z 364.3= [M+H]+ (97% @ 215 nm).

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Example 5.35.

No.(1,1-Dimethylprop-2-ynyl)-4-[[2-[4-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

The title compound was prepared from 4-amino-A1,1-dimethylprop-2-ynyl)pyridin-2-carboxamide (Example 78, Step 1) and 2-[4-(trifluoromethyl)phenyl]acetic acid analogously to Example 5.

¹ H NMR (500 MHz, DMSO-06) δ 10.84 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.31 (s, 1H), 8.19 ( d, J=2.0 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.70 (d, J=8.l Hz, 2H), 7, 56 (d, J=8.1 Hz, 2H), 3.86 (s, 2H), 3.20 (s, 1H), 1.64 (s, 6H).

LC-MS (Method A): Rt 3.53 min; MS m/z 390.2= [M+H]+ (100% @ 215 nm).

Example 5.36.

No.(1,1-Dimethylprop-2-ynyl)-4-[[2-[3-(trifluoromethyl)-1H-pyrazol-4-yl]acetyl]amino]pyridine-2carboxamide

Step 1: 2-[3-(Trifluoromethyl)-1H-pyrazol-4-yl]acetic acid

Periodic acid (278 mg, 1.22 mmol) was added to MeCN (4.5 ml) and stirred at room temperature for 20 min. To this solution was added 2-[3-(trifluoromethyl)-III-pyrazol-4yl]ethanol (100 mg, 0.56 mmol) in MeCN (0.93 ml), and the mixture was cooled to 0°C. Pyridinium chlorochromate (8 mg, 0.04 mmol) was added and the mixture was gradually warmed to room temperature and stirred for 90 hours. The resulting mixture was diluted with excess water, acidified with 3 M sulfuric acid and quenched with saturated aqueous sodium thiosulfate. After 3 days, the mixture was filtered and washed with water to obtain the title compound as a pale yellow solid.

^1H NMR (400 MHz, DMSO-06) δ 13.44 (s, 1H), 12.38 (s, 1H), 7.85 (s, 1H), 3.53 (s, 2H).

LC-MS (Method E): Rt 0.77 min; MS m/z 195.0 = [M+H]+ (95% @ 215 nm).

Step 2: N-(1,1-Dimethylprop-2-ynyl)-4-[[2-[3-(trifluoromethyl)-1H-pyrazol-4yl]acetyl]amino]pyridine-2-carboxamide

The title compound was prepared from 4-amino-A1,1-dimethylprop-2-ynyl)pyridin-2-carboxamide (Example 78, Step 1) and 2-[3-(trifluoromethyl)-1H-pyrazol-4-yl]acetic acid (stage 1) similar to example 5.

1H NMR (400 MHz, DMSO-06) δ 13.50 (s, 1H), 10.74 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.32 (s , 1H), 8.20 (d, J=2.1 Hz, 1H), 7.91 (s, 1H), 7.80 (dd, J=5.5, 2.1 Hz, 1H), 3 .73 (s, 2H), 3.21 (s, 1H), 1.64 (s, 6H).

LC-MS (Method A): Rt 2.69 min; MS m/z 380.2 = [M+H]+ (100% @ 215 nm).

Example 5.37.

No.(1,1-Dimethylprop-2-ynyl)-4-[[2-[3-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

The title compound was prepared from 4-amino-A1,1-dimethylprop-2-ynyl)pyridin-2-carboxamide (Example 78, Step 1) and 2-[3-(trifluoromethyl)phenyl]acetic acid analogously to Example 5.

1H NMR (500 MHz, DMSO-06) δ 10.84 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.31 (s, 1H), 8.19 (d , J=2.0 Hz, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.72-7.69 (m, 1H), 7.66-7, 61 (m, 2H), 7.61-7.55 (m, 1H), 3.88 (s, 2H), 3.21 (s, 1H), 1.64 (s, 6H).

LC-MS (Method A): Rt 3.51 min; MS m/z 390.2 = [M+H]+ (100% @ 215 nm).

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Example 5.38.

N-(1,1-Dimethylprop-2-ynyl)-4-[[2-[2-(trifluoromethyl)phenyl] acetyl] amino] pyridine-2-carboxamide

The title compound was prepared from 4-amino-I-(1,1-dimethylprop-2-ynyl)pyridine-2carboxamide (Example 78, Step 1) and 2-[2-(trifluoromethyl)phenyl]acetic acid analogously to Example 5.

1H NMR (500 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.32 (s, 1H), 8.18 (d , J=2.0 Hz, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.67 (t, J=7.6 Hz, 1H), 7.52 (dd, J=18.5, 7.7 Hz, 2H), 4.01 (s, 2H), 3.21 (s, 1H) , 1.64 (s, 6H).

LC-MS (Method A): Rt 3.53 min; MS m/z 390.2 = [M+H]+ (100% @ 215 nm).

Example 5.39.

4-[[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)acetyl]amino]-A1,1-dimethylprop-2-ynyl)pyridin-2carboxamide

The title compound was prepared from 4-amino-I-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Example 78, Step 1) and 2-(2,3-dihydro-1,4-benzoxazine-4 -yl)acetic acid as in example 5.

¹ H NMR (500 MHz, DMSO-06) δ 10.65 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.31 (s, 1H), 8.20 ( d, J=2.1 Hz, 1H), 7.86 (dd, J=5.5, 2.2 Hz, 1H), 6.74-6.67 (m, 2H), 6.59-6 .52 (m, 2H), 4.26-4.21 (m, 2H), 4.17 (s, 2H), 3.523.47 (m, 2H), 3.21 (s, 1H), 1, 64 (s, 6H).

LC-MS (Method A): Rt 3.32 min; MS m/z 379.2 = [M+H]+ (90% @ 215 nm).

Example 6.

No. tert-Butyl-4-[[2-(5-cyano-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide

Step 1: 4-[[2-(5-Bromo-2-methoxyphenyl)acetyl]amino]-Ntert-butylpyridine-2-carboxamide

2-(5-Bromo-2-methoxyphenyl)acetic acid (348 mg, 1.42 mmol) in thionyl chloride (1.25 ml, 14.2 mmol) was stirred at 70 °C under an inert atmosphere for 1 h. The resulting solution cooled to room temperature and concentrated in vacuo (azeotropically distilled with toluene and DCM). The dry acid chloride was dissolved in anhydrous DCM (10 ml) and added dropwise to a solution of 4-amino-I-tert-butylpyridine-2-carboxamide (Example 3, Step 1) (274 mg, 1.42 mmol) and DIPEA (0 .5 ml, 2.84 mmol) in anhydrous DCM (10 ml). The reaction mixture was stirred under an inert atmosphere at room temperature. After 1 hour the mixture was diluted with DCM (25 ml) and washed with water (2x25 ml). Organic extracts were dried over Na ₂ SO ₄ and concentrated in vacuo. The resulting crude oil was purified by chromatography on silica gel, eluting with EtOAc in heptane. The column was washed with methanol, and the eluent was collected and concentrated in vacuo to give a beige solid. The solid was purified again by chromatography on silica gel, eluting with 0-10% MeOH in DCM, and product fractions were concentrated in vacuo and dried in a vacuum oven at 40°C for 2 hours to give the title compound.

1H NMR (500 MHz, DMSO-06) δ 10.70 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.17 (d, J=2.0 Hz, 1H ), 8.03 (s, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.47-7.38 (m, 2H), 7.01-6, 92 (m, 1H), 3.74 (s, 3H), 3.71 (s, 2H), 1.40 (s, 9H).

LC-MS (Method A): Rt 3.62 min; MS m/z 420.2, 422.2 = [M+H]+ (100% @ 215 nm).

Step 2: N-tert-Butyl-4-[[2-(5-cyano-2-methoxyphenyl)acetyl]amino]pyridine-2-carboxamide

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A solution of 4-[[2-(5-bromo-2-methoxyphenyl)acetyl]amino]-N-tert-butylpyridine-2-carboxamide (step 1) (75 mg, 0.18 mmol) in DMF (2 ml) was degassed with nitrogen for 5 minutes before adding tetrakis(triphenylphosphine)palladium(0) (21 mg, 0.02 mmol). The mixture was purged with nitrogen for an additional 5 min, then treated with zinc cyanide (27 mg, 0.23 mmol). The resulting mixture was stirred at 100°C for 16 hours. An additional portion of zinc cyanide (27 mg, 0.23 mmol) and tetrakis(triphenylphosphine)palladium(0) (21 mg, 0.02 mmol) was added, the mixture was purged with nitrogen and stirred continued at 100°C for an additional 24 hours. The mixture was diluted with EtOAc (20 ml) and washed with water (20 ml), aqueous NaHCO ₃ (sat.) (20 ml) and saturated aqueous sodium chloride (20 ml). The organic phases were dried over Na ₂ SO ₄ and concentrated in vacuo. The crude material was purified by chromatography on silica gel, eluting with EtOAc in heptane. Product fractions were concentrated in vacuo and dried in a vacuum oven to give the title compound as a yellow solid.

¹ H NMR (500 MHz, Chloroform-d) δ 8.40 (d, J=5.6 Hz, 1H), 8.39 (br.s, 1H), 8.20 (dd, J=5.6 , 2.2 Hz, 1H), 8.04 (s, 1H), 7.75-7.69 (m, 1H), 7.63 (dd J=8.6, 2.1 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 6.99 (d, J=8.6 Hz, 1h), 3.95 (s, 3H), 3.77 (s, 2H), 1.47 (s, 9H).

LC-MS (Method E): Rt 1.13 min; MS m/z 367.1 = [M+H]+ (95% @ 215 nm).

Step 3: N-tert-Butyl-4-[[2-(5-cyano-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide

To a solution of N-tert-butyl-4-[[2-(5-cyano-2-methoxyphenyl)acetyl]amino]pyridine-2-carboxamide (step 2) (20 mg, 0.05 mmol) in DCM (2 ml) 1 M BBr ₃ in DCM (164 µl, 0.16 mmol) was added. The resulting mixture was stirred under an inert atmosphere for 2 hours. An additional portion of 1 M BBr ₃ in DCM (164 μl, 0.16 mmol) was added and the mixture was stirred at room temperature for an additional 16 hours. An additional portion of 1 M BBr ₃ in DCM (164 μl, 0.16 mmol) and the mixture was stirred for 24 h at room temperature under nitrogen. The mixture was diluted with DCM (20 ml) and washed with water (2x20 ml). The organic portion was dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by C18 reverse phase chromatography, eluting with 0100% MeCN in water with 0.1% formic acid. Product fractions were freeze-dried to obtain the title compound as a white solid.

1H NMR (500 MHz, DMSO-06) δ 10.78 (br. s, 1H), 10.75 (s, 1H), 10.90-10.60 (m, 2H), 8.44 (d, J=5.5 Hz, 1H), 8.16 (d, J=1.9 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.63 (d, J=2.1 Hz, 1H), 7.57 (dd, J=8.4, 2.2 Hz, 1H), 6.93 (d, J=8 .4 Hz, 1H), 3.72 (s, 2H), 1.40 (s, 9H).

LC-MS (Method A): Rt 2.84 min; MS m/z 353.3 = [M+H]+ (94% @ 215 nm).

Example 7.

3-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-^(1,1,2,2-tetramethylpropyl)benzamide

Step 1: Methyl 3-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]benzoate

Solution of 2-(5-chloro-2-methoxyphenyl)acetic acid (1200 mg, 5.98 mmol), EDCI (1376 mg, 7.18 mmol), HOAt (814 mg, 5.98 mmol), DIPEA (2, 61 ml, 14.95 mmol) and methyl 3-amine benzoate (904 mg, 5.98 mmol) in DMF (5 ml) were stirred at room temperature for 17 hours. The reaction mixture was diluted with water (35 ml) and extracted with EtOAc ( 2x40 ml). The combined organic portions were washed with water (2x40 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The crude material was purified by silica gel chromatography, eluting with 10-70% EtOAc in heptane. Product fractions were concentrated in vacuo to give the title compound as a white solid with metal

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1H NMR (500 MHz, DMSO-b6) δ 10.32 (s, 1H), 8.29 (t, J=1.8 Hz, 1H), 7.82 (ddd, J=8.1, 2, 1, 1.0 Hz, 1H), 7.63 (dt, J=7.7, 1.2 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 7.32- 7.28 (m, 2H), 7.05-6.95 (m, 1H), 3.84 (s, 3H), 3.76 (s, 3H), 3.66 (s, 2H).

LC-MS (Method E): Rt 1.21 min; MS m/z 334.1/ 336.1 = [M+H]+ (96% @ 215 nm).

Step 2: 3-[[2-(5-Chloro-2-methoxyphenyl)acetyl]amino]benzoic acid

I

CH ₃

M LiOH (7.71 mL, 15.42 mmol) was added to a solution of methyl 3-[[2-(5-chloro-2methoxyphenyl)acetyl]amino]benzoate (step 1) (1751 mg, 5.14 mmol) in THF (8 ml). The reaction mixture was stirred at room temperature for 7 hours. The resulting mixture was concentrated in vacuo, diluted with water (8 ml) and acidified to pH 2 with aqueous 2 M HCl. A precipitate formed which was collected by vacuum filtration and washed with Et ₂ O (2x20 ml). The solid was dried in a vacuum oven at 40°C for 3 hours to obtain the title compound as a pale beige solid.

1H NMR (500 MHz, DMSO-b6) δ 10.32 (s, 1H), 8.23 (s, 1H), 7.87-7.74 (m, 1H), 7.61 (d, J= 7.7 Hz, 1H), 7.41 (t, J=7.9 Hz, 1H), 7.31-7.27 (m, 2H), 7.03-6.95 (m, 1H), 3.76 (s, 3H), 3.66 (s, 2H).

LC-MS (Method E): Rt 1.07 min; MS m/z 320.1/322.1 = [M+H]+ (100% @ 215 nm).

Step 3: 3-[[2-(5-Chloro-2-methoxyphenyl)acetyl]amino]-N-(1,1,2,2-tetramethylpropyl)benzamide

I dn ₃

3-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]benzoic acid solution (step 2) (70 mg, 0.22 mmol), EDCI (50 mg, 0.26 mmol), HOAt (36 mg, 0.26 mmol), DIPEA (0.11 ml, 0.66 mmol) and 2,3,3trimethylbutan-2-amine hydrochloride (33 mg, 0.22 mmol) in DMF (0.5 ml) were stirred at room temperature for 3 hours. The resulting mixture was diluted with EtOAc (5 ml) and water (5 ml). The aqueous layer was extracted with EtOAc (5 ml) and the combined organic extracts were washed with water (5 ml), and saturated aqueous sodium chloride (5 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The crude residue was purified by preparative HPLC (acidic pH early elution method) and product fractions were concentrated in vacuo to give the title compound as a white, metallic powder.

1H NMR (500 MHz, DMSO-d^δ 10.19 (s, 1H), 7.85 (s, 1H), 7.74 (dt, J=6.8, 2.1 Hz, 1H), 7 .37-7.32 (m, 2H), 7.32-7.26 (m, 2H), 7.09 (s, 1H), 7.02-6.98 (m, 1H), 3.76 (s, 3H), 3.65 (s, 2H), 1.39 (s, 6H), 0.97 (s, 9H).

LC-MS (Method E): Rt 1.32 min; MS m/z 417.2/ 419.2 = [M+H]+ (97% @ 215 nm).

Step 4: 3-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1,1,2,2-tetramethylpropyl)benzamide

To a cooled (0°C) solution of 3-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]-A1,1,2,2tetramethylpropyl)benzamide (step 3) (53 mg, 0.13 mmol) in DCM (0.5 ml), 1 M BBr ₃ in DCM (0.38 ml, 0.38 mmol) was added and the mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with water (5 ml) and extracted with EtOAc (2x8 ml). The combined organic extracts were dried over Na ₂ SO ₄ and concentrated in vacuo. The crude residue was purified by preparative HPLC (acidic pH early elution method) and product fractions were concentrated in vacuo to give the title compound as a white, metallic powder.

1H NMR (500 MHz, DMSO) δ 10.19 (s, 1H), 9.81 (br. s, 1H), 7.86 (s, 1H), 7.75 (dt, J=6.6, 2.2 Hz, 1H), 7.38-7.31 (m, 2H), 7.20 (d, J=2.7 Hz, 1H), 7.13-7.05 (m, 2H), 6.80 (d, J=8.6 Hz, 1H), 3.61 (s, 2H), 1.39 (s, 6H), 0.97 (s, 9H).

LC-MS (Method D): Rt 4.52 min; MS m/z 403.2/405.2 = [M+H]+ (100% @ 215 nm).

The compounds of the following tabulated examples (Table 6) were prepared analogously to Example 7 from the corresponding amino ester and acid (step 1) and replacing 2,3,3-trimethylbutan-2-amine hydrochloride (step 3) with the appropriate commercially available amine. The amide condensation step was carried out using either (i) EDCl/HOAt/DIPEA or (ii) TBTU/TEA or (iii) T3P®/TEA

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Table 6

Example Structure and name Condensing agents 1NMR LC-MS retention time, [M+H]+, 7.1 CH ₃ 0 3 - [[2-(5-Chloro-2-hydroxyphenyl)acetyl] amino] -N-(1,1 dimethylbutyl)benzamide EDCl/HOAt/ DIPEA 1H NMR (500 MHz, DMSO-bb) δ 10.19 (s, 1H), 9.74 (br. s, 1H), 7.87 (t, J=1.8 Hz, 1H), 7.84 -7.71 (m, 1H), 7.56 (s, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.33 (t, J=7.9 Hz, 1H) , 7.20 (d, J=2.7 Hz, 1H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.61 (s, 2H), 1.78-1.64 (m, 2H), 1.37-1.20 (m, 8H), 0.86 (t, J=7.3 Hz , ZN). LC-MS (Method D): Rt 4.40 min; MS m/z 389.2/ 391.2= [M+H]+ (98% @ 215 nm) 7.2 CH ₃ 0 _u 4- [[2-(5-Chloro-2-hydroxyphenyl)acetyl] amino] -N-(1,1 dimethylbutyl)pyridine-2-carboxamide EDCl/HOAt/ DIPEA 1H NMR (250 MHz, DMSO-bb) δ 10.69 (br.s, 1H), 9.86 (br.s, 1H), 8.44 (d, J=5.8 Hz, 1H), 8 .17 (d, J=l,8 Hz, 1H), 7.95 (s, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz 1H), 6.80 (d, J=8.6 Hz, 1H), 3.67 (s , 2H), 1.80-1.63 (m, 2H), 1.35 (s, 6H), 1.32-1.16 (m, 2H), 0.87 (t, J=7.3 Hz, ZN). LC-MS (Method A): Rt 3.79 min; MS m/z 390.2/392 = [M+H]+ (100% @ 215 nm) 7.3 II ⁰ 3 - [[2-(5-Chloro-2-hydroxyphenyl)acetyl] amino] -Ncyclohexylbenzamide EDCl/HOAt/ DIPEA 1H NMR (500 MHz, DMSO-bb) δ 10.23 (s, 1H), 9.79 (s, 1H), 8.16 (d, J=8.0 Hz, 1H), 7.96 (t , J=l,8 Hz, 1H), 7.80-7.75 (m, 1H), 7.48 (d, J=7.8 Hz, 1H), 7.35 (t, J=7, 9 Hz, 1H), 7.20 (d, J=2.7 Hz, 1H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J= 8.6 Hz, 1H), 3.793.69 (m, 1H), 3.61 (s, 2H), 1.84-1.68 (m, 4H), 1.64-1.57 (m, 1H ), 1.36-1.23 (m, 4H), 1.171.06 (m, 1H). LC-MS (Method A): Rt 3.31 min; MS m/z 387.2/ 389.2 = [M+H]+ (100% @ 215 nm) 7.4 ABOUT 3 - [[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-Ntetrahydropyran-4-ylbenzamide EDCl/HOAt/ DIPEA 1H NMR (500 MHz, DMSO-bb) δ 10.22 (s, 1H), 9.80 (br. s, 1H), 8.29 (d, J=7.8 Hz, 1H), 7.99 (t, J=l.8 Hz, 1H), 7.87-7.69 (m, 1H), 7.49 (d, J=7.9 Hz, 1H), 7.37 (t, J= 7.9 Hz, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.98 (m, 1H), 3.92-3.80 (m, 2H), 3.61 (s, 2H), 3.413.36 (m, 2H), 1.80-1.65 (m, 2H), 1.63-1.51 (m, 2H). LC-MS (Method A): Rt 2.57 min; MS m/z 389.2/ 391.2 = [M+H]+ (100% @215 nm)

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7.5 CH ₃ 0 3 - [[2-(5-Chloro-2-hydroxyphenyl)acetyl] amino] -N-(1,1,2trimethylpropyl)benzamide EDCl/HOAt/ DIPEA 1H NMR (500 MHz, DMSO-bb) δ 10.19 (s, 1H), 9.80 (br. s, 1H), 7.87 (t, J=1.8 Hz, 1H), 7.81 -7.71 (m, 1H), 7.52 (s, 1H), 7.39 (dd, J=6.5, 1.3 Hz, 1H), 7.33 (t, J=7.8 Hz, 1H), 7.20 (d, J=2.7 Hz, 1H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8 .6 Hz, 1H), 3.61 (s, 2H), 1.27 (s, 6H), 0.85 (d, J=6.9 Hz, 6H). LC-MS (Method A): Rt 3.52 min; MS m/z 389.3/ 391.3 = [M+H]+ (100% @215 nm) 7.6 CH ₃ O 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl] amino]-N-(1,1,2trimethylpropyl)pyridine-2-carboxamide EDCl/HOAt/ DIPEA 1H NMR (500 MHz, DMSO-bb) δ 10.71 (br.s, 1H), 9.86 (br.s, 1H), 8.44 (d, J=5.6 Hz, 1H), 8 .17 (d, J=2.0 Hz, 1H), 7.99 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.66 ( s, 2H), 2.36-2.28 (m, 1H), 1.32 (s, 6H), 0.88 (d, J=6.9 Hz, 6H). LC-MS (Method A): Rt 3.74 min; MS m/z 390.2/ 392.2 = [M+H]+ (99% @ 215 nm) 7.7 CH ₃ O _n 4- [[2-(5-Chloro-2-hydroxyphenyl)acetyl] amino] -N- TBTU/TEA 1H NMR (500 MHz, DMSO-bb) δ 10.69 (br.s, 1H), 9.77 (br.s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8 .39 (d, J=8.4 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H) , 7.21 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 isopropylpyridine-2-carboxamide Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 4.16-4.03 (m, 1H), 3.66 (s, 2H), 1.18 (d, J =6.6 Hz, 6H). LC-MS (Method A): Rt 2.89 min; MS m/z 348.1/ 350.1 = [M+H]+ (99% @ 215 nm) 7.8 3-[[2-(5 methylte 0 yuuga” -Chloro-2-hydroxyphenyl)acetyl]amino]-X-(4;trahydropyran-4-yl)benzamide EDCl/HOAt/ DIPEA 1H NMR (500 MHz, DMSO-bb) δ 10.21 (s, 1H), 9.80 (s, 1H), 7.99-7.84 (m, 1H), 7.807.60 (m, 1H) , 7.72 (s, 1H), 7.44 (d, J=7.7 Hz, 1H), 7.35 (t, J=7.9 Hz, 1H), 7.20 (d, J= 2.7 Hz, 1H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.67-3, 52 (m, 6H), 2.262.19 (m, 2H), 1.58-1.49 (m, 2H), 1.38 (s, ZN). LC-MS (Method A): Rt 2.79 min; MS m/z 403.2/ 405.2 = [M+H]+ (100% @215 nm) 7.9 4-[[2-(5 methylte 0 UgUpT -Chloro-2-hydroxyphenyl)acetyl]amino]-X-(4;trahydropyran-4-yl)pyridin-2-carboxamide T3P®/TEA 1H NMR (500 MHz, DMSO-bb) δ 10.72 (br.s, 1H), 9.74 (br.s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8 .18 (d, J=2.1 Hz, 1H), 8.11 (s, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.70- 3.60 (m, 4H), 3.553.46 (m, 2H), 2.23-2.14 (m, 2H), 1.67-1.58 (m, 2H), 1.42 (s, ZN). LC-MS (Method A): Rt 2.90 min; MS m/z 404.2/ 406.2 = [M+H]+ (96% @ 215 nm)

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7.10 %\ snP ^{n a} >XCr 3 - [[2-(5-Chloro-2-hydroxyphenyl)acetyl] amino] -N-(1 methylcyclobutyl)benzamide EDCl/HOAt/ DIPEA 1H NMR (500 MHz, DMSO-bb) δ 10.20 (s, 1H), 9.80 (s, 1H), 8.32 (s, 1H), 7.95 (t, J=l.8 Hz , 1H), 7.77-7.42 (m, 1H), 7.49-7.44 (m, 1H), 7.34 (t, >7.9 Hz, 1H), 7.20 (d , >2.7 Hz, 1H), 7.11 (dd, >8.6, 2.7 Hz, 1H), 6.80 (d, >8.6 Hz, 1H), 3.61 (s, 2H), 2.34-2.28 (m, 2H), 2.00-1.92 (m, 2H), 1.84-1.75 (m, 2H), 1.45 (s, ZN) . LC-MS (Method A): Rt 3.15 min; MS m/z 373.2/ 375.1 = [M+H]+ (99% @ 215 nm) 7.11 ⁰ n 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl] amino] -Ntetrahydropyran-4-ylpyridin-2-carboxamide TBTU/TEA 1H NMR (500 MHz, DMSO-bb) δ 10.69 (br.s, 1H), 9.86 (br.s, 1H), 8.58 (d, >8.5 Hz, 1H), 8, 48 (d, >5.5 Hz, 1H), 8.20 (d, >2.0 Hz, 1H), 7.82 (dd, >5.5, 2.2 Hz, 1H), 7.21 (d, >2.7 Hz, 1H), 7.12 (dd, >8.6, 2.7 Hz, 1H), 6.80 (d, >8.6 Hz, 1H), 4.06- 3.95 (m, 1H), 3.89-3.83 (m, 2H), 3.66 (s, 2H), 1.75-1.61 (m, 4H). LC-MS (Method A): Rt 2.57 min; MS m/z 390.2/ 392.2 = [M+H]+ (98% @ 215 nm) 7.12 ^HO sA\ AULU 4-[2-(5-Chloro-2-hydroxyphenyl)acetamido]-M-[(18,48)-4-hydroxycyclohexyl]pyridine-2-carboxamide EDCl/HOAt/ DIPEA 1H NMR (500 MHz, DMSO-bb) δ 10.68 (s, 1H), 9.82 (br. s, 1H), 8.47 (d, >5.5 Hz, 1H), 8.30 ( d, >8.2 Hz, 1H), 8.19 (d, >2.0 Hz, 1H), 7.81 (dd, >5.5, 2.2 Hz, 1H), 7.22 (d , >2.7 Hz, 1H), 7.12 (dd, >8.6, 2.7 Hz, 1H), 6.80 (d, >8.6 Hz, 1H), 4.41 (d, >3.4 Hz, 1H), 3.87-3.76 (m, 1H), 3.74-3.68 (m, 1H), 3.66 (s, 2H), 1.83-1, 66 (m, 2H), 1.65-1.47 (m, 6H). LC-MS (Method A): Rt 2.45 min; MS m/z 404.2/ 406.2 = [M+H]+ (100% @ 215 nm) 7.13 CH ₃ O _n 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl] amino]-N-secbutylpyridine-2-carboxamide TZR®/TEA 1H NMR (500 MHz, DMSO-bb) δ 10.69 (br.s, 1H), 9.82 (br.s, 1H), 8.47 (d, >5.5 Hz, 1H), 8, 34 (d, >8.9 Hz, 1H), 8.18 (d, >2.0 Hz, 1H), 7.82 (dd, >5.5, 2.2 Hz, 1H), 7.22 (d, >2.7 Hz, 1H), 7.12 (dd, >8.6, 2.7 Hz, 1H), 6.80 (d, >8.6 Hz, 1H), 3.96- 3.85 (m, 1H), 3.66 (s, 2H), 1.64-1.44 (m, 2H), 1.15 (d, >6.6 Hz, ZN), 0.84 ( t, >7.4 Hz, ZN). LC-MS (Method A): Rt 3.16 min; MS m/z 362.1/ 364.1 = [M+H]+ (98% @ 215 nm)

- 91 046966

7.14 CH ₃ ⁰ _n Χσχχχ 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl] amino] -N-(2hydroxy-1,1,2-trimethylpropyl)pyridine-2-carboxamide TZR®/TEA 1H NMR (500 MHz, DMSO-bb) δ 10.67 (s, 1H), 9.81 (br. s, 1H), 8.71 (s, 1H), 8.44 (d, J=5, 5 Hz, 1H), 8.18 (d, J=2.0 Hz, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J= 2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 4.99 (s, 1H), 3.67 (s, 2H), 1.39 (s, 6H), 1.16 (s, 6H). LC-MS (Method A): Rt 3.01 min; MS m/z 406.2/ 408.2 = [M+H]+ (99% @ 215 nm) 7.15 P n .Cl th Ilj Yjfj HO X-(3-Bicyclo[1.1.1]pentanyl)-4-[[2-(5-chloro-2hydroxyphenyl)acetyl] amino] pyrid in-2-carboxamide TZR®/TEA 1H NMR (500 MHz, DMSO-bb) δ 10.71 (br.s, 1H), 9.82 (br.s, 1H), 9.09 (s, 1H), 8.46 (d, J= 5.5 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H), 7.84 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J=2.7 Hz, 1H), 7.13 (dd, J=8.6, 2.7 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 3.67 ( s, 2H), 2.45 (s, 1H), 2.10 (s, 6H). LC-MS (Method A): Rt 3.21 min; MS m/z 372.1/ 374.1 = [M+H]+ (98% @ 215 nm) 7.16 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-( 1 - *TZR®/TEA 1H NMR (500 MHz, DMSO-bb) δ 10.73 (s, 1H), 9.82 (br. s, 1H), 9.59 (s, 1H), 8.52 (d, J=5, 5 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.88 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J= 2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.81 (d, cyanocyclobutyl)pyridine-2-carboxamide J=8.6 Hz, 1H), 3.68 (s, 2H), 2.69-2.62 (m, 2H), 2.59-2.53 (m, 2H), 2.11-1 .93 (m, 2H). LC-MS (Method A): Rt 2.89 min; MS m/z 385.1/ 387.1= [M+H]+ (95% @ 215 nm)

Example 8.

tert-Butyl-3 -[[3-[ [2-(5-chloro-2-hydroxyphenyl)acetyl] amino] benzoyl] amino] piperidine-1 carboxylate

Step 1: 3-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-A3-piperidyl)benzamide

The title compound was prepared analogously to Example 7, replacing 2,3,3-trimethylbutan-2amine hydrochloride (Step 3) with tert-butyl-3-aminepiperidine-1-carboxylate.

1H NMR (500 MHz, DMSO-06) δ 10.22 (s, 1H), 8.15 (d, J=7.9 Hz, 1H), 7.98 (s, 1H), 7.82-7 .70 (m, 1H), 7.50-7.46 (m, 1H), 7.36 (t, J=7.9 Hz, 1H), 7.20 (d, J=2.7 Hz, 1H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.88-3.80 (m, 1H ), 3.61 (s, 2H), 3.02-2.95 (m, 1H), 2.88-2.80 (m, 1H), 2.48-2.42 (m, 2H), 1.90-1.77 (m, 1H), 1.74-1.59 (m, 1H), 1.54-1.37 (m, 2H).

LC-MS (Method A): Rt 1.66 min; MS m/z 388.2/ 390.2 = [M+H]+ (96% @ 215 nm).

Step 2: tert-Butyl 3-[[3-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]benzoyl]amino]piperidine 1-carboxylate

To a solution of 3-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]X(3-piperidyl)benzamide (step 1) (19 mg, 0.05 mmol) in THF (0.5 ml) was added BOC anhydride (12 mg, 0.06 mmol). The resulting mixture was stirred at room temperature for 3 hours. An additional portion of BOC anhydride (12 mg, 0.06 mmol) was added and stirring was continued for an additional hour. The reaction mixture was concentrated in vacuo, and the crude product was purified by silica chromatography

- 92 046966 le, eluting with EtOAc in heptane, gave the title compound in the form of a white powder with a metallic tint.

1H NMR (500 MHz, DMSO-06) δ 10.26 (br.s, 1H), 9.81 (br.s, 1H), 8.24 (d, J=7.0 Hz, 1H), 7 .99 (s, 1H), 7.83-7.74 (m, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.37 (m, 1H), 7.20 ( d, J=2.7 Hz, 1H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 4, 05-3.67 (m, 3H), 3.61 (s, 2H), 3.03-2.70 (m, 2H), 1.91-1.81 (m, 1H), 1.76- 1.67 (m, 1H), 1.60-1.46 (m, 1H), 1.45-1.31 (m, 10H).

LC-MS (Method A): Rt 3.41 min; MS m/z 488.3/ 490.4 = [M+H]+ (99% @ 215 nm).

Example 8.1.

tert-Butyl-3-[[4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2carbonyl]amino]piperidine-1-carboxylate

Step 1: Methyl 4-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]pyridine-2-carboxylate

2-(5-Chloro-2-methoxyphenyl)acetic acid (24.19 g, 120.59 mmol) was suspended in thionyl chloride (103.68 ml, 1427.48 mmol) and heated at 70°C for 1.5 h After cooling to room temperature, the mixture was concentrated in vacuo. The residue was then dissolved in DCM (135 ml) and re-concentrated. The resulting brown viscous oil was dissolved in DCM (135 ml) and added dropwise to a cooled (ice bath) suspension of methyl 4-aminopyridine-2-carboxylate (17.9 g, 117.65 mmol) and DIPEA (30.82 ml, 176.47 mmol) in DCM (225 ml). The reaction mixture was left to warm to room temperature and stirred overnight. The resulting mixture was diluted with water (180 ml) and stirred for 10 minutes. The organic portion was separated, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with EtOAc to give the title compound as an orange glassy solid.

1H NMR (500 MHz, DMSO-06) δ 10.72 (s, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.30 (d, J=1.9 Hz, 1H ), 7.77 (dd, J=5.5, 2.2 Hz, 1H), 7.32-7.29 (m, 2H), 7.02-6.99 (m, 1H), 3, 86 (s, 3H), 3.75 (s, 3H), 3.71 (s, 2H).

LC-MS (Method E): Rt 1.04 min; MS m/z 335.0/337.0 = [M+H]+ (98% @ 215 nm).

Step 2: 4-[[2-(5-Chloro-2-methoxyphenyl)acetyl]amino]pyridine-2-carboxylic acid

About “Hash” I

CH ₃

To a solution of methyl 4-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]pyridine-2-carboxylate (step 1) (95%, 38.09 g, 108.1 mmol) in THF (200 ml) a 2 M aqueous solution of lithium hydroxide hydroxide (162.15 ml, 324.29 mmol) was added and the resulting mixture was stirred at room temperature for 1 hour. The volatile organic phases were removed in vacuo and the aqueous residue was cooled (ice bath) and worked up by gradually adding 3 M aqueous HCl (150 ml). The resulting suspension was filtered, washed with water (3x200 ml), diethyl ether (2x250 ml), dried under vacuum and then further dried under high vacuum in an oven at 40°C to obtain the title compound as a beige solid.

1H NMR (500 MHz, DMSO-06) δ 10.78 (s, 1H), 8.53 (d, J=5.6 Hz, 1H), 8.27 (d, J=2.0 Hz, 1H ), 7.81 (dd, J=5.6, 2.2 Hz, 1H), 7.34-7.28 (m, 2H), 7.04-6.98 (m, 1H), 3, 75 (s, 3H), 3.72 (s, 2H).

LC-MS (Method E): Rt 0.88 min; MS m/z 320.9/ 323.0 = [M+H]+ (97% @ 215 nm).

Step 3: tert-Butyl-3-[[4-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]pyridine-2carbonyl]amino]piperidine-1-carboxylate

- 93 046966

4-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]pyridine-2-carboxylic acid solution (step 2) (70 mg, 0.22 mmol), EDCI (50 mg, 0.26 mmol) , HOAt (36 mg, 0.26 mmol), DIPEA (0.08 ml, 0.44 mmol) and tert-butyl 3-aminepiperidine-1-carboxylate (27.2 μl, 0.26 mmol) in DMF (0.5 ml) was stirred at room temperature for 20 hours. The resulting mixture was diluted with EtOAc (5 ml) and water (5 ml). The aqueous layer was extracted with EtOAc (5 ml) and the combined organic extracts were washed with water (5 ml) and saturated aqueous sodium chloride (5 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by preparative HPLC (acidic pH, early elution method) to obtain the title compound as a white solid with a metallic tint.

1H NMR (500 MHz, DMSO-06) δ 10.71 (br.s, 1H), 8.52 (br.s, 1H), 8.46 (m, 1H), 8.19 (br.s, 1H), 7.87-7.79 (m, 1H), 7.35-7.26 (m, 2H), 7.08-6.93 (m, 1H), 3.87-3.78 ( m, 1H), 3.75 (s, 3H), 3.71 (s, 2H), 3.17-2.83 (m, 2H), 1.87-1.77 (m, 1H), 1 .77-1.58 (m, 2H), 1.57-1.20 (m, 10H). LC-MS (Method E): Rt 1.28 min; MS m/z 503.3/505.2 = [M+H]+ (93% @ 215 nm).

Step 4 and 5: tert-Butyl-3-[[4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2carbonyl]amino]piperidine-1-carboxylate

The title compound was prepared analogously to Example 8 from tert-butyl-3-[[4-[[2-(5-chloro2-methoxyphenyl)acetyl]amino]pyridine-2-carbonyl]amino]piperidine-1-carboxylate (Step 3 ).

1H NMR (500 MHz, DMSO-06) δ 10.71 (br.s, 1H), 9.83 (br.s, 1H), 8.61-8.40 (m, 2H), 8.20 ( s, 1H), 7.83 (dd, J=5.5, 2.0 Hz, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8 ,6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.903.76 (m, 2H), 3.66 (s, 2H), 3.57-3 .49 (m, 1H), 3.11-2.80 (m, 1H), 1.87-1.76 (m, 1H), 1.75-1.57 (m, 2H), 1.45 -1.27 (m, 10H).

LC-MS (Method A): Rt 3.51 min; MS m/z 489.3/ 491.3 = [M+H]+ (99% @ 215 nm).

The compounds of the following tabular examples (Table 7) were prepared similarly

Example 8 from the corresponding aryl acid, replacing tert-butyl 3-aminepiperidine-1carboxylate (Example 8, Step 1) with the appropriate commercially available amine.

Table 7

Example Structure and name 1H NMR; LC-MS retention time, [M+HJ+, 8.2 CH, H ₃ C^1 H3C^O O _n “UTPU tert-Butyl-4- [[3 -[ [2-(5-chloro-2-hydroxyphenyl)acetyl]amino]benzoyl]amino]-4-methylpiperidin1- carboxylate 1HNMR (500 MHz, DMSO-ab) δ 10.20 (s, 1H), 9.81 (br. s, 1H), 7.92-7.85 (m, 1H), 7.81-7.77 (m, 1H), 7.70 (s, 1H), 7.42 (d, J=7.8 Hz, 1H), 7.34 (t, J=7.9 Hz, 1H), 7.20 (d, J=2.7 Hz, 1H), 7.10 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3 .66-3.54 (m, 4H), 3.08 (m, 2H), 2.29-2.21 (m, 2H), 1.45-1.36 (m, IN), 1.35 (s, ZN). LC-MS (Method A): Rt 3.61 min; MS m/z 524.2/ 526.2 = [M+Na]+ (99% @ 215 nm) 8.3 CH, ^H3C ^x H ₃ CO ALA o tert-Butyl- (1 g, 5 s,6s)-6- { 4-[2-(5-chloro-2 hydroxyphenyl)acetamido] pyridine-2-amido } - 3 azabicyclo[3.1.0]hexane-3-carboxylate 1H NMR (500 MHz, DMSO-bb) δ 10.74 (br.s, 1H), 9.86 (br.s, 1H), 8.85 (d, J=4.9 Hz, 1H), 8 .46 (d, J=5.5 Hz, 1H), 8.16 (d, J=2.1 Hz, 1H), 7.84 (dd, J=5.5, 2.2 Hz, 1H) , 7.21 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.66 (s, 2H), 3.52 (m, 2H), 2.54-2.52 (m, 1H), 1.951.82 (m, 2H), 1.40 (s, 9H ). LC-MS (Method A): Rt 3.44 min; MS m/z 487.2/ 489.2 = [M+H]+ (99% @ 215 nm)

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Example 9.

X-tert-Butyl-3 - [[2-(5-chloro-2-hydroxyphenyl)acetyl] amino]-4-fluorobenzamide

Step 1: 3-Amino-X-tert-butyl-4-fluorobenzamide

To a solution of 3-amino-4-fluorobenzoic acid (205 mg, 1.32 mmol) in DCM (5 ml), 2-methylpropan-2-amine (306 μl, 2.91 mmol), DIPEA (0. 92 ml, 5.29 mmol) and HATU (553 mg, 1.46 mmol), and the mixture was shaken at room temperature overnight. The resulting mixture was washed with 2 M HCl (5 ml) and sat. NaHCO ₃ solution (5 ml). The organic phase was separated by passing through a hydrophobic glass filter and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 0-100% EtOAc in heptane, afforded the title compound as a white metallic solid.

1H NMR (500 MHz, Chloroform-d) δ 7.25-7.19 (m, 1H), 6.99-6.95 (m, 2H), 5.82 (s, 1H), 3.82 ( s, 2H), 1.45 (s, 9H).

LC-MS (Method E): Rt 0.95 min; MS m/z 211.1 = [M+H]+ (97% @ 215 nm).

Step 2: X-tert-Butyl-3-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-4-fluorobenzamide

A suspension of 3-amino-X-tert-butyl-4-fluorobenzamide (step 1) (105 mg, 0.5 mmol) and 5-chloro-3Hbenzofuran-2-one (84 mg, 0.5 mmol) in toluene (3 ml) was heated to 110°C in a sealed tube for 4 days. After cooling to room temperature, the mixture was concentrated in vacuo and the crude residue was purified by preparative HPLC (acidic pH, early elution method) to obtain the title compound as a white, metallic powder.

1H NMR (500 MHz, MeOD) δ 8.28 (dd, J=7.4, 2.1 Hz, 1H), 7.56-7.49 (m, 1H), 7.24-7.18 ( m, 2H), 7.10 (dd, J=8.6, 2.6 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 3.74 (s, 2H), 1.43 (s, 9H).

LC-MS (Method A): Rt 3.18 min; MS m/z 379.1/381.1 = [M+H]+ (97% @ 215 nm).

Example 9.1.

X-tert-Butyl-3 - [[2-(5-chloro-2-hydroxyphenyl)acetyl] amino]-5-methylbenzamide

received

The title compound is analogous to Example 9, replacing 3-amino-4-fluorobenzoic acid (Step 1) with 3-amino-5-methylbenzoic acid.

1H NMR (500 MHz, Methanol^) δ 7.67 (s, 1H), 7.50 (s, 1H), 7.28 (s, 1H), 7.19 (d, J=2.6 Hz, 1H), 7.08 (dd, J=8.6, 2.6 Hz, 1H), 6.78 (d, J=8.6 Hz, 1H), 3.67 (s, 2H), 2, 36 (s, 3H), 1.44 (s, 9H).

LC-MS (Method A): Rt 3.32 min; MS m/z 375.2/ 377.2 = [M+H]+ (99% @ 215 nm).

Example 9.2.

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-(1,1-dimethylpropyl)pyridine-2-carboxamide

Step 1: 4-Amino-X-(1,1-dimethylpropyl)pyridine-2-carboxamide

To a mixture of 2-methylbutan-2-amine (1.69 ml, 14.48 mmol), TBTU (1023 mg, 3.19 mmol) and TEA (0.81 ml, 5.79 mmol) was added 4-aminopyridine-2 -carboxylic acid (400 mg, 2.9 mmol), and the mixture was stirred at room temperature for 5 hours.

The resulting mixture was partitioned between water (40 ml) and DCM (40 ml). The phases were separated and the organic portion was concentrated in vacuo. The crude product was purified by C18 reverse phase chromatography

- 95 046966 graphy, eluting MeCN in H2O with 0.1% ammonium hydroxide to obtain the title compound as a white solid.

1H NMR (500 MHz, DMSO) δ 7.97 (d, J=5.6 Hz, 1H), 7.92 (s, 1H), 7.17 (d, J=2.3 Hz, 1H), 6.56 (dd, J=5.6, 2.4 Hz, 1H), 6.32 (s, 2H), 1.74 (k, J=7.5 Hz, 2H), 1.31 (s , 6H), 0.80 (t, J=7.5 Hz, 3H).

LC-MS (Method F): Rt 1.55 min; MS m/z 208.3 = [M+H]+ (100% @ 215 nm).

Step 2: 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N(1,1-dimethylpropyl)pyridine-2carboxamide

The title compound was prepared analogously to Example 9 (Step 2) from 4-amino-N-(1,1dimethylpropyl)pyridin-2-carboxamide and 5-chloro-3H-benzofuran-2-one.

^1H NMR (500 MHz, Methanol^) δ 8.42 (d, J=5.6 Hz, 1H), 8.13-8.08 (m, 1H), 7.91 (dd, J=5, 5, 2.2 Hz, 1H), 7.19 (d, J=2.6 Hz, 1H), 7.09 (dd, J=8.6, 2.6 Hz, 1H), 6.77 ( d, J=8.6 Hz, 1H), 3.71 (s, 2H), 1.86 (k, J=7.5 Hz, 2H), 1.42 (s, 6H), 0.91 ( t, J=7.5 Hz, 3H).

LC-MS (Method A): Rt 3.50 min; MS m/z 376.0/ 378.0 = [M+H]+ (98% @ 215 nm).

Example 10.

No. tert-Butyl-4-[[2-(5-tert-butyl-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide

Step 1: N-tert-Butyl-4-[[2-(5-tert-butyl-2-methoxyphenyl)acetyl]amino]pyridine-2-carboxamide

I

CH ₃

The title compound was prepared from 4-amino-N-tert-butylpyridine-2-carboxamide (Example 3, Step 1) and commercially available 2-(5-tert-butyl-2-methoxyphenyl)acetic acid analogously to Example 4.

1H NMR (500 MHz, Chloroform-d) δ 8.45 (br. s, 1H), 8.38 (d, J=5.7 Hz, 1H), 8.29 (d, J=5.3 Hz , 1H), 8.16 (br. s, 1H), 7.57 (s, 1H), 7.34 (dd, J=8.6, 2.5 Hz, 1H), 7.28 (d, J=2.5 Hz, 1H), 6.92 (d, J=8.6 Hz, 1H), 3.98 (s, 3H), 3.75 (s, 2H), 1.48 (s, 9H), 1.30 (s, 9H).

LC-MS (Method E): Rt 1.31 min; MS m/z 398.2 = [M+H]+ (85% @ 215 nm).

Step 2: N-tert-Butyl-4-[[2-(5-tert-butyl-2-hydroxyphenyl)acetyl]amino]pyridine-2carboxamide

The title compound was prepared analogously to Example 3 (Step 3) from N-tert-butyl-4[[2-(5-tert-butyl-2-methoxyphenyl)acetyl]amino]pyridine-2-carboxamide.

1H NMR (500 MHz, Methanol^) δ 8.42 (d, J=5.5 Hz, 1H), 8.09 (d, J=1.8 Hz, 1H), 7.91 (dd, J= 5.5, 2.2 Hz, 1H), 7.21 (d, J=2.5 Hz, 1H), 7.15 (dd, J=8.4, 2.5 Hz, 1H), 6, 75 (d, J=8.4 Hz, 1H), 3.72 (s, 2H), 1.47 (s, 9H), 1.28 (s, 9H).

LC-MS (Method A): Rt 3.81 min; MS m/z 384.3 = [M+H]+ (97% @ 215 nm).

Example 11.

No. tert-Butyl-5-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-2-hydroxybenzamide

Step 1: Methyl 5-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-2-methoxy-benzoate

A mixture of 5-chloro-3H-benzofuran-2-one (75 mg, 0.44 mmol) and methyl 5-amino-2-methoxybenzoate (81 mg, 0.44 mmol) in toluene (2 ml) was stirred at 100° C in a hermetically sealed test tube for 2 hours. The resulting mixture was left to cool to room temperature, toluene was added, and the suspension was filtered, washing with toluene. The solid was dried in vacuo to obtain the title compound as a white solid with a metallic tint.

1H NMR (500 MHz, Chloroform-d) δ 7.79 (s, 1H), 7.77 (d, J=2.8 Hz, 1H), 7.72 (dd, J=9.0, 2, 8 Hz, 1H), 7.14 (dd, J=8.6, 2.6 Hz, 1H), 7.08 (d, J=2.6 Hz, 1H), 6.93 (d, J= 9.0 Hz, 1H), 6.90 (d, J=8.6 Hz, 1H), 3.88 (s, 3H),

- 96 046966

3.87 (s, 3H), 3.67 (s, 2H).

LC-MS (Method E): Rt 1.05 min; MS m/z 350.0/351.9 = [M+H]+ (98% @ 215 nm).

Step 2: 5-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-2-methoxybenzoic acid

To a solution of methyl 5-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-2-methoxybenzoate (step 1) (105 mg, 0.29 mmol) in 1,4-dioxane (2 ml) aqueous 2 M LiOH (0.29 ml, 0.59 mmol) was added and the mixture was shaken at room temperature for 5 hours. An additional equivalent of aqueous 2 M LiOH (0.15 ml, 0.29 mmol) was added. and shaking was continued for one hour. The dioxane was removed in vacuo and the resulting mixture was acidified to pH 1 with 1 M HCl (1 ml). The mixture was extracted with EtOAc (2x5 ml) and the combined extracts were dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound as a white metallic solid.

1H NMR (500 MHz, DMSO-dg) δ 12.60 (br.s, 1H), 10.05 (s, 1H), 9.79 (s, 1H), 7.89 (d, J=2, 7 Hz, 1H), 7.70 (dd, J=9.0, 2.8 Hz, 1H), 7.19 (d, J=2.7 Hz, 1H), 7.10 (dd, J= 8.6, 2.7 Hz, 1H), 7.07 (d, J=9.1 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.77 (s, 3H), 3.57 (s, 2H).

LC-MS (Method E): Rt 0.99 min; MS m/z 336.0/ 338.0 = [M+H]+ (99% @ 215 nm).

Step 3: N-tert-Butyl-5-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-2-methoxybenzamide

The title compound was prepared from 5-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-2methoxy-benzoic acid (Step 2) analogously to Example 1, Step 3.

1H NMR (500 MHz, DMSO-de) δ 10.13 (s, 1H), 9.80 (s, 1H), 7.90 (d, J=2.8 Hz, 1H), 7.85 (s , 1H), 7.74 (dd, J=8.9, 2.8 Hz, 1H), 7.18 (d, J=2.7 Hz, 1H), 7.09 (dd, J=8, 6, 2.7 Hz, 1H), 7.07 (d, J=9.0 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H), 3.86 (s, 3H) , 3.56 (s, 2H), 1.36 (s, 9H).

LC-MS (Method A): Rt 3.34 min; MS m/z 391.2/ 393.2 = [M+H]+ (99% @ 215 nm).

Step 4: N-tert-Butyl-5-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-2-hydroxybenzamide

The title compound was prepared from N-tert-butyl-5-[[2-(5-chloro-2hydroxyphenyl)acetyl]amino]-2-methoxy-benzamide (Step 3) analogously to Example 3, Step 3.

1H NMR (500 MHz, DMSO-de) δ 11.50 (br.s, 1H), 9.94 (s, 1H), 9.82 (s, 1H), 8.24 (s, 1H), 7 .98-7.88 (m, 1H), 7.60-7.53 (m, 1H), 7.19 (d, J=2.6 Hz, 1H), 7.10 (dd, J=8 ,6, 2.7 Hz, 1H), 6.83 (d, J=8.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.56 (s, 2H ), 1.38 (s, 9H).

LC-MS (Method A): Rt 3.29 min; MS m/z 377.2/379.2 = [M+H]+ (95% @ 215 nm).

Example 12.

No. tert-Butyl-3-[[2-(5-cyano-2-hydroxyphenyl)acetyl]amino]benzamide

Step 1: 3-[[2-(5-Bromo-2-methoxyphenyl)acetyl]amino]-Ntert-butylbenzamide

The title compound was prepared analogously to Example 4 from 3-amino-M-tert-butylbenzamide hydrochloride (Example 2, Step 1b) and 2-(5-bromo-2-methoxyphenyl)acetic acid.

1H NMR (500 MHz, DMSO-dg) δ 10.19 (s, 1H), 7.89 (s, 1H), 7.74 (d, 1H), 7.70 (s, 1H), 7.44 -7.40 (m, 3H),

7.33 (t, J=7.9 Hz, 1H), 6.99-6.92 (m, 1H), 3.76 (s, 3H), 3.65 (s, 2H), 1.36 (s, 9H).

LC-MS (Method A): Rt 3.41 min; MS m/z 419.2, 421.2 = [M+H]+ (100% @ 215 nm).

Steps 2-3: N-tert-Butyl-3-[[2-(5-cyano-2-hydroxyphenyl)acetyl]amino]benzamide

The title compound was prepared analogously to Example 6, Steps 2 and 3 from 3-[[2-(5-bromo2-methoxyphenyl)acetyl]amino]-M-tert-butylbenzamide (Step 1).

1H NMR (500 MHz, DMSO-dg) δ 10.76 (br. s, 1H), 10.23 (s, 1H), 7.89 (t, J=1.8 Hz, 1H), 7.80 -7.72 (m,

- 97 046966

1H), 7.70 (s, 1H), 7.61 (d, J=2.1 Hz, 1H), 7.56 (dd, J=8.4, 2.2 Hz, 1H), 7, 42 (d, J=7.8 Hz, 1H), 7.33 (m, 1H), 6.93 (d, J=8.4 Hz, 1H), 3.66 (s, 2H), 1, 36 (s, 9H).

LC-MS (Method A): Rt 2.66 min; MS m/z 352.2 = [M+H]+ (98% @ 215 nm).

Example 13.

Methyl 3-[2-[[2-(tert-butylcarbamoyl)-4-pyridyl]amino]-2-oxo-ethyl]-4-hydroxybenzoate

Step 1: 4-[[2-(5-Bromo-2-hydroxyphenyl)acetyl]amino]-Ntert-butylpyridine-2-carboxamide

A solution of 4-[[2-(5-bromo-2-methoxyphenyl)acetyl]amino]^-tert-butylpyridine-2-carboxamide (Example 6, Step 1) (500 mg, 1.19 mmol) in DCM (25 ml ) was treated with 1 M BBr ₃ in DCM (3.57 ml, 3.57 mmol) and stirred at room temperature under nitrogen overnight. The resulting mixture was diluted with DCM (50 ml) and washed with water (25 ml x 2). Organic extracts were dried over Na ₂ SO ₄ and concentrated in vacuo. Purification of the crude C18 solid by reverse phase chromatography, eluting with 0-100% MeCN in water with 0.1% formic acid, afforded the title compound as a light yellow solid.

1H NMR (500 MHz, DMSO-dg) δ 10.69 (s, 1H), 9.86 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.17 (d , J=2.0 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1h), 7.34 (d, J=2, 5 Hz, 1H), 7.24 (dd, J=8.6, 2.6 Hz, 1H), 6.76 (d, J=8.6 Hz, 1H), 3.67 (s, 2H) , 1.40 (s, 9H).

LC-MS (Method A): Rt 3.34 min; MS m/z 406.1/ 408.1 = [M+H]+ (90% @ 215 nm).

Step 2: Methyl 3-[2-[[2-(tert-butylcarbamoyl)-4-pyridyl]amino]-2-oxoethyl]-4-hydroxybenzoate

All reagents are loaded into the CO generation apparatus (carbon monoxide generation system) according to the following procedure; Sodium carbonate (53 mg, 0.50 mmol), 4-[[2-(5-bromo-2-hydroxyphenyl)acetyl]amino]-Ntert-butylpyridine-2-carboxamide (step 1) (75) was added to chamber A mg, 0.16 mmol), XantPhos Pd-G3 (third generation Buchwald precatalyst (G3)) (8 mg, 0.01 mmol) and toluene (2 ml). The reaction mixture was degassed for 5 min and MeOH (0.25 ml) was added. Formic acid (19 μl, 0.50 mmol) in toluene (2 ml) was added to chamber B, followed by the addition of mesyl chloride (39 μl, 0.50 mmol). Both chambers were sealed and TEA (139 μL, 0.99 mmol) was added to chamber B to generate carbon monoxide. The CO generation apparatus was heated at 75°C for 7 hours. The resulting mixture was concentrated in vacuo, dissolved in EtOAc (20 ml) and washed with water (2x20 ml). The organic portion was concentrated in vacuo and purified by preparative HPLC (acid pH, early elution method). Product fractions were isolated and freeze-dried to obtain the title compound as a white metallic solid.

^1H NMR (500 MHz, DMSO-de) δ 10.78 (br.s, 1H), 10.55 (br.s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.17 (d, J=2.0 Hz, 1H), 8.03 (s, 1H), 7.83-7.80 (m, 2H), 7.74 (dd, J=8.5, 2.2 Hz, 1H), 6.88 (d, J=8.5 Hz, 1H), 3.79 (s, 3H), 3.72 (s, 2H), 1.40 (s, 9H) .

LC-MS (Method A): Rt 2.94 min; MS m/z 386.3= [M+H]+ (95% @ 215 nm).

Example 14.

No. tert-Butyl-3-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-4-hydroxybenzamide

Step 1: Methyl 3-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]-4-methoxybenzoate

dc ₃ dc ₃

The title compound was prepared analogously to Example 6 (Step 1) from methyl 3-amino-4methoxybenzoate and 2-(5-chloro-2-methoxyphenyl)acetic acid.

- 98 046966

1H NMR (500 MHz, Chloroform-d) δ 8.98 (m, 1H), 8.28 (s, 1H), 7.77 (dd, J=8.6, 2.1 Hz, 1H), 7 .31 (d, J=2.6 Hz, 1H), 7.24 (dd, J=8.7, 2.6 Hz, 1H), 6.86 (dd, J=8.7, 6.1 Hz, 2H), 3.90 (s, 3H), 3.90 (s, 3H), 3.86 (s, 3H), 3.71 (s, 2H).

LC-MS (Method E): Rt 1.20 min; MS m/z 364.1/366.1 = [M+H]+ (72% @ 215 nm).

Step 2: 3-[[2-(5-Chloro-2-methoxyphenyl)acetyl]amino]-4-methoxybenzoic acid

To a solution of methyl 3-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]-4-methoxybenzoate (step 1) (301 mg, 0.83 mmol) in 1,4-dioxane (4 ml) aqueous 2 M LiOH (1.24 ml, 2.48 mmol) was added and the mixture was shaken at room temperature overnight. The dioxane was removed in vacuo and the resulting mixture was acidified to pH 1 with 1 M HCl. The mixture was washed with EtOAc (2x5 ml). The aqueous phase was concentrated in vacuo and the resulting solid was sonicated with MeOH (20 ml). The suspension was filtered, washed with additional MeOH (5 ml), and the combined filtrate was concentrated in vacuo to give a white metallic solid.

1H NMR (500 MHz, DMSO-de) δ 9.26 (s, 1H), 8.56 (s, 1H), 7.68 (dd, J=8.5, 2.1 Hz, 1H), 7 .35-7.20 (m, 3H), 7.13 (d, J=8.6 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 3.92 (s, 3H), 3.82 (s, 2H), 3.80 (s, 3H).

LC-MS (Method E): Rt 1.08 min; MS m/z 350.1/352.1 = [M+H]+ (85% @ 215 nm).

Step 3: N-tert-Butyl-3-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]-4-methoxybenzamide

To a solution of 3-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]-4-methoxybenzoic acid (step 2) (201 mg, 0.57 mmol) in DMF (2 ml) was added EDCI ( 110 mg, 0.57 mmol), HOAt (78 mg, 0.57 mmol), DIPEA (251 µl, 1.44 mmol) and 2-methylpropan-2-amine (79 µl, 0.75 mmol). The reaction mixture was shaken at room temperature overnight and then partitioned between DCM (6 ml) and water (6 ml). The organic layer was collected using a hydrophobic frit and concentrated in vacuo. Chromatography on silica gel, eluting with EtOAc in heptane, afforded the title compound as a colorless glass.

1H NMR (500 MHz, Chloroform-d) δ 8.63 (d, J=2.2 Hz, 1H), 8.36 (s, 1H), 7.64 (dd, J=8.6, 2, 3 Hz, 1H), 7.30 (d, J=2.6 Hz, 1H), 7.25 (dd, J=8.8, 2.6 Hz, 1H), 6.87 (dd, J= 10.9, 8.7 Hz, 2H), 5.99 (s, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.70 (s, 2H), 1, 43 (s, 9H).

LC-MS (Method E): Rt 1.20 min; MS m/z 405.1/407.1 = [M+H]+ (62% @ 215 nm).

Step 4: N-tert-Butyl-3-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-4-hydroxybenzamide

The title compound was prepared from N-tert-butyl-3-[[2-(5-chloro-2methoxyphenyl)acetyl]amino]-4-methoxybenzamide (Step 3) analogously to Example 3, Step 3.

1H NMR (500 MHz, Methanol^) δ 8.23 (d, J=2.2 Hz, 1H), 7.48 (s, 1H), 7.39 (dd, J=8.4, 2.2 Hz, 1H), 7.24 (d, J=2.6 Hz, 1H), 7.11 (dd, J=8.6, 2.6 Hz, 1H), 6.86 (d, J=8 .4 Hz, 1H), 6.82 (d, J=8.6 Hz, 1H), 3.72 (s, 2H), 1.43 (s, 9H).

LC-MS (Method A): Rt 2.93 min; MS m/z 377.3/ 379.2 = [M+H]+ (99% @ 215 nm).

Example 15.

No. tert-Butyl-4-[[2-(2-hydroxy-5-methylphenyl)acetyl]amino]pyridine-2-carboxamide

Step 1: N-tert-Butyl-4-[[2-(2-methoxy-5-methylphenyl)acetyl]amino]pyridine-2-carboxamide

To a solution of 4-[[2-(5-bromo-2-methoxyphenyl)acetyl]amino]-M-tert-butylpyridine-2-carboxamide (example 6, step 1) (200 mg, 0.48 mmol) and potassium carbonate (132 mg, 0.95 mmol) in diglyme (5 ml) at

- 99 046966 Pd(dppf) ₂ Cl ₂ (17 mg, 0.02 mmol) was added followed by the addition of 2,4,6-trimethyl-1,3,5,2,4,6trioxatriborinane in THF (50%, 0. 16 ml, 0.57 mmol). The resulting mixture was degassed with nitrogen for 5 min and then stirred in a pressurized tube at 100°C for 16 h. The resulting mixture was diluted with EtOAc (25 ml) and washed with water (2x25 ml) and saturated aqueous sodium chloride (2x25 ml) . The organic portion was dried over Na ₂ SO ₄ , concentrated in vacuo and purified by chromatography on silica gel, eluting with EtOAc in heptane. Product fractions were concentrated in vacuo to give the title compound as a beige solid.

1H NMR (500 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.43 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.0 Hz, 1H ), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.06-7.01 (m, 2H), 6.86 (d, J=8.2 Hz, 1H), 3.71 (s, 3H), 3.65 (s, 2H), 2.23 (s, 3H), 1.40 (s, 9H).

LC-MS (Method E): Rt 1.22 min; MS m/z 356.2 = [M+H]+ (97% @ 215 nm).

Step 2: N-tert-Butyl-4-[[2-(2-hydroxy-5-methylphenyl)acetyl]amino]pyridine-2-carboxamide

The title compound was prepared from N-tert-butyl-4-[[2-(2-methoxy-5-methylphenyl)acetyl]amino]pyridine-2-carboxamide (Step 1) analogously to Example 3 (Step 3).

1H NMR (500 MHz, DMSO-d6) δ 10.63 (s, 1H), 9.25 (s, 1H), 8.43 (d, J=5.5 Hz, 1H), 8.18 (d , J=2.0 Hz, 1H), 8.03 (s, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 6.94 (d, J=1, 9 Hz, 1H), 6.87 (dd, J=8.1, 1.9 Hz, 1H), 6.68 (d, J=8.1 Hz, 1H), 3.61 (s, 2H) , 2.18 (s, 3H), 1.40 (s, 9H).

LC-MS (Method A): Rt 3.19 min; MS m/z 342.3 = [M+H]+ (100% @ 215 nm).

Example 16.

No. tert-Butyl-3-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-4-methoxybenzamide

The title compound was prepared from methyl 3-amino-4-methoxybenzoate and 5-chloro-3Hbenzofuran-2-one analogously to Example 11, steps 1-3.

1H NMR (500 MHz, Methanol^) δ 8.36 (d, J=2.1 Hz, 1H), 7.51 (dd, J=8.6, 2.2 Hz, 1H), 7.24 ( d, J=2.6 Hz, 1H), 7.12 (dd, J=8.6, 2.6 Hz, 1H), 7.03 (d, J=8.6 Hz, 1H), 6, 83 (d, J=8.6 Hz, 1H), 3.91 (s, 3H), 3.72 (s, 2H), 1.43 (s, 9H).

LC-MS (Method A): Rt 3.18 min; MS m/z 391.2/393.2 = [M+H]+ (95% @ 215 nm).

Example 17.

No. tert-Butyl-5-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-2-fluoro-benzamide

Steps 1-2: 5-[[2-(5-Chloro-2-methoxyphenyl)acetyl]amino]-2-fluorobenzoic acid

The title compound was prepared from methyl 5-amino-2-fluorobenzoate and 2-(5-chloro-2methoxyphenyl)acetic acid in the same manner as Example 7, Steps 1 and 2.

1H NMR (500 MHz, DMSO-06) δ 13.25 (br.s, 1H), 10.29 (s, 1H), 8.14 (dd, J=6.6, 2.8 Hz, 1H) , 7.83-7.76 (m, 1H), 7.32-7.28 (m, 2H), 7.25 (dd, J=10.5, 9.0 Hz, 1H), 7.03 -6.98 (m, 1H), 3.77 (s, 3H), 3.65 (s, 2H).

LC-MS (Method E): Rt 1.04 min; MS m/z 338.0, 340.1 = [M+H]+ (95% @ 215 nm).

Step 3: ^tert-Butyl-5-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]-2-fluorobenzamide

To a mixture of 5-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]-2-fluorobenzoic acid (step 2) (100 mg, 0.28 mmol), TBTU (108 mg, 0.34 mmol) and TEA (0.08 ml, 0.56 mmol) in DMF (1.5 ml) added 2

- 100 046966 methylpropan-2-amine (35 μl, 0.34 mmol) and the mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated in vacuo and the residue was partitioned between water (10 ml) and DCM (10 ml). The organic phase was separated and concentrated in vacuo. Purification of the crude product by chromatography on silica gel, eluting with EtOAc in heptane, afforded the title compound as a white solid.

1H NMR (500 MHz, DMSO-06) δ 10.21 (s, 1H), 7.83 (s, 1H), 7.73 (dd, J=6.3, 2.7 Hz, 1H), 7 .65 (ddd, J=8.8, 4.4, 2.8 Hz, 1H), 7.32-7.29 (m, 1H), 7.29-7.27 (m, 1H), 7 .17 (t, J=9.4 Hz, 1H), 7.02-6.98 (m, 1H), 3.76 (s, 3H), 3.63 (s, 2H), 1.34 ( s, 9H).

LC-MS (Method E): Rt 1.22 min; MS m/z 393.2, 395.1 = [M+H]+ (99% @ 215 nm).

Step 4: ^tert-Butyl-5-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-2-fluorobenzamide

The title compound was prepared from N-tert-butyl-5-[[2-(5-chloro-2methoxyphenyl)acetyl]amino]-2-fluorobenzamide (Step 3) analogously to Example 7, Step 4.

1H NMR (500 MHz, DMSO) δ 10.21 (s, 1H), 9.84 (s, 1H), 7.83 (s, 1H), 7.73 (dd, J=6.3, 2, 7 Hz, 1H), 7.66 (dd, J=8.9, 4.4, 2.8 Hz, 1H), 7.24-7.13 (m, 2H), 7.11 (dd, J =8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.59 (s, 2H), 1.34 (s, 9H).

LC-MS (Method A): Rt 3.30 min; MS m/z 379.2/381.1 = [M+H]+ (99% @ 215 nm).

Example 18.

No. tert-Butyl-3-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-5-fluoro-benzamide

CH ₃ O

Step 1: 3-Amino-N-tert-butyl-5-fluorobenzamide

The title compound was prepared from 3-amino-5-fluorobenzoic acid analogously to Example 9, Step 1.

1H NMR (500 MHz, Chloroform-d) δ 6.85-6.80 (m, 1H), 6.69 (dt, J=9.1, 1.8 Hz, 1H), 6.45 (dt, J=10.2, 2.2 Hz, 1H), 5.81 (s, 1H), 3.89 (s, 2H), 1.45 (s, 9H).

LC-MS (Method E): Rt 0.96 min; MS m/z 211.1 = [M+H]+ (100% @ 215 nm).

Steps 2-3: N-tert-Butyl-3-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-5-fluoro-benzamide

The title compound was prepared from 3-amino-I-tert-butyl-5-fluorobenzamide (Step 1) analogously to Example 3, Steps 2 and 3.

1H NMR (500 MHz, DMSO-06) δ 10.41 (s, 1H), 9.81 (s, 1H), 7.81 (s, 1H), 7.75 (dt, J=11.2, 2.0 Hz, 1H), 7.66 (s, 1H), 7.32-7.24 (m, 1H), 7.20 (d, J=2.7 Hz, 1H), 7.11 ( dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.62 (s, 2H), 1.36 (s, 9H).

LC-MS (Method A): Rt 3.34 min; MS m/z 379.1/381.1 = [M+H]+ (97% @ 215 nm).

Example 19.

No. tert-Butyl-4-[[2-(3-hydroxy-2-pyridyl)acetyl]amino]pyridine-2-carboxamide sn ₃ o

Step 1: N tert-Butyl-4-[[2-(3-methoxy-2-pyridyl)acetyl]amino]pyridine-2-carboxamide sn, o

The title compound was prepared from 4-amino-I-tert-butylpyridin-2-carboxamide (Example 3, Step 1) and 2-(3-methoxy-2-pyridyl)acetic acid analogously to Example 5.

1H NMR (500 MHz, DMSO-06) δ 10.75 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H ), 8.07 (dd, J=4.7, 1.3 Hz, 1H), 8.03 (s, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H) , 7.42 (dd, J=8.3, 1.2 Hz, 1H), 7.30 (dd, J=8.3, 4.7 Hz, 1H), 3.88 (s, 2H), 3.81 (s, 3H), 1.40 (s, 9H).

LC-MS (Method A): Rt 2.11 min; MS m/z 343.2 = [M+H]+ (100% @ 215 nm).

Step 2: ^tert-Butyl-4-[[2-(3-hydroxy-2-pyridyl)acetyl]amino]pyridine-2-carboxamide

The title compound was prepared from N-tert-butyl-4-[[2-(3-methoxy-2pyridyl)acetyl]amino]pyridine-2-carboxamide (Step 1) analogously to Example 7, Step 4.

1H NMR (500 MHz, DMSO-06) δ 10.73 (s, 1H), 10.01 (br.s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H), 8.03 (s, 1H), 7.95 (dd, J=4.4, 1.6 Hz, 1H), 7.81 (dd, J= 5.5, 2.2 Hz, 1H), 7.20-7.09 (m, 2H), 3.84 (s, 2H),

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1.40 (s, 9H).

LC-MS (Method A): Rt 1.60 min; MS m/z 329.1 = [M+H]+ (98% @ 215 nm).

Example 20.

No. tert-Butyl-4-[[2-(5-fluoro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide

Step 1: N-tert-Butyl-4-[[2-(5-fluoro-2-methoxyphenyl)acetyl]amino]pyridine-2-carboxamide

I

CH ₃

A solution of 2-(5-fluoro-2-methoxyphenyl)acetic acid (57 mg, 0.31 mmol) in thionyl chloride (246 μl, 2.79 mmol) was heated at 70°C for 1 h. Excess thionyl chloride was removed in vacuo. subjected to azeotropic distillation with DCM. The residue was added to a mixture of 4-amino-N-tert-butylpyridin-2carboxamide (Example 3, Step 1) (60 mg, 0.31 mmol) and DIPEA (65 μl, 0.37 mmol) in DCM (30 ml), and this mixture was stirred at room temperature. After 1 hour, the mixture was partitioned between water (25 ml) and DCM (25 ml). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification of the crude residue by chromatography on silica gel, eluting with EtOAc in heptane, followed by freeze-drying of product fractions afforded the title compound as a white solid.

1H NMR (500 MHz, DMSO-^) δ 10.68 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.17 (d, J=2.0 Hz, 1H ), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.12 (dd, J=9.2, 3.2 Hz, 1H) , 7.08 (td, J=8.6, 3.2 Hz, 1H), 6.98 (dd, J=9.0, 4.6 Hz, 1H), 3.74 (s, 3H), 3.71 (s, 2H), 1.40 (s, 9H).

LC-MS (Method E): Rt 1.16 min; MS m/z 360.1 = [M+H]+ (98% @ 215 nm).

Step 2: N-tert-Butyl-4-[[2-(5-fluoro-2-hydroxyphenyl) acetyl]amino]pyridine-2-car boxamide

To a solution of N-tert-butyl-4-[[2-(5-fluoro-2-methoxyphenyl)acetyl]amino]pyridine-2-carboxamide (step 1) (54.1 mg, 0.15 mmol) in DCM (1 .3 ml) 1 M BBr ₃ in DCM (452 µl, 0.45 mmol) was added slowly at room temperature. The reaction mixture was stirred at room temperature for 2.5 hours and then concentrated in vacuo. The residue was partitioned between H ₂ O (10 ml) and EtOAc (10 ml), and the organic portion was separated and concentrated in vacuo. The crude product was purified by preparative HPLC (acidic pH, early elution method) to obtain the title compound as a white solid.

^1H NMR (500 MHz, DMSO^) δ 10.67 (s, 1H), 9.52 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.18 (d , J=2.1 Hz, 1H), 8.03 (s, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.01 (dd, J=9, 4, 3.2 Hz, 1H), 6.91 (td, J=8.6, 3.2 Hz, 1H), 6.77 (dd, J=8.8, 4.9 Hz, 1H), 3.67 (s, 2H), 1.40 (s, 9H).

LC-MS (Method A): Rt 3.01 min; MS m/z 346.1 = [M+H]+ (98% @ 215 nm).

Example 21.

Racemic N-tert-butyl-4-[[-indan-1-carbonyl]amino]pyridine-2-carboxamide

A mixture of 4-amino-M-tert-butylpyridine-2-carboxamide (example 3, step 1) (100 mg, 0.52 mmol) and indane-1-carboxylic acid (84 mg, 0.52 mmol) in 1.4 -dioxane (1 ml) was treated with a 50% T3P® solution in EtOAc (616 µl, 1.03 mmol) and TEA (181 µl, 1.03 mmol) and stirred at room temperature for 1.5 hours. The resulting mixture was diluted with EtOAc (20 ml) and water (20 ml). The organic portion was separated, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography eluting with EtOAc in heptane to give racemic N-tert-butyl-4-[[-indan-1-carbonyl]amino]pyridine-2-carboxamide.

Example 21a: X-tert-Butyl-4-[[(11G) or (^)-indan-1-carbonyl]amino]pyridine-2-carboxamide and Example 21b: X-tert-Butyl-4-[[(11G ) or (^)-indan-1-carbonyl]amino]pyridine-2-carboxamide

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(R)-isomer (S)-isomer

Chiral separation of racemic Na-tert-butyl-4-[[-indan-1-carbonyl]amino]pyridine-2carboxamide using supercritical liquid chromatography [chiral phase column (25% IPA: 75% CO2 with Chiralcel OD-H 25 cm column at 15 ml/min)] gave individual enantiomers.

Example 21a: First eluting peak: N-tert-Butyl-4-[[(^)-indan-1-carbonyl]amino]pyridine-2-carboxamide or N-tert-Butyl-4-[[(^)-indan-1-carbonyl ]amino]pyridine-2-carboxamide

UHPLC retention time: 5.46 min, MS m/z 338.3 = [M+H]+ (100% @ 215 nm) ^1H NMR (500 MHz, DMSO-D,) δ 10.85 (s, 1H ), 8.46 (d, J=5.5 Hz, 1H), 8.23 (d, J=2.0 Hz, 1H), 8.03 (s, 1H), 7.87 (dd, J =5.5, 2.2 Hz, 1H), 7.32 (d, J=7.4 Hz, 1H), 7.28 (d, J=7.3 Hz, 1H), 7.20 (m , 1H), 7.16 (m, 1H), 4.16 (m, 1H), 3.11-3.03 (m, 1H), 2.95-2.87 (m, 1H), 2, 40-2.27 (m, 2H), 1.40 (s, 9H).

i.e. 100%.

Example 21b: Second eluting peak: N-tert-Butyl-4-[[(^)-indan-1-carbonyl]amino]pyridine-2-carboxamide or N-tert-Butyl-4-[[(^)-indan-1-carbonyl ]amino]pyridine-2-carboxamide

UHPLC retention time: 8.00 min, MS m/z 338.3 = [M+H]+ (91% @ 215 nm)

1H NMR (500 MHz, DMSO-D,) δ 10.85 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.23 (d, J=2.0 Hz, 1H), 8.03 (s, 1H), 7.87 (dd, J=5.5, 2.2 Hz, 1H), 7.32 (d, J=7.3 Hz, 1H), 7, 28 (d, J=7.3 Hz, 1H), 7.20 (m, 1H), 7.16 (m, 1H), 4.16 (m, 1H), 3.11-3.03 (m , 1H), 2.95-2.87 (m, 1H), 2.39-2.27 (m, 2H), 1.40 (s, 9H).

i.e. 88%.

Example 22.

No. tert-Butyl-4-[(2-phenylacetyl)amino]pyridine-2-carboxamide

To a mixture of 4-amino-M-tert-butylpyridin-2-carboxamide (Example 3, Step 1) (50 mg, 0.26 mmol) in DCM (2.59 ml) was added TEA (113 μl, 0.65 mmol) and 2-phenylacetyl chloride (41 µl, 0.31 mmol) and the mixture was stirred for 16 hours. The resulting mixture was diluted with DCM (10 ml) and washed with water (2x10 ml) followed by saturated aqueous NaHCO ₃ (10 ml). The organic layer was separated and dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude residue was dissolved in DMSO:MeCN (800 µl, 1:1), filtered and purified by preparative HPLC (acidic pH, early elution method). The product fractions were combined, the mixture was adjusted to pH 7 using saturated aqueous NaHCO ₃ (20 ml) and extracted with DCM (3x20 ml). The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound as a white metallic solid.

1H NMR (500 MHz, DMSO-06) δ 10.75 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.18 (d, J=1.9 Hz, 1H ), 8.02 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.33 (d, J=4.4 Hz, 4H), 7.29 -7.23 (m, 1H), 3.71 (s, 2H), 1.39 (s, 9H).

LC-MS (Method A): Rt 3.23 min; MS m/z 312.2 = [M+H]+ (100% @ 215 nm).

Example 22.1.

4-(3,3-Dimethylbutanoylamino)-M-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide

The title compound was prepared from 4-amino-M-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Example 78, Step 1) and 3,3-dimethylbutanoyl chloride as in Example 22.

¹ H NMR (500 MHz, DMSO-dg) δ 10.41 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.31 (s, 1H), 8.22 ( d, J=2.1 Hz, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 3.21 (s, 1H), 2.25 (s, 2H), 1.64 (s, 6H), 1.02 (s, 9H).

LC-MS (Method A): Rt 3.22 min; MS m/z 302.2 = [M+H]+ (100% @ 215 nm).

Example 22.2.

4-[(2-Cyclopentylacetyl)amino]-M-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide

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The title compound was prepared from 4-amino-N-(1,1-dimethylprop-2-ynyl)pyridin-2-carboxamide (Example 78, Step 1) and 2-cyclopentylacetyl chloride as in Example 22.

¹ H NMR (500 MHz, DMSO-66) δ 10.47 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.31 (s, 1H), 8.21 ( d, J=2.l Hz, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 3.21 (s, 1H), 2.39-2.35 (m , 2H), 2.28-2.19 (m, 1H), 1.80-1.72 (m, 2H), 1.64 (s, 6H), 1.63-1.56 (m, 2H ), 1.56-1.47 (m, 2H), 1.23-1.13 (m, 2H).

LC-MS (Method A): Rt 3.33 min; MS m/z 314.2 = [M+H]+ (97% @ 215 nm).

Example 22.3.

4-[[2-(3-Chloro-4-pyridyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide

The title compound was prepared from 4-amino-N-(1,1-dimethylprop-2-ynyl)pyridin-2-carboxamide (Example 78, Step 1) and 2-(3-chloro-4-pyridyl)acetic acid hydrochloride analogously to Example 22.

¹ H NMR (500 MHz, DMSO-b6) δ 10.95 (s, 1H), 8.63 (s, 1H), 8.49 (t, J=5.3 Hz, 2H), 8.32 ( s, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.51 (d, J=4 .9 Hz, 1H), 3.99 (s, 2H), 3.21 (s, 1H), 1.64 (s, 6H).

LC-MS (Method A): Rt 2.53 min; MS m/z 357.1/359.1 = [M+H]+ (100% @ 215 nm).

Example 23.

4-[[2-(4-Chlorophenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide

Step 1: 4-Amino-N-(1-cyanocyclopropyl)pyridine-2-carboxamide

To a mixture of 4-aminopyridine-2-carboxylic acid (1 g, 7.24 mmol), TBTU (2.79 g, 8.69 mmol) and TEA (1.21 ml, 8.69 mmol) in DMF (8 ml ) 1-aminocyclopropanecarbonitrile (22.82 ml, 8.69 mmol) was added and the mixture was stirred at 40°C for 2 days. The resulting mixture was concentrated in vacuo and the crude residue was dissolved in EtOAc (15 ml). The mixture was washed with water (20 ml), NaHCO ₃ (15 ml) was dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound as an orange solid.

¹ H NMR (500 MHz, DMSO-66) δ 9.41 (s, 1H), 8.01 (d, J=5.6 Hz, 1H), 7.22 (d, J=2.3 Hz, 1H), 6.62 (dd, J=5.6, 2.4 Hz, 1H), 6.37 (s, 2H), 1.51-1.47 (m, 2H), 1.31-1 .27 (m, 2H).

LC-MS (Method E): Rt 0.25 min; MS m/z 203.1 = [M+H]+.

Step 2: 4-[[2-(4-Chlorophenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide

To a solution of 4-amino-N-(1-cyanocyclopropyl)pyridine-2-carboxamide (step 1) (100 mg, 0.45 mmol), 2-(4-chlorophenyl)acetic acid (83.52 mg, 0.49 mmol) and TEA (155 µl, 0.89 mmol) in 1,4dioxane (2 ml), a 50% T3P® solution in EtOAc (529.41 µl, 0.89 mmol) was slowly added. The reaction mixture was stirred at room temperature for 1 hour and concentrated in vacuo. The crude residue was dissolved in EtOAc (10 ml), washed with NaHCO ₃ (15 ml) and saturated aqueous sodium chloride (15 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by preparative HPLC (acidic pH, early elution method) yielded the title compound as a white solid with a metallic tint.

¹ H NMR (500 MHz, DMSO-66) δ=10.80 (s, 1H), 9.65 (s, 1H), 8.49 (d, J=5.5, 1H), 8.21 ( d, J=1.9, 1H), 7.86 (dd, J=5.5, 2.2, 1H), 7.41-7.34 (m, 4H), 3.74 (s, 2H ), 1.55-1.51 (m, 2H), 1.34-1.30 (m, 2H).

LC-MS (Method A): Rt 2.92 min; MS m/z 355.3 = [M+H]+ (98% @ 215 nm).

The compounds of the following tabular examples (Table 8) were prepared analogously to example 23, replacing 1-aminocyclopropanecarbonitrile (step 1) with the corresponding amine and, replacing 2-(4

- 104 046966 chlorophenyl)acetic acid (step 2) with an appropriate commercially available acid.

Table 8

Example Structure and name 1NMR LC-MS retention time, [M+HJ+, 23.1 ,Ν K rV\/\ ⁿ ' /G hK JJ ¹¹ T p ⁰ Cl 4- [[2-(3-Chlorophenyl)acetyl] amino] -N-( 1 cyanocyclopropyl)pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-bb) 5=10.81 (s, 1H), 9.66 (s, 1H), 8.50 (d, J=5.5, 1H), 8.21 (d , J=2.0, 1H), 7.86 (dd, J=5.5, 2.2, 1H), 7.42-7.41 (m, 1H), 7.39-7.28 ( m, ZN), 3.76 (s, 2H), 1.551.51 (m, 2H), 1.34-1.31 (m, 2H). LC-MS (Method A): Rt 2.92 min; MS m/z 355.3/357.3 = [M+H]+ (96% @ 215 nm) 23.2 // 4-[[2-(2-Chloro-5-fluorophenyl)acetyl]amino]-T4-(1cyanocyclopropyl)pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-bb) 5=10.89 (s, 1H), 9.66 (s, 1H), 8.50 (d, J=5.5, 1H), 8.21 (d , J=2.0, 1H), 7.85 (dd, J=5.5, 2.2, 1H), 7.51 (dd, J=8.8, 5.3, 1H), 7, 37 (dd, J=9.4, 3.1, 1H), 7.21 (td, J=8.5, 3.1, 1H), 3.94 LC-MS (Method A): Rt 2.86 min; MS m/z 373.3/375.3 = [M+H]+ (99% @ 215 nm) 23.3 X-tert-Butyl-4-(indan-2-carbonylamino)pyridine-2carboxamide 1H NMR (500 MHz, DMSO-bb) 5 10.64 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.22 (d, J=2.0 Hz, 1H ), 8.03 (s, 1H), 7.86 (dd, J=5.5, 2.2 Hz, 1H), 7.25-7.20 (m, 2H), 7.17-7, 13 (m, 2H), 3.45 (p, J=8.4 Hz, 1H), 3.25-3.13 (m, 4H), 1.40 (s, 9H). LC-MS (Method A): Rt 3.62 min; MS m/z 338.2 = [M+H]+ (3.62% @215 nm) 23.4 CH ₃ O ,, F^^F T4-tert-Butyl-4-[[2-[2- (difluoro methox and) phenyl] acetyl] amino] pyrid in-2-carboxamide 1H NMR (500 MHz, Methanol-b4) 5 8.44 (d, J=5.5 Hz, 1H), 8.17-8.14 (m, 1H), 7.90 (dd, J=5, 5, 2.2 Hz, 1H), 7.39 (dd, J=7.5, 1.5 Hz, 1H), 7.36 (td, J=7.9, 1.7 Hz, 1H), 7.24 (td, J=7.5, 1.1 Hz, 1H), 7.20-7.18 (m, 1H), 6.78 (t, J=74.2 Hz, 1H), 3 .85 (s, 2H). LC-MS (Method A): Rt 3.42 min; MS m/z 378.3 = [M+H]+ (99% @ 215 nm) 23.5 CH ₃ O H ₃ C^1 ³ II n 1 X-tert-Butyl-4-[[2-[2-(difluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-bb) 5 10.80 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.0 Hz, 1H ), 8.03 (s, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.54 -7.50 (m, 1H), 7.46-7.42 (m, 2H), 7.20 (t, J=54.8 Hz, 1H), 3.96 (s, 2H), 1, 40 (s, 9H). LC-MS (Method A): Rt 3.41 min; MS m/z 362.2 = [M+H]+

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23.6 CH ₃ 0 _w Ν -tert-Butyl-4-[[2-(3,4-difluorophenyl)acetyl] amino] pyridine2-carboxamide 1H NMR (500 MHz, Methanol-b4) δ 8.45 (dd, >5.5, 0.5 Hz, 1H), 8.15 (dd, >2.2, 0.5 Hz, 1H), 7 .91 (dd, >5.5, 2.2 Hz, 1H), 7.32-7.20 (m, 2H), 7.18-7.13 (m, 1H), 3.75 (s, 2H), 1.49 (s, 9H). LC-MS (Method A): Rt 3.43 min; MS m/z 348.3 = [M+H]+ (99% @ 215 nm) 23.7 CH _{3 Osh} F N -tert-Butyl-4-[[2-(3,5-difluorophenyl)acetyl] amino] pyridine2-carboxamide 1H NMR (500 MHz, Methanol-b4) δ 8.45 (dd, >5.7, 0.5 Hz, 1H), 8.15 (dd, >2.2, 0.5 Hz, 1H), 7 .91 (dd, >5.5, 2.2 Hz, 1H), 7.03-6.95 (m, 2H), 6.88 (tg, >9.2, 2.3 Hz, 1H), 3.78 (s, 2H), 1.49 (s, 9H). LC-MS (Method A): Rt 3.46 min; MS m/z 348.3 = [M+H]+ (97% @ 215 nm) 23.8 CH ₃ O ,, F X-tert-Butyl-4-[[2-(2,3-difluorophenyl)acetyl]amino]pyridine2-carboxamide 1H NMR (500 MHz, Methanol-b4) δ 8.45 (dd, >5.5, 0.4 Hz, 1H), 8.15 (dd, >2.2, 0.5 Hz, 1H), 7 .92 (dd, >5.5, 2.2 Hz, 1H), 7.25-7.12 (m, ZN), 3.89 (d, >1.4 Hz, 2H), 1.49 ( s, 9H). LC-MS (Method A): Rt 3.36 min; MS m/z 348.2 = [M+H]+ (98% @ 215 nm) 23.9 XJ ⁰ 4-[[2-(2-Chlorophenyl)acetyl]amino]-X-tetrahydropyran-4ylpyridin-2-carboxamide 1H NMR (500 MHz, DMSO-bb) δ 10.83 (s, 1H), 8.59 (d, >8.5 Hz, 1H), 8.50 (d, >5.5 Hz, 1H), 8.21 (d, >1.9 Hz, 1H), 7.82 (dd, >5.5, 2.2 Hz, 1H), 7.48-7.42 (m, 2H), 7.35 -7.31 (m, 2H), 4.063.97 (m, 1H), 3.92 (s, 2H), 3.89-3.84 (m, 2H), 3.43-3.36 (m , 2H), 1.72-1.63 (m, 4H). LC-MS (Method A): Rt 2.64 min; MS m/z 374.2/376.2 = [M+H]+ (100% @ 215 nm) 23.11 XVrCQ N-(1-Cyanocyclobutyl)-4-[[2-(6quinolyl)acetyl]amino]pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-bb) δ 10.90 (s, 1H), 9.59 (s, 1H), 8.88 (dd, >4.2, 1.7 Hz, 1H), 8. 53 (d, >5.7 Hz, 1H), 8.39-8.32 (m, 1H), 8.22 (d, >1.9 Hz, 1H), 7.99 (d, >8, 6 Hz, 1H), 7.937.84 (m, 2H), 7.75 (dd, >8.7, 2.0 Hz, 1H), 7.52 (dd, >8.3, 4.2 Hz, 1H), 3.96 (s, 2H), 2.73-2.61 (m, 2H), 2.59-2.51 (m, 2H), 2.09-1.94 (m, 2H) . LC-MS (Method A): Rt 1.65 min; MS m/z 386.3 = [M+H]+ (98% @ 215 nm) 23.12 CH ₃ O ,, X-tert-Butyl-4-[[2-[2(trifluoromethyl)phenyl] acetyl] amino] pyr adine-2-carboxamide 1HNMR (500 MHz, DMSO-bb) δ 10.81 (s, 1H), 8.45 (d, >5.5 Hz, 1H), 8.17 (d, >2.1 Hz, 1H), 8 .03 (s, 1H), 7.78 (dd, >5.5, 2.2 Hz, 1H), 7.72 (d, >7.8 Hz, 1H), 7.69-7.63 ( m, 1H), 7.57-7.47 (m, 2H), 4.00 (s, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 3.58 min; MS m/z 380.2 = [M+H]+ (100% @215 nm)

- 106 046966

23.13 CH ₃ O ,, 4- [[2-(2-Bromophenyl)acetyl] amino] -T\G-tert-butylpyridine-2carboxamide 1HNMR (500 MHz, DMSO-bb) δ 10.83 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.0 Hz, 1H) , 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.62 (dd, J=8.0, 1.1 Hz, 1H), 7.43 (dd, J=7.6, 1.7 Hz, 1H), 7.41-7.30 (m, 1H), 7.27-7.20 (m, 1H), 3.92 ( s, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 3.49 min; MS m/z 390.2/392.2 = [M+H]+ (99% @ 215 nm) 23.14 CH _{3 Osh} Ν -tert-Butyl-4-[[2-(2-cyanophenyl)acetyl] amino] pyrid in-2carboxamide 1H NMR (500 MHz, DMSO-bb) δ 10.92 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.0 Hz, 1H ), 8.03 (s, 1H), 7.85 (dd, J=7.7, 1.1 Hz, 1H), 7.80 (dd, 3=5.5,2.2Hz, 1H), 7.72-7.66 (m, 1H), 7.57 (d, J=7.3 Hz, 1H), 7.53-7.44 (m, 1H), 4.03 (s, 2H) , 1.40 (s, 9H). LC-MS (Method A): Rt 3.06 min; MS m/z 337.3 = [M+H]+ (100% @215 nm) 23.15 Cl 4-[[2-(2-Chlorophenyl)acetyl]amino]-T4-(4- cyanonotetrahydropyran-4-yl)pyridin-2-carboxamide 1H NMR (500 MHz, DMSO-bb) δ 10.89 (s, 1H), 9.01 (s, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.24 (d , J=2.1 Hz, 1H), 7.86 (dd, J=5.5, 2.2 Hz, 1H), 7.49-7.42 (m, 2H), 7.36-7, 28 (m, 2H), 3.93 (s, 2H), 3.87 (dt, J=12.2, 3.8 Hz, 2H), 3.62-3.54 (m, 2H), 2 .39-2.34 (m, 2H), 2.12-2.03 (m, 2H). LC-MS (Method A): Rt 2.83 min; MS m/z 399.2/401.3 = [M+H]+ (100% @ 215 nm) 23.16 ^{Ν n} O J LJL 2 X-(4-Cyanotetrahydropyran-4-yl)-4-[[2-(6quinolyl)acetyl] amino] pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-bb) δ 10.91 (s, 1H), 9.01 (s, 1H), 8.88 (dd, J=4.2, 1.7 Hz, 1H), 8 .54 (d, J=5.5 Hz, 1H), 8.36-8.33 (m, 1H), 8.26 (d, J=2.l Hz, 1H), 8.00 (d, J=8.7 Hz, 1H), 7.91 (d, J=l.6 Hz, 1H), 7.89 (dd, J=5.5, 2.2 Hz, 1H), 7.75 ( dd, J=8.7, 2.0 Hz, 1H), 7.52 (dd, J=8.3, 4.2 Hz, 1H), 3.97 (s, 2H), 3.86 (dt , J=12.2, 3.8 Hz, 2H), 3.61-3.56 (m, 2H), 2.37 (d, J=13.5 Hz, 2H), 2.07 (td, J=10.l, 5.2 Hz, 2H) LC-MS (Method A): Rt 1.52 min; MS m/z 416.3 = [M+H]+ (100% @215 nm)

Example 24.

4-[[2-(2-Chloro-5-methoxyphenyl)acetyl]amino]-^(1-cyanocyclopropyl)pyridine-2-carboxamide

Steps 1 and 2: N(1-Cyanocyclopropyl)-4-[[2-(3-methoxyphenyl)acetyl]amino]pyridine-2carboxamide.

The title compound was prepared analogously to Example 23, replacing 2-(4-chlorophenyl)acetic acid (step 2) with 2-(3-methoxyphenyl)acetic acid.

1H NMR (500 MHz, DMSO-06) δ=10.77 (s, 1H), 9.65 (s, 1H), 8.49 (d, J=5.5, 1H), 8.21 (d , J=2.1, 1H), 7.86 (dd, J=5.5, 2.2, 1H), 7.24 (t, J=7.8, 1H), 6.92-6, 88 (m, 2H), 6.83 (dd, J=8.0, 2.1, 1H), 3.74 (s, 3H), 3.68, (s, 2H), 1.55-1 .51 (m, 2H), 1.34-1.30 (m, 2H).

LC-MS (Method E): Rt 1.03 min; MS m/z 351.0 = [M+H]+ (97% @ 215 nm).

Step 2: 4-[[2-(2-Chloro-5-methoxyphenyl)acetyl]amino]-^(1-cyanocyclopropyl)pyridine-2carboxamide

To a solution of Na(1-cyanocyclopropyl)-4-[[2-(3-methoxyphenyl)acetyl]amino]pyridine-2-carboxamide (step 1) (81 mg, 0.23 mmol) in MeCN (33.7 ml) NCS (77 mg, 0.58 mmol) was added and the mixture was stirred at 60°C for 16 hours. The resulting mixture was concentrated in vacuo to leave a crude solid. The dry residue was dissolved in EtOAc (10 ml), washed with water (10 ml), NaHCO ₃ (10 ml) and concentrated in vacuo. Purification by preparative HPLC (acidic pH, standard elution method) yielded the title compound as a white solid with a metallic tint.

1H NMR (500 MHz, DMSO-a ₆ ) δ 10.84 (s, 1H), 9.66 (s, 1H), 8.50 (d, J=5.5 Hz, 1H), 8.21 ( d, J=2.0 Hz, 1H), 7.86 (dd, J=5.5, 2.2 Hz, 1H), 7.35 (d, J=8.8 Hz, 1H), 7, 04 (d, J=3.1 Hz, 1H), 6.90 (dd, J=8.8, 3.1) Hz, 1H), 3.87 (s, 2H), 3.76 (s, 3H), 1.55-1.51 (m, 2H), 1.35-1.30 (m, 2H).

- 107 046966

LC-MS (Method A): Rt 2.84 min; MS m/z 385.2/387.2 = [M+H]+ (100% @ 215 nm).

Example 25.

X-(3-Bicyclo[1.1.1]pentanyl)-4-[[2-(5-tert-butyl-2-hydroxyphenyl)acetyl]amino]pyridine-2 carboxamide

Step 1: Methyl 4-[[2-(5-tert-butyl-2-methoxyphenyl)acetyl]amino]pyridine-2-carboxylate

2-(5-tert-Butyl-2-methoxyphenyl)acetic acid (700 mg, 3.15 mmol) was dissolved in thionyl chloride (2.5 ml, 28.37 mmol) and stirred at 70°C for 30 min. The resulting mixture was concentrated in vacuo and azeotroped with toluene (3x5 ml). The residue was dissolved in DCM (15 ml) to form an acid chloride solution and added to a stirred solution of methyl 4-aminopyridine-2-carboxylate (527 mg, 3.46 mmol) in DCM (15 ml). After stirring for 10 minutes, the mixture was concentrated in vacuo to yield a brown gum. The resin was purified by silica gel chromatography eluting with 25-100% EtOAc in heptane to give the title compound as a dark yellow glassy solid.

¹ H NMR (250 MHz, DMSO-06) δ 10.68 (s, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.31 (d, J=2.0 Hz, 1H), 7.77 (dd, J=5.5, 2.1 Hz, 1H), 7.29-7.20 (m, 2H), 6.89 (d, J=9.3 Hz, 1H ), 3.86 (s, 3H), 3.72 (s, 3H), 3.68 (s, 2H), 1.26 (s, 9H).

LC-MS (Method E): Rt 1.17 min; MS m/z 357 = [M+H]+.

Step 2: 4-[[2-(5-tert-Butyl-2-methoxyphenyl)acetyl]amino]pyridine-2-carboxylic acid

I

CH ₃

To a solution of methyl 4-[[2-(5-tert-butyl-2-methoxyphenyl)acetyl]amino]pyridine-2-carboxylate (step 1) (594 mg, 1.55 mmol) in THF (12 ml) was added 1 M sodium hydroxide solution (1.86 ml, 1.86 mmol), and this mixture was stirred for 30 minutes. The pH of the resulting mixture was adjusted to pH 4 by adding hydrochloric acid. The mixture was partitioned between EtOAc (20 ml) and water (20 ml), at which point a precipitate formed in the organic layer. The organic suspension was washed with water (20 ml) and saturated aqueous sodium chloride (20 ml), filtered through a phase separator and dried to obtain the title compound as a fine powder.

1H NMR (250 MHz, DMSO-bb) δ 10.70 (s, 1H), 8.52 (d, J=5.6 Hz, 1H), 8.28 (d, J=1.9 Hz, 1H ), 7.80 (dd, J=5.6, 2.2 Hz, 1H), 7.29-7.20 (m, 2H), 6.89 (d, J=9.4 Hz, 1H) , 3.72 (s, 3H), 3.69 (s, 2H), 1.26 (s, 9H).

LC-MS (Method E): Rt 0.98 min; MS m/z 343= [M+H]+.

Step 3: 4-[[2-(5-tert-Butyl-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid

An ice-cold suspension of 4-[[2-(5-tert-butyl-2-methoxyphenyl)acetyl]amino]pyridine-2carboxylic acid (step 2) (330 mg, 0.93 mmol) in DCM (9 ml) was treated with 1 M BBr ₃ in DCM (1.85 ml, 1.85 mmol) and stirred for 70 min. The reaction mixture was quenched with methanol (1 ml) and the mixture was partitioned between EtOAc (20 ml) and water (20 ml) resulting in the formation of a fine white precipitate. The precipitate was filtered and dried to obtain the title compound as a solid.

1H NMR (250 MHz, DMSO-06) δ 11.51 (s, 1H), 8.65 (d, J=6.4 Hz, 1H), 8.51 (d, J=2.2 Hz, 1H ), 8.14 (dd, J=6.4, 2.3 Hz, 1H), 7.18 (d, J=2.4 Hz, 1H), 7.10 (dd, J=8.4, 2.5 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 3.75 (s, 2H), 1.23 (s, 9H).

LC-MS (Method E): Rt 0.97 min; MS m/z 329 = [M+H]+ (91% @ 215 nm).

- 108 046966

Step 4: N-(3-Bicyclo[1.1.1]pentanyl)-4-[[2-(5-tert-butyl-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide

To a suspension of 4-[[2-(5-tert-butyl-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (step 3) (25 mg, 0.08 mmol) in DMF (0.5 ml) bicyclo[1.1.1]pentan-3-amine hydrochloride (11 mg, 0.09 mmol), DIPEA (0.05 ml, 0.3 mmol) and HATU (43 mg, 0.11 mmol) were added. After stirring at room temperature for 18 hours, the mixture was partitioned between EtOAc (10 ml) and water (10 ml), and the aqueous portion was extracted with EtOAc (2x20 ml). The combined organic extracts were washed with water (20 ml), and saturated aqueous sodium chloride (20 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The crude residue was purified by C18 reverse phase chromatography, eluting with 45-65% MeCN in water with 0.1% formic acid to give the title compound as a white powder.

1H NMR (500 MHz, DMSO-b6) δ 10.70 (s, 1H), 9.28 (s, 1H), 9.07 (s, 1H), 8.44 (d, J=5.5 Hz , 1H), 8.16 (d, J=2.1 Hz, 1H), 7.84 (dd, J=5.5, 2.2 Hz, 1H), 7.16 (d, J=2, 5 Hz, 1H), 7.08 (dd, J=8.4, 2.5 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 3.65 (s, 2H) , 2.44 (s, 1H), 2.09 (s, 6H), 1.23 (s, 9H).

LC-MS (Method A): Rt 3.71 min; MS m/z 394 = [M+H]+.

Example 25.1.

4-[[2-(5-tert-Butyl-2-hydroxyphenyl)acetyl]amino]A-(4-cyanotetrahydropyran-4-yl)pyridin-2carboxamide

The title compound was prepared from 4-[[2-(5-tert-butyl-2hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 25, Step 3) and 4-aminotetrahydropyran-4-carbonitrile analogously to Example 25, Step 4 .

1H NMR (500 MHz, MethanolA) δ 8.47 (d, J=5.5 Hz, 1H), 8.17 (d, J=1.8 Hz, 1H), 7.94 (dd, J=5 .5, 2.2 Hz, 1H), 7.22 (d, J=2.4 Hz, 1H), 7.15 (dd, J=8.4, 2.5 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 3.96 (dt, J=12.5, 4.0 Hz, 2H), 3.80-3.74 (m, 2H), 3.72 ( s, 2H), 2.49-2.43 (m, 2H), 2.14-2.07 (m, 2H), 1.28 (s, 9H).

LC-MS (Method A): Rt 3.22 min; MS m/z 437 = [M+H]+ (100% @ 215 nm).

Example 26.

No. tert-Butyl-4-[[2-(2-hydroxy-5-phenylphenyl)acetyl]amino]pyridine-2-carboxamide

Step 1: N-tert-butyl-4-[[2-(2-methoxy-5-phenylphenyl)acetyl]amino]pyridine-2-carboxamide

CH ₃

A high-pressure tube was loaded with 4-[[2-(5-bromo-2-methoxyphenyl)acetyl]amino]A-tert-butylpyridine-2-carboxamide (Example 6, Step 1) (250 mg, 0.59 mmol), tripotassium phosphate (379 mg, 1.78 mmol), phenylboronic acid (80 mg, 0.65 mmol) in 1,4-dioxane (4 ml), and the suspension was degassed with nitrogen. Bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloromethane; dichloropalladium (24 mg, 0.03 mmol) was added under nitrogen and the sealed tube was heated to 80°C for 23 hours. The reaction mixture was concentrated in vacuo and the crude residue was redissolved in EtOAc. The mixture was filtered through Celite® (filter material) and the filtrate was concentrated in vacuo to give a brown oil. The oils were purified by silica gel chromatography eluting with 25-100% EtOAc in heptane to give the title compound as a white solid.

1H NMR (250 MHz, Chloroform-d) δ 8.38 (d, J=5.6 Hz, 1H), 8.26-8.14 (m, 2H), 7.97 (s, 1H), 7 .59-7.50 (m, 5H), 7.46-7.37 (m, 2H), 7.37-7.28 (m, 1H), 7.05 (d, J=8.3 Hz , 1H), 4.01 (s, 3H), 3.80 (s, 2H), 1.47 (s, 9H).

LC-MS (Method E): Rt 1.29 min; MS m/z 418 = [M+H]+.

Step 2: N-tert-Butyl-4-[[2-(2-hydroxy-5-phenyl-phenyl)acetyl]amino]pyridine-2-carboxamide

To an ice-cold solution of N-tert-butyl-4-[[2-(2-methoxy-5-phenylphenyl)acetyl]amino]pyridine-2-carboxamide (Step 1) (160 mg, 0.38 mmol) in DCM ( 2.5 ml) adding

- 109 046966 drop 1 M BBr3 in DCM (1.92 ml, 1.92 mmol). After stirring for 10 min, the reaction mixture was quenched by adding methanol (1 ml). The resulting mixture was concentrated in vacuo and the residue was partitioned between EtOAc (20 ml) and water (20 ml). The organic layer was separated and the aqueous portion was re-extracted with EtOAc (2x20 ml). The combined organic extracts were washed with water (20 ml), and saturated aqueous sodium chloride (20 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound as an amber glass.

1H NMR (500 MHz, Chloroform-d) δ 10.14-9.39 (m, 2H), 8.32 (d, J=5.6 Hz, 1H), 8.16 (s, 1H), 8 .04 (dd, J=5.6, 1.9 Hz, 1H), 7.94 (s, 1H), 7.42 (d, J=7.3 Hz, 2H), 7.39 (d, J=2.1 Hz, 1H), 7.36-7.29 (m, 3H), 7.25 (t, J=7.3 Hz, 1H), 7.00 (d, J=8.3 Hz, 1H), 3.83 (s, 2H), 1.49 (s, 9H).

LC-MS (Method A): Rt 3.64 min; MS m/z 404 = [M+H]+.

Example 27.

No. tert-Butyl-4-[[2-[5-chloro-2-hydroxy-4-(pyrrolidin-1-ylmethyl)phenyl]acetyl]amino]pyridine-2carboxamide

Step 1: 2-(4-Bromo-5-chloro-2-methoxyphenyl)acetic acid

I

CH ₃

2-(4-Bromo-2-methoxyphenyl)acetic acid (2 g, 8.16 mmol) and NCS (1.14 g, 8.57 mmol) were dissolved in MeCN (40.8 ml) and stirred at 50°C for 22 hours. The resulting mixture was concentrated in vacuo and the residue was purified by chromatography on silica gel, eluting with 20-100% EtOAc in heptane. The product was further purified by dissolving in EtOAc (100 ml) and extracting into saturated aqueous NaHCO ₃ (3x100 ml). The combined aqueous extracts were acidified with 1 M HCl and extracted with EtOAc (3x150 ml). The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound as a colorless solid.

1H NMR (250 MHz, DMSO-b6) δ 11.97 (s, 1H), 7.46 (s, 1H), 7.34 (s, 1H), 3.79 (s, 3H), 3.50 (s, 2H).

LC-MS (Method E): Rt 1.07 min; MS m/z was not observed = [M+H]+.

Step 2: 4-[[2-(4-Bromo-5-chloro-2-methoxyphenyl)acetyl]amino]-and-tert-butylpyridine-2carboxamide

CH ₃

The title compound was prepared from 4-amino-and-tert-butylpyridine-2-carboxamide and 2(4-bromo-5-chloro-2-methoxyphenyl)acetic acid (Step 1) analogously to Example 3.5b, Step 1

1H NMR (250 MHz, DMSO-b6) δ 10.70 (s, 1H), 8.44 (d, J=5.6 Hz, 1H), 8.16 (d, J=1.9 Hz, 1H ), 8.03 (s, 1H), 7.79 (dd, J=5.5, 2.2 Hz, 1H), 7.51 (s, 1H), 7.36 (s, 1H), 3 .78 (s, 3H), 3.71 (s, 2H), 1.40 (s, 9H).

LC-MS (Method E): Rt 1.28 min; MS m/z 454 = [M+H]+ 97% @ 215 nm).

Step 3: N-tert-Butyl-4-[[2-[5-chloro-2-methoxy-4-(pyrrolidin-1ylmethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

dn ₃

4-[[2-(4-bromo-5-chloro-2-methoxyphenyl)acetyl]amino]-and-tert-butylpyridine-2carboxamide (step 2) (100 mg, 0.21 mmol), trifluoropyrroline- Potassium 1-ylmethyl)borohydride (45 mg, 0.23 mmol), Xphos (6 mg, 0.01 mmol), Pd(Oac) ₂ (1.4 mg, 0.01 mmol) and Cs ₂ CO ₃ (209 mg, 0.64 mmol) and placed under nitrogen atmosphere. THF:water (1 ml of a 10:1 mixture) was added and the mixture was heated at 80°C for 20 hours. The resulting mixture was diluted with water (2 ml) and extracted with DCM (3x10 ml). The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc in heptane to give the title

- 110 046966 compound in the form of a colorless solid.

1H NMR (500 MHz, DMSO^b) δ 10.68 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.16 (dd, J=6.4, 2, 0 Hz, 1H), 8.03 (s, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.29 (s, 1H), 7.07 (s, 1H), 3.75 (s, 3H), 3.69 (s, 2H), 3.65 (s, 2H), 2.512.49 (hidden m, 4H), 1.73-1.71 (m, 4H), 1.40 (s, 9H).

LC-MS (Method E): Rt 1.04 min; MS m/z 459/461 = [M+H]+ (78% @ 215 nm).

Step 4: N-tert-Butyl-4-[[2-[5-chloro-2-hydroxy-4-(pyrrolidin-1-ylmethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

The title compound was prepared from N-tert-butyl-4-[[2-[5-chloro-2-methoxy-4(pyrrolidin-1-ylmethyl)phenyl]acetyl]amino]pyridine-2-carboxamide N-tert-butyl -4-[[2-[5- (stage 3) similar to example 26, stage 2.

1H NMR (500 MHz, DMSO-b6) δ 10.72 (s, 1H), 9.70 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.17 (d , J=2.0 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.18 (s, 1H), 6 .97 (s, 1H), 3.64 (s, 2H), 3.57 (s, 2H), 2.51-2.49 (hidden m, 4H), 1.72-1.70 (m, 4H), 1.40 (s, 9H).

LC-MS (Method A): Rt 2.08 min; MS m/z 445.3/447.3 = [M+H]+ (99% @ 215 nm).

The compounds of the following tabular examples (Table 9) were prepared analogously to example 27, replacing potassium trifluoropyrrolin-1-ylmethyl)borohydride (step 3) with the corresponding borohydride

Table 9

Example Structure and name 1NMR LC-MS retention time, [M+HJ+, 27.1 H ₃ C5 ^H 3 ? N F F .N. CI ⁿ e ^s i rif ⁿ sn ₃ ⁵ X-tert-Butyl-4-[[2-[4-[(tert-butylamine) methyl]-5-chloro-2hydroxyphenyl]acetyl]amino]pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-bb) δ 10.67 (s, 1H), 9.66 (s, 1H), 8.43 (d, J=5.5 Hz, 1H), 8.17 (d , J=2.l Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.16 (s, 1H), 7 .06 (s, 1H), 3.63-3.61 (m, 4H), 1.40 (s, 9H), 1.09 (s, 9H). LC-MS (Method A): Rt 2.08 min; MS m/z 445.4/447.4 = [M+H]+ (99% @ 215 nm) 27.2 n ₃ Sm ^{CH3 η n} I ^{0 n} Mo X-tert-Butyl-4-[[2-[5-chloro-2-hydroxy-4(morpholinomethyl)phenyl]acetyl]amino]pyridine-2carboxamide 1H NMR (500 MHz, DMSO-bb) δ 10.68 (s, 1H), 9.74 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.17 (d , J=2.0 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.21 (s, 1H), 6 .98 (s, 1H), 3.65 (s, 2H), 3.62-3.56 (m, 4H), 3.46 (s, 2H), 2.42-2.40 (m, 4H ), 1.40 (s, 9H). LC-MS (Method A): Rt 1.91 min; MS m/z 459.3/460.3 = [M+H]+ (100% @215 nm) 27.3 ,, CH ₃ O μ. р-Н С 1 II g ЖГУСС-сУ N -tert-Butyl-4-[[2-[5-chloro-4-[(3,3-difluoropyrrolidin-1 yl)methyl]-2-hydroxyphenyl] acetyl] amino] pir id in-2carboxamide 1H NMR (500 MHz, DMSO-bb) δ 10.70 (s, 1H), 9.78 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.17 (d , J=2.l Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (s, 1H), 6 .95 (s, 1H), 3.64 (s, 2H), 2.93 (t, J=13.3 Hz, 2H), 2.76 (t, J=7.0 Hz, 2H), 2 .31-2.22 (m, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 2.6 min; MS m/z 481.3/483.3 = [M+H]+ (98% @ 215 nm)

Example 28.

^tert-butyl-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-5-fluoro-pyridine-2-carboxamide

Step 1: ^(2-Chloro-5-fluoro-4-pyridyl)-2-(5-chloro-2-methoxyphenyl)cetamide

Н //Ϊ У XJ

I dn ₃

A solution of 2-(5-chloro-2-methoxyphenyl)acetic acid (753 mg, 3.75 mmol) in thionyl chloride (6.01 ml, 68.24 mmol) was stirred at 70°C for 1 hour. The resulting mixture was concentrated to dryness and subjected to azeotropic distillation with toluene (2x10 ml). The crude residue was dissolved in DMF (10 ml) and treated dropwise with a solution of 2-chloro-5-fluoropyridin-4-amine (500 mg, 3.41 mmol) in DMF (3 ml) followed by DIPEA (1.49 ml, 8.53 mmol). After stirring at room temperature under an inert atmosphere for 16 hours, the mixture was diluted with EtOAc (100 ml) and washed with water

- 111 046966 (2x50 ml) and saturated aqueous sodium chloride solution (2x50 ml). The organic portion was dried over Na ₂ SO ₄ and concentrated in vacuo. The crude material was purified by C18 reverse phase chromatography, eluting with 0-100% MeCN in water modified with 0.1% formic acid to give the title compound as a light yellow solid.

1H NMR (250 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.41 (d, J=2.7 Hz, 1H), 8.24 (d, J=5.6 Hz, 1H ), 7.33-7.28 (m, 2H), 7.01 (d, J=9.5 Hz, 1H), 3.83 (s, 2H), 3.75 (s, 3H).

LC-MS (Method E): Rt 1.25 min; MS m/z 328.9, 330.9 = [M+H]+.

Step 2: ^tert-Butyl-4-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]-5-fluoropyridine-2carboxamide

C.I.

All reagents were loaded into a CO generation apparatus (carbon monoxide generation system) according to the following procedure; N(2-chloro-5-fluoro-4-pyridyl)-2-(5-chloro2-methoxyphenyl)acetamide (step 1) (170 mg, 0.52 mmol), sodium carbonate (164 mg, 1 .55 mmol), XantPhos Pd-G3 (third generation Buchwald precatalyst (G3)) (49 mg, 0.05 mmol) and toluene (5 ml) followed by the addition of 2-methylpropan-2-amine (64 mg, 0.88 mmol). The resulting solution was degassed with nitrogen for 5 min. Formic acid (49 μl, 1.29 mmol) in toluene (5 ml) was added to chamber B, followed by the addition of mesyl chloride (100 μl, 1.29 mmol). The vessel was sealed and TEA (288 μL, 2.07 mmol) was added to chamber B to generate carbon monoxide. The CO generating apparatus was heated at 100°C overnight and allowed to cool to room temperature. The resulting mixture was concentrated in vacuo, dissolved in EtOAc (30 ml) and washed with water (2x25 ml). The organic portion was dried over Na ₂ SO ₄ and concentrated in vacuo. Purification of the crude residue by preparative HPLC (acidic pH, early elution method) yielded the title compound as a beige solid.

1H NMR (250 MHz, Methanol^) δ 8.91 (d, J=6.5 Hz, 1H), 8.41 (d, J=2.6 Hz, 1H), 7.29-7.23 ( m, 2H), 7.00-6.94 (m, 1H), 3.84 (s, 3H), 3.79 (s, 2H), 1.45 (s, 9H).

LC-MS (Method E): Rt 1.25 min; MS m/z 394.1, 396.1 = [M+H]+ (97% @ 215 nm).

Step 3: ^tert-Butyl-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-5-fluoropyridine-2carboxamide

To a cooled (0°C) solution of N-tert-butyl-4-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]-5-fluoropyridine-2-carboxamide (step 2) (30 mg, 0. 08 mmol) in DCM (2 ml) was added 1 M BBr ₃ in DCM (190 μl, 0.19 mmol). The reaction mixture was allowed to warm to room temperature and stirring was continued for an additional 1 hour. The reaction mixture was quenched by adding water (0.5 ml) and concentrated in vacuo. The crude material was redissolved in EtOAc (2 ml) and washed with sat. NaHCO ₃ (2 ml). The organic portion was concentrated in vacuo and the crude residue was purified using C18 reverse phase chromatography (0-100% MeCN in water modified with 0.1% formic acid). Product fractions were concentrated in vacuo and freeze-dried to give the title compound as a white solid.

1H NMR (500 MHz, DMSO-d6) δ 10.02 (br.s, 1H), 8.82 (d, J=6.6 Hz, 1H), 8.54 (d, J=2.5 Hz , 1H), 7.91 (s, 1H), 7.22 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6 .81 (d, J=8.6 Hz, 1H), 3.79-3.74 (m, 2H), 1.38 (s, 9H).

LC-MS (Method A): Rt 3.37 min; MS m/z 380.3/381.3/382.3 = [M+H]+ (99% @ 215 nm).

Example 28.1.

^tert-Butyl-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-3-fluoropyridine-2-carboxamide

The title compound was prepared from 2-chloro-3-fluoro-pyridin-4-amine and 2-(5-chloro-2methoxyphenyl)acetic acid analogously to Example 28, steps 1-3.

1H NMR (500 MHz, DMSO-d6) δ 8.29-8.25 (m, 2H), 8.02 (s, 1H), 7.21 (d, J=2.7 Hz, 1H), 7 .12 (dd, J=8.6, 2.7 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 3.78 (s, 2H), 1.38 (s, 9H).

LC-MS (Method A): Rt 3.30 min; MS m/z 380.2/382.2 = [M+H]+.

Example 30.

4-[[2-(2-Chlorophenyl)acetyl]amino]-U-(1-cyanocyclobutyl)pyridine-2-carboxamide

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Step 1: Methyl 4-[[2-(2-chlorophenyl)acetyl]amino]pyridine-2-carboxylate

To a stirred solution of 2-(2-chlorophenyl)acetic acid (3.08 g, 18.07 mmol), methyl 4-aminopyridine-2-carboxylate (2.5 g, 16.43 mmol) and TEA (4.3 mL, 24.65 mmol) in 1,4-dioxane (40 ml) was added a 50% T3P® solution in EtOAc (14.68 ml, 24.65 mmol). The resulting mixture was stirred at room temperature for 2 hours and then diluted with EtOAc (100 ml) and water (100 ml). The organic layer was separated, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with 10-100% EtOAc in heptane to give the title compound as a pale orange solid.

1H NMR (500 MHz, DMSO-06) δ 10.85 (s, 1H), 8.55 (d, J=5.5 Hz, 1H), 8.31 (d, J=1.9 Hz, 1H ), 7.77 (dd, J=5.5, 2.2 Hz, 1H), 7.48-7.40 (m, 2H), 7.36-7.28 (m, 2H), 3, 91 (s, 2H), 3.86 (s, 3H).

LC-MS (Method E): Rt 1.00 min; MS m/z 305.0/307.0 = [M+H]+ (96% @ 215 nm).

Step 2: 4-[[2-(2-Chlorophenyl)acetyl]amino]pyridine-2-carboxylic acid

M LiOH (16.07 mL, 32.13 mmol) was added to a stirred solution of methyl 4-[[2-(2chlorophenyl)acetyl]amino]pyridine-2-carboxylate (step 2) (3.4 g, 10.71 mmol) in THF (40 ml) and stirred at room temperature for 20 min. The resulting mixture was partially concentrated in vacuo to remove the volatile solvent and acidified to pH 2 with 2 M aq. HCl. The resulting suspension was filtered and dried in a vacuum oven at 40°C to obtain the title compound as a white metallic solid.

1H NMR (500 MHz, DMSO-06) δ 10.89 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.27 (d, J=2.1 Hz, 1H ), 7.79 (dd, J=5.5, 2.2 Hz, 1H), 7.49-7.41 (m, 2H), 7.35-7.29 (m, 2H), 3, 92 (s, 2H).

LC-MS (Method E): Rt 0.89 min; MS m/z 290.9/292.9 = [M+H]+ (100% @ 215 nm).

Step 3: 4-[[2-(2-Chlorophenyl)acetyl]amino]-M-(1-cyanocyclobutyl)pyridine-2-carboxamide

A solution of 1-aminocyclobutanecarbonitrile (33 mg, 0.34 mmol), DIPEA (0.07 ml, 0.41 mmol), HATU (131 mg, 0.34 mmol) and 4-[[2-(2-chlorophenyl)acetyl ]amino]pyridine-2-carboxylic acid (step 2) (100 mg, 0.34 mmol) in DMF (2 ml) was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo and the residue was partitioned between EtOAc ( 10 ml) and water (10 ml). The organic layer was separated, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by preparative HPLC (acidic pH, early elution method) and product fractions were lyophilized overnight to give the title compound as a white, metallic powder.

1H NMR (500 MHz, DMSO-06) δ 10.87 (s, 1H), 9.60 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.20 (d , J=1.9 Hz, 1H), 7.87 (dd, J=5.5, 2.2 Hz, 1H), 7.52-7.38 (m, 2H), 7.38-7, 24 (m, 2H), 3.92 (s, 2H), 2.70-2.62 (m, 2H), 2.592.52 (m, 2H), 2.09-1.93 (m, 2H) .

LC-MS (Method A): Rt 3.02 min; MS m/z 369.2 = [M+H]+ (100% @ 215 nm).

Example 30.1.

4-[[2-(2-Chlorophenyl)acetyl]amino]-M-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide ns^ sn ₃ o _w

A solution of 2-methylbut-3-yn-2-amine (14 mg, 0.17 mmol), DIPEA (0.08 ml, 0.43 mmol), HATU (65 mg, 0.17 mmol) and 4-[[ 2-(2-chlorophenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 30, Step 2) (50 mg, 0.17 mmol) in DMF (1 ml) was stirred at room temperature for 2 hours. The resulting mixture concentrated in vacuo, then the residue was partitioned between EtOAc (10 ml) and water (10 ml). The organic layer was separated, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by preparative HPLC (acid pH, early elution method) and product fractions were combined and lyophilized overnight to give the title compound as a white powder with

- 113 046966 metallic shade.

1H NMR (500 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.32 (s, 1H), 8.19 (d , J=2.0 Hz, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.49-7.39 (m, 2H), 7.37-7, 29 (m, 2H), 3.92 (s, 2H), 3.21 (s, 1H), 1.64 (s, 6H).

LC-MS (Method A): Rt 3.25 min; MS m/z 356.3/358.2 = [M+H]+ (100% @ 215 nm).

Example 30.2.

4-[[2-(2-Chlorophenyl)acetyl]amino]-A4-fluoro-1-bicyclo[2.1.1]hexanyl)pyridine-2-carboxamide

F

A solution of 4-fluorobicyclo[2.1.1]hexan-1-amine hydrochloride (26 mg, 0.17 mmol), DIPEA (0.08 ml, 0.43 mmol), HATU (65 mg, 0.17 mmol) and 4 -[[2-(2-chlorophenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 30, Step 2) (50 mg, 0.17 mmol) in DMF (1 ml) stirred at room temperature for 2 hours The resulting mixture was concentrated in vacuo and the residue was partitioned between EtOAc (10 ml) and water (10 ml). The organic layer was separated, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by preparative HPLC (acid pH, early elution method) and product fractions were combined and lyophilized overnight to give the title compound as a white, metallic powder.

1H NMR (500 MHz, DMSO-d6) δ 10.83 (s, 1H), 9.05 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.16 (d , J=2.0 Hz, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.54-7.40 (m, 2H), 7.40-7, 25 (m, 2H), 3.91 (s, 2H), 2.14-2.08 (m, 2H), 2.082.04 (m, 2H), 2.00-1.94 (m, 2H) , 1.87-1.81 (m, 2H).

LC-MS (Method A): Rt 3.39 min; MS m/z 388.3/390.3 = [M+H]+ (99% @ 215 nm).

Example 30.3.

4-[[2-(2-Chlorophenyl)acetyl]amino]^-(1-cyclopropyl-1-methylethyl)pyridine-2-carboxamide

The title compound was prepared from 4-[[2-(2-chlorophenyl)acetyl]amino]pyridine-2carboxylic acid (Example 30, Step 2) and 2-cyclopropylpropan-2-amine as in Example 30, Step 3.

1H NMR (500 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.20 (d, J=2.1 Hz, 1H ), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.49-7.42 (m, 2H), 7.35-7, 31 (m, 2H), 3.92 (s, 2H), 1.41-1.34 (m, 1H), 1.31 (s, 6H), 0.43-0.36 (m, 4H) .

LC-MS (Method A): Rt 3.73 min; MS m/z 372.2/374.2 = [M+H]+ (100% @ 215 nm).

The compounds of the following tabular examples (Table 9a) were prepared analogously to example 30, replacing 1-aminocyclobutanecarbonitrile (step 3) with the appropriate commercially available amine.

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Table 9a

Example Structure and name 1NMR LC-MS retention time, [M+HJ+, 30.3a CH ₃ O _n 4-[[2-(2-Chlorophenyl)acetyl]amino]-X-(1-cyano-1methylethyl)pyridine-2-carboxamide 1HNMR (500 MHz, DMSO-bb) δ 10.89 (s, 1H), 8.84 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.23 (d, J=2.0 Hz, 1H), 7.87 (dd, J=5.5, 2.2 Hz, 1H), 7.507.42 (m, 2H), 7.38-7.29 (m, 2H ), 3.93 (s, 2H), 1.73 (s, 6H). LC-MS (Method A): Rt 2.96 min; MS m/z 357.2/359.3 = [M+H]+ (99% @ 215 nm) 30.4 ^{ns 0} AX 4-[[2-(2-Chlorophenyl)acetyl]amino]-X-(1-methyl-3bicyclo[1.1.1]pentanyl)pyridine-2-carboxamide 1HNMR (500 MHz, DMSO-bb) δ 10.82 (s, 1H), 8.99 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.13 (d, J=2.0 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.497.40 (m, 2H), 7.36-7.29 (m, 2H ), 3.91 (s, 2H), 1.96 (s, 6H), 1.22 (s, ZN). LC-MS (Method A): Rt 3.65 min; MS m/z 370.3/372.3 = [M+H]+ (97% @215 nm) 30.5 Ww 4-[[2-(2-Chlorophenyl)acetyl]amino]-X-(1-cyano-3bicyclo[1.1.1]pentanyl)pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-ab) δ 10.84 (s, 1H), 9.49 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.14 (d , J=2.0 Hz, 1H), 7.84 (dd, J=5.5, 2.2 Hz, 1H), 7.497.38 (m, 2H), 7.36-7.28 (m, 2H), 3.91 (s, 2H), 2.57 (s, 6H). LC-MS (Method A): Rt 3.08 min; MS m/z 381.2/383.2 = [M+H]+ (100% @215 nm) 30.6 X 1 Χχχχ 4-[[2-(2-Chlorophenyl)acetyl]amino]-X-(2,2- difluorocyclopropyl)pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-ab) δ 10.85 (s, 1H), 9.07 (t, J=3.3 Hz, 1H), 8.50 (d, J=5.5 Hz, 1H ), 8.21 (d, J=2.0 Hz, 1H), 7.84 (dd, J=5.5, 2.2 Hz, 1H), 7.56-7.40 (m, 2H) , 7.40-7.25 (m, 2H), 3.92 (s, 2H), 3.57-3.42 (m, 1H), 2.03-1.80 (m, 2H). LC-MS (Method A): Rt 3.04 min; MS m/z 366.1/368.2 = [M+H]+ (99% @215 nm) 30.7 ,Ν aln n ^N Ίτ ιΓ ΠΊ Cl 4-[[2-(2-Chlorophenyl)acetyl]amino]-X-(1-cyanocyclopropyl)pyridine-2-carboxamide W NMR (500 MHz, DMSO-ab) δ 10.87 (s, 1H), 9.66 (s, 1H), 8.50 (d, J=5.5 Hz, 1H), 8.22 (d , J=2.l Hz, 1H), 7.86 (dd, J=5.5, 2.2 Hz, 1H), 7.507.40 (m, 2H), 7.36-7.27 (m, 2H), 3.92 (s, 2H), 1.59-1.46 (m, 2H), 1.371.28 (m, 2H). LC-MS (Method A): Rt 2.77 min; MS m/z 355.2/357.2 = [M+H]+ (98% @215 nm) 30.8 A/ ^CH3 p ^{n z} —A AA ^Ν Ίτ P GT Τι ⁿ nU ¹ o AJ CI 4-[[2-(2-Chlorophenyl)acetyl]amino]-X-(1methylcyclopropyl)pyridine-2-carboxamide 1HNMR (500 MHz, DMSO-ab) δ 10.81 (s, 1H), 8.76 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.16 (d, J=2.l Hz, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.44 (m, 2H), 7.36-7.17 (m, 2H ), 3.91 (s, 2H), 1.36 (s, ZN), 0.91-0.72 (m, 2H), 0.72-0.57 (m, 2H). LC-MS (Method A): Rt 3.02 min; MS m/z 344.2/346.2 = [M+H]+ (100% @215 nm)

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30.9 ⁰ Arro 4-[[2-(2-Chlorophenyl)acetyl]amino]-X-(3-fluoro-1bicyclo[1.1.1]pentanyl)pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-bb) δ 10.84 (s, 1H), 9.37 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.15 (d , J=2.0 Hz, 1H), 7.84 (dd, >5.5, 2.2 Hz, 1H), 7.487.40 (m, 2H), 7.35-7.30 (m, 2H ), 3.91 (s, 2H), 2.41 (d, >2.2 Hz, 6H). LC-MS (Method A): Rt 3.30 min; MS m/z 374.3/376.2 = [M+H]+ (100% @215 nm) 30.10 CH ₃ O 4-[[2-(2-Chlorophenyl)acetyl]amino]-X-(2-fluoro-1,1dimethylethyl)pyridine-2-carboxamide 1HNMR (500 MHz, DMSO-bb) δ 10.85 (s, 1H), 8.47 (d, >5.5 Hz, 1H), 8.20 (d, >2.0 Hz, 1H), 8 .12 (s, 1H), 7.81 (dd, >5.5, 2.2 Hz, 1H), 7.44 (d, >11.9 Hz, 2H), 7.35-7.31 ( m, 2H), 4.58 (d, >47.5 Hz, 2H), 3.92 (s, 2H), 1.39 (d, >1.9 Hz, 6H). LC-MS (Method A): Rt 3.32 min; MS m/z 364.2/366.2 = [M+H]+ (100% @215 nm) 30.11* NS CI 4-[[2-(2-Chlorophenyl)acetyl]amino]-X-(4- ethynyltetrahydropyran-4-yl)pyridin-2-carboxamide. 1HNMR (500 MHz, DMSO-ab) δ 10.86 (s, 1H), 8.50 (d, >5.5 Hz, 1H), 8.45 (s, 1H), 8.20 (d, > 2.1 Hz, 1H), 7.83 (dd, >5.5, 2.2 Hz, 1H), 7.487.41 (m, 2H), 7.35-7.30 (m, 2H), 3 .92 (s, 2H), 3.76 (dt, >11.7, 3.9 Hz, 2H), 3.67-3.59 (m, 2H), 3.38 (s, 1H), 2 .19-2.13 (m, 2H), 2.09-2.01 (m, 2H). LC-MS (Method A): Rt 2.95 min; MS m/z 398.2/400.2 = [M+H]+ (100% @215 nm) 30.12 A T Ζ / ° ^< m ^> Ζ t U 1HNMR (500 MHz, DMSO-ab) δ 10.88 (s, 1H), 9.05 (s, 1H), 8.52 (d, >5.5 Hz, 1H), 8.22 (d, > 1.9 Hz, 1H), 7.85 (dd, >5.5, 2.2 Hz, 1H), 7.487.42 (m, 2H), 7.35-7.30 (m, 2H), 3 .92 (s, 2H), 2.33-2.27 (m, 4H), 1.791.72 (m, 4H). 4-[[2-(2-Chlorophenyl)acetyl]amino]-X-(1- cyanocyclopentyl)pyridine-2-carboxamide LC-MS (Method A): Rt 3.24 min; MS m/z 383.2/385.2 = [M+H]+ (99% @ 215 nm) 30.13 ⁿ =c a 2 ⁿ AAguo 4-[[2-(2-Chlorophenyl)acetyl]amino]-X-(2,2-difluoro-1,1dimethylethyl)pyridine-2-carboxamide 1HNMR (500 MHz, DMSO-ab) δ 10.86 (s, 1H), 8.49 (d, >5.5 Hz, 1H), 8.29 (s, 1H), 8.22 (d, > 2.0 Hz, 1H), 7.82 (dd, >5.5, 2.2 Hz, 1H), 7.477.41 (m, 2H), 7.34-7.30 (m, 2H), 6 .46 (t, >57.0 Hz, 1H), 3.92 (s, 2H), 1.44 (s, 6H) LC-MS (Method A): Rt 3.53 min; MS m/z 382.2/384.2 = [M+H]+

* Example 30.11: amine, 4-ethynyltetrahydropyran-4-amine hydrochloride was prepared according to the procedure described in Journal of Organic Chemistry, 71(18), 7110-7112; 2006.

Example 31.

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-^(4-cyanotetrahydropyran-4-yl)pyridin-2carboxamide

Step 1: 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid

M BBr ₃ in DCM (308.67 ml, 308.67 mmol) was added slowly over 1 hour to a suspension of 4-[[2-(5chloro-2-methoxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 8.1 , step 2) (25.0 g, 77.17 mmol, 99%) in DCM (500 ml) at 0-5°C under an inert atmosphere of N ₂ . The mixture was allowed to warm to room temperature and stirred for an additional hour. The reaction mixture was concentrated in vacuo and the residue was suspended in EtOAc (500 ml) and water (500 ml) at 0°C. The resulting mixture was left to warm to room temperature, and the aqueous layer was adjusted to pH 4 by adding saturated. aq. NaHCO ₃ (350 ml). The precipitate was collected by filtration, washed with water (2x100 ml), EtOAc (2x100 ml), diethyl ether (2x150 ml) and dried under high vacuum in an oven at 40°C to obtain the title compound as a beige solid.

1H NMR (500 MHz, DMSO-06) δ 10.72 (s, 1H), 9.82 (br.s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.27 (d, J=2.0 Hz, 1H), 7.80 (dd, J=5.6, 2.2 Hz, 1H), 7.22 (d, J=2.7 Hz, 1H), 7 .13 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz,

- 116 046966

1H), 3.67 (s, 2H).

LC-MS (Method E): Rt 0.86 min; MS m/z 306.9/308.9 = [M+H]+ (97% @ 215 nm).

Step 2: 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]^-(4-cyanotetrahydropyran-4yl)pyridin-2-carboxamide

HATU (19.34 g, 50.86 mmol) was added to a stirred solution of 4-[[2-(5-chloro-2hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 31, Step 1) (13 g, 42.39 mmol), 4-aminotetrahydropyran-4-carbonitrile (8.02 g, 63.58 mmol) and DIPEA (18.51 ml, 105.97 mmol) in DMF (150 ml), and the reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with 0.5 M aq. NaOH (100 ml) and stirred at room temperature for 30 min. Water (500 ml) and EtOAc (500 ml) were added and the resulting precipitate was removed by filtration. The aqueous portion was extracted with EtOAc (250 ml) and the combined organic parts were washed with water (2x750 ml), sat. NaHCO ₃ (500 ml), and saturated aqueous sodium chloride (700 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give a yellow oil. The material was purified by chromatography on silica gel, eluting with 0-100% EtOAc in heptane, then 0-15% MeOH in EtOAc. The product fractions were combined and concentrated in vacuo. The residue was purified successively on KP-NH silica gel, eluting with 50-100% EtOAc in heptane, then 0-15% MeOH in EtOAc. Pure product fractions were combined and concentrated in vacuo and azeotroped with MeCN (3x500 ml) to give the title compound.

1H NMR (500 MHz, DMSO) δ 10.74 (br.s, 1H), 9.83 (s, 1H), 9.00 (s, 1H), 8.52 (d, J=5.5 Hz , 1H), 8.23 (d, J=2.1 Hz, 1H), 7.87 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J=2, 7 Hz, 1H), 7.13 (dd, J=8.6, 2.7 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 3.86 (td, J= 12.5 Hz, 3.9 Hz, 2H), 3.68 (s, 2H), 3.64-3.53 (m, 2H), 2.41-2.32 (m, 2H), 2.122, 00 (m, 2H).

LC-MS (Method A): Rt 2.67 min; MS m/z 415.2/417.2 = [M+H]+.

Step 3: Recrystallization of 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-U-(4cyanonotetrahydropyran-4-yl)pyridin-2-carboxamide.

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-Y-(4-cyanotetrahydropyran-4-yl)pyridin-2carboxamide (step 2) (1881 mg, 4.44 mmol) suspended in MeCN (16 ml) and heated at boiling for 10 minutes. An additional portion of MeCN (2 ml) was added and the mixture was heated at reflux for 30 min, at which point it was observed that all of the material had gone into solution. The heating was reduced to 55°C, and the mixture was seeded with a crystal of 4-[[2-(5-chloro-2hydroxyphenyl)acetyl]amino]-Y-(4-cyanotetrahydropyran-4-yl)pyridin-2-carboxamide. The temperature of the mixture was maintained at 55°C for 1 hour and then allowed to cool slowly to room temperature overnight. The resulting crystals were collected by filtration, washed with a minimum volume of ice-cold MeCN (~5 ml) and dried in a vacuum oven at 40°C for 2 hours to obtain the title compound as a white crystalline solid with a metallic tint.

1H NMR (500 MHz, DMSO-06) δ 10.74 (br.s, 1H), 9.82 (br.s, 1H), 9.00 (s, 1H), 8.53 (d, J= 5.5 Hz, 1H), 8.23 (d, J=2.0 Hz, 1H), 7.87 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J=2.7 Hz, 1H), 7.13 (dd, J=8.6, 2.7 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 3.86 ( td, J=12.5 Hz, 3.9 Hz, 2H), 3.68 (s, 2H), 3.63-3.54 (m, 2H), 2.40-2.34 (m, 2H ), 2.122.03 (m, 2H).

LC-MS (Method A): Rt 2.68 min; MS m/z 415.3/417.2 = [M+H]+ (99% @ 215 nm).

Example 31.2.

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-U-(1-ethynylcyclopentyl)pyridine-2-carboxamide

The title compound was prepared from 4-[[2-(5-chloro-2hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 31, Step 1) and 1ethynylcyclopentanamine hydrochloride analogously to Example 31, Step 2.

1H NMR (500 MHz, DMSO-dA δ 10.70 (s, 1H), 9.82 (br. s, 1H), 8.48-8.45 (m, 2H), 8.17 (d, J =1.9 Hz, 1H), 7.84 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J=2.7 Hz, 1H), 7.12 (dd , J=8.6, 2.7 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 3.67 (s, 2H), 3.16 (s, 1H), 2 .30-2.22 (m, 2H), 2.14-2.05 (m, 2H), 1.77-1.66 (m, 4H).

LC-MS (Method A): Rt 3.34 min; MS m/z 398.2/400.2 = [M+H]+ (100% @ 215 nm).

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Example 31.3.

4-[2-(5-Chloro-2-hydroxyphenyl)acetamido]^-[(^^)-2-hydroxycyclohexyl]pyridine-2carboxamide

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N(2-hydroxycyclohexyl)pyridine-2-carboxamide was prepared from 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl] amino]pyridine-2-carboxylic acid (example 31, step 1) and trans-2-aminocyclohexanol as in example 31, step 2.

1H NMR (500 MHz, DMSO-d6) δ 10.74 (s (br), 1H), 9.82 (s (br), 1H), 8.47 (d, J=5.5 Hz, 1H), 8.34 (d, J=8.l Hz, 1H), 8.19 (d, J=2.1 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.21 (d, J=2.6 Hz, 1H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.79 (d, J=8 .6 Hz, 1H), 4.68 (d, J=5.5 Hz, 1H), 3.66 (s, 2H), 3.60-3.53 (m, 1H), 3.45-3 .41 (m, 1H), 1.941.85 (m, 2H), 1.67-1.57 (m, 2H), 1.30-1.18 (m, 4H).

LC-MS (Method A): Rt 2.64 min; MS m/z 404.3/406.3 = [M+H]+ (97% @ 215 nm).

Example 31.3 a.

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]^-[^^)-2-hydroxycyclohexyl]pyridine-2carboxamide or 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl ]amino]-X-[(^^)-2hydroxycyclohexyl]pyridine-2-carboxamide

(18,28)-isomer (lR,2R)-H3OMep

Chiral separation.

4-[2-(5-chloro-2-hydroxyphenyl)acetamido]^-[(^^)-2-hydroxycyclohexyl]pyridine-2-k arboxamide (Example 31.3) using UHPLC supercritical liquid chromatography (15% methanol+0 .2% DEA: 85% CO ₂ with a 25 cm Chiralcel OJ-H column at 4 ml/min) gave the title compound.

UHPLC retention time (second eluted peak) = 23.32 min MS (ESI pos.): m/z=404.1 (M+H)+.

^1H NMR (500 MHz, DMSO-d6) δ 8.47 (d, J=5.5 Hz, 1H), 8.34 (d, J=8.1 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.20 (d, J=2.5 Hz, 1H), 7.10 ( dd, J=8.6, 2.6 Hz, 1H), 6.78 (d, J=8.6 Hz, 1H), 4.69 (d, J=5.5 Hz, 1H), 3, 66 (s, 2H), 3.61-3.53 (m, 1H), 3.47-3.41 (m, 1H), 1.95-1.86 (m, 2H), 1.68- 1.58 (m, 2H), 1.281.23 (m, 4H).

LC-MS (Method A): Rt 2.64 min; MS m/z 404.2/406.2 = [M+H]+ (100% @ 215 nm).

Example 31.4.

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N(4-ethynyltetrahydropyran-4-yl)pyridin-2carboxamide

Step 1: 2-Methyl-X-tetrahydropyran-4-ylidene-propane-2-sulfinamide

N A ^CHz 'S CH ₃

ABOUT

A solution of tetrahydropyran-4-one (2.4 g, 23.97 mmol) in THF (50 ml) under an inert atmosphere was treated with tetraethoxytitanium (9.57 g, 41.95 mmol) followed by the addition of 2-methylpropane-2sulfinamide (2, 91 g, 23.97 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was poured into sat. aq. NaHCO ₃ (100 ml) and stirred for 5 minutes. The resulting suspension was filtered and the solid was washed with water (50 ml) and EtOAc (100 ml).

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The filtrate was separated and the aqueous layer was washed again with EtOAc (50 ml). The combined organic portions were washed with saturated aqueous sodium chloride (50 ml), dried over Na2SO4 and concentrated in vacuo to give a crude oil. The oil was purified by silica gel chromatography, eluting with 0-100% EtOAc in heptane to give the title compound as a colorless oil.

LC-MS (Method E): Rt 0.74 min; MS m/z 204.0 = [M+H]+ (100% @ 215 nm).

Step 2: 4-Ethynyltetrahydropyran-4-amine hydrochloride

Г Ί HCI ns^ nh ₂

A cooled (-78°C) solution of ethynyl(trimethyl)silane (725 mg, 7.38 mmol) in toluene (10 ml) under nitrogen was treated dropwise with n-BuLi (1.6 M in a mixture of hexanes) (3.38 ml, 5.41 mmol). After stirring at -78°C for 15 minutes, the mixture was treated with a cooled (-78°C) solution of 2-methylNtetrahydropyran-4-ylidene-propan-2-sulfinamide (500 mg, 2.46 mmol) in toluene (5 ml) and trimethylaluminum (1.48 ml, 2.95 mmol) through the canula. Stirring was continued at -78°C for 2 hours and then the solution was allowed to warm to room temperature and stirred overnight. The resulting mixture was cooled to 0°C and quenched with sat. aq. Na ₂ SO ₄ (~20 ml). The mixture was filtered and washed with EtOAc (~50 ml). The biphasic filtrate was separated and the organic portion was further washed with water (25 ml). The aqueous layer was back-extracted with EtOAc (50 ml) and the combined organic extracts were washed with saturated aqueous sodium chloride (25 ml), dried over Na2SO4 and concentrated in vacuo to give a white metallic solid. The solid was dissolved in anhydrous dioxane (2 ml) and treated with 4 M HCl (2 ml). After stirring at room temperature for 4 hours, the resulting precipitate was filtered and washed with cold dioxane to obtain the title compound as a beige solid.

1H NMR (500 MHz, DMSO-b6) δ 8.98 (s, 3H), 3.91 (s, 1H), 3.91-3.86 (m, 2H), 3.48 (td, J= 11.9, 2.0 Hz, 2H), 1.95 (td, J=12.4, 4.5 Hz, 2H), 1.89-1.84 (m, 2H).

LC-MS (Method E): Rt 0.2 min; MS m/z 126.0 = [M+H]+.

Step 3: 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-(4-ethynyltetrahydropyran-4yl)pyridine-2-carboxamide

The title compound was prepared from 4-[[2-(5-chloro-2hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 31, Step 1) and 4ethynyltetrahydropyran-4-amine hydrochloride (Step 2) analogously to Example 31 , stage 2.

1H NMR (500 MHz, DMSO-b6) δ 10.70 (s, 1H), 9.81 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.45 (s , 1H), 8.19 (d, J=2.1 Hz, 1H), 7.85 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J=2, 7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1h), 6.80 (d, J=8.6 Hz, 1H), 3.76 (dt, J= 7.7, 4.0 Hz, 2H), 3.68 (s, 2H), 3.66-3.60 (m, 2H), 3.38 (s, 1H), 2.18-2.13 (m, 2H), 2.09-2.01 (m, 2H).

LC-MS (Method A): Rt 2.80 min; MS m/z 414.2/416.2 = [M+H]+ (99% @ 215 nm).

Example 32.

N[(6-Amino-2-pyridyl)methyl]-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl] amino]pyridine-2carboxamide

ABOUT

Step 1: tert-butyl No.[6-[[[4-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]pyridine-2 carbonyl]amino]methyl]-2-pyridyl]carbamate

dn ₃

To a solution of 4-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 8.1, step 2) (100 mg, 0.3 mmol) in DMF (1 ml) was added tert-butyl Na[6-(aminomethyl)-2pyridyl]carbamate (68 mg, 0.3 mmol) followed by the addition of DIPEA (63 μL, 0.36 mmol) and the mixture was stirred at room temperature for 15 min. HATU (126 mg, 0.33 mmol) was added and stirring was continued at room temperature for 1 hour. The resulting mixture was diluted with H2O (2 ml) and the pH was adjusted to pH 6 by adding sat. aq. NH4Cl. The mixture was extracted with EtOAc (2x5 ml) and the combined organic extracts were washed with saturated aqueous sodium chloride, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude residue was ground with

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MeCN and water to obtain the title compound as a white solid.

1H NMR (500 MHz, DMSO-06) δ 10.71 (s, 1H), 9.70 (s, 1H), 9.23 (t, J=6.1 Hz, 1H), 8.52 (d , J=5.5 Hz, 1H), 8.22 (d, J=2.1 Hz, 1H), 7.84 (dd, J=5.5, 2.2 Hz, 1H), 7.69 -7.63 (m, 2H), 7.32-7.29 (m, 2H), 7.03-7.00 (m, 1H), 6.91 (dd, J=6.9, 1, 2 Hz, 1H), 4.49 (d, J=6.1 Hz, 2H), 3.75 (s, 3H), 3.72 (s, 2H), 1.46 (s, 9H).

LC-MS (Method A): Rt 3.78 min; MS m/z 526.3/528.2 = [M+H]+ (100% @ 215 nm).

Step 2: N-[(6-Amino-2-pyridyl)methyl]-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl] amino]pyridine-2carboxamide tert-Butyl-N-[6-[ [[4-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]pyridine-2-carbonyl]amino]methyl]2-pyridyl]carbamate (step 1) (107 mg, 0.2 mmol) was added to a cooled (0-5°C) suspension of 1 M BBr ₃ in DCM (895 µl, 0.9 mmol) in DCM (1.1 ml). The ice bath was removed and the mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo and the residue was partitioned between EtOAc (5 ml) and water (4 ml). The pH of the aqueous layer was adjusted to pH 7 by adding sat. aq. NaHCO ₃ and the organic layer was separated, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude residue was triturated in MeCN:H ₂ O (4:1), filtered, washed with MeCN and dried under high vacuum in an oven to give the title compound as a light brown solid.

1H NMR (500 MHz, DMSO-06) δ 10.68 (s, 1H), 9.81 (s, 1H), 9.05 (t, J=5.9 Hz, 1H), 8.50 (d , J=5.5 Hz, 1H), 8.22 (d, J=2.0 Hz, 1H), 7.84 (dd, J=5.5, 2.1 Hz, 1H), 7.31 (t, J=7.7 Hz, 1H), 7.22 (d, J=2.6 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6 .80 (d, J=8.6 Hz, 1H), 6.40 (d, J=7.2 Hz, 1H), 6.32 (d, J=8.2 Hz, 1H), 5.93 (br. s, 2H), 4.36 (d, J=5.9 Hz, 2H), 3.67 (s, 2H).

LC-MS (Method A): Rt 1.70 min; MS m/z 412.2/414.4 = [M+H]+ (97% @ 215 nm).

The compounds of the following tabular examples (Table 10) were prepared analogously to Example 32, replacing tert-butyl-N[6-(aminomethyl)-2-pyridyl]carbamate (Step 1) with the appropriate commercially available amine.

Table 10

Example Structure and name 1NMR LC-MS retention time, [M+HJ+, 32.1 he L | ⁰ n 12-[[4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]pyridin-2carbonyl]amino]dodecanoic acid 1HNMR (500 MHz, Methanol-04) δ 8.47 (d, >5.6 Hz, 1H), 8.248.17 (m, 1H), 7.93-7.89 (m, 1H), 7.19 (d, >2.4 Hz, 1H), 7.09 (d, >8.6, 2.2 Hz, 1H), 6.78 (d, >8.6 Hz, 1H), 3.72 ( s, 2H), 3.40 (t, >7.1 Hz, 2H), 2.27 (t, >7.4 Hz, 2H), 1.67-1.55 (m, 4H), 1.421, 26 (m, 14N). LC-MS (Method A): Rt 3.71 min; MS m/z 504.4/506.4 = [M+H]+ 32.2 4-[[2-(5-Chloro-2-hydroxyphenyl) acetyl]amino]-M-(3-pyridylmethyl)pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-bb) δ 10.84 (s, 1H), 9.89 (s, 1H), 9.40 (t, >6.4 Hz, 1H), 8.55 (d, >1.8 Hz, 1H), 8.49 (d, >5.5 Hz, 1H), 8.45 (dd, >4.8, 1.6 Hz, 1H), 8.21 (d, > 2.0 Hz, 1H), 7.84 (dd, >5.5, 2.2 Hz, 1H), 7.73 (dt, >7.8, 1.9 Hz, 1H), 7.34 ( dd, >7.8, 4.8 Hz, 1H), 7.21 (d, >2.9 Hz, 1H), 7.11 (dd, >8.6, 2.7 Hz, 1H), 6 .79 (d, >8.6 Hz, 1H), 4.51 (d, >6.4 Hz, 2H), 3.67 (s, 2H). LC-MS (Method A): Rt 1.80 min; MS m/z 397.2/399.2 = [M+H]+ (96% @ 215 nm)

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32.3 SpUgtssg 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-(2pyridylmethyl)pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-bb) δ 10.70 (s, 1H), 9.82 (s, 1H), 9.33 (t, J=5.7 Hz, 1H), 8.56-8 .50 (m, 2H), 8.24 (s, 1H), 7.86 (d, J=3.7 Hz, 1H), 7.76 (t, J=7.2 Hz, 1H), 7 .32 (d, J=7.9 Hz, 1H), 7.31-7.25 (m, 1H), 7.25-7.20 (m, 1H), 7.13 (dd, 1=8 ,5,2,2Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 4.62 (d, J=5.8 Hz, 2H), 3.68 (s, 2H) . LC-MS (Method A): Rt 1.98 min; MS m/z 397.2/399.2 = [M+H]+ (97% @ 215 nm) 32.4 ABOUT SOEUGSG 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-(4pyridylmethyl)pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-b6) δ 10.74 (s, 1H), 9.82 (s, 1H), 9.43 (t, J=6.4 Hz, 1H), 8.52 (d , J=5.5 Hz, 1H), 8.52-8.46 (m, 2H), 8.22 (d, J=2.1 Hz, 1H), 7.86 (dd, J=5, 5,2,2 Hz, 1H), 7.29 (d, J=6.0 Hz, 2H), 7.22 (d, J=2.7 Hz, 1H), 7.13 (dd, J= 8.6, 2.7 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 4.51 (d, J=6.4 Hz, 2H), 3.68 (s, 2H). LC-MS (Method A): Rt 1.63 min; MS m/z 397.2/399.2 = [M+H]+ (96% @ 215 nm) 32.5 soUghhh 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-[(2hydroxyphenyl)methyl]pyridine-2-carboxamide 1H NMR (500 MHz, Methanol-b4) δ 8.35 dd, J=5.01, 0.52 Hz, 1H), 8.06 (dd, J=l.71, 0.49, 1H), 7 .80 (dd, J=5.5, 2.2 Hz, 1H), 7.11 (dd, J=7.5, 1.5 Hz, 1H), 7.08 (d, J=2.6 Hz, 1H), 7.04-6.96 (m, 2H), 6.74-6.70 (m, 1H), 6.69-6.65 (m, 2H), 4.47 (s, 2H), 3.60 (s, 2H). LC-MS (Method A): Rt 3.01 min; MS m/z 412.2/414.2 = [M+H]+ (97% @ 215 nm) 32.6 o^U H _s with CH ₃ O _n 4- [[2-(5-Chloro-2-hydroxyphenyl)acetyl] amino] -N-(1,1 dimethyl-2-morpholinoethyl)pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-b6) δ 10.66 (s, 1H), 9.80 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.33 (s , 1H), 8.17 (d, J=2.1 Hz, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J=2, 7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.67 (s, 2H) , 3.58-3.54 (m, 4H), 2.57 (s, 2H), 1.37 (s, 6H), 1.24 (s, 2H). LC-MS (Method A): Rt 1.80 min; MS m/z 447.3/449.3 = [M+H]+ (100% @ 215 nm) 32.7 ^НзС \/ ^СНз n ⁿ NS < US JL Yu1 y γΎ Yjf] o AU but 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl] amino] - M-(2-hydroxy1,1-dimethylethyl)pyridine -2-carboxamide 1H NMR (500 MHz, DMSO-C16) δ 10.67 (s, 1H), 9.81 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.24 (s , 1H), 8.17 (d, J=2.0 Hz, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J=2, 7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 5.12 (t, J= 5.5 Hz, 1H), 3.67 (s, 2H), 3.44 (d, J=5.5 Hz, 2H), 1.33 (s, 6H). LC-MS (Method A): Rt 2.56 min; MS m/z 378.2/380.2 = [M+H]+ (100% @ 215 nm) 32.8 HN^^l 0 UsaUhu 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-(3,3-d iforo4-piperidyl)pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-ab) δ 10.71 (s, 1H), 9.82 (s, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.42 (d , J=9.6 Hz, 1H), 8.27 (d, J=l.9 Hz, 1H), 7.84 (dd, J=5.5, 2.2 Hz, 1H), 7.23 (d, J=2.7 Hz, 1H), 7.13 (dd, J=8.6, 2.7 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 4 .60-4.32 (m, 1H), 3.68 (s, 2H), 3.18-3.07 (m, 1H), 2.97-2.79 (m, 2H), 2.69 -2.62 (m, 1H), 1.90-1.79 (m, 1H), 1.78-1.63 (m, 1H). LC-MS (Method A): Rt 1.95 min; MS m/z 425.2/427.2 = [M+H]+ (99% @ 215 nm) 32.9 /^ ^{NH 0} H ΧχτχχΤ 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl] amino] -N-(1H-imidazol-2-yl)pyridin-2-carboxamide 1HNMR (500 MHz, DMSO-ab) δ 11.88 (s, 1H), 10.89-10.63 (m, 2H), 9.86 (s, 1H), 8.56 (d, J=5 .5 Hz, 1H), 8.38 (d, J=2.0 Hz, 1H), 7.85 (dd, J=5.5, 2.2 Hz, 1H), 7.23 (d, J =2.7 Hz, 1H), 7.13 (dd, J=8.6, 2.7 Hz, 1H), 6.91 (m, ZN), 3.69 (s, 2H). LC-MS (Method A): Rt 1.65 min; MS m/z 372.2/374.2 = [M+H]+ (97% @ 215 nm)

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Example 33.

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-[(1R,2R)-2-hydroxycyclopentyl]pyridine-2carboxamide

To a solution of 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (example 31, step 1) (100 mg, 0.33 mmol), (1R,2R)- 2-Aminocyclopentanol hydrochloride (45 mg, 0.33 mmol) and DIPEA (228 µl, 1.3 mmol) in DMF (2 ml) was added to HATU (149 mg, 0.39 mmol) and the mixture was stirred at room temperature in for 1 hour. The resulting mixture was partitioned between EtOAc (10 ml) and water (15 ml), then washed with sat. aq. NaHCO ₃ (10 ml). The combined aqueous washes were extracted with EtOAc (2x10 ml). The combined organic extracts were dried over Na ₂ SO ₄ and concentrated in vacuo. Purification of the crude residue by chromatography on silica gel using a Biotage Isolera 11 g KP-NH system, eluting with 0-15% MeOH in EtOAc, gave the title compound as a white solid with a metallic tint.

1H NMR (500 MHz, DMSO) δ 10.75 (s, 1H), 9.83 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.43 (d, J =7.6 Hz, 1H), 8.19 (d, J=2.1 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.21 (d , J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H), 4.80 (s, 1H), 4.03-3.94 (m, 2H), 3.66 (s, 2H), 2.03-1.96 (m, 1H), 1.89-1.81 (m , 1H), 1.711.58 (m, 2H), 1.54-1.42 (m, 2H).

LC-MS (Method A): Rt 2.50 min; MS m/z 390.3/392.3 = [M+H]+ (99% @ 215 nm).

Example 34.

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-(1-cyano-1-methylethyl)pyridine-2-carboxamide

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 31, Step 1) (4.0 g, 13.04 mmol) and 2-amino-2- Methyl propanenitrile hydrochloride (3.15 g, 26.08 mmol) was suspended in DMF (40 ml) and treated with DIPEA (9.11 ml, 52.17 mmol) and stirred to form a solution. HATU (5.95 g, 15.65 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was diluted with water (60 ml) and 4:1 EtOAc/heptane (100 ml). The biphasic suspension was filtered using a minimum amount of EtOAc and the organic portion was separated, washed with water, dried over Na ₂ SO ₄ and concentrated in vacuo. Purification of the residue by chromatography on silica gel, eluting with 0-100% EtOAc in heptane followed by 0-100% MeOH in EtOAc, gave a yellow glassy solid. TBME (10 ml) was added to the solid, and the mixture was heated to boiling (90°C) and gradually further TBME (90 ml) was added. MeCN was added in 0.5 ml aliquots until complete dissolution (9 ml). The mixture was cooled to 60°C, then to 0°C over 3 hours. The resulting mixture was allowed to stand at room temperature for 4 days and then filtered and dried in a vacuum oven to obtain the title compound as a white crystalline solid.

1H NMR (500 MHz, DMSO^) δ 10.88 (s, 1H), 9.87 (s, 1H), 8.82 (s, 1H), 8.50 (d, J=5.5 Hz, 1H), 8.21 (d, J=1.9 Hz, 1H), 7.86 (dd, J=5.5, 2.2 Hz, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H), 3.67 (s, 2H), 1.72 (s, 6H).

LC-MS (Method A): Rt 2.81 min; MS m/z 373.2/375.2 = [M+H]+ (98% @ 215 nm).

Example 35.

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-A3-(hydroxymethyl)tetrahydrofuran-3yl]pyridine-2-carboxamide

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (example 31, step 1) (150 mg, 0.49 mmol) and DIPEA (256.27 µl, 1 .47 mmol) was suspended in DMF (2 ml) and treated with (3-aminotetrahydrofuran-3-yl)methanol (69 mg, 0.59 mmol) and HATU (223 mg, 0.59 mmol). The reaction mixture was stirred at room temperature for 30 min and then partitioned between EtOAc (15 ml) and water (15 ml). The organic portion was washed with sat. aq. NaHCO3 (10 ml). The combined aqueous washes were extracted with EtOAc (2x10 ml), and the combined organic extracts

- 122 046966 dried over Na2SO4 and concentrated in vacuo. Purification by chromatography on silica gel using a Biotage Isolera system 11 g KP-NH eluting with 0-15% DCM/MeOH gave the title compound as a white solid with a metallic tint.

¹ H NMR (500 MHz, DMSOA) δ=10.73 (s, 1H), 9.82 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.41 (s , 1H), 8.19 (d, J=2.0 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.21 (d, J=2, 7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 5.17 (s, 1H) , 3.88-3.77 (m, 4H), 3.67 (s, 2H), 3.62-3.59 (m, 2H), 2.34-2.28 (m, 1H), 2 .00-1.94 (m, 1H).

LC-MS (Method A): Rt 2.36 min; MS m/z 406.3/408.3 = [M+H]+ (97% @ 215 nm).

Example 35a and 35b.

Enantiomers of 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-3-(hydroxymethyl)tetrahydrofuran3-ylpyridin-2-carboxamide

Chiral resolution of racemic 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N3(hydroxymethyl)tetrahydrofuran-3-ylpyridin-2-carboxamide (Example 35) using supercritical liquid chromatography [chiral column phase (5 µl at 1 mg/ml MeOH + 95/5% CO ₂ /(1POH) + 0.5% IPAm with a Chiralpak IG column (300 mm x 4.6) 20 µm at 2.4 ml/min)] gave the individual enantiomers:

Example 35a.

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-[(3R)-3-(hydroxymethyl)tetrahydrofuran-3yl]pyridin-2-carboxamide or 4-[[2-(5 -chloro-2-hydroxyphenyl)acetyl]amino]-N-[(3S)-3(hydroxymethyl)tetrahydrofuran-3 -yl]pyridin-2-carboxamide

< ^R ) ^-isomer (S)-isorner

First eluted peak: UHPLC retention time = 6.10 min ¹ H NMR (500 MHz, DMS(')-s1 ₆ ) δ 10.71 (s, 1H), 9.76 (s, 1H), 8.46 ( d, J=5.5 Hz, 1H), 8.41 (s, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.82 (dd, J=5.5, 2 .2 Hz, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J =8.6 Hz, 1H), 5.16 (t, J=5.3 Hz, 1H), 3.883.77 (m, 4H), 3.67 (s, 2H), 3.61 (m, 2H ), 2.34-2.29 (m, 1H), 2.00-1.94 (m, 1H).

LC-MS (Method A): Rt 2.23 min; MS m/z 406.2/408.2 = [M+H]+ (97% @ 215 nm).

Example 35b.

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-[(3R)-3-(hydroxymethyl)tetrahydrofuran-3yl]pyridin-2-carboxamide or 4-[[2-(5 -chloro-2-hydroxyphenyl)acetyl]amino]-N-[(3S)-3(hydroxymethyl)tetrahydrofuran-3 -yl]pyridin-2-carboxamide

< ^R ) ^-isonler (S)-isomer

Second eluting peak: UHPLC retention time = 7.70 min 1H NMR (500 MHz, DMSO-06) δ 10.72 (s, 1H), 9.77 (s, 1H), 8.46 (d, J=5 .5 Hz, 1H), 8.41 (s, 1H), 8.19 (d, J=2.1 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H ), 7.21 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz , 1H), 5.17 (s, 1H), 3.89-3.76 (m, 4H), 3.67 (s, 2H), 3.61 (d, J=3.0 Hz, 2H) , 2.35-2.28 (m, 1H), 2.01-1.93 (m, 1H).

LC-MS (Method A): Rt 2.23 min; MS m/z 406.2/408.2 = [M+H]+ (97% @ 215 nm)

The compounds of the following tabular examples (Table 11) were prepared analogously to example 35 from both 4[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (example 31, step 1) and from 3-[[2-(5-fluoro-2-hydroxyphenyl)acetyl]amino]benzoic acid (Example 41, Step 3) and the corresponding commercially available amine.

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Table 11

Example Structure and name 1NMR LC-MS retention time, [M+H]+, 35.1 n _; With. And 1 o ^no L 1 d ⁿ Arpx 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl] amino]-N-(4hydroxy-4-methylcyclohexyl)pyridine-2-carboxamide in the form of a mixture of stereoisomers 6:4 1H NMR (500 MHz, DMSO-bb) 5=8.46 (dd, J=5.6, 2.1 Hz, 1H), 8.43-8.23 (m, 1H), 8.18 (t , J=2.5 Hz, 1H), 7.83-7.80 (m, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.12 (dd, J= 8, 6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 4.35-4.00 (m, 1H), 3.84-3.67 (m, 1H ), 3.66 (s, 2H), 1.77-1.67 (m, 2H), 1.61-1.50 (m, 4H), 1.49-1.34 (m, 2H), 1.17-1.10 (m, ZN). LC-MS (Method A): Rt 2.52 min; MS m/z 418.3/420.3 = [M+H]+ (96% @ 215 nm) 35.2 BUT ^but 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-[( 1 s,2r)-2-(hydroxymethyl)cyclohexyl]pyridine-2-carboxamide 1HNMR (500 MHz, DMSO-ab) 5=10.78 (s, 1H), 9.31 (s, 1H), 8.67 (d, J=8.3 Hz, 1H), 8.47 (d , J=5.6 Hz, 1H), 8.20 (d, J=2.l Hz, 1H), 7.81 (dd, >5.5Hz, 2.2, 1H), 7.21 (d , >2.6Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H), 4.63 (t , J=4.3 Hz, 1H), 4.194.13 (m, 1H), 3.66 (s, 2H), 3.51-3.45 (m, 2H), 1.84 (s, 1H) , 1.761.69 (m, 1H), 1.61-1.53 (m, ZN), 1.51-1.44 (m, 2H), 1.36-1.28 (m, 2H). LC-MS (Method A): Rt 3.03 min; MS m/z 418.3/420.3 = [M+H]+ (99% @ 215 nm) 35.3 BUT Λί J n \ xL A / h / C PSG XXX but 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-[(1 s,3 r)-3 hydroxycyclopentyl]pyridine-2-carboxamide 1HNMR (500 MHz, DMSO-bb) 5=10.70 (s, 1H), 9.80 (s, 1H), 8.68 (d, J=8.8 Hz, 1H), 8.46 (d , J=5.5 Hz, 1H), 8.20 (d, J= 2.1 Hz, 1H), 7.81 (dd, J= 5.5, 2.2 Hz, 1H), 7.22 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6 Hz, 2.7, 1H), 6.80 (d, J=8.6 Hz, 1H), 4 .81 (d, J=2.6 Hz, 1H), 4.404.33 (m, 1H), 4.23-4.17 (m, 1H), 3.67 (s, 2H), 2.01- 1.93 (m, 2H), 1.75-1.65 (m, ZN), 1.61-1.55 (m, 1H). LC-MS (Method A): Rt 2.36 min; MS m/z 390.3/392.3 = [M+H]+ (98% @ 215 nm) 35.4 But 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-[2hydroxy-1-(hydroxymethyl)-1-methylethyl]pyridine-2carboxamide 1H NMR (500 MHz, DMSO-bb) 5=8.43 (d, J=5.6, 1H), 8.36 (s, 1H), 8.17 (d, J=2.l Hz, 1H ), 7.78 (dd, J=5.4, 2.1 Hz, 1H), 7.17 (s, 1H), 7.08 (d, J=8.2 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 4.96 (t, J=5.6 Hz, 2H), 3.64 (s, 2H), 3.59-3.62 (m, 2H) , 3.48-3.51 (m, 2H), 1.29 (s, ZN), LC-MS (Method A): Rt 2.21 min; MS m/z 394.3/337.3 = [M+H]+ (95% @ 215 nm) 35.6 II ⁰ AV/oy 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl] amino]-N-(3 hydroxycyclohexyl)pyridine-2-carboxamide as a mixture of stereoisomers 1H NMR (500 MHz, DMSO-bb) 5 8.52 (d, J=5.5 Hz, 1H), 8.37 (d, J=8.8 Hz, 1H), 8.24 (d, J =2.1 Hz, 1H), 7.88 (dd, J=5.5, 2.2 Hz, 1H), 7.27 (d, J=2.6 Hz, 1H), 7.18 (dd , J=8.6, 2.7 Hz, 1H), 6.86 (d, J=8.6 Hz, 1H), 4.54 (d, J=3.2 Hz, 1H), 4.31 -4.21 (m, 1H), 3.99 (s, 1H), 3.72 (s, 2H), 1.82-1.74 (m, ZN), 1.75-1.64 (m , 1H), 1.62-1.55 (m, 1H), 1.55-1.49 (m, 1H), 1.49-1.39 (m, 2H). LC-MS (Method A): Rt 2.56 min; MS m/z 404.2/406.2 = [M+H]+ (100% @215 nm)

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35.7 πθ 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-(3 phenoxypropyl)pyridine-2-carboxamide 1HNMR (500 MHz, DMSO-ab) δ 10.40 (s, 1H), 9.82 (s, 1H), 8.87 (t, J=6.0 Hz, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.l Hz, 1H), 7.82 (dd, 1H), 7.30-7.25 (m, 2H), 7, 21 (d, J=2.6 Hz, 1H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.96-6.89 (m, ZN), 6.79 (d, J=8.6 Hz, 1H), 4.02 (t, J=6.2 Hz, 2H), 3.66 (s, 2H), 3.46 (k, J=6.7 Hz , 2H), 2.02-1.94 (m, 2H). LC-MS (Method A): Rt 3.45 min; MS m/z 440.3/442.3 = [M+H]+ (98% @ 215 nm) 35.8 ^l =Ugga° 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-(1 methylcyclopropyl)pyridine-2-carboxamide 1HNMR (500 MHz, DMSODb) δ 10.66 (s, 1H), 9.80 (s, 1H), 8.76 (s, 1H), 8.43 (d, J=5.5 Hz, 1H) , 8.16 (d, J=l.9 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.67 (s, 2H), 1, 36 (s, ZN), 0.80-0.75 (m, 2H), 0.64-0.57 (m, 2H). LC-MS (Method A): Rt2.85 min; MS m/z 360.1/362.1 = [M+H]+ 35.9 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-[1-methyl1-(2-pyridyl)ethyl]pyridine-2-carboxamide 1HNMR (500 MHz, DMSODb) δ 10.68 (s, 1H), 9.81 (s, 1H), 9.63 (s, 1H), 8.60 (m, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.18 (d, 3=2.0Hz, 1H), 7.90-7.80 (m, 2H), 7.60 (d, J=8.l Hz , 1H), 7.39-7.27 (m, 1H), 7.22 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.67 (s, 2H), 1.76 (s, 6H). LC-MS (Method A): Rt 2.34 min; MS m/z 425.3/427.2 = [M+H]+ (98% @ 215 nm) 35.10 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-(3phenylpropyl)pyridine-2-carboxamide 1HNMR (500 MHz, DMSOD6) δ 10.81 (s, 1H), 9.83 (s, 1H), 8.78 (t, J=6,l Hz, 1H), 8.47 (d, J= 5.5 Hz, 1H), 8.18 (d, J=2.0 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.31-7, 25 (m, 2H), 7.25-7.20 (m, ZN), 7.20-7.15 (m, 1H), 7.14-7.09 (m, 1H), 6.80 ( d, 1H), 3.66 (s, 2H), 2.61 (t, J=7.8 Hz, 2H), 1.85 (p, J=7.6 Hz, 2H). LC-MS (Method A): Rt 3.53 min; MS m/z 424.3/426.3 = [M+H]+ (98% @ 215 nm) 35.11 no 1 ⁰ C^Uggxr 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-[2hydroxy-1-(2-pyridyl)ethyl]pyridine-2-carboxamide 1HNMR (500 MHz, DMSOD6) δ 10.72 (br.s, 1H), 9.80 (br.s, 1H), 9.08 (d, J=8.2 Hz, 1H), 8.60- 8.55 (m, 1H), 8.53 (d, J=5.6 Hz, 1H), 8.23 (d, J=2.0 Hz, 1H), 7.84 (dd, J=5 ,5, 2.2 Hz, 1H), 7.76 (td, J=7.7, 1.8 Hz, 1H), 7.41-7.38 (m, 1H), 7.31-7, 28 (m, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J =8.6 Hz, 1H), 5.10 (dt, J=8.2, 5.5 Hz, 1H), 5.03 (t, J=5.6 Hz, 1H), 3.87-3 .80 (m, 1H), 3.76-3.70 (m, 1H), 3.67 (s, 2H). LC-MS (Method A): Rt 2.09 min; MS m/z 427.2/429.2 = [M+H]+ (98% @ 215 nm) 35.12 ABOUT 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-[(5 - methoxy-2-pyridyl)methyl]pyridine-2-carboxamide 1HNMR (500 MHz, DMSOD6) δ 10.74 (br.s, 1H), 9.82 (br.s, 1H), 9.23 (t, J=6.0 Hz, 1H), 8.50 ( d, J=5.5 Hz, 1H), 8.23 (dd, J=9.5, 2.5 Hz, 2H), 7.84 (dd, J=5.5, 2.2 Hz, 1H ), 7.36 (dd, J=8.6, 3.0 Hz, 1H), 7.28 (d, J=8.6 Hz, 1H), 7.21 (d, J=2.7 Hz , 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H), 4.54 (d, J=6, 0 Hz, 2H), 3.81 (s, ZN), 3.67 (s, 2H). LC-MS (Method A): Rt 2.39 min; MS m/z 427.2/429.2 = [M+H]+

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(100% @215 nm) 35.13 o H ₃ C CH ₃ 0 _n pi Ethyl 3-[[4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carbonyl]amino]3-methylbutanoate 1HNMR (500 MHz, DMSO-bb) δ 10.74 (s, 1H), 9.80 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.35 (s, 1H), 8.18 (d, J=2.l Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, >2.7 Hz , 1H), 7.12 (dd, >8.6, 2.7 Hz, 1H), 6.80 (d, >8.6 Hz, 1H), 4.03 (k, >7.1 Hz, 2H), 3.67 (s, 2H), 2.81 (s, 2H), 1.47 (s, 6H), 1.11 (t, >7.1 Hz, ZH). LC-MS (Method A): Rt 3.39 min; MS m/z 434.3/436.3 = [M+H]+ (92% @ 215 nm) 35.14 ^NS > ^NP n 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl] amino]-N-(3 hydroxy-1,1-dimethylpropyl)pyridine-2-carboxamide 1HNMR (500 MHz, DMSO-bb) δ 10.71 (s, 1H), 9.82 (s, 1H), 8.53 (s, 1H), 8.42 (d, >5.5 Hz, 1H ), 8.16 (d, >2.0 Hz, 1H), 7.80 (dd, >5.5, 2.2 Hz, 1H), 7.22 (d, >2.7 Hz, 1H) , 7.12 (dd, >8.6, 2.7 Hz, 1H), 6.80 (d, >8.6 Hz, 1H), 4.63 (t, >4.7 Hz, 1H), 3.67 (s, 2H), 3.56 (k, >6.4 Hz, 2H), 1.86 (t, >6.5 Hz, 2H), 1.41 (s, 6H). LCMS (Method A): Rt 2.56 min; MS m/z 392.2/394.2 = [M+H]+ (100% @215 nm) 35.15 ABOUT X-Benzyl-4-[[2-(5-chloro-2- hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide 1HNMR (500 MHz, DMSO-bb) δ 10.70 (s, 1H), 9.81 (s, 1H), 9.25 (t, >6.4 Hz, 1H), 8.48 (d, > 5.5 Hz, 1H), 8.20 (d, >2.1 Hz, 1H), 7.83 (dd, >5.5, 2.2 Hz, 1H), 7.32 (s, 2H) , 7.31 (d, >1.2 Hz, 2H), 7.26-7.21 (m, 1H), 7.20 (d, >2.6 Hz, 1H), 7.11 (dd, >8.6, 2.6 Hz, 1H), 6.78 (d, >8.6 Hz, 1H), 4.48 (d, >6.4 Hz, 2H), 3.66 (s, 2H ). LC-MS (Method A): Rt 3.23 min; MS m/z 396.4/398.4 = [M+H]+ (100% @215 nm) 35.16 O y g Υ ΪΎΎ > O BUT 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl] amino]-M-phenylpyridine-2-carboxamide 1HNMR (500 MHz, DMSO-bb) δ 10.78 (s, 1H), 10.56 (s, 1H), 9.83 (s, 1H), 8.58 (d, >5.5 Hz, 1H ), 8.33 (d, >2.0 Hz, 1H), 7.92-7.86 (m, ZN), 7.39-7.33 (m, 2H), 7.23 (d, > 2.7 Hz, 1H), 7.16-7.08 (m, 2H), 6.81 (d, >8.6 Hz, 1H), 3.69 (s, 2H). LC-MS (Method A): Rt 3.41 min; MS m/z 382.3/384.3 = [M+H]+ (100% @215 nm) 35.17 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-T4-[(18.28)- 2-hydroxycyclopentyl]pyridine-2-carboxamide 1HNMR (500 MHz, DMSO-bb) δ 10.70 (s, 1H), 9.82 (s, 1H), 8.47 (d, >5.5 Hz, 1H), 8.43 (d, > 7.6 Hz, 1H), 8.19 (d, >1.9 Hz, 1H), 7.82 (dd, >5.5, 2.2 Hz, 1H), 7.22 (d, >2 .7 Hz, 1H), 7.12 (dd, >8.6, 2.7 Hz, 1H), 6.80 (d, >8.6 Hz, 1H), 4.80 (d, >4, 4 Hz, 1H), 4.023.94 (m, 2H), 3.67 (s, 2H), 2.03-1.95 (m, 1H), 1.90-1.81 (m, 1H), 1.71-1.59 (m, 2H), 1.54-1.42 (m, 2H). LC-MS (Method A): Rt 2.50 min; MS m/z 390.2/392.2 = [M+H]+ (99% @ 215 nm) 35.18 UUhttu 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-[(1R,2S)- 2-hydroxycyclopentyl]pyridine-2-carboxamide 1HNMR (500 MHz, DMSO-bb) δ 10.75 (s, 1H), 9.81 (s, 1H), 8.46 (d, 1H), 8.43 (d, >7.8 Hz, 1H ), 8.22 (d, >1.9 Hz, 1H), 7.81 (dd, >5.5, 2.2 Hz, 1H), 7.21 (d, >2.7 Hz, 1H) , 7.12 (dd, >8.6, 2.7 Hz, 1H), 6.79 (d, >8.6 Hz, 1H), 5.09 (s, 1H), 4.05-3, 98 (m, 2H), 3.66 (s, 2H), 1.99-1.88 (m, 1H), 1.88-1.79 (m, 1H), 1.79-1.71 ( m, 1H), 1.64-1.57 (m, 1H), 1.56-1.46 (m, 2H). LC-MS (Method A): Rt 2.58 min; MS m/z 390.3/392.3 = [M+H]+ (100% @215 nm)

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35.19 O 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-M-[(1 S,2R)- 2-hydroxycyclopentyl]pyridine-2-carboxamide 1HNMR (500 MHz, DMSO-bb) δ 10.73 (s, 1H), 9.83 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.44 (d, J=7.8 Hz, 1H), 8.22 (d, J=2.0 Hz, 1H), 7.81 (dd, J=5.5,2.2 Hz, 1H), 7.22 ( d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 5, 09 (s, 1H), 4.06-3.97 (m, 2H), 3.67 (s, 2H), 2.01-1.90 (m, 1H), 1.89-1.79 ( m, 1H), 1.80-1.71 (m, 1H), 1.65-1.58 (m, 1H), 1.57-1.46 (m, 2H). LC-MS (Method A): Rt 2.63 min; MS m/z 390.3/392.3 = [M+H]+ (99% @ 215 nm) 35.20 O ίί ⁿ \ .IXL .F ^Ν Ίτ ιΓ Π Τι ίΓ ^{НзС Η} ksJ ο 3 -[[2-(5-Fluoro-2-hydroxyphenyl)acetyl]amino]-Ν-(1 methylcyclohexyl)benzamide 1HNMR (500 MHz, DMSO-bb) δ 10.17 (s, 1H), 9.49 (s, 1H), 7.90 (t, J=l.7 Hz, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.43-7.40 (m, 2H), 7.34 (t, J=7.9 Hz, 1H), 7.00 (dd, J=9.4 , 3.2 Hz, 1H), 6.89 (td, J=8.6, 3.2 Hz, 1H), 6.77 (dd, J=8.8, 4.9 Hz, 1H), 3 .61 (s, 2H), 2.21 (d, J=13.3 Hz, 2H), 1.54-1.41 (m, 5H), 1.38-1.29 (m, 2H), 1.32 (s, ZN), 1.281.22 (m, 1H). LC-MS (Method A): Rt 3.36 min; MS m/z 385.3 = [M+H]+ (98% @215 nm) 35.21 HC^ CH ₃ O ^>ϊΑ ·σνχχ Ν-(1,1 - Dimethylprop-2-ynyl)-3 -[[2-(5-fluoro-2hydroxyphenyl)acetyl]amino]benzamide 1HNMR (500 MHz, DMSO-bb) δ 10.19 (s, 1H), 9.48 (s, 1H), 8.20 (s, 1H), 7.94 (t, J=l.8 Hz, 1H), 7.79-7.75 (m, 1H), 7.44 (dt, J=7.8, 1.29 Hz, 1H), 7.35 (t, J=7.9 Hz, 1H ), 7.00 (dd, J=9.4, 3.2 Hz, 1H), 6.89 (td, J=8.6, 3.2 Hz, 1H), 6.77 (dd, J= 8.8, 4.9 Hz, 1H), 3.62 (s, 2H), 3.08 (s, 1H), 1.59 (s, 6H). LC-MS (Method A): Rt 2.67 min; MS m/z 355.3 = [M+H]+ (97% @ 215 nm) 35.22 II ^{0 and} '= ^l a ^: g ^r X-Cyclohexyl-3-[[2-(5-fluoro-2hydroxyphenyl)acetyl]amino]benzamide 1HNMR (500 MHz, DMSO-ab) δ 10.18 (s, 1H), 9.46 (s, 1H), 8.15 (d, J=7.9 Hz, 1H), 7.96 (t, J=l.8 Hz, 1H), 7.79-7.75 (m, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.35 (t, J=7.9 Hz, 1H), 7.00 (dd, J=9.4, 3.2 Hz, 1H), 6.89 (td, J=8.6, 3.2 Hz, 1H), 6.79-6 .75 (m, 1H), 3.78-3.68 (m, 1H), 3.61 (s, 2H), 1.85-1.68 (m, 4H), 1.60 (d, J =12.6 Hz, 1H), 1.31 (k, J=10.7, 8.8 Hz, 4H), 1.18-1.06 (m, 1H). LC-MS (Method A): Rt 3.03 min; MS m/z 371.3 = [M+H]+ (98% @ 215 nm) 35.23 3-[[2-(5-Fluoro-2-hydroxyphenyl)acetyl]amino]-X-[3(hydroxymethyl)tetrahydrofuran-3-yl]benzamide 1HNMR (500 MHz, DMSO-bb) δ 10.18 (s, 1H), 9.48 (s, 1H), 8.12 (s, 1H), 7.95 (t, J=l.8 Hz, 1H), 7.81-7.75 (m, 1H), 7.50 (d, J=7.9 Hz, 1H), 7.36 (t, J=7.9 Hz, 1H), 7, 00 (dd, J=9.4, 3.2 Hz, 1H), 6.89 (td, J=8.6, 3.2 Hz, 1H), 6.77 (dd, J=8.8, 4.9 Hz, 1H), 4.97 (s, 1H), 3.89 (d, J=9.2 Hz, 1H), 3.81-3.73 (m, ZN), 3.69- 3.61 (m, 4H), 2.22 (dt, J=12.8, 6.4 Hz, 1H), 2.05 (dt, J=12.9, 7.7 Hz, 1H). LC-MS (Method A): Rt 1.98 min; MS m/z 389.2 = [M+H]+ (98% @215 nm) 35.24 And ⁴ ] ⁰ H 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl] amino]-N-(1 ethynylcyclohexyl)pyridine-2-carboxamide 1HNMR (500 MHz, DMSO-bb) δ 10.72 (s, 1H), 9.82 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.24 (s, 1H), 8.19 (d, J=l.9 Hz, 1H), 7.84 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J=2.7 Hz, 1H), 7.13 (dd, J=8.6, 2.7 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 3.68 (s, 2H), 3.27 (s, 1H), 2.15-2.08 (m, 2H), 1.95-1.86 (m, 2H), 1.62-1.50 (m, 5H), 1. 34-1.23 (m, 1H). LC-MS (Method A): Rt 3.62 min; MS m/z 412.1/414.1 = [M+H]+ (98% @ 215 nm)

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35.25 ^\g-ou 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-[1 - (hydroxymethyl)cyclobutyl]pyridine-2-carboxamide 1HNMR (500 MHz, DMSO-bb) δ 10.68 (s, 1H), 9.82 (br. s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.40 ( s, 1H), 8.21-8.14 (m, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J=2.7 Hz , 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 5.00 (t, J=5, 3 Hz, 1H), 3.67 (s, 2H), 3.61 (d, J=4.7 Hz, 2H), 2.07-2.01 (m, 2H), 1.89-1, 78 (m, 1H), 1.781.66 (m, 1H). LC-MS (Method A): Rt 2.53 min; MS m/z 390.2/392.2 = [M+H]+ (98% @ 215 nm) 35.26 "^u^uu 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-[3 - (hydroxymethyl)oxetan-3-yl]pyridin-2-carboxamide 1HNMR (500 MHz, DMSO-bb) δ 10.69 (s, 1H), 9.82 (s, 1H), 9.00 (s, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.17 (d, J=2.0 Hz, 1H), 7.84 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, W), 6.80 (d, J=8.6 Hz, 1H), 5.18 (t, J=5 .9 Hz, 1H), 4.73 (d, J=6.5 Hz, 2H), 4.53 (d, J=6.6 Hz, 2H), 3.70 (d, J=5.9 Hz, 2H), 3.67 (s, 2H). LC-MS (Method A): Rt 2.11 min; MS m/z 392.2/394.2 = [M+H]+ (98% @ 215 nm) 35.27 CH ₃ O _n ^B1C iTyyy 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl] amino]-N-(1-cyano-2-methoxy-1-methylethyl)pyridine-2-carboxamide 1HNMR (500 MHz, DMSO-ab) δ 10.78 (s, 1H), 9.77 (s, 1H), 8.77 (s, 1H), 8.52 (d, J=5.5 Hz, 1H), 8.24 (d, J=2.0 Hz, 1H), 7.87 (dd, J=5.5, 2.2 Hz, 1H), 7.23 (d, J=2.7 Hz, 1H), 7.13 (dd, J=8.6, 2.7 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 3.86 (d, J=9 .5 Hz, 1H), 3.69 (s, 2H), 3.67 (d, J=9.5 Hz, 1H), 3.42 (s, ZN), 1.71 (s, ZN). LC-MS (Method A): Rt 3.02 min; MS m/z 403.2/405.2 = [M+H]+ (98% @ 215 nm) 35.28 ? n ιΎ ΥΎγ OH ^m O A but 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl] amino] -Ν-[( 1 hydroxycyclobutyl)methyl]pyridine-2-carboxamide 1HNMR (500 MHz, DMSO-ab) δ 10.68 (s, 1H), 9.81 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.42 (t, J=5.9 Hz, 1H), 8.23 (d, J=2.l Hz, 1H), 7.82 (dd, J=5.5,2.2 Hz, 1H), 7.22 ( d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 5, 38 (s, 1H), 3.67 (s, 2H), 3.43 (d, J=5.9 Hz, 2H), 2.00-1.86 (m, 4H), 1.70-1 .57 (m, 1H), 1.57-1.41 (m, 1H). LC-MS (Method A): Rt 2.59 min; MS m/z 390.1/392.1 = [M+H]+ (95% @ 215 nm)

Example 36.

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-^(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide

To a solution of 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 31, Step 1) (20 g, 63.25 mmol, 97%), 2-methylbut -3-yne-2-amine (7.99 ml, 75.9 mmol) and DIPEA (16.57 ml, 94.88 mmol) in DMF (315 ml) was added HATU (28.86 g, 75.9 mmol ), and the mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo and the residue was dissolved in EtOAc and washed successively with 1 M HCl, 1 M NaOH and saturated aqueous sodium chloride. The acid wash was extracted with EtOAc and the combined organic extracts were washed with 1 M NaOH and saturated aqueous sodium chloride, dried over Na ₂ SO ₄ and concentrated in vacuo to give a yellow foam. The foam was absorbed onto silica gel and purified by chromatography, eluting with 0-100% EtOAc in heptanes. The isolated material was suspended in MeCN (50 ml) and heated to reflux until all solids were completely dissolved. The resulting solution was left to cool to room temperature and kept for 8 hours to obtain crystals. The crystals were filtered, washed with ice-cold MeCN and dried in a vacuum oven overnight to give Portion 1 of the title compound. The filtrate was combined with the crude fractions from the chromatography and purified by chromatography on silica gel, eluting with 0-100% EtOAc in a mixture of heptanes. The isolated material was combined with batch 1 and recrystallized again at reflux in MeCN. The solution was allowed to cool at room temperature to give crystals, which were filtered, washed with ice-cold MeCN and dried in a vacuum oven to give the title compound as a crystalline solid.

¹ H NMR (500 MHz, DMSO-ds) δ 10.71 (br.s, 1H), 9.82 (br.s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.31 (s, 1H),

- 128 046966

8.19 (d, J=1.9 Hz, 1H), 7.84 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J=2.7 Hz, 1H ), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 3.68 (s, 2H), 3.20 (s, 1H), 1.64 (s, 6H).

LC-MS (Method A): Rt 3.07 min; MS m/z 372.1/374.1 = [M+H]+ (99% @ 215 nm).

Example 37.

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N(1-cyano-1,2-dimethylpropyl)pyridine-2carboxamide

Step 1: 4-[[2-(5-Chloro-2-methoxyphenyl)acetyl]amino]-X-(1-cyano-1,2-dimethylpropyl)pyridine-2carboxamide

I dn ₃

To a solution of 4-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 8.1, step 2) (100 mg, 0.31 mmol) in DMF (2 ml) was added DIPEA (0.06 ml, 0.33 mmol) and HATU (124 mg, 0.33 mmol), and the mixture was stirred for 15 minutes. The resulting mixture was treated with 2amino-2,3-dimethylbutanenitrile (37 mg, 0.33 mmol) and stirring was continued for 55 minutes. The mixture was diluted with water (10 ml) and extracted with EtOAc (3x10 ml). The combined organic extracts were washed with water (10 ml), and saturated aqueous sodium chloride (10 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give a crude oil. The crude oil was adsorbed onto silica gel and purified by chromatography on silica gel, eluting with 10-100% EtOAc in heptane, yielding an oil. The oil was triturated with ether to obtain the title compound as a white solid.

1H NMR (250 MHz, DMSO-06) δ 10.75 (s, 1H), 8.69 (s, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.21 (d , J=1.9 Hz, 1H), 7.86 (dd, J=5.5, 2.2 Hz, 1H), 7.37-7.25 (m, 2H), 7.07-6, 95 (m, 1H), 3.75 (s, 3H), 3.73 (s, 2H), 2.63-2.53 (m, 1H), 1.61 (s, 3H), 1.08 (d, J=6.8 Hz, 3H), 0.97 (d, J=6.8 Hz, 3H).

LC-MS (Method E): Rt 1.21 min; MS m/z 415.1/417.1 = [M+H]+ (95% @215 nm).

Step 2: 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-(1-cyano-1,2-dimethylpropyl)pyridine2-carboxamide.

Chilled (0°C) solution of 4-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]-X-(1-cyano-1,2dimethylpropyl)pyridine-2-carboxamide (step 1) (84 mg , 0.19 mmol) in DCM (2 ml) was treated with 1 M BBr ₃ in DCM (962 μl, 0.96 mmol) and stirred at room temperature for 15 min. The reaction mixture was quenched with methanol (1 ml), and the resulting mixture was evaporated in vacuum. The residue was redissolved in EtOAc and washed with saturated NaHCO ₃ and saturated aqueous sodium chloride. The organic layer was separated, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was dissolved in DMSO:MeOH (800 μl, 1:1), filtered and purified by preparative HPLC (acidic pH, standard elution method). The product fractions were combined, concentrated in vacuo, and the residue was redissolved in MeCN:H ₂ O (5 mL, 1:2) and freeze-dried to give the title compound as a white powder.

1H NMR (500 MHz, DMSOC,) δ 10.76 (s, 1H), 9.83 (s, 1H), 8.68 (s, 1H), 8.51 (d, J=5.6 Hz, 1H), 8.21 (d, J=2.0 Hz, 1H), 7.87 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 3.68 (s, 2H), 2.56 (hept, J=6.8 Hz, 1H), 1.61 (s, 3H), 1.08 (d, J=6.8 Hz, 3H), 0.97 (d, J=6 ,8 Hz, 3H).

LC-MS (Method A): Rt 3.25 min; MS m/z 401.2/403.2 = [M+H]+ (100% @ 215 nm).

Example 38.

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N(1-methylcyclopentyl)pyridine-2-carboxamide

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (example 31, step 1) (100 mg, 0.33 mmol) and DIPEA (0.23 ml, 1 .3 mmol) was suspended in DMF (2.1 ml) and treated with 1methylcyclopentanamine hydrochloride (66 mg, 0.49 mmol) followed by the addition of HATU (149

- 129 046966 mg, 0.39 mmol), and this mixture was stirred at room temperature for 24 hours. The resulting mixture was diluted with EtOAc (10 ml) and washed with sat. aq. NaHCO ₃ (10 ml), water (10 ml) and saturated aqueous sodium chloride (10 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was dissolved in MeOH (800 µl), filtered and purified by preparative HPLC (acidic pH, early elution method) to give the title compound as a white solid.

¹ H NMR (500 MHz, DMSO) δ 10.69 (s, 1H), 9.82 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.17 (d, J=2.1 Hz, 1H), 8.10 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.67 (s, 2H), 2.14-2.05 (m, 2H), 1.70-1.60 (m, 6H), 1.43 (s, 3H).

LC-MS (Method A): Rt 3.54 min; MS m/z 388.2/390.2 = [M+H]+ (100% @ 215 nm).

Example 39.

N(4-tert-Butylcyclohexyl)-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (1:1 cis/trans mixture)

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (example 31, step 1) (150 mg, 0.49 mmol) and DIPEA (0.26 ml, 1 .47 mmol) was suspended in DMF (1.95 ml) and treated with 4-tert-butylcyclohexanamine (1:1 cis/trans) (91 mg, 0.59 mmol) and HATU (223 mg, 0.59 mmol), and this mixture was stirred for 3 hours. The mixture was diluted with EtOAc (10 ml) and the organic phases were washed with saturated aqueous NaHCO ₃ (2x10 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was dissolved in DMSO:MeCN (800 µl, 1:1), filtered and purified by preparative HPLC (acidic pH, early elution method). The product fractions were combined, neutralized with saturated sodium hydrogen carbonate and extracted with EtOAc (3x20 ml). The combined organic extracts were concentrated in vacuo to give the title compound as a pale yellow solid.

1H NMR (500 MHz, DMSO-^) δ 10.95-10.61 (m, 2H), 9.93-9.68 (m, 2H), 8.49 (d, J=5.6 Hz, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.36 (d, J=8.7 Hz, 1H), 8.28 (d, J=7.6 Hz, 1H) , 8.21 (d, J=2.0 Hz, 1H), 8.19 (d, J=2.1 Hz, 1H), 7.83 (d, J=2.1 Hz, 1H), 7 .81 (d, J=2.2 Hz, 1H), 7.24-7.19 (m, 2H), 7.13 (d, J=2.6 Hz, 1H), 7.12 (d, J=2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 2H), 4.13-4.07 (m, 1H), 3.68-3.65 (m, 4H ), 1.93-1.83 (m, 4H), 1.81-1.73 (m, 2H), 1.69-1.60 (m, 2H), 1.60-1.51 (m , 2H), 1.42-1.33 (m, 2H), 1.24 (s, 1H), 1.17-1.03 (m, 5H), 1.03-0.97 (m, 1H ), 0.89-0.83 (m, 18H). Contains a 1:1 mixture of cis and trans products.

LC-MS (Method A): Rt 4.34 min; MS m/z 444.4/446.4 = [M+H]+ (42% @ 215 nm).

LC-MS (Method A): Rt 4.36 min; MS m/z 444.4/446.4 = [M+H]+ (52% @ 215 nm).

Example 40.

No. tert-Butyl-4-[[2-(2-chloro-3-fluorophenyl)acetyl]amino]pyridine-2-carboxamide

F

To a solution of 2-(2-chloro-3-fluorophenyl)acetic acid (146 mg, 0.78 mmol) in THF (3 mL) was added DIPEA (271 μL, 1.55 mmol), 4-amino-M-tert- butylpyridine-2-carboxamide (Example 3, Step 1) (100 mg, 0.52 mmol) and HATU (236 mg, 0.62 mmol), and the mixture was stirred at room temperature for 90 minutes. The resulting mixture was partitioned between EtOAc (20 ml) and water (20 ml), and the aqueous portion was extracted with EtOAc (2x20 ml). The combined organic extracts were washed with water (20 ml), and saturated aqueous sodium chloride (20 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with EtOAc in heptane to give the title compound as a white amorphous solid.

1H NMR (500 MHz, Chloroform-d) δ 8.40 (d, J=5.5 Hz, 1H), 8.18 (dd, J=5.5, 2.1 Hz, 1H), 8.11 (s, 1H), 8.01 (s, 1H), 7.75 (d, J=2.l Hz, 1H), 7.30-7.23 (m, 1H), 7.21-7, 10 (m, 2H), 3.94 (s, 2H), 1.47 (s, 9H).

LC-MS (Method A): Rt 3.49 min; MS m/z 364.2/366.2 = [M+H]+ (100%@215).

- 130 046966

Example 40.1.

No. tert-Butyl-4-[[2-(2-chloro-5-fluorophenyl)acetyl]amino]pyridine-2-carboxamide

The title compound was prepared from 4-aminoA-tert-butylpyridine-2-carboxamide (Example 3, Step 1) and 2-(2-chloro-5-fluorophenyl)acetic acid analogously to Example 40.

1H NMR (500 MHz, DMSOA) δ 10.90 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H), 8.03 (s, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.51 (dd, J=8.8, 5.3 Hz, 1H), 7 .36 (dd, J=9.4, 3.1 Hz, 1H), 7.20 (td, J=8.5, 3.1 Hz, 1H), 3.93 (s, 2H), 1, 40 (s, 9H).

LC-MS (Method A): Rt 3.51 min; MS m/z 364 = [M+H]+.

Example 41.

N(4-Cyanotetrahydropyran-4-yl)-3-[[2-(5-fluoro-2-hydroxyphenyl)acetyl]amino]benzamide

Step 1: Ethyl 3-[[2-(5-fluoro-2-methoxyphenyl)acetyl]amino]benzoate

A mixture of ethyl 3-amine benzoate (300 mg, 1.82 mmol) and 2-(5-fluoro-2-methoxyphenyl)acetic acid (334 mg, 1.82 mmol) in 1,4-dioxane (5 ml) was treated with 50 % T3P® solution in EtOAc (2.31 ml, 1.82 mmol) and TEA (634 µl, 3.63 mmol). After stirring at room temperature for 2 hours, the mixture was partitioned between water (20 ml) and EtOAc (20 ml). The organic layer was separated, dried over Na ₂ SO ₄ and concentrated in vacuo. Purification of the crude residue by chromatography on silica gel, eluting with EtOAc in heptane, afforded the title compound as a white solid.

¹ H NMR (500 MHz, DMSOA) δ 10.31 (s, 1H), 8.26 (t, J=1.8 Hz, 1H), 7.86-7.82 (m, 1H), 7, 63 (dt, J=7.79, 1.2 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 7.11 (dd, J=9.2, 3.1 Hz , 1H), 7.07 (td, J=8.6, 3.2 Hz, 1H), 6.98 (dd, J=9.0, 4.6 Hz, 1H), 4.31 (k, J=7.1 Hz, 2H), 3.75 (s, 3H), 3.66 (s, 2H), 1.31 (t, J=7.1 Hz, 3H).

LC-MS (Method E): Rt 1.20 min; MS m/z 332.1 = [M+H]+ (100% @ 215 nm).

Step 2: 3-[[2-(5-Fluoro-2-methoxyphenyl)acetyl]amino]benzoic acid

Ethyl 3-[[2-(5-fluoro-2-methoxyphenyl)acetyl]amino]benzoate (step 1) (470 mg, 1.42 mmol) in THF (3 ml) and MeOH (1 ml) was treated with 2 M aqueous solution of LiOH (2.84 ml, 5.67 mmol), and this reaction mixture was stirred at room temperature for 2 hours. Volatile solvents were removed in vacuo, and the aqueous portion was diluted with water (100 ml) and acidified with 2 M HCl solution to pH 2. The resulting precipitate was collected by filtration, washed with water (30 ml) and left under vacuum to give the title compound as a white solid.

1H NMR (500 MHz, DMSOA) δ 12.92 (s, 1H), 10.26 (s, 1H), 8.23 (t, J=1.7 Hz, 1H), 7.84-7.78 (m, 1H), 7.63-7.58 (m, 1H), 7.42 (t, J=7.9 Hz, 1H), 7.11 (dd, J=9.2, 3.1 Hz, 1H), 7.07 (td, J=8.6, 3.2 Hz, 1H), 6.98 (dd, J=9.0, 4.7 Hz, 1H), 3.75 (s , 3H), 3.66 (s, 2H).

LC-MS (Method E): Rt 1.02 min; MS m/z 304.0 = [M+H]+ (98% @ 215 nm).

Step 3: 3-[[2-(5-Fluoro-2-hydroxyphenyl)acetyl]amino]benzoic acid

To a solution of 3-[[2-(5-fluoro-2-methoxyphenyl)acetyl]amino]benzoic acid (step 2) (400 mg, 1.29

- 131046966 mmol) in DCM (5 ml), 1 M BBr3 in DCM (5.17 ml, 5.17 mmol) was added, the reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated in vacuo, and the crude residue was separated between water (60 ml) and EtOAc (60 ml). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo to give the title compound as a gray-violet solid.

1H NMR (500 MHz, DMSO-06) δ 12.91 (s, 1H), 10.25 (s, 1H), 9.47 (s, 1H), 8.24 (t, 1.7 Hz, 1H ), 7.87-7.79 (m, 1H), 7.62-7.59 (m, 1H), 7.42 (t, J=7.9 Hz, 1H), 7.00 (dd, J=9.4, 3.1 Hz, 1H), 6.89 (td, J=8.6, 3.2 Hz, 1H), 6.77 (dd, J=8.8, 4.9 Hz , 1H), 3.62 (s, 2H).

LC-MS (Method E): Rt 0.98 min; MS m/z 290.0= [M+H]+ (89% @ 215 nm).

Step 4: N(4-Cyanotetrahydropyran-4-yl)-3-[[2-(5-fluoro-2hydroxyphenyl)acetyl]amino]benzamide

The title compound was prepared from 3-[[2-(5-Fluoro-2hydroxyphenyl)acetyl]amino]benzoic acid (Step 3) and 4-aminotetrahydropyran-4-carbonitrile analogously to Example 1.1, Step 3.

1H NMR (500 MHz, DMSO-06) δ 10.27 (s, 1H), 9.58 (s, 1H), 8.83 (s, 1H), 8.05 (t, J=1.8 Hz , 1H), 7.867.79 (m, 1H), 7.52 (d, J=7.8, 1.3 Hz, 1H), 7.42 (t, J=7.9 Hz, 1H), 7 .00 (dd, J=9.4, 3.2 Hz, 1H), 6.89 (td, J=8.6, 3.2 Hz, 1H), 6.78 (dd, J=8.8 , 4.9 Hz, 1H), 3.87 (dt, J=12.2, 4.0 Hz, 2H), 3.63 (s, 2H), 3.62-3.56 (m, 2H) , 2.352.28 (m, 2H), 2.04-1.97 (m, 2H).

LC-MS (Method A): Rt 2.41 min; MS m/z 398.2 = [M+H]+ (97% @ 215 nm).

Example 42.

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-A4-(2-hydroxyethyl)tetrahydropyran-4yl]pyridin-2-carboxamide

He

Step 1: Methyl 2-[4-[[4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridin-2carbonyl]amino]tetrahydropyran-4-yl]acetate

o _x sn ₃

The title compound was prepared from methyl 2-(4-aminotetrahydropyran-4-yl)acetate and 4[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 31, step 1) similar to example 33.

1H NMR (500 MHz, DMSO-06) δ 8.47 (d, J=5.6 Hz, 1H), 8.19-8.17 (m, 2H), 7.81 (dd, J=5, 5, 2.2 Hz, 1H), 7.20 (d, J=2.6 Hz, 1H), 7.10 (dd, J=8.6, 2.7 Hz, 1H), 6.78 ( d, J=8.6 Hz, 1H), 3.71-3.66 (m, 2H), 3.66 (s, 2H), 3.53-3.45 (m, 5H), 2.91 (s, 2H), 2.33-2.27 (m, 2H), 1.79-1.72 (m, 2H).

LC-MS (Method E): Rt 1.06 min; MS m/z 462.1 = [M+H]+ (87% @ 215 nm).

Step 2: 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-A4-(2-hydroxyethyl)tetrahydropyran-4yl]pyridine-2-carboxamide

Chilled (-78°C) solution of methyl 2-[4-[[4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridin2-carbonyl]amino]tetrahydropyran-4-yl]acetate ( step 1) (50 mg, 0.11 mmol) in anhydrous THF (2 ml) was treated with 2.4 M lithium aluminum hydride in THF (90 μl, 0.22 mmol) and stirred at -78°C for 10 min. An additional portion of 2.4 M lithium aluminum hydride in THF (45 µl, 0.11 mmol) was added and stirring was continued at -78°C for 5 minutes. The resulting mixture was allowed to warm to room temperature and stirred for 16 hours. 2 M NaOH (3 ml) was added and the mixture was extracted with EtOAc (10 ml). The organic phase was washed with sodium potassium tartrate solution (2x10 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by preparative HPLC (acidic pH, standard elution method) yielded the title compound as a white solid with a metallic tint.

¹ H NMR (500 MHz, DMSO-06) δ 10.70 (s, 1H), 9.87 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.18 ( d, J=1.9 Hz, 1H), 8.15 (s, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1h), 7.22 (d, J=2 .7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 4.38 (s, 1H ), 3.68-3.62 (m, 4H), 3.51-3.45 (m, 4H), 2.31-2.24 (m, 2H), 1.99 (t, J=7 .0 Hz, 2H), 1.68-1.61 (m, 2H).

LC-MS (Method A): Rt 2.32 min; MS m/z 434.2/434.6 = [M+H]+ (100% @ 215 nm).

- 132 046966

Example 43.

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-A1,1-dimethyl-3-(2,2,2trifluoroethylamine)propyl]pyridine-2-carboxamide

Step 1: tert-Butyl-A3-[[4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2carbonyl]amino]-3-methylbutyl]carbamate

The title compound was prepared from tert-butyl-I-(3-amino-3-methylbutyl)carbamate and 4[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 31 , stage 1) similar to example 33.

1H NMR (500 MHz, DMSO-06) δ=1.33 (s, 9H), 1.37 (s, 6H), 1.85-1.93 (m, 2H), 2.91-2.98 (m, 2H), 3.66 (s, 2H), 6.73 (s, 1H), 6.79 (d, J=8.6, 1H), 7.11 (dd, J=8.6 , 2.7, 1H), 7.20 (d, J=2.7, 1H), 7.81 (dd, J=5.5, 2.2, 1H), 8.00 (s, 1H) , 8.17 (d, J=2.0, 1H), 8.44 (d, J=5.5, 1H), 10.84 (s, 1H).

LC-MS (Method E): Rt 1.18 min; MS m/z 491/493 = [M+H]+ (92% @ 215 nm).

Step 2: N-(3-Amino-1,1-dimethylpropyl)-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine2-carboxamide

tert-Butyl-N -[3-[[4-[[2-(5-chloro-2-hydroxyphenyl)acetyl] amino] pyridine-2-carbonyl] amino] -3 methyl-butyl] carbamate (step 1) ( 302 mg, 0.62 mmol) was dissolved in 20% TFA in DCM (2.0 ml), and the mixture was shaken at room temperature for 18 hours. The resulting mixture was gravity loaded onto a 2 g Isolute® SCX-2 cartridge , washing the column 1:1 DCM/MeOH (100 ml). The product was eluted with 1:1 DCM/1M NH ₃ in MeOH (100 mL) to give the title compound as a white crystalline solid.

1H NMR (500 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.59 (s, 1H), 8.42 (d, J=5.5 Hz, 1H), 8.15 (d , J=2.1 Hz, 1H), 7.79 (dd, J=5.5, 2.2 Hz, 1H), 7.18 (d, J=2.6 Hz, 1H), 7.09 (dd, J=8.6, 2.7 Hz, 1H), 6.76 (d, J=8.6 Hz, 1H), 3.65 (s, 2H), 2.65-2.63 ( m, 2H), 1.83-1.77 (m, 2H), 1.39 (s, 6H). LC-MS (Method E): Rt 0.86 min; MS m/z 391.1/393.1 = [M+H]+ (99% @ 215 nm).

Step 3: 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-A1,1-dimethyl-3-(2,2,2trifluoroethylamine)propyl]pyridine-2-carboxamide

A solution of N(3-amino-1,1-dimethylpropyl)-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2carboxamide (step 2) (39 mg, 0.1 mmol) in THF (1 ml) was treated with 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.015 ml, 0.10 mmol) and stirred at room temperature for 16 hours. An additional portion of 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.015 ml, 0.10 mmol) was added. and the mixture was stirred for an additional 2 hours. The reaction mixture was concentrated in vacuo and purification of the crude product by chromatography on silica gel eluting with 75% EtOAc in heptane (isocratic gradient) afforded the title compound as a white solid.

1H NMR (500 MHz, DMSO-06) δ 10.74 (s, 1H), 9.83 (s, 1H), 8.42 (d, J=5.5 Hz, 1H), 8.36 (s , 1H), 8.15 (d, J=2.l Hz, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.21 (d, J=2, 7 Hz, 1H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H), 3.66 (s, 2H) , 3.22-3.15 (m, 2H), 2.67-2.64 (m, 2H), 2.35-2.31 (m, 1H), 1.90-1.85 (m, 2H), 1.38 (s, 6H).

LC-MS (Method A): Rt 2.10 min; MS m/z 473.2/475.2 = [M+H]+ (100% @ 215 nm).

Example 44.

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-I-(4-fluoro-1-bicyclo[2.1.1]hexanyl)pyridine-2carboxamide

- 133 046966

To a solution of 4-fluorobicyclo[2.1.1]hexan-1-amine hydrochloride (21 mg, 0.14 mmol), DIPEA (0.09 ml, 0.52 mmol) and 4-[[2-(5-chloro- 2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (example 31, step 1) (40 mg, 0.13 mmol) in DMF (1 ml) was added HATU (55 mg, 0.14 mmol), and the reaction the mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with EtOAc (10 ml) and water (10 ml). The organic layer was separated, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was dissolved in DMS(.):MeC'\:11 ₂ O (1.4 ml, 3:3:1), filtered and purified by preparative HPLC (alkaline pH, early elution method) to obtain the title compound as white solid with a metallic tint.

1H NMR (500 MHz, Methanol-BD) δ 8.47 (dd, J=5.5, 0.5 Hz, 1H), 8.14 (dd, J=1.7, 0.5 Hz, 1H) , 7.91 (dd, J=5.5, 2.2 Hz, 1H), 7.20 (d, J=2.6 Hz, 1H), 7.11 (dd, J=8.6, 2 .6 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H), 3.73 (s, 2H), 2.22-2.11 (m, 4H), 2.09-2 .05 (dd, 2H), 1.96-1.89 (m, 2H).

LC-MS (Method A): Rt 3.21 min; MS m/z 404.3/406.3 = [M+H]+ (100% @ 215 nm).

Example 45.

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-[3-(2,2-dimethylpropanoylamine)-1,1dimethylpropyl]pyridine-2-carboxamide

prepared from N(3-amino-1,1-dimethylpropyl)-4-[[2-(5-chloro-2) Title compound hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Example 43, Step 2) and 2 ,2-dimethylpropanoic acid similar to example 33.

1H NMR (500 MHz, DMSO-b6) δ 10.68 (s, 1H), 9.80 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.19 (d , J=2.0 Hz, 1H), 8.02 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.40 (t, J=5, 5 Hz, 1H), 7.22 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J= 8.6 Hz, 1H), 3.67 (s, 2H), 3.12-3.02 (m, 2H), 1.95-1.87 (m, 2H), 1.39 (s, 6H ), 1.04 (s, 9H).

LC-MS (Method A): Rt 3.0 min; MS m/z 475.4/477.4 = [M+H]+ (100% @ 215 nm).

Example 46.

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-(1-cyano-2-hydroxy-1-methylethyl)pyridine-2carboxamide

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (example 31, step 1) (120 mg, 0.39 mmol) and DIPEA (273 µl, 1.57 mmol) was suspended in THF (2 ml) and treated with 2-amino-3-hydroxy-2-methyl-propanenitrile hydrochloride (64 mg, 0.47 mmol) followed by the addition of HATU (179 mg, 0.47 mmol). After stirring at room temperature for 18 hours, the resulting mixture was partitioned between DCM (10 ml) and water (10 ml). The organic portion was separated, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with 0-100% TBME in heptane and 0-100% TBME in MeOH. The resulting residue was dissolved in DMSO:MeOH (1200 μl, 1:1) and purified by preparative HPLC (acidic pH, early elution method), and the product fractions were concentrated in vacuo to remove volatile organic fractions. The resulting aqueous mixture was treated with sat. aq. NaHCO ₃ (3 ml) and DCM (5 ml) and shake until it becomes clear. The organic portion was separated by filtration through a hydrophobic PTFE frit and concentrated in vacuo to give the title compound as a white crystalline solid.

1H NMR (500 MHz, DMSO-f,) δ 10.80 (s, 1H), 9.80 (s, 1H), 8.72 (s, 1H), 8.50 (d, J=5.6 Hz, 1H), 8.23 (d, J=2.0 Hz, 1H), 7.87 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J=2 .7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 5.90 (t, J =5.8 Hz, 1H), 3.81 (dd, J=10.9, 5.4 Hz, 1H), 3.73 (dd, J=10.9, 5.2 Hz, 1H), 3 .68 (s, 2H), 1.66 (s, 3H).

LC-MS (Method A): Rt 2.47 min; MS m/z 389.3/391.2 = [M+H]+ (99% @ 215 nm) Chiral resolution of racemic 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino ]-K-(1-cyano-2-hydroxy-1 methylethyl)pyridine-2-carboxamide using supercritical liquid chromatography [chiral phase column: 25% ethanol: 75% CO ₂ with Chiralpak IC 25 cm column at 4 ml/ min] made it possible to obtain individual enantiomers:

Example 46a.

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-K-[(^)-1-cyano-2-hydroxy-1-methylethyl]pyridine-2carboxamide or 4-[[2-( 5-chloro-2-hydroxyphenyl)acetyl]amino]-K-[(^)-1-cyano-2-hydroxy-1methylethyl]pyridine-2-carboxamide

(S)-isomer (R)-isomer

First eluting peak: UHPLC retention time=8.89 min; MS m/z 389.0/391.0.

1H NMR (500 MHz, DMSO-06) δ 10.86 (s, 1H), 9.78 (s, 1H), 8.72 (s, 1H), 8.50 (d, J=5.5 Hz , 1H), 8.22 (d, J=2.0 Hz, 1H), 7.86 (dd, J=5.5, 2.2 Hz, 1H), 7.21 (d, J=2, 7 Hz, 1H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H), 5.90 (t, J= 5.l Hz, 1H), 3.81 (dd, J=11.0, 4.6 Hz, 1H), 3.73 (dd, J=11.3, 4.7 Hz, 1H), 3, 67 (s, 2H), 1.66 (s, 3H).

100% e.e.

Example 46b: 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-C-[(^)-1-cyano-2-hydroxy-1methylethyl]pyridine-2-carboxamide or 4-[[ 2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-K-[(^)-1-cyano2-hydroxy-1-methylethyl]pyridine-2-carboxamide

(S)-isomer (R)-isomer

Second eluting peak: UHPLC retention time=10.84 min; MS m/z 389.0/391.0.

1H NMR (500 MHz, DMSO-06) δ 10.98 (s, 1H), 9.82 (s, 1H), 8.72 (s, 1H), 8.50 (d, J=5.5 Hz , 1H), 8.22 (d, J=2.0 Hz, 1H), 7.86 (dd, J=5.5, 2.1 Hz, 1H), 7.20 (d, J=2, 5 Hz, 1H), 7.10 (dd, J=8.5, 2.7 Hz, 1H), 6.78 (d, J=8.7 Hz, 1H), 5.90 (s, 1H) , 3.82 (dd, J=10.7, 3.3 Hz, 1H), 3.73 (dd, J=10.4, 2.9 Hz, 1H), 3.67 (s, 2H), 1.66 (s, 3H).

88% e.u.

Example 47.

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-K-(3-cyanotetrahydrofuran-3-yl)pyridin-2carboxamide

To a mixture containing 3-aminetetrahydrofuran-3-carbonitrile hydrochloride (31 mg, 0.21 mmol) and 4[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 31, stage 1) (60 mg, 0.18 mmol, 90%) in DMF (2 ml), EDCI (74 mg, 0.39 mmol), HOAt (53 mg, 0.39 mmol) and DIPEA (123 μl, 0.7 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The resulting mixture was diluted with water (10 ml), then acidified with 10% aqueous citric acid to pH 4 and extracted with DCM (10 ml). The organic layer was separated using a PTFE fritted tube and concentrated in vacuo. The crude residue was purified by preparative HPLC (acidic pH early elution method) and product fractions were freeze-dried to give the title compound as a white solid.

¹ H NMR (500 MHz, DMSO-06) δ 10.75 (s, 1H), 9.85 (s, 1H), 9.51 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.22 (d, J=1.9 Hz, 1H), 7.88 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J=2 .7 Hz, 1H), 7.13 (dd, J=8.6, 2.7 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 4.27 (d, J =9.5 Hz, 1H), 4.04 (d, J=9.5 Hz, 1H), 3.97-3.91 (m, 1H), 3.90-3.84 (m, 1H) , 3.68 (s, 2H), 2.742.67 (m, 1H), 2.65-2.58 (m, 1H).

LC-MS (Method A): Rt 2.68 min; MS m/z 401.1/403.1 = [M+H]+ (98% @ 215 nm)

- 135 046966

The compounds of the following tabular examples (Table 12) were prepared analogously to Example 47, replacing 3-aminotetrahydrofuran-3-carbonitrile hydrochloride with the appropriate commercially available amine.

Table 12

Example Structure and name 1NMR LC-MS retention time, [M+H]+, 47.1 o _n O Methyl-2-[4-[[4-[[2-(5-chloro-2-hydroxyphenyl)acetyl] amino] pyridin-2-carbonyl] amino] tetrahydropyran-4-yl] acetate 1H NMR (500 MHz, DMSO-ab) δ 10.71 (s, 1H), 9.84 (s, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.19 (m , 2H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.23 (d, >2.6Hz, 1H), 7.13 (dd, J=8.6, 2.7 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 3.72-3.67 (m, 4H), 3.54-3.48 (m, 5H), 2.92 (s, 2H), 2.352.28 (m, 2H), 1.80-1.72 (m, 2H). LC-MS (Method A): Rt 2.80 min; MS m/z 462.2/464.1 = [M+H]+ (98% @ 215 nm) 47.2 ⁰ _n ΑΛαιχτ Methyl-4-[[4-[[2-(5-chloro-2-hydroxyphenyl)acetyl] amino] pyrid in-2-carbonyl] amino] tetrahydropyran-4-carboxylate 1H NMR (500 MHz, DMSO-ab) δ 10.69 (s, 1H), 9.81 (s, 1H), 8.77 (s, 1H), 8.52 (d, J=5.5 Hz , 1H), 8.16 (d, J=2.0 Hz, 1H), 7.84 (dd, J=5.5, 2.1 Hz, 1H), 7.22 (d, J=2, 7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, >8.6Hz, 1H), 3.71 (dt, J=11, 7, 4.1 Hz, 2H), 3.67 (s, 2H), 3.61 (s, ZN), 3.60-3.55 (m, 2H), 2.13-2.08 (m , 2H), 2.06-1.99 (m, 2H). LC-MS (Method A): Rt 2.72 min; MS m/z 448.2/450.2 = [M+H]+ (100% @ 215 nm) 47.3 -Asgpu 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-X-(3cyanooxetan-3-yl)pyridin-2-carboxamide 1H NMR (500 MHz, DMSO-ab) δ 10.77 (br.s, 1H), 10.07 (s, 1H), 9.84 (br.s, 1H), 8.54 (d, J= 5.6 Hz, 1H), 8.22 (d, J=l.9 Hz, 1H), 7.89 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 4.94 ( d, J=7.6 Hz, 2H), 4.84 (d, J=7.6 Hz, 2H), 3.68 (s, 2H). LC-MS (Method A): Rt 2.59 min; MS m/z 387.1/389.1 = [M+H]+ (98% @ 215 nm)

Example 48.

4-[[2-(5-Fluoro-2-hydroxyphenyl)acetyl]amino]A-(1-methylcyclobutyl)pyridine-2-carboxamide

Steps 1-3: 4-[[2-(5-Fluoro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid

The title compound was prepared from methyl 4-aminopyridine-2-carboxylate and 2-(5-fluoro2-methoxyphenyl)acetic acid analogously to Example 41, steps 1-3.

1H NMR (500 MHz, DMSO-06) δ 10.72 (s, 1H), 9.51 (s, 1H), 8.52 (d, J=5.5 Hz, 1H), 8.28 (d , J=1.7 Hz, 1H), 7.81 (dd, J=5.5, 1.7 Hz, 1H), 7.02 (dd, J=9.2, 3.0 Hz, 1H) , 6.91 (td, J=8.6, 3.1 Hz, 1H), 6.77 (dd, J=8.8, 4.9 Hz, 1H), 3.67 (s, 2H).

LC-MS (Method E): Rt 0.76 min; MS m/z 291.0 = [M+H]+ (84% @ 215 nm).

Step 4: 4-[[2-(5-Fluoro-2-hydroxyphenyl)acetyl]amino]-N-(1-methylcyclobutyl)pyridine-2carboxamide

The title compound was prepared from 4-[[2-(5-fluoro-2hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (Steps 1-3) and 1-methylcyclobutanamine hydrochloride analogously to Example 47.

1H NMR (500 MHz, DMSO-06) δ 10.67 (s, 1H), 9.50 (s, 1H), 8.48 (s, 1H), 8.45 (d, J=5.5 Hz , 1H), 8.16 (d, J=2.1 Hz, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.01 (dd, J=9, 4, 3.2 Hz, 1H), 6.91 (td, J=8.6, 3.2 Hz, 1H), 6.77 (dd, J=8.8, 4.9 Hz, 1H), 3.67 (s, 2H), 2.43-2.35 (m, 2H), 2.03-1.96 (m, 2H), 1.84-1.77 (m, 2H), 1. 47 (s, 3H).

LC-MS (Method A): Rt 3.00 min; MS m/z 358.2/359.2 = [M+H]+ (95% @ 215 nm).

Example 48.1.

No.(4-Cyanotetrahydropyran-4-yl)-4-[[2-(5-fluoro-2-hydroxyphenyl)acetyl]amino]pyridin-2-136 046966 carboxamide

The title compound was prepared from 4-[[2-(5-fluoro-2hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 48, steps 1-3) and 4-aminotetrahydropyran-4-carbonitrile analogously to Example 47.

1H NMR (500 MHz, DMSO-d6) δ 10.75 (s, 1H), 9.50 (s, 1H), 9.01 (s, 1H), 8.53 (d, J=5.8 Hz , 1H), 8.24 (d, J=1.8 Hz, 1H), 7.88 (dd, J=5.5, 2.2 Hz, 1H), 7.03 (dd, J=9, 4, 3.2 Hz, 1H), 6.92 (td, J=8.6, 3.2 Hz, 1H), 6.78 (dd, J=8.8, 4.9 Hz, 1H), 3.87 (dt, J=12.2, 3.8 Hz, 2H), 3.69 (s, 2H), 3.63-3.56 (m, 2H), 2.41-2.35 ( m, 2H), 2.12-2.04 (m, 2H).

LC-MS (Method A): Rt 2.45 min; MS m/z 399.2/400.2 = [M+H]+ (99% @ 215 nm).

Example 49.

No.[3-(tert-Butylamine)-1,1-dimethyl-3-oxo-propyl]-4-[[2-(5-chloro-2hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide

Step 1: 3-[[4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carbonyl]amino]-3methylbutanoic acid

A solution of ethyl 3-[[4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carbonyl]amino]-3methylbutanoate (Example 35.13) (688 mg, 1.57 mmol) in THF (7.5 mL) was treated with 2 M aqueous sodium hydroxide (1.57 mL, 3.14 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was partitioned between DCM (25 mL) and water ( 10 ml) and 2 M aqueous KHSO ₄ (10 ml) was added. The two-phase solution was stirred until the solution became clear. The organic layer was separated, dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound as a yellow viscous gel.

1H NMR (500 MHz, DMSO-d6) δ=12.21 (s, 1H), 10.67 (s, 1H), 9.80 (s, 1H), 8.44 (d, J=5.5 , 1H), 8.39 (s, 1H), 8.17 (d, J=2.0, 1H), 7.81 (dd, J=5.5, 2.2, 1H), 7.22 (d, J=2.7, 1H), 7.12 (dd, J=8.6, 2.7, 1H), 6.79 (t, J=8.6, 1H), 3.67 ( s, 2H), 2.73 (s, 2H), 1.48 (s, 6H).

LC-MS (Method E): Rt 1.04 min; MC m/z 406.2/408.1 = [M+H]+ (83% @ 215 nm).

Step 2: N[3-(tert-Butylamine)-1,1-dimethyl-3-oxopropyl]-4-[[2-(5-chloro-2hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide

3-[[4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]pyridin-2-carbonyl]amino]-3-methylbutanoic acid (step 1) (120 mg, 0.39 mmol) and DIPEA (205 μl, 1.17 mmol) was suspended in THF (2 ml) and treated with 2-methylpropan-2-amine (62 μl, 0.59 mmol) followed by the addition of HATU (179 mg, 0.47 mmol). The resulting mixture was stirred at room temperature for 42 hours and then partitioned between DCM (10 ml) and water (10 ml). The organic portion was separated by filtration through a hydrophobic PTFE frit and concentrated in vacuo. Purification of the residue by preparative HPLC (acidic pH, early elution method) yielded the title compound as a white crystalline solid.

1H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H), 9.05 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.28 (s , 1H), 8.19 (d, J=2.0 Hz, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.59 (s, 1H), 7 .22 (d, J=2.7 Hz, 1H), 7.13 (dd, J=8.6, 2.7 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H) , 3.68 (s, 2H), 2.38 (s, 2H), 1.45 (s, 6H),

LC-MS (Method A): Rt 3.16 min; MC m/z 461.3/463.3 = [M+H]+ (99% @ 215 nm).

Example 50.

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N3-(methanesulfonamido)-1,1dimethylpropyl]pyridine-2-carboxamide

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Solution of N-(3-amino-1,1-dimethylpropyl)-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2carboxamide (Example 43, Step 2) (76 mg, 0. 19 mmol) in THF (0.5 ml) was treated with K ₂ CO ₃ (54 mg, 0.39 mmol) and the reaction mixture was stirred at room temperature. A solution of methanesulfonyl chloride (63.2 μL in 1000 μL in THF) was prepared, and a 250 μL aliquot was added dropwise to the reaction mixture and stirred for 1 hour at room temperature. The resulting mixture was partitioned between DCM and water (8 ml 1:1), and the organic portion was separated by filtration through a hydrophobic PTFE frit and concentrated in vacuo. The residue was dissolved in DMSO:MeOH (1200 µl, 1:1) and purified using (acidic pH, early elution method) and the first major product peak fractions were concentrated in vacuo. The resulting cloudy aqueous mixture was treated with saturated aqueous NaHCO ₃ (3 ml) and DCM (5 ml), and the biphasic solution was stirred until a clear biphasic solution was obtained. The organic portion was separated by filtration through a hydrophobic PTFE frit and concentrated in vacuo to give the title compound as a white crystalline solid.

¹ H NMR (500 MHz, DMSO-06) δ=10.79 (s, 1H), 9.82 (s, 1H), 8.45 (d, J=5.5, 1H), 8.18 ( d, J=1.9, 1H), 8.04 (s, 1H), 7.81 (dd, J=5.5, 2.2, 1H), 7.21 (d, J=2.7 , 1H), 7.12 (dd, J=8.6, 2.7, 1H), 6.92 (t, J=5.8, 1H), 6.79 (d, J=8.6, 1H), 3.66 (s, 2H), 2.95 (dt, J=10.9, 5.9, 2H), 2.86 (s, 3H), 1.97-2.06 (m, 2H), 1.38 (s, 6H).

LC-MS (Method A): Rt 2.73 min; MS m/z 469.2/471.2 = [M+H]+ (99% @ 215 nm).

Example 51.

No.(3-Acetamido-1,1-dimethylpropyl)-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2carboxamide

Solution of N(3-amino-1,1-dimethylpropyl)-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2carboxamide; 2,2,2-trifluoroacetic acid (TFA salt from example 43, step 2) (100 mg, 0.16 mmol) in THF (2.5 ml) was treated with DIPEA (113 μl, 0.65 mmol) followed by the addition of acetic acid anhydride (17 µl, 0.18 mmol), and this mixture was stirred at room temperature for 6 hours. 1 M aqueous NaOH (0.5 ml) was added and stirring was continued at room temperature for 1 hour. An additional portion of 1 M aqueous NaOH (0.5 ml) followed by the addition of MeOH (~0.25 ml) and the mixture was stirred overnight. The resulting mixture was partitioned between DCM (5 ml) and water (3 ml), and the organic portion was separated. The aqueous layer was concentrated in vacuo and the crude residue was dissolved in 1:1 DCM/MeOH and purified by silica gel chromatography eluting with 0-100% TBME in heptane followed by MeOH in TBME to give the title compound as a clear white crystalline solid substances.

¹ H NMR (500 MHz, DMSOA) δ=8.40 (d, J=5.5, 1H), 8.11 (d, J=1.8, 1H), 8.02 (s, 1H), 7.81-7.79 (m, 1H), 7.75 (dd, J=5.5, 2.1, 1H), 7.08 (s, 1H), 7.00 (d, J=8 ,2, 1H), 6.64 (d, J=8.1, 1H), 4.09 (s, 1H), 3.58 (s, 2H), 3.003.09 (m, 2H), 1, 88-1.95 (m, 2H), 1.73 (s, 3H), 1.38 (s, 6H).

LC-MS (Method A): Rt 2.51 min; MS m/z 433.3/435.3 = [M+H]+ (97% @ 215 nm).

Example 53.

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]A-[4-(hydroxymethyl)tetrahydropyran-4yl]pyridine-2-carboxamide

To a cooled (-78°C) solution of methyl 4-[[4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine2-carbonyl]amino]tetrahydropyran-4-carboxylate (example 47.2) ( 52 mg, 0.1161 mmol) in THF (1.5 ml) under a nitrogen atmosphere, a solution of 2.4 M lithium aluminum hydride in THF (97 μl, 0.23 mmol) was added dropwise. After stirring at -78°C for 45 minutes, the mixture was allowed to warm to room temperature and stirred for 1 hour. The solvent was removed in vacuo and purification by preparative HPLC (acid pH, early elution method) gave the title compound as white solid.

1H NMR (500 MHz, DMSOA) δ 10.70 (s, 1H), 9.87 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.19 (d, J =2.0 Hz,

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1H), 8.06 (s, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J=2.7 Hz, 1H), 7, 12 (dd, J=8.6, 2.7 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 4.89 (s, 1H), 3.71-3.65 (m, 4H), 3.62 (s, 2H), 3.54-3.47 (m, 2H), 2.23-2.16 (m, 2H), 1.66 (ddd, J=14 ,0, 10.2, 4.2 Hz, 2H).

LC-MS (Method A): Rt 2.33 min; MS m/z 420.1/422.1 = [M+H]+ (98% @ 215 nm).

Example 54.

No. tert-Butyl-4-[[2-[3-(1-hydroxyethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

Step 1: 4-[[2-(3-Bromophenyl)acetyl]amino]-M-tert-butylpyridine-2-carboxamide

The title compound was prepared from 2-(3-bromophenyl)acetic acid and 4-amino-N tert-butylpyridine-2-carboxamide (Example 3, Step 1) analogously to Example 21.

1H NMR (250 MHz, DMSO) δ 10.77 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.17 (d, J=1.9 Hz, 1H), 8.02 (s, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.57-7.54 (m, 1H), 7.47 (dt, J= 6.9, 2.1 Hz, 1H), 7.36-7.27 (m, 2H), 3.75 (s, 2H), 1.39 (s, 9H).

LC-MS (Method E): Rt 1.23 min; MS m/z 390.1/392.1 = [M+H]+(98% @ 215 nm).

Step 2: 4-[[2-(3-Acetylphenyl)acetyl]amino]-M-tert-butylpyridine-2-carboxamide

Solution of 4-[[2-(3-bromophenyl)acetyl]amino]-N-tert-butylpyridin-2-carboxamide (step 1) (200 mg, 0.51 mmol), 1-vinyloxybutane (332 µl, 2.56 mmol), triphenylphosphine (27 mg, 0.1 mmol) and TEA (107 μl, 0.61 mmol) in MeCN (1 ml) were degassed with nitrogen and treated with Pd(OAc) ₂ (12 mg, 0.05 mmol). The mixture was sealed and heated at 100°C overnight. Additional portions of 1-vinyloxybutane (332 μl, 2.56 mmol), TEA (107 μl, 0.61 mmol), triphenylphosphine (27 mg, 0.1 mmol) and Pd(OAc) ₂ (12 mg, 0.05 mmol), and heating was continued at 100°C for an additional 8 hours. The resulting mixture was filtered through Celite® and washed with EtOAc. The filtrate was absorbed onto silica gel and purification by chromatography, eluting with 0-100% EtOAc in heptane, afforded the title compound as an orange glassy solid.

1H NMR (250 MHz, Chloroform-d) δ 8.34 (d, J=5.6 Hz, 1H), 8.11 (dd, J=5.5, 2.3 Hz, 1H), 7.90 -7.84 (m, 2H), 7.59 (s, 1H), 7.50-7.43 (m, 2H), 3.77 (s, 2H), 2.56 (s, 3H), 1.39 (s, 9H).

LC-MS (Method E): Rt 1.13 min; MS m/z 354.1 = [M+H]+ (93% @ 215 nm).

Step 3: N-tert-Butyl-4-[[2-[3-(1-hydroxyethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

To a solution of 4-[[2-(3-acetylphenyl)acetyl]amino]-M-tert-butylpyridine-2-carboxamide (step 2) (45 mg, 0.12 mmol) in methanol (1 ml) at 0°C NaBH ₄ (4.5 mg, 0.12 mmol) was added and the mixture was allowed to warm to room temperature. After stirring for 1 hour, the reaction mixture was quenched by adding 3 drops of sat. NaHCO ₃ solution, and purification by preparative HPLC (acidic pH, standard elution method) gave the title compound as a colorless powder.

1H NMR (500 MHz, Methanol^) δ 8.42 (d, J=5.5 Hz, 1H), 8.14 (d, J=2.1 Hz, 1H), 7.89 (dd, J= 5.5, 2.2 Hz, 1H), 7.37 (s, 1H), 7.33-7.22 (m, 3H), 4.85-4.79 (m, 1H), 3.74 (s, 2H), 1.47 (s, 9H), 1.43 (d, J=6.5 Hz, 3H).

LC-MS (Method A): Rt 2.77 min; MS m/z 356.3 = [M+H]+.

Example 55.

No. tert-Butyl-5-chloro-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide

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Step 1: Methyl 4-amino-5-chloro-pyridine-2-carboxylate

NCS (483 mg, 3.61 mmol) was added to a solution of methyl 4-aminopyridine-2-carboxylate (500 mg, 3.29 mmol) in DMF (10 ml), and the reaction mixture was stirred at 60°C overnight . The resulting mixture was diluted with EtOAc (50 ml) and washed with water (2x50 ml) and saturated aqueous sodium chloride (2x50 ml), dried over sodium sulfate and concentrated in vacuo. The resulting crude residue was purified by KP-NH silica gel chromatography, eluting with 0-10% MeOH in DCM. The mixed fractions were combined and concentrated in vacuo. The resulting crude residue was further purified by KP-NH silica gel chromatography, eluting with 0-100% EtOAc in heptane, to obtain the title compound as a light pink solid.

¹ H NMR (250 MHz, DMSO-06) δ 8.22 (s, 1H), 7.42 (s, 1H), 6.68 (s, 2H), 3.82 (s, 3H).

LC-MS (Method C): Rt 1.61 min; MS m/z 186.8/188.8 = [M+H]+ (90% @ 215 nm).

Step 2: Methyl 5-chloro-4-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]pyridine-2-carboxylate

To a solution of 2-(5-chloro-2-methoxyphenyl)acetic acid (106 mg, 0.53 mmol) and methyl 4-amino-5chloro-pyridine-2-carboxylate (step 1) (100 mg, 0.48 mmol) in 1,4-dioxane (5 ml) was added TEA (0.17 ml, 0.96 mmol) followed by the addition of a 50% T3P® solution in EtOAc (0.57 ml, 0.96 mmol). The resulting mixture was stirred at room temperature under an inert atmosphere overnight. The reaction mixture was diluted with EtOAc (20 ml) and washed with water (2x10 ml) and saturated aqueous sodium chloride solution (10 ml). The organic portion was dried over Na ₂ SO ₄ and concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with 0-100% EtOAc in heptane to give the title compound as a white solid.

1H NMR (250 MHz, DMSO-06) δ 9.94 (s, 1H), 8.77 (s, 1H), 8.72 (s, 1H), 7.36-7.29 (m, 2H) , 7.06-6.99 (m, 1H), 3.88 (s, 2H), 3.86 (s, 3H), 3.78 (s, 3H).

LC-MS (Method E): Rt 1.15 min; MS m/z 369.0/371.0 = [M+H]+ (91% @ 215 nm).

Step 3: 5-Chloro-4-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]pyridine-2-carboxylic acid

A solution of methyl 5-chloro-4-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]pyridine-2-carboxylate (step 2) (106 mg, 0.26 mmol) in THF (3 ml) treated with 1 M NaOH (392 μl, 0.39 mmol) and stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo and the residue was dissolved in water (15 ml). The pH was adjusted to pH 5 by adding 1 M HCl, and the resulting precipitate was filtered and dried in a vacuum oven at 40°C to give the title compound as a white solid.

1H NMR (250 MHz, DMSO-06) δ 13.33 (br.s, 1H), 9.90 (s, 1H), 8.75 (s, 1H), 8.71 (s, 1H), 7 .36-7.30 (m, 2H), 7.07-7.01 (m, 1H), 3.88 (s, 2H), 3.79 (s, 3H).

LC-MS (Method E): Rt 1.05 min; MS m/z 355.0/357.0 = [M+H]+ (79% @ 215 nm).

Step 4-5: N-tert-Butyl-5-chloro-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2carboxamide

The title compound was prepared from 5-chloro-4-[[2-(5-chloro-2methoxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (step 3) and 2-methylpropan-2-amine analogously to example 32, steps 1 and 2.

1H NMR (500 MHz, DMSO-06) δ 10.30-9.70 (m, 2H), 8.74 (s, 1H), 8.61 (s, 1H), 7.94 (s, 1H) , 7.26 (d,

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J=2.7 Hz, 1H), 7.15 (dd, J=8.6, 2.7 Hz, 1H), 6.84 (d, J=8.6 Hz, 1H), 3.81 ( s, 2H), 1.39 (s, 9H). LC-MS (Method A): Rt 3.64 min; MS m/z 396.2/398.2 = [M+H]+ (97% @ 215 nm). Example 56.

^tert-Butyl-4-[[2-[5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl]acetyl]amino]pyridine-2carboxamide

N-tert-Butyl-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Example 3) (164 mg, 0.45 mmol) was suspended in anhydrous acetone (10 ml) and treated with K ₂ CO ₃ (94 mg, 0.68 mmol) followed by the addition of 1-(bromomethyl)-4-methoxybenzene (100 mg, 0.5 mmol). The reaction mixture was heated in a high pressure tube at 50°C overnight. The resulting mixture was concentrated in vacuo and then redissolved in EtOAc (25 ml). The mixture was washed with water (25 ml) and saturated aqueous sodium chloride (25 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The solid was dissolved in EtOAc/MeOH (2:1 ~15 ml) and the suspension was filtered and washed with EtOAc (20 ml) to obtain the title compound as a white solid.

1H NMR (500 MHz, DMSO-06) δ 10.65 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.11 (d, J=2.0 Hz, 1H ), 8.05 (s,

1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.34 (d, J=2.7 Hz, 1H), 7.30 (dd, J=8.7 , 2.7 Hz, 1H), 7.22 (d, J=8.7 Hz, 2H), 7.09 (d, J=8.8 Hz, 1H), 6.67-6.63 (m , 2H), 4.97 (s, 2H), 3.71 (s, 2H), 3.65 (s, 3H), 1.41 (s, 9H).

LC-MS (Method A): Rt 4.13 min; MS m/z 482.3/484.3 = [M+H]+ (91% @ 215 nm).

Example 57a.

N-tert-butyl-4-[[( 1S) or (^)-4-chloro-7-hydroxyindan-1-carbonyl]amino]pyridine-2-carboxamide and example 57b: N-tert-butyl-4-[ [(^) or (^)-4-chloro-7-hydroxyindan-1-carbonyl]amino]pyridine-2carboxamide

(S)-isomer or

(R)-isomer

Step 1: N-tert-Butyl-4-[(7-methoxyindan-1-carbonyl)amino]pyridine-2-carboxamide

To a mixture of 4-amino-^t-butylpyridin-2-carboxamide (example 3, step 1) (200 mg, 1.03 mmol) and 7-methoxyindan-1-carboxylic acid (199 mg, 1.03 mmol) in 1 ,4-dioxane (5 ml) was added to a 50% T3P® solution in EtOAc (1231 µl, 2.07 mmol) and TEA (362 µl, 2.07 mmol). The reaction mixture was stirred at room temperature under an inert atmosphere for 16 hours. The resulting mixture was diluted with EtOAc (20 ml) and the organic mixture was washed with water (20 ml), sat. NaHCO ₃ (20 ml) and saturated aqueous sodium chloride solution (20 ml). The organic portion was dried over Na ₂ SO ₄ and concentrated in vacuo. The crude residue was purified by KP-NH silica gel chromatography, eluting with 0-80% heptane in EtOAc to give the title compound as a light pink foam.

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1H NMR (500 MHz, DMSOZH) δ 10.67 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.22 (d, J=2.1 Hz, 1H), 8.03 (s, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.20 (t, J=7.8 Hz, 1H), 6.87 (d , J=7.4 Hz, 1H), 6.77 (d, J=8.1 Hz, 1H), 4.12 (dd, J=8.8, 5.4 Hz, 1H), 3.68 (s, 3H), 3.09-2.99 (m, 1H), 2.92-2.85 (m, 1H), 2.41-2.34 (m, 1H), 2.24-2 .15 (m, 1H), 1.40 (s, 9H).

LC-MS (Method E): Rt 1.21 min; MS m/z 368.1 = [M+H]+ (100% @ 215 nm).

Step 2: N-tert-Butyl-4-[(4-chloro-7-methoxyindan-1-carbonyl)amino]pyridine-2-carboxamide

λ

CH ₃

The title compound was prepared from N-tert-butyl-4-[(7-methoxyindan-1carbonyl)amino]pyridine-2-carboxamide (Step 1) analogously to Example 24, Step 2.

1H NMR (250 MHz, Chloroform-d) δ 8.83 (s, 1H), 8.37 (d, J=5.6 Hz, 1H), 8.20 (dd, J=5.6, 2, 2 Hz, 1H), 8.01 (s, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.19 (d, J=8.7 Hz, 1H), 6.74 (d, J=8.7 Hz, 1H), 4.22 (d, J=7.5 Hz, 1H), 4.02 (s, 3H), 3.23-2.77 (m, 3H) , 2.32-2.15 (m, 1H), 1.47 (s, 9H).

LC-MS (Method e): Rt 1.27 min; MS m/z 402.1/404.1 = [M+H]+.

Step 3 (example 57a): Y-tert-butyl-4-[[(%) or (^)-4-chloro-7-hydroxyindan-1carbonyl]amino]pyridine-2-carboxamide and example 57b: Y-tert- butyl-4-[[(%) or (1I)-4-\.ur-7hydroxyindan-1-carbonyl]amino]pyridine-2-carboxamide

To a solution of N-tert-butyl-4-[(4-chloro-7-methoxy-indan-1-carbonyl)amino]pyridine-2-carboxamide (step 2) (50 mg, 0.12 mmol) in DCM (2 ml ) 1 M BBr ₃ in DCM (249 µl, 0.25 mmol) was added. The resulting mixture was stirred at room temperature under an inert atmosphere for 1 hour. An additional portion of 1 M BBr3 in DCM (249 µl, 0.25 mmol) was added and the mixture was stirred for an additional 24 hours. The reaction mixture was quenched with water (1 ml) and concentrated in vacuo. The crude material was dissolved in EtOAc (20 ml) and the organic mixture was washed with sat. NaHCO ₃ (20 ml), water (20 ml) and saturated aqueous sodium chloride solution (20 ml). The organic portion was concentrated in vacuo to obtain a racemic mixture.

Chiral resolution of racemic Na-tert-butyl-4-[[4-chloro-7-hydroxy-indan-1carbonyl]amino]pyridine-2-carboxamide using supercritical liquid chromatography [chiral phase column (15% ethanol: 95% CO ₂ with a Chiralpak IC column 25 cm at 15 ml/min)] gave the individual enantiomers:

Example 57a: Y-tert-butyl-4-[[(%) or (^)-4-chloro-7-hydroxy-indan-1-carbonyl]amino]pyridine2-carboxamide UHPLC retention time: 6.00 min

1H NMR (500 MHz, DMSO-06) δ 10.77 (br.s, 1H), 9.76 (br.s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8 .19 (d, J=2.0 Hz, 1H), 8.02 (s, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.07 (d, J=8.5 Hz, 1H), 6.61 (d, J=8.5 Hz, 1H), 4.18 (dd, J=8.9, 5.2 Hz, 1H), 3.05- 2.96 (m, 1H), 2.93-2.84 (m, 1H), 2.43-2.36 (m, 1H), 2.27-2.19 (m, 1H), 1. 40 (s, 9H).

LC-MS (Method A): Rt 3.58 min; MS m/z 388.2/390.2 = [M+H]+ (96% @ 215 nm).

Example 57b: Y-tert-butyl-4-[[(%) or (^)-4-chloro-7-hydroxyindan-1-carbonyl]amino]pyridine-2carboxamide UHPLC retention time: 7.84 min

1H NMR (500 MHz, DMSO-06) δ 10.89 (br.s, 1H), 9.76 (br.s, 1H), 8.43 (d, J=5.5 Hz, 1H), 8 .19 (d, J=2.1 Hz, 1H), 8.02 (s, 1H), 7.82 (dd, J=5.5, 2.1 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 6.60 (d, J=8.5 Hz, 1H), 4.18 (dd, J=8.9, 5.1 Hz, 1H), 3.04- 2.95 (m, 1H), 2.94-2.84 (m, 1H), 2.42-2.36 (m, 1H), 2.29-2.21 (m, 1H), 1. 40 (s, 9H).

LC-MS (Method A): Rt 3.58 min; MS m/z 388.2/390.2 = [M+H]+ (95% @ 215 nm).

Example 58.

No. tert-Butyl-4-[[2-(2-cyclopropylphenyl)acetyl]amino]pyridine-2-carboxamide

A mixture containing 4-[[2-(2-bromophenyl)acetyl]amino]-N-tert-butylpyridine-2-carboxamide ((example 23.13) (100 mg, 0.25 mmol), cyclopropylboronic acid (44 mg, 0 .51 mmol), tripotassium phosphate (215 mg, 1.01 mmol), in toluene (5 ml) and water (0.5 ml) were degassed with nitrogen for 10 min and treated with Pd(OAc) ₂ (11 mg, 0. 05 mmol) and P(Cy) ₃ (28 mg, 0.1 mmol). The reaction mixture was sealed and heated at 100°C for 5 hours. After cooling to room temperature, the mixture was filtered through Celite® and the filtrate was diluted with EtOAc. (10 ml) and water (10 ml). The organic layer was separated, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude material was purified by preparative HPLC (alkaline pH, early elution method) followed by preparative purification.

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HPLC (acidic pH, early elution method). Further purification using silica gel chromatography, eluting with 0-100% EtOAc in heptane, afforded the title compound as a white, metallic solid.

1H NMR (500 MHz, Methanol^) δ 8.43 (dd, J=5.6, 0.4 Hz, 1H), 8.13 (dd, J=2.2, 0.4 Hz, 1H), 7.92 (dd, J=5.5, 2.2 Hz, 1H), 7.23 (dd, J=7.3, 1.5 Hz, 1H), 7.21-7.13 (m, 2H), 7.07 (dd, J=7.3, 1.2 Hz, 1H), 3.98 (s, 2H), 2.01-1.91 (m, 1H), 1.47 (s , 9H), 0.95-0.82 (m, 2H), 0.67-0.58 (m, 2H).

LC-MS (Method A): Rt 3.69 min; MS m/z 352.3 = [M+H]+ (99% @ 215 nm).

Example 59.

4-[[2-(3-Bromo-5-chloro-2-hydroxyphenyl)acetyl]amino]-I-tert-butylpyridine-2-carboxamide

Vg

Step 1: 2-(3-Bromo-5-chloro-2-methoxyphenyl)acetic acid

-uug

CH ₃ Br

Bromine (8 ml, 139.34 mmol) was added to a stirred solution of 2-(5-chloro-2methoxyphenyl)acetic acid (1 g, 4.98 mmol) in acetic acid (8 ml), and the mixture was stirred at room temperature in for 1 hour. The reaction mixture was cooled to 0°C and treated with EtOAc (50 ml) followed by saturated aqueous Na ₂ S ₂ O ₃ (approximately 30 ml). The organic layer was separated and concentrated in vacuo to give a yellow tarry solid. The solid was purified by C18 reverse phase chromatography eluting with 10-100% (0.1% formic acid in water: 0.1% formic acid in MeCN) to give the title compound as a white solid with a metallic tint.

1H NMR (500 MHz, DMSO-06) δ 12.53 (s, 1H), 7.67 (d, J=2.6 Hz, 1H), 7.41 (d, J=2.6 Hz, 1H ), 3.73 (s, 3H), 3.65 (s, 2H).

LC-MS (Method E): Rt 1.08 min; No MS m/z observed = [M+H]+ (100% @ 215 nm).

Step 2: 4-[[2-(3-Bromo-5-chloro-2-methoxyphenyl)acetyl]amino]-I-tert-butylpyridine-2carboxamide

CH ₃ Br

To a stirred solution of 2-(3-bromo-5-chloro-2-methoxyphenyl)acetic acid (step 1) (755 mg, 2.7 mmol), 4-amino-N-tert-butylpyridine-2-carboxamide (example 3 , stage 1) (475. mg, 2.46 mmol) and TEA (644 μl, 3.69 mmol) in 1,4-dioxane (10 ml) was added 50% T3P® solution in EtOAc (2.19 ml, 3 .69 mmol). The resulting mixture was stirred at room temperature for 2 hours and then diluted with water (40 ml) and EtOAc (50 ml). The organic layer was separated, washed with water (50 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with 0-100% EtOAc in heptane to give the title compound as a white metallic solid.

1H NMR (500 MHz, DMSO-06) δ 10.83 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.0 Hz, 1H ), 8.04 (s, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.71 (d, J=2.6 Hz, 1H), 7.48 (d, J=2.6 Hz, 1H), 3.84 (s, 2H), 3.75 (s, 3H), 1.41 (s, 9H).

LC-MS (Method E): Rt 1.29 min; MS m/z 454.0/456.0/458.0 = [M+H]+ (99% @ 215 nm).

Step 3: 4-[[2-(3-Bromo-5-chloro-2-hydroxyphenyl)acetyl]amino]-I-tert-butylpyridine-2carboxamide

M BBr ₃ in DCM (0.2 ml, 0.2 mmol) was added to a stirred suspension of 4-[[2-(3-bromo-5-chloro2-methoxyphenyl)acetyl]amino]-I-tert-butylpyridin-2- carboxamide (step 2) (30 mg, 0.07 mmol) in DCM (1 ml) at 0°C. The mixture was left to warm to room temperature and stirred for 1 hour. The reaction mixture was quenched by adding dropwise saturated. NaHCO ₃ (20 ml), then diluted with EtOAc (20 ml). The organic layer was separated, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by preparative HPLC (acidic pH early elution method) and product containing fractions were pooled and lyophilized overnight to give the title compound as a white, metallic powder.

1H NMR (500 MHz, DMSO-06) δ 10.93 (s, 1H), 9.62 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.15 (d , J=2.0 Hz,

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1H), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.52 (d, J=2.6 Hz, 1H), 7, 28 (d, J=2.5 Hz, 1H), 3.78 (s, 2H), 1.40 (s, 9H).

LC-MS (Method A): Rt 3.81 min; MS m/z 440.1/442.1 = [M+H]+ (99% @ 215 nm).

Example 60.

N(4-Fluoro-1-bicyclo[2.1.1]hexanyl)-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide

F

Step 1-2: 4-[[2-(2-Fluorophenyl)acetyl]amino]pyridine-2-carboxylic acid

The title compound was prepared from 2-(2-fluorophenyl)acetic acid and methyl 4-aminopyridine-2-carboxylate in the same manner as Example 30, Steps 1-2.

1H NMR (500 MHz, DMSO^) δ 10.82 (s, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.23 (d, J=1.8 Hz, 1H) , 7.78 (dd, J=5.5, 2.1 Hz, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.36-7.31 (m, 1H), 7.21-7.15 (m, 2H), 3.81 (s, 2H).

LC-MS (Method E): Rt 0.81 min; MS m/z 275.0 = [M+H]+ (100% @ 215 nm).

Step 3: ^(4-Fluoro-1-bicyclo[2.1.1]hexanyl)-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2carboxamide

The title compound was prepared from 4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2carboxylic acid (step 1-2) and 4-fluorobicyclo[2.1.1]hexane-1-amine hydrochloride analogously to Example 30, stage 3.

1H NMR (500 MHz, DMSO^) δ 10.82 (s, 1H), 9.05 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.16 (d, J=2.0 Hz, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.40 (td, J=7.6, 1.6 Hz, 1H), 7.36-7.31 (m, 1H), 7.21-7.15 (m, 2H), 3.81 (s, 2H), 2.13-2.05 (m, 4H), 1. 99-1.95 (m, 2H), 1.87-1.82 (m, 2H).

LC-MS (Method A): Rt 3.22 min; MS m/z 372.3 = [M+H]+ (98% @ 215 nm).

Example 60.1.

No.(1-Cyano-2-hydroxy-1-methylethyl)-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide

The title compound was prepared from 4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2carboxylic acid (step 1-2) and 2-amino-3-hydroxy-2-methylpropanenitrile hydrochloride analogously to Example 30, stage 3.

1H NMR (500 MHz, DMSO-d ₆ ) δ 10.86 (s, 1H), 8.72 (s, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.23 ( d, J=2.1 Hz, 1H), 7.86 (dd, J=5.5, 2.2 Hz, 1H), 7.43-7.37 (m, 1H), 7.37-7 .28 (m, 1H), 7.22-7.14 (m, 2H), 5.99-5.79 (m, 1H), 3.86-3.78 (m, 3H), 3.72 (dd, J=10.9, 4.7 Hz, 1H), 1.65 (s, 3H).

LC-MS (Method A): Rt 2.41 min; MS m/z 357.2 = [M+H]+ (99% @ 215 nm).

Example 60.2.

No.(1,1-Dimethylprop-2-ynyl)-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide

The title compound was prepared from 4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2carboxylic acid (step 1-2) and 2-methylbut-3-yn-2-amine analogously to Example 30, step 3.

1H NMR (500 MHz, DMSO^) δ 10.83 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.32 (s, 1H), 8.19 (d, J=2.1 Hz, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.43-7.37 (m, 1H), 7.37-7.30 (m, 1H), 7.22-7.15 (m, 2H), 3.82 (s, 2H), 3.21 (s, 1H), 1.64 (s, 6H).

LC-MS (Method A): Rt 3.08 min; MS m/z 340.2 = [M+H]+ (99% @ 215 nm).

Example 61.

No. tert-Butyl-4-[[2-(5-chloro-2-hydroxy-3-isopropylphenyl)acetyl]amino]pyridine-2-carboxamide

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Step 1: N-tert-Butyl-4-[[2-(5-chloro-3-isopropenyl-2-methoxyphenyl)acetyl]amino]pyridine-2carboxamide

The title compound was prepared from 4-[[2-(3-bromo-5-chloro-2methoxyphenyl)acetyl]amino]-Nt-tert-butylpyridine-2-carboxamide (Example 59, Step 2) and 2-isopropenyl-4,4. 5,5-tetramethyl-1,3,2-dioxaborolane similar to example 58.

^1H NMR (500 MHz, DMSO-de) δ 10.84-10.75 (m, 1H), 8.48-8.42 (m, 1H), 8.23-8.17 (m, 1H) , 8.03 (s, 1H), 7.84-7.79 (m, 1H), 7.33 (d, J=2.7 Hz, 1H), 7.17 (d, J=2.7 Hz, 1H), 5.25-5.22 (m, 1H), 5.17-5.15 (m, 1H), 3.77 (d,

J=2.8 Hz, 2H), 3.58 (s, 3H), 2.14-2.04 (m, 3H), 1.40 (s, 9H).

LC-MS (Method E): Rt 1.33 min; MS m/z 416.1 = [M+H]+ (86% @ 215 nm).

Step 2: N-tert-Butyl-4-[[2-(5-chloro-3-isopropyl-2-methoxyphenyl)acetyl]amino]pyridine-2carboxamide

10% Pd/C (9 mg, 0.01 mmol) was added to a stirred solution of N-tert-butyl-4-[[2-(5-chloro3-isopropenyl-2-methoxyphenyl)acetyl]amino]pyridine-2-carboxamide ( step 1) (120 mg, 0.17 mmol) in EtOH (10 ml). The resulting mixture was placed under a hydrogen atmosphere and after stirring for 16 hours, the mixture was filtered through Celite® and washed with EtOH (15 ml). The filtrate was concentrated in vacuo and purification by preparative HPLC (acid pH, early elution method) gave the title compound as a pale yellow solid.

¹ H NMR (500 MHz, DMSO-d,) δ 10.80 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.19 (d, J=2.0 Hz , 1H), 8.03 (s, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.26 (d, J=2.7 Hz, 1H), 7 .22 (d, J=2.7 Hz, 1H), 3.77 (s, 2H), 3.66 (s, 3H), 3.21 (hept, J=6.9 Hz, 1H), 1 .40 (s, 9H), 1.18 (d, J=6.9 Hz, 6H).

LC-MS (Method E): Rt 1.34 min; MS m/z 418.2 = [M+H]+ (99% @ 215 nm).

Step 3: N-tert-Butyl-4-[[2-(5-chloro-2-hydroxy-3-isopropylphenyl)acetyl]amino]pyridine-2carboxamide

M BBr ₃ in DCM (0.34 ml, 0.34 mmol) was added to a stirred suspension of N-tert-butyl-4[[2-(5-chloro-3-isopropyl-2-methoxyphenyl)acetyl]amino]pyridine-2 -carboxamide (step 2) (48 mg, 0.11 mmol) in DCM (2 ml). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with MeOH (5 ml) and the mixture was concentrated in vacuo. The resulting residue was diluted with EtOAc (5 ml), washed with sat. NaHCO ₃ (5 ml), and the organic portion was dried over Na ₂ SO ₄ and concentrated in vacuo. The crude material was purified by preparative HPLC (acid pH early elution method) and product containing fractions were pooled and lyophilized overnight to give the title compound as a white, metallic powder.

¹ H NMR (500 MHz, DMSO-06) δ 10.73 (s, 1H), 8.75 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.18 ( d, J=1.9 Hz, 1H), 8.03 (s, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.10-7.01 (m , 2H), 3.74 (s, 2H), 3.29-3.22 (m, 1H), 1.40 (s, 9H), 1.14 (d, J=6.8 Hz, 6H) .

LC-MS (Method A): Rt 3.25 min; MS m/z 356.3 = [M+H]+ (100% @ 215 nm).

Example 62.

No. tert-Butyl-4-[[2-[5-chloro-2-hydroxy-3-(1-methoxyethyl)phenyl]acetyl]amino]pyridine-2carboxamide

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Step 1: N-tert-Butyl-4-[[2-[5-chloro-3-(1-hydroxyethyl)-2-methoxyphenyl]acetyl]amino]pyridine2-carboxamide

The title compound was prepared from 4-[[2-(3-bromo-5-chloro-2methoxyphenyl)acetyl]amino]-Ntert-butylpyridine-2-carboxamide (Example 59, Step 2) and 1vinyloxybutane analogously to Example 54, Steps 2-3.

¹ H NMR (500 MHz, DMSO-06) δ 10.80 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.19 (d, J=2.1 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.39 (d, J=2.7 Hz, 1H), 7, 27 (d, J=2.7 Hz, 1H), 5.23 (d, J=4.5 Hz, 1H), 5.064.87 (m, 1H), 3.77 (d, J=2.6 Hz, 2H), 3.68 (s, 3H), 1.40 (s, 9H), 1.31 (d, J=6.4 Hz, 3H).

LC-MS (Method E): Rt 1.18 min; MS m/z 420.2/422.2 = [M+H]+ (100% @ 215 nm).

Step 2: N-tert-Butyl-4-[[2-[5-chloro-2-hydroxy-3-(1-methoxyethyl)phenyl]acetyl]amino]pyridine2-carboxamide

M BBr ₃ in DCM (0.5 ml, 0.5 mmol) was added to a cooled (0°C) suspension of U-tert-butyl-4-[[2[5-chloro-3-(1-hydroxyethyl)-2 -methoxyphenyl]acetyl]amino]pyridine-2-carboxamide (70 mg, 0.17 mmol) in DCM (2 ml) and stirred at room temperature for 1 hour. The reaction mixture was quenched by adding sat. NaHCO ₃ (1 ml), then diluted with DCM (7 ml). The organic layer was separated, concentrated in vacuo, and purification of the crude residue by preparative HPLC (acidic pH, early elution method) yielded the title compound as a white, metallic powder.

¹ H NMR (500 MHz, DMSO-06) δ 10.76 (s, 1H), 8.87 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.18 ( d, J=1.9 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.15 (d, J=2 ,7 Hz, 1H), 7.11 (d, J=2.7 Hz, 1H), 4.68 (k, J=6.3 Hz, 1H), 3.76 (s, 2H), 3, 17 (s, 3H), 1.40 (s, 9H), 1.29 (d, J=6.4 Hz, 3H).

LC-MS (Method A): Rt 3.80 min; MS m/z 420.3 = [M+H]+ (100% @ 215 nm).

Example 63.

4-[[2-(6-Quinolyl)acetyl]amino]-Ntetrahydropyran-4-ylpyridin-2-carboxamide

Step 1: 4-Nitro-Ntetrahydropyran-4-ylpyridin-2-carboxamide

To a stirred solution of HATU (724 mg, 1.9 mmol) in DMF (1 mL) was added DIPEA (363 μL, 2.08 mmol) and 4-nitropyridine-2-carboxylic acid (320 mg, 1.9 mmol), and this mixture was stirred for 15 minutes. Tetrahydropyran-4-amine (0.18 mL, 1.73 mmol) was added in one portion and the mixture was stirred at room temperature for 1 hour. The resulting mixture was washed with water (10 mL), NaHCO ₃ (10 mL) and extracted with EtOAc ( 2x10 ml). The combined organic extracts were dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound as a pale orange solid.

¹ H NMR (500 MHz, DMSO-d..i 8=1.70-1.75 (m, 4H), 3.37-3.44 (m, 2H), 3.88 (dt, J=11 ,2, 3.2, 2H), 4.05 (s, 1H), 8.33 (dd, J=5.3, 2.3, 1H), 8.53 (dd, J=2.3, 0.5, 1H), 8.92 (d, J=8.2, 1H), 9.02 (dd, J=5.3, 0.5, 1H).

Step 2: 4-Amino-Ntetrahydropyran-4-ylpyridin-2-carboxamide

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A mixture containing 4-nitro-K-tetrahydropyran-4-ylpyridin-2-carboxamide (step 1) (338 mg, 1.35 mmol) and 10% Pd-C (29 mg, 0.13 mmol) in EtOH (4 ml), stirred under hydrogen atmosphere for 16 hours. The resulting mixture was filtered and the filtrate was washed with EtOAc (2x10 ml). The combined organic extracts were concentrated in vacuo and purification of the crude residue by chromatography on silica gel, eluting with 0-100% EtOAc in heptane, afforded the title compound as a pale orange solid.

¹ H NMR (500 MHz, DMSO-06) δ=1.57-1.67 (m, 2H), 1.67-1.73 (m, 2H), 3.38 (td, J=11.6 , 2.3, 2H), 3.813.88 (m, 2H), 3.90-3.99 (m, 1H), 6.30 (s, 2H), 6.58 (dd, J=5.6 , 2.4, 1H), 7.21 (d, J=2.3, 1H), 8.01 (d, J=5.5, 1H), 8.37 (d, J=8.4, 1H).

LC-MS (Method C): Rt 0.32 min; MS m/z 222.0 = [M+H]+ (98% @ 215 nm).

Step 3: 4-[[2-(6-Quinolyl)acetyl]amino]-K-tetrahydropyran-4-yl-pyridin-2-carboxamide

Mixture of 4-amino-K-tetrahydropyran-4-yl-pyridin-2-carboxamide (step 2) (104 mg, 0.47 mmol) and 2-(6-quinolyl)acetic acid (87.99 mg, 0.47 mmol) in 1,4-dioxane (2 ml) were treated with a 50% T3P® solution in EtOAc (1118 µl, 0.94 mmol) and TEA (164 µl, 0.94 mmol). After stirring at room temperature for 1.5 hours, the mixture was concentrated in vacuo. The crude residue was washed with water (15 ml), NaHCO ₃ (10 ml) and extracted with EtOAc (2x10 ml). The combined organic extracts were dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by chromatography on silica gel, eluting with 0-20% EtOAc/MeOH, afforded the title compound as a white solid with a metallic tint.

¹ H NMR (500 MHz, DMSO-06) δ=1.64-1.73 (m, 4H), 3.38 (td, J=11.4, 3.2, 2H), 3.83-3 .89 (m, 2H), 3.95 (s, 2H), 3.97-4.05 (m, 1H), 7.50-7.55 (m, 1H), 7.74 (dd, J =8.7, 2.0, 1H), 7.84 (dd, J=5.5, 2.2, 1H), 7.90 (d, J=1.7, 1H), 7.99 ( d, J=8.6, 1H), 8.22 (d, J=2.0, 1H), 8.35 (d, J=7.4, 1H), 8.49 (d, J=5 ,5, 1H), 8.58 (d, J=8.4, 1H), 8.88 (dd, J=4.2, 1.7, 1H), 10.86 (s, 1H).

LC-MS (Method A): Rt 1.51 min; MS m/z 391.0 = [M+H]+ (99% @ 215 nm).

Example 64.

4-(Benzylcarbamoylamine)-N-tert-butylpyridine-2-carboxamide

A mixture of isocyanatomethylbenzene (72 μl, 0.52 mmol) and 4-amino-N-tert-butylpyridin-2carboxamide (example 3, step 1) (100 mg, 0.52 mmol) in anhydrous DMF (1 ml) was stirred at 80° C overnight. The resulting mixture was concentrated in vacuo and the residue was partitioned between EtOAc (2 ml) and saturated aqueous sodium chloride (2 ml). The organic portion was separated and the aqueous layer was re-extracted with EtOAc (2 ml). The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was dissolved in DMSO:MeCN:H ₂ O (1.1 ml, 5:4:1), filtered and purified by preparative HPLC (acidic pH, early elution method) to obtain the title compound as a white solid with a metallic tint .

1H NMR (250 MHz, DMSO-06) δ 9.34 (s, 1H), 8.31 (d, J=5.6 Hz, 1H), 8.05-7.97 (m, 2H), 7 .62 (dd, J=5.6, 2.3 Hz, 1H), 7.38-7.20 (m, 5H), 6.97 (t, J=5.9 Hz, 1H), 4, 32 (d, J=5.9 Hz, 2H), 1.39 (s, 9H).

LC-MS (Method A): Rt 2.74 min; MS m/z 327.3 = [M+H]+ (98% @ 215 nm)

The compounds of the following tabular examples (Table 13) were prepared from 4-amino-N-tert-butylpyridine-2-carboxamide (example 3, step 1) and the corresponding isocyanate analogously to example 64

- 147 046966

Table 13

Example Structure and name 1NMR LC-MS retention time, [M+HJ+, 64.1 NeSkhG ³ Y N N A ⁿ = th ΥΎ Υ T4-tert-Butyl-4(cyclohexylmethylcarbamoylamine)pyridine-2carboxamide 1HNMR (250 MHz, DMSO-bb) δ 9.10 (s, 1H), 8.30 (d, J=5.5 Hz, 1H), 8.01 (s, 1H), 7.96 (d, >2.0 Hz, 1H), 7.58 (dd, >5.6, 2.3 Hz, 1H), 6.43 (t, >5.8 Hz, 1H), 2.96 (t, > 6.3 Hz, 2H), 1.75-1.55 (m, 5H), 1.48-1.31 (m, JN), 1.29-1.08 (m, ZN), 0.99 -0.80 (m, 2H). LC-MS (Method A): Rt 3.21 min; MS m/z 333.3 = [M+H]+ (98% @ 215 nm) 64.2 ^Sn z O _{sh sh} N ₃ S. I II NN ^ns i ΥΎ Υ Υ । Ν^Υ ⁰ X-tert-Butyl-4-(2-phenylethylcarbamoylamine)pyridine2-carboxamide 1HNMR (500 MHz, DMSO-bb) δ 9.23 (s, 1H), 8.30 (d, >5.6 Hz, 1H), 8.01 (s, 1H), 7.97 (d, > 2.1 Hz, 1H), 7.60 (dd, >5.6, 2.2 Hz, 1H), 7.337.29 (m, 2H), 7.26-7.17 (m, ZN), 6 .42 (t, >5.6 Hz, 1H), 3.39-3.34 (m, 2H), 2.77 (t, >7.2 Hz, 2H), 1.39 (s, 9H) . LC-MS (Method A): Rt 2.91 min; MS m/z 341.3 = [M+H]+ (95% @215 nm) 64.3 CH ₃ O AH N ₃ C. | || ^{n H n} ' ^s ΥΓΎ Υ Ν^Υ O CH ₃ T4-tert-Butyl-4-[[(1R)-1 - phenylethyl]carbamoylamino]pyridine-2-carboxamide 1HNMR (500 MHz, DMSO-bb) δ 9.10 (s, 1H), 8.30 (d, >5.6 Hz, 1H), 8.00 (s, 1H), 7.95 (d, > 2.2 Hz, 1H), 7.57 (dd, >5.6, 2.3 Hz, 1H), 7.377.33 (m, 4H), 7.26-7.22 (m, 1H), 6 .93 (d, >7.8 Hz, 1H), 4.84 (p, >7.0 Hz, 1H), 1.41 (d, >7.0 Hz, ZN), 1.38 (s, 9H). LC-MS (Method A): Rt 2.92 min; MS m/z 341.4 = [M+H]+ (98% @215 nm) 64.4 CH, O N ₃ Cx| || НН Y\ YY / ^Ν χ / ^N x ^CH, n ₃ s ν ΥΥ γ γ ^σ δ T4-tert-Butyl-4-[[(18)-1phenylethyl]carbamoylamino]pyridine-2-carboxamide 1HNMR (500 MHz, Methanol-sM) δ 8.34 (d, >5.7 Hz, 1H), 7.94-7.89 (m, 1H), 7.75 (dd, >5.7, 2 ,1 Hz, 1H), 7.41-7.31 (m, 4H), 7.30-7.22 (m, 1H), 4.95 (k, >7.0 Hz, 1H), 1, 51 (d, >7.0 Hz, ZN), 1.48 (s, 9H). LC-MS (Method A): Rt 2.91 min; MS m/z 341.3 = [M+H]+ (99% @ 215 nm) 64.5 CL χ^\ n ₃ s< ^Нз jj Η η ||] Yk Yk ζχ/Υ/Υ Υγ. Υ n ₃ s ν ΥΥ Υτ 71 Η ^{11 11} Ο T4-tert-Butyl-4-[(2-chlorophenyl)methylcarbamoylamino]pyridine-2carboxamide 1H NMR (500 MHz, Methanol-b4) δ 8.34 (d, >5.3 Hz, 1H), 7.92 (s, 1H), 7.79-7.73 (m, 1H), 7, 45 (dd, >7.4, 1.8 Hz, 1H), 7.42 (dd, >7.6, 1.6 Hz, 1H), 7.35-7.24 (m, 2H), 4 .52 (s, 2H), 1.48 (s, 9H). LC-MS (Method A): Rt 3.07 min; MS m/z 361.2/363.2 = [M+H]+ (100% @215 nm) 64.6 n ₃ sU ^Hz jj NN n ₃ s ν XV γ ΥΛΧ ^η Μ θ ΥΥ T4-tert-butyl-4-( 1 H-indole-3 - ylcarbamoylamine)pyridine-2-carboxamide 1H NMR (500 MHz, Methanol-b4) δ 8.38 (d, >5.6 Hz, 1H), 8.29 (s, 1H), 7.99 (d, >2.0 Hz, 1H), 7.85 (dd, >5.6, 2.2 Hz, 1H), 7.55 (dt, >8.1, 0.9 Hz, 1H), 7.50 (s, 1H), 7.40 -7.35 (m, 1H), 7.19-7.12 (m, 1H), 7.11-7.03 (m, 1H), 1.50 (s, 9H). LC-MS (Method A): Rt 2.68 min; MS m/z 352.3 = [M+H]+ (99% @ 215 nm)

- 148 046966

64.7 CI ycT ³ N ^{n n} M] ⁿ = ^s ΎΎ Y ⁰ X-tert-Butyl-4-[(3-chlorophenyl)methylcarbamoylamino]pyridine-2carboxamide 1HNMR (500 MHz, Methanol-04) δ 8.38-8.33 (m, 1H), 7.96-7.91 (m, 1H), 7.77 (dd, J=5.6, 2, 3 Hz, 1H), 7.38 (s, 1H), 7.38 (t, J=l.5 Hz, 1H), 7.31-7.25 (m, 2H), 4.42 (s, 2H), 1.49 (s, 9H). LC-MS (Method A): Rt 3.12 min; MS m/z 361.3/363.3 = [M+H]+ (100% @215 nm) 64.8 ^C1 n ₃ cT ³ Η n n ]|f H ₃ C N Ti aG If ⁿ M I X-tert-butyl-4-[(4-chlorophenyl)methylcarbamoylamino]pyridine-2carboxamide 1HNMR (500 MHz, Methanol-b4) δ 8.37-8.32 (m, 1H), 7.95-7.91 (m, 1H), 7.77 (dd, J=5.6, 2, 3 Hz, 1H), 7.35 (s, 4H), 4.41 (s, 2H), 1.49 (s, 9H). LC-MS (Method A): Rt 3.12 min; MS m/z 361.3/363.2 = [M+H]+ (100% @215 nm)

Example 65.

No. tert-Butyl-4-[(2-hydroxyphenyl)carbamoylamino]pyridine-2-carboxamide

Step 1: U-tert-Butyl-4-[(2-methoxyphenyl)carbamoylamino]11iridine-2-carboxamide

The title compound was prepared from 1-isocyanato-2-methoxybenzene and 4-amino-N-tert-butylpyridine-2-carboxamide (Example 3, Step 1) analogously to Example 64.

1H NMR (500 MHz, DMSO-a ₆ ) δ 9.95 (s, 1H), 8.43-8.37 (m, 2H), 8.11 (dd, J=8.0, 1.6 Hz , 1H), 8.06-8.03 (m, 2H), 7.63 (dd, J=5.5, 2.3 Hz, 1H), 7.06-6.98 (m, 2H), 6.92 (td, J=7.8, 1.5 Hz, 1H), 3.89 (s, 3H), 1.41 (s, 9H).

LC-MS (Method A): Rt 3.21 min; MS m/z 343.2 = [M+H]+ (100% @ 215 nm).

Step 2: N-tert-Butyl-4-[(2-hydroxyphenyl)carbamoylamino]pyridine-2-carboxamide N-tert-Butyl-4-[(2-methoxyphenyl)carbamoylamino]pyridine-2-carboxamide (Step 1) (41 mg , 0.12 mmol) was added to a suspension of 1 M BBr ₃ in DCM (532 μl, 0.53 mmol) in DCM (1 ml) at 0-5°C. After stirring at room temperature for 2.5 hours, the mixture was concentrated in vacuo and the residue was partitioned between EtOAc (4 ml) and water (4 ml). The pH of the aqueous layer was adjusted to pH 5-6 using sat. aq. NaHCO ₃ and the organic layer was separated, washed with saturated aqueous sodium chloride (2 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was dissolved in MeCN:H ₂ O (1.1 ml, 4:1), filtered and purified by preparative HPLC (acidic pH, early elution method) to give the title compound as a beige solid.

1H NMR (250 MHz, DMSO-a ₆ ) δ 10.38-9.64 (m, 2H), 8.50-8.26 (m, 2H), 8.07-7.99 (m, 3H) , 7.63 (dd, J=5.6, 2.3 Hz, 1H), 6.89-6.72 (m, 3H), 1.40 (s, 9H).

LC-MS (Method A): Rt 2.72 min; MS m/z 329.3 = [M+H]+ (100% @ 215 nm).

Example 65.1.

No. tert-Butyl-4-[(2-methoxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide

The title compound was prepared from 4-amino-N-tert-butylpyridin-2-carboxamide (Example 3, Step 1) and 1-(isocyanatomethyl)-2-methoxybenzene analogously to Example 65, Step 1.

1H NMR (500 MHz, DMSO-a ₆ ) δ 9.33 (s, 1H), 8.31 (d, J=5.6 Hz, 1H), 8.02 (s, 1H), 7.98 ( d, J=2.1 Hz, 1H), 7.60 (dd, J=5.6, 2.3 Hz, 1H), 7.29-7.21 (m, 2H), 7.03-6 .99 (m, 1H), 6.94-6.88 (m, 1H), 6.75 (t, J=5.9 Hz, 1H), 4.28 (d, J=5.9 Hz, 2H), 3.84 (s, 3H), 1.40 (s, 9H).

LC-MS (Method A): Rt 2.86 min; MS m/z 357.3 = [M+H]+ (99% @ 215 nm).

Example 65.2.

- 149 046966 No. tert-Butyl-4-[(2-hydroxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide

The title compound was prepared from K-tert-butyl-4-[(2methoxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide (Example 65.1) analogously to Example 65, Step 2

Ή NMR (500 MHz, DMSO-06) δ 9.60 (s, 1H), 9.31 (s, 1H), 8.31 (d, J=5.6 Hz, 1H), 8.01 (s , 1H), 7.96 (d, J=2.1 Hz, 1H), 7.60 (dd, J=5.6, 2.3 Hz, 1H), 7.16 (dd, J=7, 5, 1.5 Hz, 1H), 7.08 (td, J=7.8, 1.7 Hz, 1H), 6.82 (dd, J=8.0, 1.0 Hz, 1H), 6.76 (td, J=7.4, 1.1 Hz, 1H), 6.72 (t, J=5.9 Hz, 1H), 4.24 (d, J=5.8 Hz, 2H ), 1.39 (s, 9H).

LC-MS (Method A): Rt 2.56 min; MS m/z 343.2 = [M+H]+ (97% @ 215 nm).

Example 65.3.

No. tert-Butyl-4-[(3-hydroxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide

The title compound was prepared from 4-amino-K-tert-butylpyridin-2-carboxamide (Example 3, Step 1) and 1-(isocyanatomethyl)-3-methoxybenzene analogously to Example 65, Steps 1 and 2.

1H NMR (500 MHz, Methanol^ ₄ ) δ 8.34 (d, J=5.6 Hz, 1H), 7.92 (d, J=2.1 Hz, 1H), 7.77 (dd, J =5.6, 2.2 Hz, 1H), 7.16 (t, J=7.8 Hz, 1H), 6.83-6.77 (m, 2H), 6.72-6.65 ( m, 1H), 4.35 (s, 2H), 1.48 (s, 9H).

LC-MS (Method A): Rt 2.24 min; MS m/z 343.3 = [M+H]+ (96% @ 215 nm).

Example 65.4.

C-tert-Butyl-4-[(4-hydroxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide

The title compound was prepared from 4-amino-K-tert-butylpyridin-2-carboxamide (Example 3, Step 1) and 1-(isocyanatomethyl)-4-methoxybenzene analogously to Example 65, Steps 1 and 2.

1H NMR (500 MHz, Methanol^) δ 8.34 (d, J=5.6 Hz, 1H), 7.91 (d, J=1.9 Hz, 1H), 7.77 (dd, J= 5.6, 2.3 Hz, 1H), 7.21-7.14 (m, 2H), 6.80-6.73 (m, 2H), 4.31 (s, 2H), 1.48 (s, 9H).

LC-MS (Method A): Rt 2.16 min; MS m/z 343.3 = [M+H]+ (98% @ 215 nm).

Example 66.

C-tert-Butyl-4-[[2-[2-hydroxy-5-(1-hydroxyethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

Step 1: 4-[[2-(5-Acetyl-2-methoxyphenyl)acetyl]amino]-C-tert-butylpyridine-2-carboxamide

4-[[2-(5-Bromo-2-methoxyphenyl)acetyl]amino]-C-tert-butylpyridine-2-carboxamide (example 6, step 1) (985 mg, 2.34 mmol), ZnF ₂ (218 mg, 1.87 mmol) and Pd(dba) ₂ (135 mg, 0.23 mmol) were dissolved in anhydrous DMF (10 ml) at room temperature and degassed with N2 in a sealed pressure vessel. To this mixture was added tri-tert-butylphosphine (1 M in toluene, 0.47 mL, 0.47 mmol) followed by trimethyl(vinyloxy)silane (0.42 mL, 2.81 mmol), and the vessel was heated at 70°C overnight. An additional portion of trimethyl(vinyloxy)silane (105 μl, 0.70 mmol) was added and the mixture was heated at 70°C for an additional 4 hours. After cooling to room temperature, the mixture was diluted with TBME (40 ml) and filtered through a pad of kieselguhr. The filtrate was concentrated in vacuo and purification of the residue by chromatography on silica gel, eluting with 0-100% TBME in heptane, afforded the title compound as a yellow solid.

1H NMR (500 MHz, Chloroform-d) δ 8.40-8.37 (m, 1H), 8.21 (dd, J=5.6, 2.2 Hz, 1H), 7.99-7, 92 (m, 3H), 7.83 (s, 1H), 7.53 (d, J=2.2 Hz, 1H), 7.02 (d, J=8.6 Hz, 1H), 4, 02 (s, 3H), 3.78 (s, 2H), 2.58 (s, 3H), 1.47 (s, 9H).

- 150 046966

LC-MS (Method E): Rt 1.11 min; MS m/z 384.1 = [M+H]+ (78% @ 215 nm).

Step 2: N-tert-Butyl-4-[[2-[5-(1-hydroxyethyl)-2-methoxyphenyl]acetyl]amino]pyridine-2carboxamide

I dn ₃

A solution of 4-[[2-(5-acetyl-2-methoxyphenyl)acetyl]amino]-N-tert-butylpyridine-2-carboxamide (step 1) (45 mg, 0.09 mmol) in MeOH (1 ml) was treated NaBH ₄ (4 mg, 0.1 mmol) and stirred at room temperature for 2 hours. The reaction mixture was quenched by adding 10% aq. H ₃ PO ₄ (1 ml) and this mixture was extracted with EtOAc (2x2 ml). The combined organic extracts were washed with water (2 ml) and saturated aqueous sodium chloride (2 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound as a white metallic solid.

1H NMR (500 MHz, DMSO-06) δ 10.66 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H ), 8.04 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.23-7.17 (m, 2H), 6.94-6, 89 (m, 1H), 4.65 (k, J=6.4 Hz, 1H), 3.73 (s, 3H), 3.68 (s, 2H), 1.40 (s, 9H), 1.29 (d, J=6.4 Hz, 3H)

LC-MS (Method E): Rt 1.06 min; MS m/z 386.1 = [M+H]+ (97% @ 215 nm).

Step 3: N-tert-Butyl-4-[[2-[2-hydroxy-5-(1-hydroxyethyl)phenyl]acetyl]amino]pyridine-2-carboxamide N-tert-butyl-4-[[2-[5-( 1-Hydroxyethyl)-2-methoxyphenyl]acetyl]amino]pyridine-2-carboxamide (step 2) (39 mg, 0.09 mmol) was added to a suspension of 1 M BBr ₃ in DCM (303 μl, 0.3 mmol) in DXM (1 ml) in DXM (1 ml) at 0-5°C. After stirring at room temperature for 2 hours, the mixture was concentrated in vacuo and the residue was partitioned between EtOAc (4 ml) and water (4 ml). The pH of the aqueous layer was adjusted to pH 5-6 using sat. aq. NaHCO ₃ and the organic layer was separated, washed with saturated aqueous sodium chloride (2 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was dissolved in MeCN:H ₂ O (1.1 ml, 4:1), filtered and purified by preparative HPLC (acidic pH, early elution method) to obtain the title compound as a beige powder.

1H NMR (500 MHz, DMSO) δ 10.64 (br.s, 1H), 9.34 (br.s, 1H), 8.43 (d, J=5.5 Hz, 1H), 8.18 (d, J=1.9 Hz, 1H), 8.03 (s, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.12 (d, J= 2.1 Hz, 1H), 7.03 (dd, J=8.2, 2.2 Hz, 1H), 6.73 (d, J=8.2 Hz, 1H), 4.93 (d, J=4.1 Hz, 1H), 4.63-4.57 (m, 1H), 3.64 (s, 2H), 1.40 (s, 9H), 1.27 (d, J=6 ,4 Hz, 3H).

LC-MS (Method A): Rt 2.45 min; MS m/z 372.3 = [M+H]+ (99% @ 215 nm).

Example 67.

No. tert-Butyl-4-[[2-[2-hydroxy-5-[1-(2,2,2-trifluoroethylamine)ethyl]phenyl]acetyl]amino]pyridine-2carboxamide

Step 1: No. tert-Butyl-4-[[2-[2-methoxy-5-[1-(2,2,2trifluoroethylamine)ethyl]phenyl]acetyl]amino]pyridine-2-carboxamide

I

CH ₃

To a solution of 4-[[2-(5-acetyl-2-methoxyphenyl)acetyl]amino]-N-tert-butylpyridine-2-carboxamide (Example 66, Step 1) (73 mg, 0.15 mmol) in dichloroethane ( 1.5 ml) 2,2,2-trifluoroethanamine (14 µl, 0.18 mmol) and acetic acid (17 µl, 0.3 mmol) were added and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (40 mg, 0.19 mmol) was added and the reaction mixture was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo and the residue was dissolved in EtOAc (4 ml). The mixture was washed with sat. aq. NaHCO ₃ (4 ml) and saturated aqueous sodium chloride (4 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by preparative HPLC (acidic pH, early elution method), and the product fractions were combined and the pH was adjusted to pH 8 with sat. aq. _NaHCO3 . The mixture was extracted with DCM using a hydrophobic phase separator and the filtrate was concentrated in vacuo with

- 151 046966 obtaining the title compound in the form of a white solid with a metallic tint.

LC-MS (Method E): Rt 1.07 min; MS m/z 467.2 = [M+H]+ (99% @ 215 nm).

Step 2: N-tert-Butyl-4-[[2-[2-hydroxy-5-[1-(2,2,2trifluoroethylamine)ethyl]phenyl]acetyl]amino]pyridine-2-carboxamide

The title compound was prepared from N-tert-butyl-4-[[2-[2-methoxy-5-[1-(2,2,2trifluoroethylamine)ethyl]phenyl]acetyl]amino]pyridine-2-carboxamide (Step 1 ) similar to example 66, stage 3.

¹ H NMR (500 MHz, DMSO-b6) δ 10.63 (s, 1H), 9.39 (s, 1H), 8.43 (d, J=5.5 Hz, 1H), 8.18 ( d, J=2.1 Hz, 1H), 8.03 (s, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.08 (d, J=2 .0 Hz, 1H), 7.04 (dd, J=8.2, 2.2 Hz, 1H), 6.75 (d, J=8.2 Hz, 1H), 3.71-3.62 (m, 3H), 3.03-2.91 (m, 2H), 2.67 (k, J=8.7, 8.1 Hz, 1H), 1.40 (s, 9H), 1, 23 (d, J=6.6 Hz, 3H).

LC-MS (Method A): Rt 2.22 min; MS m/z 453.3 = [M+H]+ (97% @ 215 nm).

Example 68.

No. tert-Butyl-4-[[2-[3 -(cyanomethyl)phenyl] acetyl] amino] pyridine-2-carboxamide

Step 1: 4-[[2-[3-(Bromomethyl)phenyl]acetyl]amino]-N-tert-butylpyridine-2-carboxamide

The title compound was prepared from 2-[3-(bromomethyl)phenyl]acetic acid and 4-amino-N-tert-butylpyridine-2-carboxamide (Example 3, Step 1) analogously to Example 3.5b, Step 1.

LC-MS (Method E): Rt 1.20 min; MS m/z 404.0/406.0 = [M+H]+ (44% @ 215 nm).

Step 2: N-tert-Butyl-4-[[2-[3-(cyanomethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

4-[[2-[3-(Bromomethyl)phenyl]acetyl]amino]-N-tert-butylpyridine-2-carboxamide (Step 1) (50 mg, 0.05 mmol) was treated with sodium cyanide (5 mg, 0. 11 mmol) and tetrabutylammonium bromide (2 mg, 0.01 mmol) in a 1:1 mixture of DCM:water (2 ml) and stirred at room temperature for 18 hours. The resulting mixture was diluted with sat. aq. NaHCO ₃ (5 ml) and extracted with DCM (3x5 ml). The combined organic extracts were concentrated in vacuo and the residue was dissolved in DMSO:MeCN (800 µl, 1:1), filtered and purified by preparative HPLC (acidic pH, early elution method) to give the title compound as a colorless glassy solid.

¹ H NMR (500 MHz, DMSOA) δ 10.78 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.0 Hz, 1H) , 8.02 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.36 (t, J=7.6 Hz, 1H), 7.33- 7.28 (m, 2H), 7.24 (d, J=7.7 Hz, 1H), 4.04 (s, 2H), 3.74 (s, 2H), 1.39 (s, 9H ).

LC-MS (Method A): Rt 3.04 min; MS m/z 351.2 = [M+H]+ (96% @ 215 nm).

Example 69.

No. tert-Butyl-4-[[2-[3 -(methoxymethyl)phenyl] acetyl] amino] pyridine-2-carboxamide

4-[[2-(3-bromophenyl)acetyl]amino]-N-tert-butylpyridine-2-carboxamide (example 54, step 1) (50 mg, 0.13 mmol) PdCl ₂ dppf (3 mg) was loaded into the vessel ), potassium trifluoro(methoxymethyl)borohydride (0.45 ml, 0.26 mmol), 2 M aq. sodium carbonate (0.26 ml, 0.51 mmol) and heated at 80°C for 16 hours. The mixture was left to cool to room temperature, poured into water (20 ml) and extracted with EtOAc (3x20 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (50 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was dissolved in DMSO:MeCN (800 µl, 1:1), filtered and purified by preparative HPLC (acidic pH, early elution method) to give the title compound as a white solid with a metallic tint.

¹ H NMR (500 MHz, DMSOA) δ 10.76 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H) , 8.02 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.34-7.27 (m, 2H), 7.25 (d, J =7.7 Hz, 1H), 7.20 (d, J=7.5 Hz, 1H), 4.40 (s, 2H), 3.71 (s, 2H), 3.29 (s, 3H ), 1.39 (s, 9H).

LC-MS (Method C): Rt 3.18 min; MS m/z 356.3 = [M+H]+ (94% @ 215 nm).

Example 70.

- 152 046966 No. tert-Butyl-4-[[2-[2-hydroxy-5-(morpholinomethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

The title compound was prepared from 4-[[2-(5-bromo-2-methoxyphenyl)acetyl]amino]-Ntert-butylpyridine-2-carboxamide (Example 6, Step 1) and potassium trifluoro(morpholinomethyl)borohydride analogously to Example 27, stages 3 and 4.

1H NMR (500 MHz, DMSO-06) δ 10.64 (br.s, 1H), 9.43 (br.s, 1H), 8.43 (d, J=5.5 Hz, 1H), 8 .18 (d, J=2.1 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.06 (d, J=2.0 Hz, 1H), 6.99 (dd, J=8.1, 2.1 Hz, 1H), 6.74 (d, J=8.1 Hz, 1H), 3.64 ( s, 2H), 3.55-3.51 (m, 4H), 2.34-2.25 (m, 4H), 1.40 (s, 9H).

LC-MS (Method A): Rt 1.66 min; MS m/z 427.4 = [M+H]+ (98% @ 215 nm).

Example 71.

3-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-(3-cyanotetrahydrofuran-3-yl)benzamide

Step 1: Methyl 3-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]benzoate

A solution containing methyl 3-amine benzoate (1 g, 6.62 mmol) and 2-(5-chloro-2-methoxyphenyl)acetic acid (1.39 g, 6.95 mmol) in DMF (10 ml) was treated DIPEA (1.73 ml, 9.92 mmol) followed by the addition of HATU (3019 mg, 7.94 mmol) and stirred at room temperature for 1 hour. The resulting mixture was diluted with water (50 ml) and EtOAc (60 ml) with formation of a two-phase solution. Heptane (15 ml) was added and the organic portion was separated, washed with water, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was treated with TBME (50 ml) and the resulting suspension was filtered, washing with TBME, and dried in vacuo to give the title compound as a white, metallic powder.

1H NMR (500 MHz, DMSO-06) δ 10.31 (s, 1H), 8.28 (t, J=1.8 Hz, 1H), 7.84-7.80 (m, 1H), 7 .63 (dt, J=7.7, 1.2 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 7.29 (dd, J=6.5, 2.9 Hz, 2H), 7.03-6.98 (m, 1H), 3.84 (s, 3H), 3.76 (s, 3H), 3.66 (s, 2H).

LC-MS (Method E): Rt 1.17 min; MS m/z 334.0/336.0 = [M+H]+ (98% @ 215 nm).

Step 2: 3-[[2-(5-Chloro-2-methoxyphenyl)acetyl]amino]benzoic acid

dn ₃

The title compound was prepared from methyl 3-[[2-(5-chloro-2methoxyphenyl)acetyl]amino]benzoate (Step 1) analogously to Example 41, Step 2.

1H NMR (500 MHz, DMSO-06) δ 12.82 (s, 1H), 10.26 (s, 1H), 8.22 (s, 1H), 7.81 (dd, J=8.1, 1.1 Hz, 1H), 7.61 (dt, J=7.7, 1.2 Hz, 1H), 7.41 (t, J=7.9 Hz, 1H), 7.29 (dd, J=6.9, 2.7 Hz, 2H), 7.03-6.98 (m, 1H), 3.76 (s, 3H), 3.66 (s, 2H).

LC-MS (Method E): Rt 1.06 min; MS m/z 319.9/321.7 = [M+H]+ (99% @ 215 nm).

Step 3: 3-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]benzoic acid

The title compound was prepared from 3-[[2-(5-chloro-2methoxyphenyl)acetyl]amino]benzoic acid (Step 2) analogously to Example 41, Step 3.

1H NMR (500 MHz, DMSO-06) δ 12.91 (br.s, 1H), 10.25 (s, 1H), 9.78 (s, 1H), 8.23 (t, J=1, 8 Hz, 1H), 7.82 (dd, J=8.1, 1.1 Hz, 1H), 7.61 (dt, J=7.7, 1.2 Hz, 1H), 7.42 ( t, J=7.9 Hz, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.11

- 153 046966 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.62 (s, 2H).

LC-MS (Method E): Rt 1.01 min; MS m/z 305.9/308.0 = [M+H]+ (99% @ 215 nm).

Step 4: 3-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-A3-cyanotetrahydrofuran-3yl)benzamide

To a solution of 3-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]benzoic acid (step 3) (150 mg, 0.49 mmol), 3-aminotetrahydrofuran-3-carbonitrile hydrochloride (73 mg, 0 .49 mmol) and DIPEA (343 µl, 1.96 mmol) in DMF (1.5 ml), HATU (224 mg, 0.59 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The resulting mixture diluted with EtOAc and washed with 1 M NaOH (3x20 ml). The aqueous layer was extracted with EtOAc (2x10 ml), then acidified with 1 M HCl, and the remaining product was extracted with EtOAc (3x30 ml). The combined organic extracts were dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by preparative HPLC (acidic pH, early elution method) yielded the title compound as a white solid with a metallic tint.

1H NMR (500 MHz, DMSO-b6) δ 10.29 (s, 1H), 9.82 (br.s, 1H), 9.21 (s, 1H), 8.08 (t, J=1, 8 Hz, 1H), 7.81 (dd, J=8.1, 1.1 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.43 (t, J= 7.9 Hz, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 4.26 (d, J=9.5 Hz, 1H), 3.96 (d, J=9.5 Hz, 1H), 3.94-3.86 ( m, 2H), 3.62 (s, 2H), 2.62-2.55 (m, 2H).

LC-MS (Method A): Rt 2.64 min; MS m/z 400.3/402.2 = [M+H]+ (99% @ 215 nm).

Example 71.1.

- [[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-(1-methylcyclohexyl)benzamide

The title compound was prepared from 3-[[2-(5-chloro-2hydroxyphenyl)acetyl]amino]benzoic acid (Example 71, Step 3) and 1-methylcyclohexanamine analogously to Example 71.

1H NMR (500 MHz, Methanol^) δ 7.94 (t, J=1.8 Hz, 1H), 7.75-7.72 (m, 1H), 7.51-7.47 (m, 1H ), 7.42 (t, J=7.9 Hz, 1H), 7.24 (d, J=2.6 Hz, 1H), 7.12 (dd, J=8.6, 2.6 Hz , 1H), 6.83 (s, 1H), 3.72 (s, 2H), 2.27 (d, J=13.1 Hz, 2H), 1.68-1.56 (m, 5H) , 1.54-1.47 (m, 2H), 1.46 (s, 3H), 1.45-1.36 (m, 1H).

LC-MS (Method A): Rt 3.58 min; MS m/z 401.2/403.2 = [M+H]+ (96% @ 215 nm).

Example 72.

4-[[2-(5-Fluoro-2-hydroxyphenyl)acetyl]amino]-N-[3-(hydroxymethyl)tetrahydrofuran-3yl]pyridine-2-carboxamide

The title compound was prepared from 4-[[2-(5-fluoro-2hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 49, steps 1-3) and (3-aminotetrahydrofuran-3-yl)methanol analogously to Example 35 .

1H NMR (500 MHz, DMSO-b6) δ 9.52 (br.s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.42 (s, 1H), 8.20 (d, J=2.1 Hz, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.02 (dd, J=9.4, 3.2 Hz, 1H), 6.91 (td, J=8.6, 3.2 Hz, 1H), 6.79-6.75 (m, 1H), 5.17 (s, 1H), 3.90-3 .77 (m, 4H), 3.67 (s, 2H), 3.62 (s, 2H), 2.35-2.29 (m, 1H), 2.01-1.95 (m, 1H ).

LC-MS (Method A): Rt 1.99 min; MS m/z 390.2/392.3 = [M+H]+ (100% @ 215 nm).

Example 73.

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-[1 -(hydroxymethyl)-2-methoxy-1 methylethyl]pyridine-2-carboxamide CH ₃

The title compound was prepared from 4-[[2-(5-chloro-2hydroxyphenyl)acetyl]amino]pyridin-2-carboxylic acid (Example 31, Step 1) and 2-amino-3methoxy-2-methylpropan-1-ol hydrochloride (prepared according to Tetrahedron, Volume 56, Issue 23, June 2, 2000, pages 3799-3816) analogously to Example 35.

1H NMR (500 MHz, Methanol^) δ 8.45 (dd, J=5.5, 0.5 Hz, 1H), 8.19-8.14 (m, 1H), 7.91 (dd, J =5.5, 2.2

- 154 046966

Hz, 1H), 7.20 (d, J=2.6 Hz, 1H), 7.10 (dd, J=8.6, 2.6 Hz, 1H), 6.79 (d, J=8 .6 Hz, 1H), 3.83 (d, J=11.1 Hz, 1H),

3.76-3.69 (m, 3H), 3.65 (d, J=9.1 Hz, 1H), 3.59 (d, J=9.1 Hz, 1H), 3.42 (s , 3H), 1.44 (s, 3H).

LC-MS (Method A): Rt 2.63 min; MS m/z 408.2 = [M+H]+ (99% @ 215 nm).

Example 73.1.

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-K-(1,1-dimethylbut-2-ynyl)pyridine-2-carboxamide

The title compound was prepared from 4-[[2-(5-chloro-2hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 31, Step 1) and 2-methylpent-3-yne2-amine hydrochloride (prepared in according to WO 03048128 A1, page 55) similar to example 73.

¹ H NMR (500 MHz, DMSO-de) δ 10.70 (br.s, 1H), 9.81 (br.s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.25 (s, 1H), 8.18 (d, J=2.0 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d , J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.67 (s, 2H), 1.78 (s, 3H), 1.63 (s, 6H).

LC-MS (Method A): Rt 3.31 min; MS m/z 386.3/388.2 = [M+H]+ (97% @ 215 nm).

Example 74.

3-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-K-(1,1-dimethylprop-2-ynyl)benzamide

2-Methylbut-3-yne-2-amine (49 mg, 0.59 mmol) and 3-[[2-(5-chloro-2hydroxyphenyl)acetyl]amino]benzoic acid (Example 71, Step 3) (150 mg , 0.49 mmol) was dissolved in DMF (1 ml) and treated with TEA (0.26 ml, 1.47 mmol) followed by the addition of HATU (224 mg, 0.59 mmol) and stirred for 2 hours. The resulting mixture was diluted EtOAc and washed with sat. aq. Na ₂ CO ₃ (10 ml). The aqueous layer was extracted with EtOAc (2x10 ml) and the combined organic extracts were washed with 1 M NaOH (3x20 ml). The aqueous layer was acidified with 1 M HCl and the remaining product was extracted with EtOAc (3x30 ml). The combined organic extracts were neutralized by washing with saturated aqueous sodium hydrogen carbonate, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude residue was purified by preparative HPLC (acidic pH early elution method) to give the title compound as a white foamy solid with a metallic tint.

1H NMR (500 MHz, DMSO-d6) δ 10.21 (s, 1H), 9.79 (s, 1H), 8.20 (s, 1H), 7.94 (t, J=1.8 Hz , 1H), 7.807.74 (m, 1H), 7.47-7.42 (m, 1H), 7.36 (t, J=7.9 Hz, 1H), 7.20 (d, J= 2.7 Hz, 1H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.61 (s, 2H), 3.08 (s, 1H), 1.59 (s, 6H).

LC-MS (Method A): Rt 2.92 min; MS m/z 371.2/373.2 = [M+H]+ (97% @ 215 nm).

Example 74.1.

3-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-^[3-(hydroxymethyl)tetrahydrofuran-3yl]benzamide

BUT

The title compound was prepared from 3-[[2-(5-chloro-2hydroxyphenyl)acetyl]amino]benzoic acid (Example 71, Step 3) and (3-aminotetrahydrofuran-3yl)methanol analogously to Example 74.

1H NMR (500 MHz, DMSO^ ₆ ) δ 10.20 (s, 1H), 9.80 (s, 1H), 8.12 (s, 1H), 7.95 (t, J=1.8 Hz , 1H), 7.817.74 (m, 1H), 7.53-7.47 (m, 1H), 7.36 (t, J=7.9 Hz, 1H), 7.20 (d, J= 2.7 Hz, 1H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 4.97 (t, J=5.8 Hz, 1H), 3.89 (d, J=9.2 Hz, 1H), 3.81-3.73 (m, 3H), 3.67 (dd, J=10.8 , 5.7 Hz, 1H), 3.64-3.59 (m, 3H), 2.23 (dt, J=12.8, 6.4 Hz, 1H), 2.05 (dt, J= 12.9, 7.7 Hz, 1H).

LC-MS (Method A): Rt 2.24 min; MS m/z 405.2/407.2 = [M+H]+ (100% @ 215 nm).

Example 75.

No. tert-Butyl-4-[[2-[2-hydroxy-5-(3-hydroxypropyl)phenyl]acetyl]amino]pyridine-2-carboxamide

- 155 046966

Step 1: Ethyl (E)-3-[3-[2-[[2-(tert-butylcarbamoyl)-4-pyridyl]amino]-2-oxoethyl]-4methoxyphenyl]prop-2-enoate

dn ₃

Mixture containing 4-[[2-(5-bromo-2-methoxyphenyl)acetyl]amino]-M-tert-butylpyridine-2carboxamide (example 6, step 1) (500 mg, 1.19 mmol), ethylprop-2 -enoate (0.52 ml, 4.76 mmol), Pd ₂ (dba) ₃ (109 mg, 0.12 mmol), tri-o-tolylphosphine (109 mg, 0.36 mmol), TEA (1.04 ml, 5.95 mmol) in DMF (10 ml) under nitrogen, stirred at 90°C for 18 hours. The resulting mixture was filtered, diluted with EtOAc (10 ml) and washed with saturated aqueous sodium chloride (1x10 ml). The saturated aqueous sodium chloride solution was re-extracted with EtOAc (2x10 ml) and the combined organic extracts were dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc in heptane to give the title compound as an orange/brown solid.

^1H NMR (250 MHz, DMSO-06) δ 10.69 (s, 1H), 8.44 (d, J=5.6 Hz, 1H), 8.19-8.16 (m, 1H), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.67-7.60 (m, 2H), 7.56 (s, 1H) , 7.04 (d, J=9.2 Hz, 1H), 6.46 (d, J=16.0 Hz, 1H), 4.17 (k, J=7.1 Hz, 2H), 3 .80 (s, 3H), 3.72 (s, 2H), 1.40 (s, 9H), 1.25 (t, J=7.1 Hz, 3H).

LC-MS (Method E): Rt 1.23 min; MS m/z 440.0 = [M+H]+ (65% @ 215 nm).

Step 2: Ethyl 3-[3-[2-[[2-(tert-butylcarbamoyl)-4-pyridyl]amino]-2-oxoethyl]-4methoxyphenyl]propanoate

I dn ₃

Ethyl-(E)-3-[3-[2-[[2-(tert-butylcarbamoyl)-4-pyridyl]amino]-2-oxo-ethyl]-4-methoxyphenyl]prop2-enoate (step 1) ( 625 mg, 0.92 mmol) in EtOH (9.24 ml) under nitrogen, treated with 10% Pd-C (50% w/w, 20 mg, 0.09 mmol) and placed under hydrogen. After stirring at room temperature for 19 hours, the mixture was filtered through kieselguhr (diatomaceous earth) and washed with EtOAc. The filtrate was concentrated in vacuo to give the title compound as a white solid with a metallic tint.

1H NMR (250 MHz, DMSO-06) δ 10.64 (s, 1H), 8.43 (d, J=5.5 Hz, 1H), 8.18 (d, J=1.8 Hz, 1H ), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.13-7.04 (m, 2H), 6.89 (d, J=8.3 Hz, 1H), 4.02 (cd, J=7.1, 1.1 Hz, 2H), 3.72 (s, 3H), 3.65 (s, 2H), 2, 78 (t, J=7.4 Hz, 2H), 2.60-2.52 (m, 2H), 1.40 (s, 9H), 1.14 (t, J=7.2 Hz, 3H ).

LC-MS (Method E): Rt 1.23 min; MS m/z 442.3 = [M+H]+ (61% @ 215 nm).

Step 3: 3-[3-[2-[[2-(tert-Butylcarbamoyl)-4-pyridyl]amino]-2-oxo-ethyl]-4methoxyphenyl]propanoic acid

I dn ₃

To a solution of ethyl 3-[3-[2-[[2-(tert-butylcarbamoyl)-4-pyridyl]amino]-2-oxo-ethyl]-4methoxyphenyl]propanoate (step 2) (332 mg, 0.75 mmol) in THF (4.3 ml)/water (1 ml), 1 M LiOH (631 mg, 15.04 mmol) was added and the reaction mixture was stirred at room temperature for 5.5 hours. The resulting mixture was extracted with EtOAc, and the aqueous layer was diluted with water and acidified to pH 3-4 with 6 M HCl. The resulting mixture was extracted with EtOAc (3x25 ml) and the combined organic extracts were filtered, dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound as a yellow oil.

1H NMR (500 MHz, DMSO-06) δ 10.64 (s, 1H), 8.43 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.0 Hz, 1H ), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.11-7.06 (m, 2H), 6.89 (d, J=8.3 Hz, 1H), 3.72 (s, 3H), 3.66 (s, 2H), 2.75 (t, J=7.7 Hz, 2H), 1.40 (s, 9H).

LC-MS (Method E): Rt 1.08 min; MS m/z 414.2 = [M+H]+ (79% @ 215 nm).

- 156 046966

Step 4: ^tert-Butyl-4-[[2-[5-(3-hydroxypropyl)-2-methoxyphenyl]acetyl]amino]pyridine-2carboxamide

To a cooled (0°C) solution of 3-[3-[2-[[2-(tert-butylcarbamoyl)-4-pyridyl]amino]-2-oxoethyl]4-methoxyphenyl]propanoic acid (step 3) (196 mg , 0.47 mmol) in THF (3.96 ml) was added TEA (0.17 ml, 1.19 mmol) followed by dropwise addition of methyl carbonochloridate (0.09 ml, 1.19 mmol). The reaction mixture was stirred for 30 min at 0°C, then treated with NaBH ₄ (90 mg, 2.37 mmol) followed by dropwise addition of MeOH (0.5 ml). After stirring at 0°C for an additional 90 min, the mixture was diluted with water and extracted with EtOAc (3x20 ml). The combined organic extracts were washed with saturated NaHCO3 (10 ml) and saturated aqueous sodium chloride (20 ml), then dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc in heptane to give the title compound as a white metallic solid.

1H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.43 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H ), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.08-7.03 (m, 2H), 6.88 (d, J=8.3 Hz, 1H), 4.42 (t, J=5.1 Hz, 1H), 3.72 (s, 3H), 3.66 (s, 2H), 3.40 (k, J=6.4 Hz, 2H), 1.71-1.64 (m, 2H), 1.40 (s, 9H).

LC-MS (Method E): Rt 1.09 min; MS m/z 400.1 = [M+H]+ (100% @ 215 nm).

Step 5: N-tert-Butyl-4-[[2-[2-hydroxy-5-(3-hydroxypropyl)phenyl]acetyl]amino]pyridine-2carboxamide

The title compound was prepared from N-tert-butyl-4-[[2-[5-(3-hydroxypropyl)-2methoxyphenyl]acetyl]amino]pyridine-2-carboxamide (Step 4) analogously to Example 41, Step 3.

1H NMR (500 MHz, Methanol^) δ 8.41 (d, J=5.5 Hz, 1H), 8.10 (d, J=2.0 Hz, 1H), 7.90 (dd, J= 5.5, 2.2 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 6.96 (dd, J=8.2, 2.2 Hz, 1H), 6, 74 (d, J=8.2 Hz, 1H), 3.70 (s, 2H), 3.55 (t, J=6.5 Hz, 2H), 2.63-2.54 (m, 2H ), 1.84-1.75 (m, 2H), 1.47 (s, 9H).

LC-MS (Method A): Rt 2.57 min; MS m/z 386.3 = [M+H]+ (97% @ 215 nm).

Example 76.

4-[[2-(5-Chloro-4-fluoro-2-hydroxyphenyl)acetyl]amino]-N(1-methylcyclobutyl)pyridine-2carboxamide

Step 1: 4-Amino-N(1-methylcyclobutyl)pyridine-2-carboxamide

4-Aminopyridine-2-carboxylic acid (700 mg, 5.07 mmol) and DIPEA (3.54 ml, 20.27 mmol) were suspended in DMF (39 ml) and treated with 1-methylcyclobutanamine hydrochloride (924 mg, 7.6 mmol) and HATU (2312 mg, 6.08 mmol). After stirring at room temperature for 4 days, the reaction mixture was filtered and the solid was washed with DMF (2x2 ml). The filtrate was concentrated in vacuo and the crude residue was dissolved in EtOAc (20 ml) and washed with sat. NaHCO ₃ solution (20 ml). The aqueous layer was re-extracted with EtOAc (20 ml) and the combined organic layers were washed with saturated aqueous sodium chloride (2x20 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. Purification of the crude C18 residue by reverse phase chromatography, eluting with 5-100% MeCN in water, gave the title compound as a white solid ¹ H NMR (500 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.99 (d, J=5.7 Hz, 1H), 7.17 (d, J=2.3 Hz, 1H), 6.60 (dd, J=5.7, 2.3 Hz, 1H ), 6.53 (br. s, 2H), 2.40-2.32 (m, 2H), 2.00-1.94 (m, 2H), 1.83-1.76 (m, 2H ), 1.45 (s, 3H).

LC-MS (Method E): Rt 0.62 min; MS m/z 206.0 = [M+H]+ (99% @ 215 nm).

Step 2: 4-[[2-(5-Chloro-4-fluoro-2-methoxyphenyl)acetyl]amino]^-(1-methylcyclobutyl)pyridine-2carboxamide

- 157 046966

A solution of 4-amino-N-(1-methylcyclobutyl)pyridine-2-carboxamide (step 1) (81 mg, 0.4 mmol) and 2(5-chloro-4-fluoro-2-methoxyphenyl)acetic acid (100 mg , 0.36 mmol) in DMF (1.9 ml) was treated with TEA (0.16 ml, 0.9 mmol) and T3P® (50% solution in EtOAc) (0.21 ml, 0.72 mmol) and stirred at room temperature for 17 hours. The reaction mixture was quenched with sat. NaHCO ₃ (2 ml) and extracted with EtOAc (3x5 ml).

The combined organic extracts were washed with saturated aqueous sodium chloride (5 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc in heptane to give the title compound as a white metallic solid.

1H NMR (500 MHz, Methanol^) δ 8.49-8.47 (m, 1H), 8.15 (dd, J=2.2, 0.4 Hz, 1H), 7.92 (dd, J =5.5, 2.2 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 6.97 (d, J=11.2 Hz, 1H), 3.86 (s , 3H), 3.74 (s, 2H), 2.49 (dd, J=9.7, 2.4 Hz, 2H), 2.19-2.13 (m, 2H), 1.99- 1.93 (m, 2H), 1.59 (s, 3H).

LC-MS (Method E): Rt 1.22 min; MS m/z 406.1/408.2 = [M+H]+ (79% @ 215 nm).

Step 3: 4-[[2-(5-Chloro-4-fluoro-2-hydroxyphenyl)acetyl]amino]A-(1-methylcyclobutyl)pyridine-2 carboxamide

The title compound was obtained from

4-[[2-(5-chloro-4-fluoro-2methoxyphenyl)acetyl]amino]A-(1-methylcyclobutyl)pyridine-2-carboxamide (step 2) analogous to example 41, step 3.

1H NMR (500 MHz, DMSO^) δ 10.76 (br.s, 1H), 10.32 (br.s, 1H), 8.48-8.43 (m, 2H), 8.13 (d , J=2.1 Hz, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.35 (d, J=8.7 Hz, 1H), 6.75 (d, J=11.0 Hz, 1H), 3.65 (s, 2H), 2.43-2.38 (m, 2H), 2.03-1.96 (m, 2H), 1, 85-1.77 (m, 2H), 1.47 (s, 3H).

LC-MS (Method A): Rt 3.34 min; MS m/z 392.2/394.2 = [M+H]+ (100% @ 215 nm).

Example 77.

4-[[2-(2,5-Difluorophenyl)acetyl]amino]-M-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide

Step 1: Methyl 4-[[2-(2,5-difluorophenyl)acetyl]amino]pyridine-2-carboxylate

2-(2,5-Difluorophenyl)acetic acid (407 mg, 2.37 mmol) was dissolved in thionyl chloride (1.8 ml, 20.43 mmol) and the mixture was heated at 70°C for 1 hour. The resulting mixture concentrated in vacuo and the residue was subjected to azeotropic distillation with toluene. The crude acid chloride was dissolved in DCM (4 ml) and added dropwise to a cooled (0°C) solution of methyl 4-aminopyridine-2-carboxylate (300 mg, 1.97 mmol) and DIPEA (0.69 ml, 3.94 mmol ) in DXM (6 ml). The mixture was left to warm to room temperature and stirred overnight. The resulting mixture was transferred to a separatory funnel and washed successively with water (10 ml) and sat. NaHCO ₃ solution (10 ml). The organic portion was separated, dried over Na ₂ SO ₄ and concentrated in vacuo. Purification of the crude material by chromatography on silica gel, eluting with 50-100% EtOAc in heptane, afforded the title compound as a colorless glass.

1H NMR (500 MHz, Chloroform-d) δ 8.56 (d, J=5.2 Hz, 1H), 8.04 (s, 1H), 7.89-7.81 (m, 2H), 7 .12-7.06 (m, 2H), 7.04-6.99 (m, 1H), 3.98 (s, 3H), 3.76-3.74 (m, 2H)

LC-MS (Method E): Rt 0.99 min; MS m/z 307.0 = [M+H]+.

Step 2: 4-[[2-(2,5-Difluorophenyl)acetyl]amino]pyridine-2-carboxylic acid

To a solution of methyl 4-[[2-(2,5-difluorophenyl)acetyl]amino]pyridine-2-carboxylate (step 1) (364 mg, 1.07 mmol) in THF (2 ml)/MeOH (2 ml )/water (2 ml) was added 1 M LiOH (31 mg, 1.28 mmol), and given

- 158 046966 The mixture was stirred at room temperature overnight. An additional 0.5 equivalent of 1 M LiOH was added and stirring was continued for 2 hours. The resulting mixture was acidified to pH 2 using a solution of 1 M HCl (2 ml), resulting in the formation of a precipitate. Water (5 ml) was added to the mixture, stirred for 5 minutes, and the solid was filtered and dried in a vacuum oven to obtain the title compound as a colorless powder.

^1H NMR (500 MHz, DMSO-f,) δ 10.87 (s, 1H), 8.55 (d, J=5.5 Hz, 1H), 8.27 (d, J=2.0 Hz , 1H), 7.79 (dd, J=5.6, 2.2 Hz, 1H), 7.31-7.27 (m, 1H), 7.26-7.22 (m, 1H), 7.20-7.15 (m, 1H), 3.83 (s, 2H).

LC-MS (Method E): Rt 0.83 min; MS m/z 293.0 = [M+H]+.

Step 3: 4-[[2-(2,5-Difluorophenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2carboxamide

To a solution of 4-[[2-(2,5-difluorophenyl)acetyl]amino]pyridine-2-carboxylic acid (step 2) (50 mg, 0.16 mmol) and DIPEA (60 μl, 0.34 mmol) in DMF (1 ml) was added to HATU (68 mg, 0.18 mmol), and the mixture was stirred for 5 min, then treated with 2-methylbut-3-yn-2-amine (19 μl, 0.18 mmol). The resulting mixture was stirred at room temperature for 1 hour and then diluted with EtOAc. The mixture was washed with a solution of 1 M HCl and saturated aqueous sodium chloride, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude residue was purified by preparative HPLC to obtain the title compound as a colorless powder.

^1H NMR (500 MHz, DMSO-f,) δ 10.85 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.32 (s, 1H), 8.18 (d, J=1.9 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.31-7.27 (m, 1H), 7.24 ( dt, J=9.1, 4.6 Hz, 1H), 7.21-7.14 (m, 1H), 3.83 (s, 2H), 3.21 (s, 1H), 1.64 (s, 6H).

LC-MS (Method A): Rt 3.16 min; MS m/z 358.2 = [M+H]+.

Example 77.1.

4-[[2-(2,5-Difluorophenyl)acetyl]amino]-N(4-fluoro-1-bicyclo[2.1.1]hexanyl)pyridine-2carboxamide

The title compound was prepared from 4-[[2-(2,5-difluorophenyl)acetyl]amino]pyridine-2carboxylic acid (Example 77, Step 2) and 4-fluorobicyclo[2.1.1]hexane-1-amine hydrochloride similarly example 77, stage 3.

^1H NMR (500 MHz, DMSO-b6) δ 10.83 (s, 1H), 9.05 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.14 ( d, J=2.1 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.31-7.27 (m, 1H), 7.27-7 .22 (m, 1H), 7.20-7.15 (m, 1H), 3.83 (s, 2H), 2.132.09 (m, 2H), 2.08-2.04 (m, 2H ), 1.99-1.95 (m, 2H), 1.86-1.82 (m, 2H).

LC-MS (Method A): Rt 3.28 min; MS m/z 390.2 = [M+H]+.

Example 78.

4-[[2-(4-Chloro-2-hydroxyphenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide

Step 1: 4-Amino-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide

To a mixture of 4-aminopyridine-2-carboxylic acid (2 g, 14.48 mmol), TBTU (5.58 g, 17.38 mmol) and TEA (2.42 ml, 17.38 mmol) in DMF (36 ml ) 2-methylbut-3-yne-2-amine (22.82 mL, 17.38 mmol) was added and the mixture was stirred at room temperature for 3 days. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude residue was dissolved in EtOAc (40 ml) and washed with sat. NaHCO3 solution (40 ml). The aqueous was further extracted with EtOAc (40 ml) and the combined organic portions were washed with saturated aqueous sodium chloride (2x40 ml), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The crude material was triturated with a minimal amount of ether at 0°C to obtain the title compound as a white crystalline solid with a metallic tint.

^1H NMR (500 MHz, DMSO-f,) δ 8.23 (s, 1H), 7.99 (d, J=5.6 Hz, 1H), 7.19 (d, J=2.3 Hz , 1H), 6.59 (dd, J=5.6, 2.4 Hz, 1H), 6.36 (s, 2H), 3.19 (s, 1H), 1.62 (s, 6H) .

LC-MS (Method F): Rt 1.28 min; MS m/z 204.3 = [M+H]+.

- 159 046966

Step 2: 4-[[2-(4-Chloro-2-methoxyphenyl)acetyl]amino]-M-(1,1-dimethylprop-2-ynyl)pyridine-2carboxamide

CH ₃

The title compound was prepared from 4-amino-M-(1,1-dimethylprop-2-ynyl)pyridin-2-carboxamide (Step 1) and 2-(4-chloro-2-methoxyphenyl)acetic acid analogously to Example 3.5b.

1H NMR (500 MHz, DMSO-06) δ 10.71 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.32 (s, 1H), 8.19 (d , J=2.1 Hz, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.25 (d, J=8.1 Hz, 1H), 7.07 (d, J=2.0 Hz, 1H), 6.99 (dd, J=8.0, 2.0 Hz, 1H), 3.79 (s, 3H), 3.70 (s, 2H) , 3.21 (s, 1H), 1.65 (s, 6H).

LC-MS (Method A): Rt 3.44 min; MS m/z 386.2/388.2 = [M+H]+ (96% @ 215 nm).

Step 3: 4-[[2-(4-Chloro-2-hydroxyphenyl)acetyl]amino]-M-(1,1-dimethylprop-2-ynyl)pyridine-2carboxamide

The title compound was prepared from 4-[[2-(4-chloro-2-methoxyphenyl)acetyl]amino]-M(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Step 2) analogously to Example 3 , stage 3.

1H NMR (500 MHz, DMSO-de) δ 10.71 (br.s, 1H), 10.04 (br.s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8 .31 (s, 1H), 8.18 (d, J=1.9 Hz, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.17 (d, J=7.8 Hz, 1H), 6.83-6.79 (m, 2H), 3.65 (s, 2H), 3.20 (s, 1H), 1.64 (s, 6H).

LC-MS (Method A): Rt 3.09 min; MS m/z 372.2/374.2 = [M+H]+ (99% @ 215 nm).

Example 78.1.

No.(1,1-Dimethylprop-2-ynyl)-4-[[2-[2-hydroxy-4-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2carboxamide

The title compound was prepared from 4-amino-M-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Example 78, Step 1) and 2-[2-methoxy-4-(trifluoromethyl)phenyl]acetic acid similar to example 78, stages 2 and 3.

1H NMR (500 MHz, DMSO-dg) δ 10.79 (s, 1H), 10.30 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.31 (s , 1H), 8.19 (d, J=2.0 Hz, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.38 (d, J=7, 8 Hz, 1H), 7.10 (d, J=7.9 Hz, 1H), 7.07 (s, 1H), 3.76 (s, 2H), 3.21 (s, 1H), 1 .64 (s, 6H).

LC-MS (Method A): Rt 3.27 min; MS m/z 406.2 = [M+H]+ (98% @ 215 nm).

Example 78.2.

No.(1,1-Dimethylprop-2-ynyl)-4-[[2-[2-hydroxy-5-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2carboxamide

The title compound was prepared from 4-amino-M-(1,1-dimethylprop-2-ynyl)pyridine-2carboxamide (Example 78, Step 1) and 2-[2-methoxy-5-(trifluoromethyl)phenyl]acetic acid similar to example 78, stages 2 and 3.

1H NMR (500 MHz, DMSO-dg) δ 10.79 (s, 1H), 10.48 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.32 (s , 1H), 8.19 (d, J=2.0 Hz, 1H), 7.84 (dd, J=5.5, 2.2 Hz, 1H), 7.54 (d, J=2, 2 Hz, 1H), 7.45 (dd, J=8.5, 2.1 Hz, 1H), 6.96 (d, J=8.4 Hz, 1H), 3.77 (s, 2H) , 3.21 (s, 1H), 1.65 (s, 6H).

LC-MS (Method A): Rt 3.25 min; MS m/z 406.2 = [M+H]+ (98% @ 215 nm).

Example 79.

4-[(2-Chroman-4-ylacetyl)amino]-M-(1,1-dimethylprop-2-ynyl)pyridin-2-carboxamide

- 160 046966

The title compound was prepared from 4-amino-A1,1-dimethylprop-2-ynyl)pyridin-2-carboxamide (Example 78, Step 1) and 2-chroman-4-ylacetic acid analogously to Example 3.5b.

1H NMR (500 MHz, Methanol^ ₄ ) δ 8.46 (d, J=5.5 Hz, 1H), 8.19 (d, J=1.7 Hz, 1H), 7.92 (dd, J =5.5, 2.2 Hz, 1H), 7.16 (d, J=7.7 Hz, 1H), 7.09-7.04 (m, 1H), 6.81 (td, J= 7.5, 1.2 Hz, 1H), 6.75 (dd, J=8.2, 1.1 Hz, 1H), 4.224.18 (m, 2H), 3.44 (dk, J=10 ,4, 5.1 Hz, 1H), 2.92 (dd, J=14.7, 5.7 Hz, 1H), 2.73 (s, 1H), 2.62 (dd, J=14, 7, 9.3 Hz, 1H), 2.20-2.11 (m, 1H), 1.94-1.84 (m, 1H), 1.73 (s, 6H).

LC-MS (Method A): Rt 3.38 min; MS m/z 378.3 = [M+H]+ (98% @ 215 nm).

Example 79.1.

No.(1,1-Dimethylprop-2-ynyl)-4-[[2-(1-isopropyl-3,5-dimethylpyrazol-4-yl)acetyl]amino]pyridine2-carboxamide

The title compound was prepared from 4-amino-I-(1,1-dimethylprop-2-ynyl)pyridin-2-carboxamide (Example 78, Step 1) and 2-(1-isopropyl-3,5-dimethyl-pyrazole-4 -yl)acetic acid as in example 3.5b.

1H NMR (500 MHz, DMSO-06) δ 10.62 (s, 1H), 8.46 (d, 1H), 8.31 (s, 1H), 8.19 (d, J=1.9 Hz , 1H), 7.84 (dd, J=5.5, 2.2 Hz, 1H), 4.43-4.34 (m, 1H), 3.43 (s, 2H), 3.21 ( s, 1H), 2.18 (s, 3H), 2.08 (s, 3H), 1.64 (s, 6H), 1.31 (d, J=6.6 Hz, 6H).

LC-MS (Method A): Rt 2.54 min; MS m/z 382.3 = [M+H]+ (100% @ 215 nm).

Example 79.2.

No.(1,1-Dimethylprop-2-ynyl)-4-[[2-(1H-indazol-4-yl)acetyl]amino]pyridine-2-carboxamide

NS^. dn ₃

H ₃ C N

N-NH

The title compound was prepared from 4-amino-I-(1,1-dimethylprop-2-ynyl)pyridin-2-carboxamide (Example 78, Step 1) and 2-(N-indazol-4-yl)acetic acid analogously to Example 3.5 b.

^1H NMR (500 MHz, Methanol^) δ 8.44 (dd, J=5.4, 0.5 Hz, 1H), 8.19 (d, J=1.0 Hz, 1H), 8.17 (dd, J=2.3, 0.5 Hz, 2H), 7.93 (dd, J=5.6, 2.2 Hz, 1H), 7.47 (d, J=8.5 Hz, 1H), 7.36 (dd, J=8.4, 7.0 Hz, 1H), 7.13-7.10 (m, 1H), 4.56 (br.s, 1H), 4.08 (s, 2H), 2.72 (s, 1H), 1.72 (s, 6H).

LC-MS (Method A): Rt 2.51 min; MS m/z 362.2 = [M+H]+.

Example 79.3 No. (1,1-Dimethylprop-2-ynyl)-4-[[2-(1H-indol-7-yl)acetyl]amino]pyridine-2-carboxamide

The title compound was prepared from 4-amino-A1,1-dimethylprop-2-ynyl)pyridin-2-carboxamide (Example 78, Step 1) and 2-(1H-indol-7-yl)acetic acid analogously to Example 3.5b.

1H NMR (500 MHz, DMSO^) δ 11.05 (br.s, 1H), 10.82 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.32 ( s, 1H), 8.21 (d, J=2.0 Hz, 1H), 7.86 (dd, J=5.5, 2.1 Hz, 1H), 7.46 (d, J=7 .5 Hz, 1H), 7.36 (t, J=2.7 Hz, 1H), 7.02-6.94 (m, 2H), 6.48-6.42 (m, 1H), 4 .01 (s, 2H), 3.21 (s, 1H), 1.65 (s, 6H).

LC-MS (Method A): Rt 3.19 min; MS m/z 361.2 = [M+H]+.

Example 80.

3-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)benzamide

Step 1: 3-[[2-[5-Chloro-2-[(4-methoxyphenyl)methoxy]phenyl]acetyl]amino]benzoic acid

- 161 046966

K ₂ CO ₃ (619 mg, 4.48 mmol) and 1-(bromomethyl)-4methoxybenzene (751 mg, 3.73 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with water (10 ml) to form a precipitate, which was filtered and washed with water. The solid was dissolved in THF (7 ml) and treated with aq. 1 M LiOH (8.96 ml, 8.96 mmol) and stirred at room temperature for 20 hours. Volatile solvents were removed in vacuo, resulting in the formation of a precipitate. The mixture was diluted with water (50 ml) and neutralized with aqueous solution. 3 M HCl. The precipitate was filtered and washed with water to obtain the title compound as a white metallic solid.

¹ H NMR (500 MHz, DMSO-06) δ 10.24 (s, 1H), 8.20 (s, 1H), 7.82 (d, J=8.9 Hz, 1H), 7.62 ( dt, J=7.7, 1.1 Hz, 1H), 7.42 (t, J=7.9 Hz, 1H), 7.32 (d, J=2.7 Hz, 1H), 7, 30-7.24 (m, 3H), 7.08 (d, J=8.8 Hz, 1H), 6.70-6.66 (m, 2H), 5.00 (s, 2H), 3 .67 (s, 2H), 3.66 (s, 3H).

LC-MS (Method E): Rt 1.18 min; MS m/z 448.0/450.1 = [M+Na]+ (96% @ 215 nm).

Step 2: 3-[[2-[5-Chloro-2-[(4-methoxyphenyl)methoxy]phenyl]acetyl]amino]-N-(4cyanonotetrahydropyran-4-yl)benzamide

The title compound was prepared from 3-[[2-[5-chloro-2-[(4methoxyphenyl)methoxy]phenyl]acetyl]amino]benzoic acid (Step 1) and 4-aminotetrahydropyran-4carbonitrile analogously to Example 31, Step 2.

1H NMR (500 MHz, DMSO) δ 10.26 (s, 1H), 8.82 (s, 1H), 8.04 (t, J=1.7 Hz, 1H), 7.83 (d, J =9.4 Hz, 1H), 7.56 (dt, J=7.6, 1.1 Hz, 1H), 7.44 (t, J=7.9 Hz, 1H), 7.32 (d , J=2.7 Hz, 1H), 7.30-7.26 (m, 3H), 7.08 (d, J=8.8 Hz, 1H), 6.73-6.70 (m, 2H, 5.00 (s, 2H), 3.90-3.84 (m, 2H), 3.68 (s, 2H), 3.67 (s, 3H), 3.63-3.57 ( m, 2H), 2.33 (d, J=13.5 Hz, 2H), 2.04-1.97 (m, 2H).

LC-MS (Method E): Rt 1.20 min; MS m/z 556.1/558.0 = [M+H]+ (95% @ 215 nm).

Step 3: 3-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-A4-cyanotetrahydropyran-4yl)benzamide

- [[2-[5-Chloro-2-[(4-methoxyphenyl)methoxy]phenyl]acetyl]amino]-I-(4-cyanotetrahydropyran-4yl)benzamide (step 2) (70 mg, 0.13 mmol) dissolved in 1 M HCl in dioxane (1.97 ml, 1.97 mmol) and stirred at room temperature for 4 hours. The reaction mixture was diluted with EtOAc (5 ml) and water (5 ml). The organic portion was separated, dried over Na ₂ SO ₄ and concentrated in vacuo. Purification of the crude material by preparative HPLC (acidic pH, standard elution method) yielded the title compound as a white solid with a metallic tint.

1H NMR (500 MHz, DMSO) δ 10.27 (s, 1H), 9.66 (br. s, 1H), 8.82 (s, 1H), 8.04 (t, J=1.8 Hz , 1H), 7.84-7.79 (m, 1H), 7.52 (dt, J=7.6, 1.0 Hz, 1H), 7.42 (t, J=7.9 Hz, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.91-3.83 (m, 2H), 3.62 (s, 2H), 3.62-3.57 (m, 2H), 2.35-2.29 (m, 2H), 2.041.97 (m, 2H).

LC-MS (Method A): Rt 2.66 min; MS m/z 414.2/416.2 = [M+H]+ (100% @ 215 nm).

Example 81.

N(1-Cyano-1-methylethyl)-4-[[2-(5-fluoro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide

Step 1: Methyl 4-[[2-(5-fluoro-2-methoxyphenyl)acetyl]amino]pyridine-2-carboxylate

- 162 046966

The title compound was prepared from methyl 4-aminopyridine-2-carboxylate and 2-(5-fluoro2-methoxyphenyl)acetic acid analogously to Example 8, Step 1.

¹ H NMR (250 MHz, DMSO-de) δ 10.71 (s, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.30 (d, J=1.9 Hz, 1H), 7.77 (dd, J=5.5, 2.2 Hz, 1H), 7.15-7.03 (m, 2H), 7.02-6.93 (m, 1H), 3 .86 (s, 3H), 3.74 (s, 3H), 3.71 (s, 2H).

LC-MS (Method E): Rt 0.99 min; MS m/z 319.0 (83% @ 215 nm).

Step 2: 4-[[2-(5-Fluoro-2-methoxyphenyl)acetyl]amino]pyridine-2-carboxylic acid

dn ₃

The title compound was prepared from methyl 4-[[2-(5-fluoro-2methoxyphenyl)acetyl]amino]pyridine-2-carboxylate (Step 1) analogously to Example 7, Step 2.

¹ H NMR (500 MHz, DMSO-d,) δ 10.77 (s, 1H), 8.53 (d, J=5.6 Hz, 1H), 8.27 (d, J=2.0 Hz , 1H), 7.80 (dd, J=5.6, 2.2 Hz, 1H), 7.14-7.05 (m, 2H), 6.98 (dd, J=9.0, 4 .6 Hz, 1H), 3.74 (s, 3H), 3.72 (s, 2H).

LC-MS (Method A): Rt 0.87 min; MS m/z 305.0 = [M+H]+.

Step 3: C-(1-Cyano-1-methylethyl)-4-[[2-(5-fluoro-2-methoxyphenyl)acetyl]amino]pyridine-2carboxamide

I

CH ₃

The title compound was prepared from 4-[[2-(5-fluoro-2methoxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (Step 2) and 2-amino-2-methylpropanenitrile hydrochloride analogously to Example 77, Step 3.

1H NMR (500 MHz, DMSO-d,) δ 10.74 (s, 1H), 8.82 (s, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.22 ( d, J=1.9 Hz, 1H), 7.86 (dd, J=5.5, 2.2 Hz, 1H), 7.17-7.05 (m, 2H), 6.99 (dd , J=9.0, 4.6 Hz, 1H), 3.74 (s, 3H), 3.73 (s, 2H), 1.72 (s, 6H).

LC-MS (Method E): Rt 1.09 min; MS m/z 371.1 = [M+H]+ (87% @ 215 nm).

Step 4: C-(1-Cyano-1-methylethyl)-4-[[2-(5-fluoro-2-hydroxyphenyl)acetyl]amino]pyridine-2carboxamide

The title compound was prepared from K-(1-cyano-1-methylethyl)-4-[[2-(5-fluoro-2methoxyphenyl)acetyl]amino]pyridine-2-carboxamide (Step 3) analogously to Example 3, Step 3 .

1H NMR (500 MHz, DMSO-d,) δ 10.72 (br.s, 1H), 9.52 (br.s, 1H), 8.82 (s, 1H), 8.50 (d, J =5.5 Hz, 1H), 8.22 (d, J=2.0 Hz, 1H), 7.87 (dd, J=5.5, 2.1 Hz, 1H), 7.02 (dd , J=9.4, 3.1 Hz, 1H), 6.91 (td, J=8.6, 3.2 Hz, 1H), 6.77 (dd, J=8.8, 4.9 Hz, 1H), 3.68 (s, 2H), 1.72 (s, 6H).

LC-MS (Method A): Rt 2.53 min; MS m/z 357.2 = [M+H]+ (99% @ 215 nm).

Example 81.1.

K-(1-Cyano-2-hydroxy-1-methylethyl)-4-[[2-(5-fluoro-2-hydroxyphenyl)acetyl]amino]pyridine-2carboxamide

The title compound was prepared from 4-[[2-(5-fluoro-2methoxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 81, Step 2) and 2-amino-3hydroxy-2-methylpropanenitrile analogously to Example 81. stages 3 and 4.

1H NMR (500 MHz, DMSO-d,) δ 10.76 (br.s, 1H), 9.53 (br.s, 1H), 8.73 (s, 1H), 8.50 (d, J =5.5 Hz, 1H), 8.24 (d, J=2.1 Hz, 1H), 7.87 (dd, J=5.5, 2.2 Hz, 1H), 7.02 (dd , J=9.3, 3.2 Hz, 1H), 6.95-6.87 (m, 1H), 6.78 (dd, J=8.8, 4.9 Hz, 1H), 5, 91 (t, J=5.8 Hz, 1H), 3.82 (dd, J=11.1, 5.2 Hz, 1H), 3.73 (dd, J=10.9, 4.9 Hz , 1H), 3.68 (s, 2H), 1.66 (s, 3H).

LC-MS (Method A): Rt 2.20 min; MS m/z 373.3 = [M+H]+ (100% @ 215 nm).

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Example 81.2.

4-[[2-(5-Fluoro-2-hydroxyphenyl)acetyl]amino]-I-isopropylpyridine-2-carboxamide

The title compound was prepared from 4-[[2-(5-fluoro-2methoxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 81, Step 2) and analogously to Example 81, Steps 3 and 4.

¹ H NMR (500 MHz, DMSO-06) δ 10.65 (br.s, 1H), 9.50 (br.s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.37 (d, J=8.4 Hz, 1H), 8.18 (d, J=1.9 Hz, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H ), 7.00 (dd, J=9.4, 3.2 Hz, 1H), 6.95-6.86 (m, 1H), 6.76 (dd, J=8.8, 4.9 Hz, 1H), 4.16-4.02 (m, 1H), 3.66 (s, 2H), 1.17 (d, J=6.6 Hz, 6H).

LC-MS (Method A): Rt 2.56 min; MS m/z 322.2 = [M+H]+ (100% @ 215 nm).

Example 81.3.

No.(1,1-Dimethylprop-2-ynyl)-4-[[2-(5-fluoro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide HC. CH ₃ O _n

The title compound was prepared from 4-[[2-(5-fluoro-2methoxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 81, Step 2) and 2-methylbut-3-yne-2amine analogously to Example 81. stages 3 and 4.

1H NMR (500 MHz, DMSO-06) δ 10.70 (br.s, 1H), 9.52 (br.s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8 .31 (s, 1H), 8.18 (d, J=2.0 Hz, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.01 (dd, J=9.4, 3.2 Hz, 1H), 6.90 (td, J=8.6, 3.2 Hz, 1H), 6.77 (dd, J=8.8, 4.9 Hz , 1H), 3.67 (s, 2H), 3.20 (s, 1H), 1.64 (s, 6H).

LC-MS (Method A): Rt 2.84 min; MS m/z 356.2 = [M+H]+ (97% @ 215 nm).

Example 81.4.

N(4-Fluoro-1-bicyclo[2.1.1]hexanyl)-4-[[2-(5-fluoro-2-hydroxyphenyl)acetyl]amino]pyridine-2carboxamide

The title compound was prepared from 4-[[2-(5-fluoro-2methoxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 81, Step 2) and 4fluorobicyclo[2.1.1]hexane-1-amine hydrochloride similarly example 81, stages 3 and 4.

1H NMR (500 MHz, DMSO-06) δ 10.68 (s, 1H), 9.51 (br.s, 1H), 9.04 (s, 1H), 8.46 (d, J=5, 5 Hz, 1H), 8.15 (d, J=2.1 Hz, 1H), 7.84 (dd, J=5.5, 2.1 Hz, 1H), 7.01 (dd, J= 9.3, 3.1 Hz, 1H), 6.91 (td, J=8.6, 3.1 Hz, 1H), 6.77 (dd, J=8.8, 4.9 Hz, 1H ), 3.67 (s, 2H), 2.16-2.02 (m, 4H), 2.00-1.91 (m, 2H), 1.89-1.79 (m, 2H).

LC-MS (Method A): Rt 2.97 min; MS m/z 388.2 = [M+H]+ (98% @ 215 nm).

Example 81.5.

4-[[2-(5-Fluoro-2-hydroxyphenyl)acetyl]amino]-N-[1-(hydroxymethyl)cyclobutyl]pyridine-2carboxamide

The title compound was prepared from 4-[[2-(5-fluoro-2methoxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 81, Step 2) and (1aminecyclobutyl)methanol hydrochloride analogously to Example 81, Steps 3 and 4 .

¹ H NMR (500 MHz, DMSO-06) δ 10.68 (s, 1H), 9.52 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.40 ( s, 1H), 8.18 (d, J=2.1 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.01 (dd, J=9 ,4, 3.2 Hz, 1H), 6.91 (td, J=8.6, 3.2 Hz, 1H), 6.77 (dd, J=8.8, 4.9 Hz, 1H) , 5.00 (s, 1H), 3.67 (s, 2H), 3.61 (s, 2H), 2.09-2.01 (m, 2H), 1.88-1.79 (m , 1H), 1.78-1.67 (m, 1H).

LC-MS (Method A): Rt 2.33 min; MS m/z 374.2 = [M+H]+ (96% @ 215 nm).

Example 82.

No. tert-Butyl-6-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]pyrimidine-4-carboxamide

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dn ₃

Step 1: 2-(5-Chloro-2-methoxyphenyl)-I-(6-chloropyrimidin-4-yl)acetamide

N ^S| LJ ^{N S|}

T π T T T

O JJ

-CHH- ₀ 'CHH'

I CH ₃

A suspension of 6-chloropyrimidin-4-amine (250 mg, 1.93 mmol) and 2-(5-chloro-2-methoxyphenyl)acetic acid (0.14 ml, 2.03 mmol) in 1,4-dioxane (2 .5 ml) was treated with DIPEA (1.01 ml, 5.79 mmol) followed by the addition of T3P® (50% in EtOAc) (2754 µl, 2.32 mmol), and the mixture was stirred at room temperature for 2 hours. The resulting mixture was partitioned between EtOAc (10 ml) and saturated aq. NaHCO ₃ (10 ml), and the organic portion was separated, washed with water, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with a gradient of 0 to 100% EtOAc in heptane followed by a gradient of 0 to 100% MeOH in EtOAc to give the title compound as an orange powdery solid.

1H NMR (500 MHz, DMSO-06) δ 11.40 (s, 1H), 8.77 (d, J=1.0 Hz, 1H), 8.07 (d, J=1.0 Hz, 1H ), 7.33-7.29 (m, 2H), 7.03-6.98 (m, 1H), 3.79 (s, 2H), 3.74 (s, 3H).

LC-MS (Method E): Rt 1.14 min; MS m/z 311.9/313.9 = [M+H]+ (100% @ 215 nm).

Step 2: ^tert-Butyl-6-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]pyrimidine-4-carboxamide

The following procedure is based on the literature reference: CA 2915356 page 131. All reagents loaded into the device for generating CO (carbon monoxide generation system):

Chamber A: Aryl chloride, 2-methylpropan-2-amine, BINAP, Pd(OAc) ₂ , TEA 1,4-dioxane.

Chamber B: formic acid, MsCl, TEA, 1,4-dioxane.

2-(5-chloro-2-methoxyphenyl)-I-(6-chloropyrimidin-4-yl)acetamide (step 1) (202 mg, 0.65 mmol), Pd(OAc) ₂ (15 mg) was added to chamber A , 0.06 mmol), 2-methylpropan-2-amine (95 mg, 1.29 mmol) and BINAP (81 mg, 0.13 mmol). The reaction vessel was purged with nitrogen, then 1,4-dioxane (2.5 ml) was added. 1,4-dioxane (2.5 mL) was added to chamber B, followed by the addition of mesyl chloride (125 μL, 1.62 mmol) and formic acid (61 μL, 1.62 mmol), and the mixtures were stirred. Triethylamine (283 μL, 1.94 mmol) was added to chamber A and triethylamine (361 μL, 2.59 mmol) was added to chamber B, which rapidly released CO gas. The CO generating apparatus was heated at 80°C for 22 hours and left to cool to room temperature. The mixture from chamber A was partitioned between DCM (5 ml) and water (5 ml), and the organic portion was separated by filtration through a hydrophobic fritted PTFE tube. The filtrate was concentrated in vacuo and the residue was purified by preparative HPLC (acid pH, standard elution method). The product fractions were combined and concentrated in vacuo to remove volatile solvents. The aqueous residue was treated with DCM (10 ml) and saturated aqueous NaHCO ₃ (10 ml), and the organic portion was separated by filtration through a hydrophobic PTFE frit. The filtrate was concentrated in vacuo to give the title compound as a peach colored crystalline solid.

1H NMR (500 MHz, DMSO-06) δ 11.29 (s, 1H), 8.95 (d, J=1.2 Hz, 1H), 8.53 (d, J=1.2 Hz, 1H ), 8.04 (s, 1H), 7.33-7.29 (m, 2H), 7.03-6.99 (m, 1H), 3.80 (s, 2H), 3.74 ( s, 3H), 1.39 (s, 9H).

LC-MS (Method A): Rt 3.56 min; MS m/z 377.2/379.2 = [M+H]+ (97% @ 215 nm).

Example 83.

N(1-Cyano-1-methylethyl)-4-(thiophene-3-carbonylamino)pyridine-2-carboxamide

Step 1: 4-Amino-M-(1-cyano-1-methylethyl)pyridine-2-carboxamide

To a mixture of 4-aminopyridine-2-carboxylic acid (15 g, 108.6 mmol), TBTU (41.84 g, 130.32 mmol) and triethylamine (37.84 ml, 271.5 mmol) in DMF (271, 52 ml) 2-amino-2-methyl-propanenitrile hydrochloride (14.4 g, 119.46 mmol) was added and the mixture was stirred at room temperature for 3 days. The reaction mixture was filtered and the solid was washed with DMF (2x30 ml). Unite

- 165 046966 The resulting filtrate was concentrated in vacuo and the crude residue was dissolved in EtOAc (300 ml) and washed with sat. NaHCO ₃ solution (2x300 ml). The aqueous solution was re-extracted with EtOAc (30 ml) and the organic layers were combined, washed with saturated aqueous sodium chloride (160 ml x 2), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. Purification of the resulting solid by chromatography on silica gel, eluting with 0-100% EtOAc in heptane, gave a solid which was triturated with ice-cold TBME:heptane (3:1 mixture) to give the title compound as a colorless crystalline solid.

¹ H NMR (400 MHz, DMSO-66) δ 8.60 (s, 1H), 8.03 (d, J=5.6 Hz, 1H), 7.21 (d, J=2.3 Hz, 1H), 6.62 (dd, J=5.6, 2.4 Hz, 1H), 6.40 (s, 2H), 1.70 (s, 6H).

LC-MS (Method E) Rt 0.35 min; MS m/z 205.0 = [M+H]+.

Step 2: N-(1-Cyano-1-methylethyl)-4-(thiophene-3-carbonylamino)pyridine-2-carboxamide

Oxalyl chloride (29 µl, 0.331 mmol) was added to a stirred solution of thiophene-3-carboxylic acid (47 mg, 0.368 mmol) dissolved in DMF (1 drop, ~5 µl) in 1,4-dioxane (1 ml). The mixture was sealed and stirred at room temperature for 1 hour. The resulting acid chloride mixture was treated with a mother solution (1.6 ml) of 4-amino-Al-cyano-1methylethyl)pyridine-2-carboxamide (step 1) (45 mg, 0 .22 mmol) and TEA (100 µl, 0.72 mmol) in 1,4dioxane (1.5 ml). The mixture was resealed and stirred at room temperature overnight. The resulting mixture was concentrated in vacuo and purification of the crude residue by preparative HPLC (acid pH, standard elution method) yielded the title compound as a white, metallic powder.

1H NMR (500 MHz, DMSO-66) δ 10.63 (s, 1H), 8.85 (s, 1H), 8.56 (d, J=5.5 Hz, 1H), 8.49-8 .46 (m, 1H), 8.44 (d, J=2.1 Hz, 1H), 8.09 (dd, J=5.5, 2.2 Hz, 1H), 7.71-7, 69 (m, 1H), 7.68-7.66 (m, 1H), 1.74 (s, 6H).

LC-MS (Method A) Rt 2.60 min; MS m/z 315.2 = [M+H]+ (99% @ 215 nm)

The compounds of the following tabular examples (Table 14) were prepared from 4-amino-Al-cyano-1methylethyl)pyridine-2-carboxamide (Example 83, Step 1) analogously to Example 83, Step 2, replacing the thiophene-3-carboxylic acid with the corresponding commercially available acid.

Table 14

Example Structure and name 1H NMR, LCMS retention time, [M+HJ+, 83.1 H ₃ CCH ₃ O n N-(1-Cyano-1-methylethyl)-4-[(2-cyclohexylacetyl)amino] pyrid in-2-carboxamide 1H NMR (500 MHz, DMSO-bb) δ 10.50 (s, 1H), 8.81 (s, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.24 (d , J=2.0 Hz, 1H), 7.84 (dd, J=5.5,2.2 Hz, 1H), 2.26 (d, J=7.1 Hz, 2H), 1.83 -1.75 (m, 1H), 1.72 (s, 6H), 1.71-1.64 (m, 4H), 1.63-1.58 (m, 1H), 1.28-1 .09 (m, ZN), 1.03-0.93 (m, 2N). 83.2 ^Н з ^с СНз° Н Al N-(1-Cyano-1-methylethyl)-4-(cyclohexane carbonylamino)pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-bb) δ 10.46 (s, 1H), 8.81 (s, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.24 (d , J=2.0 Hz, 1H), 7.87 (dd, J=5.5, 2.2 Hz, 1H), 2.41-2.34 (m, 1H), 1.87-1, 80 (m, 2H), 1.79-1.74 (m, 2H), 1.72 (s, 6H), 1.68-1.62 (m, 1H), 1.41 (cd, J= 12.4, 2.8 Hz, 2H), 1.33-1.14 (m, ZN). 83.3 ⁿ A ^SNz ? ⁿ HAr N-(1-Cyano-1-methylethyl)-4-[(3,3-difluorocyclopentanecarbonyl)amino]pyridine-2carboxamide 1H NMR (500 MHz, DMSO-bb) δ 10.65 (s, 1H), 8.83 (s, 1H), 8.52 (d, J=5.5 Hz, 1H), 8.26-8 .21 (m, 1H), 7.87 (dd, >5.5, 2.2 Hz, 1H), 3.16 (p, J=8.6 Hz, 1H), 2.432.31 (m, 2H ), 2.27-2.05 (m, ZN), 1.98-1.90 (m, 1H), 1.73 (s, 6H).

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LC-MS (Method A) Rt 2.74 min; MS m/z 337.3 = [M+H]+ (97% @ 215 nm) 83.4 ⁿ 3S SI ₃ O n k) Άν Ν-(1-Cyano-1-methylethyl)-4-[(1-methylcyclopentanecarbonyl)amino]pyridine-2carboxamide 1HNMR (500 MHz, DMSO-ab) δ 9.92 (s, 1H), 8.81 (s, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.36 (d, J=2.l Hz, 1H), 7.99 (dd, J=5.5, 2.2 Hz, 1H), 2.18-2.07 (m, 2H), 1.73 (s, 6H ), 1.70-1.56 (m, 4H), 1.55-1.49 (m, 2H), 1.32 (s, ZN). LC-MS (Method A) Rt 3.08 min; MS m/z 315.3 = [M+H]+ (100% @ 215 nm) 83.5 |_| g~ C N o ζ/χΑ Ν-(1-Cyano-1-methylethyl)-4-(3-cyclohexylpropanoylamine)pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-ab) δ 10.51 (s, 1H), 8.81 (s, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.23 (d , J=2.0 Hz, 1H), 7.84 (dd, J=5.5, 2.2 Hz, 1H), 2.41-2.36 (m, 2H), 1.75-1, 64 (m, JN), 1.63-1.57 (m, 1H), 1.54-1.47 (m, 2H), 1.28-1.07 (m, 4H), 0.94- 0.85 (m, 2H). LC-MS (Method A) Rt 3.64 min; MS m/z 343.3 = [M+H]+ (100% @ 215 nm) 83.6 B x ¹ t 1H NMR (500 MHz, DMSO-ab) δ 10.50 (s, 1H), 8.81 (s, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.23 (d , J=l.9 Hz, 1H), 7.84 (dd, J=5.5, 2.2 Hz, 1H), 2.38-2.32 (m, 1H), 4-(2-{Bicyclo[2.2.1]heptan-2-yl} acetamide ο)-Ν-(1-cyano-1-methylethyl)pyridine-2-carboxamide 2.24-2.18 (m, 2H), 2.00-1.97 (m, 1H), 1.94-1.87 (m, 1H), 1.72 (s, 6H), 1. 52-1.40 (m, ZN), 1.38-1.33 (m, 1H), 1.21-1.06 (m, 4H). LC-MS (Method A) Rt 3.39 min; MS m/z 341.3 = [M+H]+ (99% @ 215 nm) 83.7 n ₃ s, ^{c n} zon _n sn ₃ ^{N n 0} N-(1-Cyano-1-methylethyl)-4-[[2-(1-methylcyclohexyl)acetyl]amino]pyr idin-2 carboxamide 1H NMR (500 MHz, DMSO-ab) δ 10.45 (s, 1H), 8.82 (s, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.24 (d , J=2.0 Hz, 1H), 7.85 (dd, J=5.5, 2.2 Hz, 1H), 2.29 (s, 2H), 1.72 (s, 6H), 1 .52-1.36 (m, 7N), 1.36-1.27 (m, ZN), 1.02 (s, ZN). LC-MS (Method A) Rt 3.56 min; MS m/z 343.3 = [M+H]+ (100% @ 215 nm) 83.8 ⁿ s ^{with CH} 3O _n ΐρΆ^ A n ΐχΓ ^Η Ο Ν-[2-[(1-Cyano-1-methylethyl)carbamoyl]-4-pyridyl]-2-cyclopropylpyrimidine-5carboxamide 1H NMR (500 MHz, DMSO-ab) δ 11.02 (s, 1H), 9.13 (s, 2H), 8.88 (s, 1H), 8.60 (d, J=5.5 Hz , 1H), 8.42 (d, J=2.0 Hz, 1H), 8.05 (dd, J=5.5, 2.2 Hz, 1H), 2.35-2.29 (m, 1H), 1.74 (s, 6H), 1.20-1.15 (m, 2H), 1.131.09 (m, 2H). LC-MS (Method A) Rt 2.56 min; MS m/z 351.3 = [M+H]+ (99% @ 215 nm)

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83.9 n ₃ s n ₃ s . ^сн EO _n O'NA _C h ₃ ^{Ν H 0} X-[2-[(1-Cyano-1-methylethyl)carbamoyl]-4-pyridyl]-3-isobutylisoxazole-5carboxamide 1H NMR (500 MHz, DMSO-ab) δ 11.28 (br.s, 1H), 8.88 (s, 1H), 8.60 (d, J=5.5 Hz, 1H), 8.47 (d, J=2.1 Hz, 1H), 8.03 (dd, J=5.5, 2.2 Hz, 1H), 7.25 (s, 1H), 2.61 (d, J= 7.1 Hz, 2H), 2.05-1.96 (m, 1H), 1.74 (s, 6H), 0.94 (d, >6.7 Hz, 6H). LC-MS (Method A) Rt 3.23 min; MS m/z 356.3 = [M+H]+ (100% @ 215 nm) 83.10 F Ν-(1-Cyano-1-methylethyl)-4-[[2-(4,4-difluorocyclohexyl)acetyl] amino] pyrid in-2carboxamide 1H NMR (500 MHz, DMSO-ab) δ 10.57 (s, 1H), 8.82 (s, 1H), 8.50 (d, J=5.5 Hz, 1H), 8.24 (d , >2.0 Hz, 1H), 7.83 (dd, J=5.5,2.2 Hz, 1H), 2.35 (d, J=7.1 Hz, 2H), 2.03- 1.92 (m, ZN), 1.90-1.83 (m, 1H), 1.82-1.75 (m, ZN), 1.72 (s, 6H), 1.31-1, 21 (m, 2H). LC-MS (Method A) Rt 2.99 min; MS m/z 365.3 = [M+H]+ (100% @ 215 nm) 83.11 4-[( 1 -Benzylcyclopropanecarbonyl)amino]-M-(1-cyano-1-methylethyl)pyridine-2carboxamide 1HNMR (500 MHz, DMSO-ab) δ 9.94 (s, 1H), 8.80 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.28 (d, >2.0 Hz, 1H), 7.90 (dd, J=5.6, 2.2 Hz, 1H), 7.28-7.23 (m, 4H), 7.20-7.14 ( m, 1H), 3.12 (s, 2H), 1.72 (s, 6H), 1.24 (k, >4.2 Hz, 2H), 0.87 (k, J=4.4 Hz , 2H). LC-MS (Method A) Rt 3.26 min; MS m/z 363.3 = [M+H]+ (100% @ 215 nm) 83.13 ^H3C x/ ^CH3 and ^H Ν-(1-Cyano-1-methylethyl)-4-[3-(2-methoxy-4-pyridyl)propanoylamino]pyridine-2carboxamide 1H NMR (500 MHz, DMSO-ab) δ 10.61 (s, 1H), 8.83 (s, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.22 (d , >2.0 Hz, 1H), 8.06 (d, J=5.3 Hz, 1H), 7.83 (dd, J=5.5,2.2 Hz, 1H), 6.90 ( dd, J=5.3, 1.3 Hz, 1H), 6.70 (s, 1H), 3.82 (s, ZN), 2.91 (t, J=7.5 Hz, 2H), 2.75 (t, J=7.5 Hz, 2H), 1.73 (s, 6H). LC-MS (Method A) Rt 2.29 min; MS m/z 368.3 = [M+H]+ (97% @ 215 nm) 83.14 ⁿ =\/ ^СНз о Н ^Н,С ' ^m Л ^сн = ΑΑίΜΜν ben, Ν ]f CH. Ν Η ^{3 Μ} Ο 4-[(5-tert-Butyl-2-methylpyrazole-3-carbonyl)amino]-M-(1-cyano-1-methylethyl)pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-ab) δ 10.66 (s, 1H), 8.86 (s, 1H), 8.58-8.55 (m, 1H), 8.45-8.41 ( m, 1H), 8.05 (dd, J=5.5, 2.2 Hz, 1H), 7.06 (s, 1H), 4.05 (s, ZN), 1.74 (s, 6H ), 1.29 (s, 9H). LC-MS (Method A) Rt 3.32 min; MS m/z 369.3 = [M+H]+ (100% @ 215 nm) 83.15 ⁿ zS si ₃ o n ΙίΑ A 1H NMR (500 MHz, DMSO-ab) δ 10.86 (s, 1H), 8.83 (s, 1H), 8.51 (d, >5.5 Hz, 1H), 8.23 (d, >1.6 Hz, 1H), 8.19 (d, >2.4 Hz, 1H), 7.82-7.79 (m, 1H), 7.71-7.65 (m, ZN), 7.59 (d, >1.6 Hz, 1H), 7.55-7.51 (m,

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N-(1-Cyano-1-methylethyl)-4-[(2-pyrazol-1-ylbenzoyl)amino]pyride in-2carboxamide 1H), 6.47-6.45 (m, 1H), 1.73 (s, 6H). LC-MS (Method A) Rt 2.50 min; MS m/z 375.30 = [M+H]+ (98% @ 215 nm) 83.16 ⁿ z ^s . CH ₃ O H [f ⁴ ] N-[2-[(l-Cyano-1-methylethyl)carbamoyl]-4-pyridyl]-6-(trifluoromethyl)pyridine-2carboxamide 1H NMR (500 MHz, DMSO-bb) δ 11.05 (s, 1H), 8.88 (s, 1H), 8.64 (d, >2.1 Hz, 1H), 8.62 (d, >5.5 Hz, 1H), 8.43 (d, >7.5 Hz, 1H), 8.38 (t, >7.8 Hz, 1H), 8.22 (d, 1H), 8, 18 (dd, >5.5, 2.2 Hz, 1H), 1.75 (s, 6H). LC-MS (Method A) Rt 3.23 min; MS m/z 378.20 = [M+H]+ (100% @ 215 nm) 83.17 N-[2-[(l-Cyano-1-methylethyl)carbamoyl]-4-pyridyl]-3-oxo-4H-1,4-benzoxazine-7carboxamide 1H NMR (500 MHz, DMSO-bb) δ 11.04 (s, 1H), 10.68 (s, 1H), 8.85 (s, 1H), 8.56 (d, >5.5 Hz, 1H), 8.46 (d, >2.1 Hz, 1H), 8.09 (dd, >5.5, 2.2 Hz, 1H), 7.67-7.64 (m, 2H), 7.03 (d, >8.0 Hz, 1H), 4.68 (s, 2H), 1.74 (s, 6H). LC-MS (Method A) Rt 2.32 min; MS m/z 380.20 = [M+H]+ (94% @ 215 nm) 83.18 ^N n JjT I < _СНз 1H NMR (500 MHz, DMSO-s16) δ 10.86 (s, 1H), 8.86 (s, 1H), 8.57 (d, >5.5 Hz, 1H), 8.52 (d, >2.0 Hz, 1H), 8.07 (dd, >5.5, 2.2 Hz, 1H), 7.74 (d, >7.9 Hz, 1H), N-[2-[(1-Cyano-1-methylethyl)carbamoyl]-4-pyridyl]-1-ethyl-indole-2-carboxamide 7.62 (d, >8.4 Hz, 1H), 7.49 (s, 1H), 7.377.33 (m, 1H), 7.18-7.14 (m, 1H), 4.61 ( k, >7.0 Hz, 2H), 1.75 (s, 6H), 1.34 (t, >7.0 Hz, ZN). LC-MS (Method A) Rt 3.64 min; MS m/z 376.3 = [M+H]+ (94% @ 215 nm) 83.19 HoC sn,o N F X-(1-Cyano-1-methylethyl)-4-[[2-(2,2,2-trifluoroethyl)pyrazole-3carbonyl] amino]pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-bb) δ 10.92 (s, 1H), 8.88 (s, 1H), 8.60 (d, >5.5 Hz, 1H), 8.44 (d, >2.1 Hz, 1H), 8.01 (dd, >5.5, 2.2 Hz, 1H), 7.81 (d, >2.0 Hz, 1H), 7.33 (d, > 2.0 Hz, 1H), 5.53 (k, >8.9 Hz, 2H), 1.74 (s, 6H). LC-MS (Method A) Rt 2.85 min; MS m/z 381.3 = [M+H]+ (100% @ 215 nm) 83.20 And M-[2-[(1-Cyano-1-methylethyl)carbamoyl]-4-pyridyl]-3-phenylisoxazole-4carboxamide 1H NMR (500 MHz, DMSO-bb) δ 11.07 (s, 1H), 9.64 (s, 1H), 8.87 (s, 1H), 8.57 (d, >5.5 Hz, 1H), 8.32 (d, >2.1 Hz, 1H), 7.91 (dd, >5.5, 2.2 Hz, 1H), 7.75-7.71 (m, 2H), 7.54-7.49 (m, ZN), 1.73 (s, 6H). LC-MS (Method A) Rt 3.02 min; MS m/z 376.3 = [M+H]+ (99% @ 215 nm)

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83.21 H _s with CH ₃ O n U-7 ^{3 3} I ¹ N—/ ^{N n} ° 4-[( 1 -Benzylpyrazol-4-carbonyl)amino]-M-(1-cyano-1-methylethyl)pyridin- 2 carboxamide 1H NMR (500 MHz, DMSO-bb) δ 10.42 (s, 1H), 8.84 (s, 1H), 8.53 (d, J=5.6 Hz, 2H), 8.36 (d , J=2.1 Hz, 1H), 8.12 (s, 1H), 8.03 (dd, J=5.6, 2.2 Hz, 1H), 7.40-7.36 (m, 2H), 7.34-7.28 (m, ZH), 5.41 (s, 2H), 1.73 (s, 6H). LC-MS (Method A) Rt 2.89 min; MS m/z 389.3 = [M+H]+ (100% @ 215 nm) 83.22 ^H 3 ^C x m H ₃ C CH ₃ O H N Ι\κ μ II I ^Η O N-(1-Cyano-1-methylethyl)-4-[(2-methyl-5-phenylpyrazole-3-carbonyl)amino ] pyridine2-carboxamide 1H NMR (500 MHz, DMSO-bb) δ 10.86 (s, 1H), 8.88 (s, 1H), 8.60 (d, J=5.5 Hz, 1H), 8.46 (d , J=2.l Hz, 1H), 8.06 (dd, J=5.5, 2.2 Hz, 1H), 7.85-7.80 (m, 2H), 7.58 (s, 1H), 7.47 (t, J=7.7 Hz, 2H), 7.36 (t, J=7.4 Hz, 1H), 4.16 (s, ZN), 1.75 (s, 6H). LC-MS (Method A) Rt 3.44 min; MS m/z 389.3 = [M+H]+ (100% @ 215 nm) 83.23 H ₃ C s _n o n lf% N^O N H ₃ C 1H NMR (500 MHz, DMSO-bb) δ 11.16 (s, 1H), 8.87 (s, 1H), 8.58 (d, J=5.5 Hz, 1H), 8.31 (d , >1.9Hz, 1H), 8.11-8.07 (m, 1H), 7.89 (dd, J=5.5, 2.0 Hz, 1H), 7.857.76 (m, ZN) , 2.32 (s, ZN), 1.74 (s, 6H). LC-MS (Method A) Rt 2.61 min; MS N-(1-Cyano-1-methylethyl)-4-[[2-(3-methyl-1,2,4-oxadiazol-5yl)benzoyl]amino]pyridine-2-carboxamide m/z 391.3 = [M+H]+ (96% @ 215 nm) 83.24 ^H 3 ^C h m ^H 3 ^C _V ^CH 3° ? In Ν-/Λ N-(1-Cyano-1-methylethyl)-4-[(3-methyl-1-phenylpyrazole-4-carbonyl)amino]pyridine2-carboxamide 1H NMR (500 MHz, DMSO-bb) δ 10.43 (s, 1H), 9.15 (s, 1H), 8.86 (s, 1H), 8.56 (d, J=5.5 Hz , 1H), 8.35 (d, J=2.l Hz, 1H), 8.06 (dd, J=5.5, 2.2 Hz, 1H), 7.83-7.79 (m, 2H), 7.59-7.54 (m, 2H), 7.39 (t, J=7.4 Hz, 1H), 1.74 (s, 6H). Pyrazole CH3 behind the DMSO peak at 2.50. LC-MS (Method A) Rt 3.32 min; MS m/z 389.3 = [M+H]+ (99% @ 215 nm) 83.25 ^Н ,С СНР Н lf> ^Н 0 0^^ Μ Т\Г-[2-[(1-Cyano-1-methylethyl)carbamoyl]-4-pyridyl]-2-phenoxypyridine-3carboxamide 1HNMR (500 MHz, dmso-ab) δ 11.11 (s, 1H), 8.87 (s, 1H), 8.58 (d, J=5.5 Hz, 1H), 8.35 (d, J=2.0 Hz, 1H), 8.27 (dd, J=4.9, 1.9 Hz, 1H), 8.15 (dd, J=7.4, 1.9 Hz, 1H), 7.99 (dd, J=5.5, 2.1 Hz, 1H), 7.45-7.40 (m, 2H), 7.29 (dd, J=7.4, 4.9 Hz, 1H), 7.25-7.20 (m, ZN), 1.73 (s, 6H). LC-MS (Method A) Rt 3.24 min; MS m/z 402.3 = [M+H]+ (100% @ 215 nm)

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83.26 lA N-(1-Cyano-1-methylethyl)-4-[[2,5-dimethyl-1-(2-thienylmethyl)pyrrole-3carbonyl]amino]pyridine-2-carboxamide 1HNMR (500 MHz, DMSO-ab) δ 9.90 (s, 1H), 8.80 (s, 1H), 8.47 (d, J=5.6 Hz, 1H), 8.44 (d, J=2.l Hz, 1H), 8.05 (dd, >5.6, 2.2 Hz, 1H), 7.45 (dd, >5.1, 1.2 Hz, 1H), 6, 99 (dd, >5.1, 3.5 Hz, 1H), 6.92 (dd, >3.4, 1.0 Hz, 1H), 6.56 (s, 1H), 5.30 (s , 2H), 2.53 (s, ZN), 2.24 (s, ZN), 1.73 (s, 6H). LC-MS (Method A) Rt 3.47 min; MS m/z 422.3 = [M+H]+ (100% @ 215 nm) 83.27 CH ₃ o' n ₃ c sn _z o H ^N '°\ L=\ N ' 1—1 ^{11 11 H 0} X-[2-[(1-Cyano-1-methylethyl)carbamoyl]-4-pyridyl]- 5-(2-methoxyphenyl)isoxazole3-carboxamide 1H NMR (500 MHz, DMSO-ab) δ 11.39 (s, 1H), 8.88 (s, 1H), 8.62 (d, >5.5 Hz, 1H), 8.56 (d, >2.1 Hz, 1H), 8.08 (dd, >5.5, 2.2 Hz, 1H), 7.95 (dd, >7.8, 1.7 Hz, 1H), 7.59 -7.55 (m, 1H), 7.30-7.28 (m, 2H), 7.19-7.14 (m, 1H), 4.00 (s, ZN), 1.75 (s , 6H). LC-MS (Method A) Rt 3.58 min; MS m/z 406.2 = [M+H]+ (77% @ 215 nm) 83.28 H ₃ C ^H 3 ^C _V ^CH 3° Η γν=\ 1H NMR (500 MHz, DMSO-ab) δ 10.85 (s, 1H), 8.87 (s, 1H), 8.58 (d, >5.5 Hz, 1H), 8.40 (d, >2.1 Hz, 1H), 8.02-7.97 (m, ZN), 7.58-7.54 (m, ZN), 2.69 (s, ZN), 1.74 N-[2-[(l-Cyano-1-methylethyl)carbamoyl]-4-pyridyl]-4-methyl-2-phenylthiazol-5carboxamide (s, 6H). LC-MS (Method A) Rt 3.52 min; MS m/z 406.2 = [M+H]+ (100% @ 215 nm) 83.29 ^H O 4-[(4-Acetamidobenzoyl)amino]-M-(1-cyano-1-methylethyl)pyridine-2-carboxamide LC-MS (Method A) Rt 2.29 min; MS m/z 366.2 = [M+H]+ (94% @ 215 nm) 83.30 n ₃ with sn ₃ o n A Ν-[2-[(1-Cyano-1-methylethyl)carbamoyl]-4-pyridyl]-1,3-benzothiazole-7carboxamide 1H NMR (500 MHz, DMSO-ab) δ 11.13 (s, 1H), 9.54 (s, 1H), 8.90 (s, 1H), 8.62 (d, >5.5 Hz, 1H), 8.57 (d, >2.1 Hz, 1H), 8.45 (d, >7.5 Hz, 1H), 8.41-8.38 (m, 1H), 8.15 ( dd, >5.5, 2.2 Hz, 1H), 7.81 (t, >7.8 Hz, 1H), 1.75 (s, 6H). LC-MS (Method A) Rt 2.71 min; MS m/z 366.2 = [M+H]+ (94% @ 215 nm) 83.31 ^{N Н} ° ^сн з N-(1-Cyano-1-methylethyl)-4-[3-(4-fluorophenyl)butanoylamino]pyridin-2 carboxamide 1H NMR (500 MHz, DMSO-ab) δ 10.52 (s, 1H), 8.81 (s, 1H), 8.48 (d, >5.5 Hz, 1H), 8.20 (d, >2.0 Hz, 1H), 7.79 (dd, >5.5, 2.2 Hz, 1H), 7.34-7.28 (m, 2H), 7.15-7.07 (m , 2H), 3.30-3.26 (m, 1H), 2.68-2.62 (m, 2H), 1.72 (s, 6H), 1.25 (d,

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Example 84.

No. tert-Butyl-3-[[2-(2-hydroxycyclohexyl)acetyl]amino]benzamide

HATU (268 mg, 0.7 mmol) was added to a stirred solution of 2-(2oxocyclohexyl)acetic acid (100 mg, 0.64 mmol), 3-aminoA-tert-butylbenzamide hydrochloride (146 mg, 0.64 mmol) and DIPEA (0.28 ml, 1.6 mmol) in DMF (2 ml), the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc (10 ml) and water (10 ml). The aqueous layer was extracted with EtOAc (10 ml) and the combined organic extracts were washed with water (2x20 ml) and saturated aqueous sodium chloride (15 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The crude material was then dissolved in MeOH (2 ml) and treated with NaBH4 (36 mg, 0.96 mmol). The resulting mixture was stirred at room temperature for 10 minutes and then concentrated in vacuo. The crude residue was partitioned between water (20 ml) and EtOAc (20 ml). The organic layer was separated, dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by preparative HPLC (acidic pH, early elution method) yielded the title compound as a white, metallic powder as a 7:3 mixture of diastereoisomers.

1H NMR (400 MHz, DMSO-06) δ 9.93 (s, 1H), 7.93-7.81 (m, 1H), 7.82-7.73 (m, 1H), 7.71- 7.63 (m, 1H), 7.43-7.36 (m, 1H), 7.31 (t, J=7.8 Hz, 1H), 4.70-4.18 (m, 1H) , 3.74-2.93 (m, 1H), 2.87-2.35 (m, 1H), 2.27-1.97 (m,

1H), 1.96-1.77 (m, 1H), 1.76-0.88 (m, 17H).

LC-MS (Method A) Rt 2.63 min; MS m/z 333.3 = [M+H]+ (61% @ 215 nm); RT 2.65 min; MS m/z 333.3 = [M+H]+ (38% @ 215 nm).

Example 85.

No. tert-Butyl-6-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyrimidine-4-carboxamide

The title compound was prepared from Y-tert-butic-6-||2-(5-chloro-2methoxyphenyl)acetyl]amino]pyrimidine-4-carboxamide (Example 82) and analogously to Example 1, Step 2.

1H NMR (500 MHz, DMSO-06) δ 11.30 (s, 1H), 9.84 (s, 1H), 8.94 (d, J=1.2 Hz, 1H), 8.54 (d , J=1.2 Hz, 1H), 8.04 (s, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.11 (dd, J=8.6, 2, 7 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H), 3.75 (s, 2H), 1.39 (s, 9H).

LC-MS (Method A) Rt 3.16 min; MS m/z 363.2 = [M+H]+ (98% @ 215 nm).

Example 86.

4-[[2-(5-Chloro-2-hydroxyphenyl) acetyl]amino]-N-[1-cyano-2-methoxy-1 (methoxymethyl)ethyl] pyridine-2-carboxamide CH ₃

Step 1: Methyl 2-(5-chloro-2-hydroxyphenyl) acetate

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Methyl 2-(2-hydroxyphenyl) acetate (1.68 g, 10.11 mmol), NCS (1.35 g, 10.11 mmol) and triphenylphosphine sulfide (298 mg, 1.01 mmol) were dissolved in chloroform (40 ml) and stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo and the residue was dissolved in EtOAc (50 ml). The mixture was washed with water (2x50 ml), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with 0-50% EtOAc in heptane to give the title compound as a colorless viscous oil, which solidified on standing at room temperature.

1H NMR (500 MHz, DMSO-dg) δ 9.81 (br.s, 1H), 7.18 (d, J=2.7 Hz, 1H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H), 3.59 (s, 3H), 3.56 (s, 2H).

LC-MS (Method E): Rt 1.02 min; No MS m/z ionization was observed.

Step 2: Methyl 2-[5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl]acetate

Methyl 2-(5-chloro-2-hydroxyphenyl) acetate (step 1) (1.83 ml, 7.76 mmol) was suspended in anhydrous acetone (50 ml) and treated with K ₂ CO ₃ (1.61 g, 11 .64 mmol) followed by the addition of 1(bromomethyl)-4-methoxybenzene (1.2 ml, 8.55 mmol). After heating at reflux (60°C) for 2 hours, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc (50 ml) and washed with water (50 ml) and saturated aqueous sodium chloride (50 ml), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The resulting crude residue was purified by silica gel chromatography, eluting with 025% EtOAc in heptane, to give the title compound as a viscous yellow oil.

1H NMR (500 MHz, DMSO-de) δ 7.32-7.27 (m, 4H), 7.07 (d, J=8.6 Hz, 1H), 6.96-6.92 (m, 2H), 5.01 (s, 2H), 3.75 (s, 3H), 3.62 (s, 2H), 3.55 (s, 3H).

LC-MS (Method E): Rt 1.23 min; MS m/z ionization was not observed = [M+H]+.

Step 3: Lithium 2-[5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl]acetate

Methyl 2-[5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl]acetate (step 2) (2.4 g, 6.57 mmol) was dissolved in THF (5 ml) and treated with 2 M aqueous solution lithium hydroxide hydrate (3.45 ml, 6.9 mmol). After stirring at room temperature for 1 hour, MeOH (5 ml) was added to the two-phase mixture and stirring was continued at room temperature for 1 hour. An additional portion of lithium hydroxide hydrate (13.8 mg, 0.33 mmol, 0. 05 eq.), and the solution was stirred for an additional hour. An additional portion of lithium hydroxide hydrate (13.8 mg, 0.33 mmol, 0.05 eq.) was added and stirring was continued for 1 hour. The resulting mixture was concentrated in vacuo and azeotroped with MeCN (3x50 ml). The solid was suspended in diethyl ether (50 ml), filtered, washed with diethyl ether (2x25 ml) and dried under pump vacuum to give the title compound as a white powdery solid.

1H NMR (500 MHz, DMSO-dg) δ 7.40-7.36 (m, 2H), 7.22 (d, J=2.7 Hz, 1H), 7.07 (dd, J=8, 7, 2.8 Hz, 1H), 6.94-6.89 (m, 3H), 4.97 (s, 2H), 3.75 (s, 3H), 3.17 (s, 2H).

LC-MS (Method E): Rt 1.17 min; MS m/z 260.9 = [M-H]- (95% @ 215 nm) [observed major massion for decarboxylated fragment ion].

Step 4: Methyl-4-[[2-[5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl]acetyl]amino]pyridine-2 carboxylate

To a mixture of lithium 2-[5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl]acetate (step 3) (1.5 g, 4.8 mmol) and methyl 4-aminopyridine-2-carboxylate (0 .8 g, 5.28 mmol) in anhydrous 1,4-dioxane (50 ml) at the same time

- 173 046966 but a 50% T3P® solution in EtOAc (5.71 ml, 9.59 mmol) and TEA (3.35 ml, 19.19 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and then quenched by careful addition of NaHCO ₃ (50 ml). H2O (10 ml) was added to dissolve excess salts and the mixture was extracted with EtOAc (2x50 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (50 ml), dried over Na ₂ SO ₄ and concentrated in vacuo.

Purification by NH silica gel chromatography, eluting with a gradient of 0-100% EtOAc in heptane, afforded the title compound as a white metallic solid.

1H NMR (500 MHz, DMSO-de) δ 10.65 (s, 1H), 8.54 (d, J=5.4 Hz, 1H), 8.21 (d, J=2.0 Hz, 1H ), 7.75 (dd, J=5.5, 2.1 Hz, 1H), 7.33 (d, J=2.7 Hz, 1H), 7.30 (dd, J=8.7, 2.7 Hz, 1H), 7.22 (d, J=8.7 Hz, 2H), 7.09 (d, J=8.7 Hz, 1H), 6.65-6.61 (m, 2H), 4.97 (s, 2H), 3.87 (s, 3H), 3.70 (s, 2H), 3.64 (s, 3H).

LC-MS (Method F): Rt 1.63 min; MS m/z 441.2/443.2 = [M+H]+ (100% @ 215 nm).

Step 5: 4-[[2-[5-Chloro-2-[(4-methoxyphenyl)methoxy]phenyl]acetyl]amino]pyridine-2-carboxylic acid

Methyl 4-[[2-[5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl]acetyl]amino]pyridine-2-carboxylate (step 4) (1.98 g, 4.49 mmol) dissolved in THF (2.5 ml) and MeOH (2.5 ml) and treated with 2 M aqueous lithium hydroxide hydrate (2.47 ml, 4.94 mmol) and stirred at room temperature for 1 hour. Additional THF was added ( 2.5 ml), MeOH (2.5 ml) and water (2.5 ml), and stirring was continued at room temperature overnight. The resulting mixture was diluted with EtOAc (50 ml) and water (50 ml). The pH was adjusted to pH 5 using 2 M KHSO4 (2 ml) and the precipitate was filtered. The filter cake was washed with water (20 ml), EtOAc (20 ml), diethyl ether (20 ml) and dried in vacuo to give the title compound as a white solid.

1H NMR (500 MHz, DMSO^) δ 10.61 (s, 1H), 8.43 (d, J=5.5 Hz, 1H), 8.11 (d, J=1.7 Hz, 1H) , 7.75 (dd, J=5.6, 2.1 Hz, 1H), 7.33 (d, J=2.6 Hz, 1H), 7.30 (dd, J=8.7, 2 .6 Hz, 1H), 7.23 (d, J=8.6 Hz, 2H), 7.08 (d, J=8.8 Hz, 1H), 6.68-6.64 (m, 2H ), 4.98 (s, 2H), 3.71 (s, 2H), 3.65 (s, 3H) [OH not observed].

LC-MS (Method E): Rt 1.04 min; MS m/z 427.0/429.0 = [M+H]+ (98% @ 215 nm).

Step 6: 2-Amino-3-methoxy-2-(methoxymethyl)propanenitrile

... NH _a N // o o HjC''SN _L

Ammonium chloride (226 mg, 4.23 mmol) was added to a suspension of 1,3-dimethoxypropan-2-one (400 mg, 3.39 mmol) in 7 M ammonia in MeOH (4.84 mL, 33.86 mmol). followed by the addition of sodium cyanide (207 mg, 4.23 mmol). After stirring at room temperature for 15 minutes, water (2.4 ml) was added and stirring was continued for 3 hours. The mixture was diluted with EtOAc (30 ml) and washed with sat. sodium carbonate solution (3x20 ml) and saturated aqueous sodium chloride solution (2x20 ml). The organic portion was separated, dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound as a colorless oil.

1H NMR (500 MHz, Methanol-ar δ 3.55 (d, J=9.5 Hz, 2H), 3.45 (d, J=9.5 Hz, 2H), 3.45 (s, 6H) .

LC-MS (Method E): Rt 0.66 min; MS m/z 145.1 = [M+H]+ (67% @ 215 nm).

Step 7: 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-N-[1-cyano-2-methoxy-1(methoxymethyl)ethyl]pyridine-2-carboxamide

To a solution of DIPEA (0.25 ml, 1.41 mmol), 4-[[2-[5-chloro-2-[(4methoxyphenyl)methoxy]phenyl]acetyl]amino]pyridine-2-carboxylic acid (step 5) (200 mg, 0.47 mmol) and 50% T3P® solution in EtOAc (0.6 ml, 0.94 mmol) in DMF (2 ml) was added 2-amino-3methoxy-2-(methoxymethyl)propanenitrile (step 6 ) (101 mg, 0.7 mmol), and the reaction mixture was stirred at room temperature for 6 hours. The resulting mixture was diluted with EtOAc (10 ml) and washed with saturated aqueous sodium chloride (10 ml). The aqueous layer was re-extracted with EtOAc (10 ml) and the combined organic extracts were dried over Na ₂ SO ₄ and concentrated in vacuo. The crude residue was dissolved in dioxane (2 ml) and treated with 4N HCl in dioxane (2 ml, 8.0 mmol). After stirring at room temperature for 2 hours, the mixture was concentrated in vacuo and purification of the crude product by preparative HPLC (acid pH, early elution method) gave the title compound as a white solid with a metallic tint.

1H NMR (500 MHz, Methanol-a ₄ ) δ 8.48 (d, J=5.5 Hz, 1H), 8.21 (d, J=1.8 Hz, 1H), 7.96 (dd, J=5.5, 2.2 Hz, 1H), 7.21 (d, J=2.6 Hz, 1H), 7.11 (dd, J=8.6, 2.6 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 4.00 (d, J=9.5 Hz, 2H), 3.83 (d,

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J=9.5 Hz, 2H), 3.73 (s, 2H), 3.50 (s, 6H).

LC-MS (Method A): Rt 3.09 min; MS m/z 433.1= [M+H]+ (98% @ 215 nm).

Example 87: 4-[[2-(3-Amino-4-tert-butyl-phenyl)acetyl]amino]-M-tert-butylpyridine-2carboxamide and Example 88: 4-[[2-(2-amino-4 -tert-butylphenyl)acetyl]amino]-M-tert-butylpyridine-2carboxamide

Step 1: Mixture of 2-(4-tert-butyl-2-nitrophenyl)acetic acid and 2-(4-tert-butyl-3-nitrophenyl)acetic acid

A stirred solution of 2-(4-tert-butylphenyl)acetic acid (1.0 g, 5.2 mmol) in water (5 ml) was treated dropwise with nitric acid (0.65 ml, 15.6 mmol) and sulfuric acid ( 0.55 ml, 10.4 mmol), and the mixture was stirred at room temperature for 10 hours. The resulting mixture was diluted with EtOAc (10 ml) and washed with saturated aqueous sodium chloride (10 ml). The organic portion was separated, washed with saturated aqueous sodium chloride (2 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by chromatography on silica gel, eluting with 0-100% EtOAc in heptane, gave the title mixture as a yellow oil.

1H NMR (500 MHz, DMSO-de) δ 8.01 (d, J=2.1 Hz, 1H), 7.76 (dd, J=8.0, 2.1 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.48-7.42 (m, 2H), 3.95 (s, 2H) , 3.66 (s, 2H), 1.34 (s, 9H), 1.33 (s, 9H).

LC-MS (Method E): Rt 1.13 min; MS m/z=ionization was not observed.

Step 2: Mixture of N-tert-butyl-4-[[2-(4-tert-butyl-2-nitrophenyl)acetyl]amino]pyridine-2-carboxamide and N-tert-butyl-4-[[2-(4-tert- butyl-3-nitrophenyl)acetyl]amino]pyridine-2-carboxamide

To a solution of DIPEA (1.36 ml, 7.76 mmol), 50% T3P® solution in EtOAc (0.6 ml, 5.17 mmol) and a mixture of 2-(4-tert-butyl-2-nitrophenyl)acetic acid and 2-(4-tert-butyl-3-nitrophenyl)acetic acid (step 1) (720 mg, 3.03 mmol) in DMF (5 ml) was added 4-amino-M-tert-butylpyridine-2carboxamide (645 mg , 3.34 mmol), and the reaction mixture was stirred at room temperature for 6 hours. The resulting mixture was diluted with EtOAc (10 ml) and washed with saturated aqueous sodium chloride (10 ml). The aqueous layer was re-extracted with EtOAc (10 ml) and the combined extracts were dried over Na2SO4 and concentrated in vacuo to give the title compounds as a yellow oil.

1H NMR (500 MHz, DMSO-de) δ 10.81 (m, 2H), 8.46 (m, 2H), 8.16 (m, 2H), 8.03 (m, 3H), 7.84 -7.74 (m, 3H), 7.64 (d, J=8.1 Hz, 1H), 7.55-7.47 (m, 3H), 4.15 (s, 2H), 3, 81 (s, 2H), 1.40 (s, 18H), 1.34 (s, 18H).

LC-MS (Method E): Rt 1.29 min; MS m/z 413.5= [M+H]+ (100% @ 215 nm).

Step 3: 4-[[2-(3-Amino-4-tert-butyl-phenyl)acetyl]amino]-M-tert-butylpyridine-2-carboxamide and 4-[[2-(2-amino-4- tert-butyl-phenyl)acetyl]amino]-M-tert-butylpyridine-2-carboxamide

To a mixture of N-tert-butyl-4-[[2-(4-tert-butyl-2-nitrophenyl)acetyl]amino]pyridine-2-carboxamide and N-tert-butyl-4-[[2-(4-tert- butyl-3-nitrophenyl)acetyl]amino]pyridine-2-carboxamide (step 2) (950 mg, 2.3 mmol) in EtOH (5 ml) was added 10% Pd-C (123 mg, 1.15 mmol), and the mixture was stirred under a hydrogen atmosphere for 18 hours. The resulting mixture was filtered through Celite® and washed with methanol. The filtrate was concentrated in vacuo and purification of the crude product by preparative HPLC (alkaline pH, early elution method) gave the following compounds as white solids:

Example 87.

4-[[2-(3-Amino-4-tert-butylphenyl)acetyl]amino]-M-tert-butylpyridine-2-carboxamide

1H NMR (500 MHz, DMSO-de) δ 10.67 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H ), 8.03 (s, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 6.59 (d, J=1.9 Hz, 1H), 6.48 (dd, J=8.0, 1.9 Hz, 1H), 4.76 (s, 2H), 3.50 (s, 2H) , 1.40 (s, 9H), 1.31 (s, 9H).

LC-MS (Method A): Rt 3.56 min; MS m/z 383.3= [M+H]+ (100% @ 215 nm).

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Example 88.

4-[[2-(2-Amino-4-tert-butylphenyl)acetyl]amino]-Ntert-butylpyridine-2-carboxamide

1H NMR (500 MHz, DMSO-06) δ 10.69 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H ), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 6.97 (d, J=8.0 Hz, 1H), 6.73 (d, J=2.0 Hz, 1H), 6.59 (dd, J=7.9, 2.0 Hz, 1H), 4.96 (s, 2H), 3.52 (s, 2H) , 1.40 (s, 9H), 1.22 (s, 9H).

LC-MS (Method A): Rt 3.58 min; MS m/z 383.3= [M+H]+ (99% @ 215 nm).

Example 89.

X-tert-Butyl-4-[[2-(4-tert-butyl-3-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide

To a cooled (0°C) solution of 4-[[2-(3-amino-4-tert-butylphenyl)acetyl]amino]-X-tert-butylpyridine-2-carboxamide (Example 87) (100 mg, 0.26 mmol) in water (0.2 ml) added sulfuric acid (0.02 ml, 0.29 mmol) in water (0.3 ml) followed by the addition of sodium nitrite (20 mg, 0.29 mmol) in water (0.5 ml). After stirring at 5°C for 3 hours, copper sulfate pentahydrate (326 mg, 1.31 mmol) and copper oxide (112.23 mg, 0.78 mmol) in water (0.5 ml) were added. and the mixture was stirred at room temperature for 12 hours. The resulting mixture was diluted with EtOAc (10 ml) and water (10 ml). The organic layer was separated, dried over Na ₂ SO ₄ and concentrated in vacuo.

Purification of the crude material by preparative HPLC (acidic pH, early elution method) yielded the title compound as a white solid.

1H NMR (400 MHz, DMSO-06) δ 10.71 (s, 1H), 9.30 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.20 (d , J=2.1 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.08 (d, J=8, 0 Hz, 1H), 6.76 (d, J=1.7 Hz, 1H), 6.68 (dd, J=7.9, 1.7 Hz, 1H), 3.56 (s, 2H) , 1.40 (s, 9H), 1.32 (s, 9H).

LC-MS (Method A): Rt 3.76 min; MS m/z 384.2= [M+H]+ (99% @ 215 nm).

Example 90.

No. tert-Butyl-4-[[2-(4-tert-butyl-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide

The title compound was prepared from 4-[[2-(2-amino-4-tert-butyl-phenyl)acetyl]amino]N-tert-butylpyridine-2-carboxamide (Example 88) analogously to Example 89.

1H NMR (500 MHz, DMSO-06) δ 10.64 (s, 1H), 9.36 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.18 (d , J=2.0 Hz, 1H), 8.03 (s, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.06 (d, J=7, 9 Hz, 1H), 6.84 (d, J=1.9 Hz, 1H), 6.79 (dd, J=7.9, 1.9 Hz, 1H), 3.61 (s, 2H) , 1.40 (s, 9H), 1.25 (s, 9H).

LC-MS (Method A): Rt 3.76 min; MS m/z 384.2 = [M+H]+ (100% @ 215 nm).

Example 91.

X-tert-Butyl-4-[[2-(4-tert-butyl-2-fluoro-5-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide

To a solution of N-tert-butyl-4-[[2-(2-fluoro-5-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Example 3.13b) (300 mg, 0.87 mmol) in DCM (12 ml ) tert-butanol (332 µl, 3.47 mmol) and H2SO4 (250 µl, 0.87 mmol) were added and the mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo and partitioned between EtOAc (20 ml ) and water (20 ml). The organic portion was separated, washed with saturated aqueous sodium chloride (20 ml) and concentrated in vacuo. Purification of the residue by preparative HPLC (acid pH, standard elution method) yielded the title compound as a white solid.

1H NMR (500 MHz, DMSO-06) δ 10.78 (s, 1H), 9.31 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.19 (d , J=2.0 Hz, 1H), 8.03 (s, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 6.87 (d, J=11, 9 Hz, 1H), 6.74 (d, J=7.0 Hz, 1H), 3.65 (s, 2H),

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1.40 (s, 9H), 1.32 (s, 9H).

LC-MS (Method A): Rt 3.89 min; MS m/z 402.3 = [M+H]+ (96% @ 215 nm).

Example 92.

4-[[2-(4-Chloro-3-hydroxyphenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridin-2carboxamide

Step 1: Methyl 4-[[2-(4-chloro-3-methoxyphenyl)acetyl]amino]pyridine-2-carboxylate

The title compound was prepared from 2-(4-chloro-3-methoxyphenyl)acetic acid and methyl 4-aminopyridine-2-carboxylate analogously to Example 41, Step 1.

^1H NMR (400 MHz, DMSO^) δ 10.77 (s, 1H), 8.55 (d, J=5.5 Hz, 1H), 8.29 (d, J=2.0 Hz, 1H ), 7.78 (dd, J=5.5, 2.1 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 7.12 (d, J=1.7 Hz , 1H), 6.91 (dd, J=8.1, 1.7 Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.73 (s, 2H) .

LC-MS (Method E): Rt 1.03 min; MS m/z 335.0/337.0 = [M+H]+ (95% @ 215 nm).

Step 2: 4-[[2-(4-Chloro-3-methoxyphenyl)acetyl]amino]pyridine-2-carboxylic acid

The title compound was prepared from methyl 4-[[2-(4-chloro-3methoxyphenyl)acetyl]amino]pyridine-2-carboxylate (Step 1) analogously to Example 41, Step 2.

1H NMR (500 MHz, DMSO-06) δ 10.77 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.26 (d, J=2.0 Hz, 1H ), 7.79 (dd, J=5.5, 2.2 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 7.13 (d, J=1.8 Hz , 1H), 6.91 (dd, J=8.1, 1.9 Hz, 1H), 3.85 (s, 3H), 3.73 (s, 2H).

LC-MS (Method E): Rt 0.88 min; MS m/z 321.0/322.9 = [M+H]+ (100% @ 215 nm).

Step 3: 4-[[2-(4-Chloro-3-hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid

The title compound was prepared from 4-[[2-(4-Chloro-3methoxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (Step 2) and BBr ₃ analogously to Example 31, Step 1.

LC-MS (Method E): Rt 0.80 min; MS m/z 306.9/308.9 = [M+H]+ (62% @ 215 nm).

Step 4: 4-[[2-(4-Chloro-3-hydroxyphenyl)acetyl]amino]-N(4-cyanotetrahydropyran-4yl)pyridin-2-carboxamide

To a solution of 4-[[2-(4-chloro-3-hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (step 3) (65%, 50 mg, 0.11 mmol), 4-aminotetrahydropyran-4- carbonitrile (16 mg, 0.13 mmol) and DIPEA (0.04 ml, 0.21 mmol) in DMF (0.5 ml) was added HATU (48 mg, 0.13 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with 0.5 M NaOH (aq, 0.4 ml), stirred for 5 minutes, then acidified to pH 5 with 2 M aqueous HCl. The aqueous layer was extracted with EtOAc (2x5 ml) and the combined organic extracts were washed with water (5 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. Preparative HPLC purification (acidic pH, early elution method) followed by lyophilization of the pure fractions yielded the title compound as a white powder with a metallic tint.

1H NMR (500 MHz, DMSO-f,) δ 10.79 (s, 1H), 10.11 (br.s, 1H), 9.00 (s, 1H), 8.53 (d, J=5 .5 Hz, 1H), 8.23 (d, J=2.1 Hz, 1H), 7.85 (dd, J=5.5, 2.2 Hz, 1H), 7.26 (d, J =8.1 Hz, 1H), 6.94 (d, J=1.9 Hz, 1H), 6.76 (dd,

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J=8.2, 1.9 Hz, 1H), 3.90-3.82 (m, 2H), 3.63 (s, 2H), 3.62-3.53 (m, 2H), 2 .39-2.33 (m, 2H), 2.13-2.00 (m, 2H).

LC-MS (Method a): Rt 2.50 min; MS m/z 415.1/417.1 = [M+H]+ (100% @ 215 nm)

The compounds of the following tabular examples (Table 15) were prepared from 4-[[2-(4-chloro-3hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (example 92, step 3) analogously to example 92, step 4, replacing 4 -aminotetrahydropyran-4-carbonitrile with a corresponding commercially available amine.

Table 15

Example Structure and name 1NMR Retention time LC-MS, [M+H]+, 92.1 ^C G ⁵ i ⁿ He 4-[[2-(4-Chloro-3-hydroxyphenyl)acetyl] amino]-N-(1 cyano-1-methylethyl)pyr idin-2 carboxamide 1H NMR (500 MHz, DMSO-bb) δ 10.79 (s, 1H), 10.14 (br.s, 1H), 8.83 (s, 1H), 8.51 (d, J=5, 5 Hz, 1H), 8.23 (d, J=2.0 Hz, 1H), 7.85 (dd, J=5.5, 2.2 Hz, 1H), 7.26 (d, J= 8.l Hz, 1H), 6.94 (s, 1H), 6.76 (d, J=7.5 Hz, 1H), 3.63 (s, 2H), 1.72 (s, 6H) . LC-MS (Method A): Rt 2.63 min; MS m/z 373.1/375.1 = [M+H]+ (95% @215 nm) 92.2 SI _E 0 _n ffggr,, He 4-[[2-(4-Chloro-3-hydroxyphenyl)acetyl] amino]-N-(1,1 dimethylprop-2-ynyl)pyridine-2carboxamide 1H NMR (500 MHz, DMSO-bb) δ 10.76 (s, 1H), 10.12 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.31 (s , 1H), 8.20 (d, J=2.0 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.26 (d, J=8, l Hz, 1H), 6.94 (d, J=2.0 Hz, 1H), 6.76 (dd, J=8.2, 2.0 Hz, 1H), 3.63 (s, 2H) , 3.21 (s, 1H), 1.64 (s, 6H). LC-MS (Method A): Rt 2.90 min; MS m/z 372.1/374.1 = [M+H]+ (97% @ 215 nm) 92.3 Way He 4-[[2-(4-Chloro-3- hydroxyphenyl)acetyl] amino] -N- [(ls,2s)-2- hydroxycyclopentyl]pyridine-2- carboxamide 1H NMR (500 MHz, DMSO-bb) δ 10.73 (s, 1H), 10.13 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.44 (d , J=7.6 Hz, 1H), 8.19 (d, J=2.1 Hz, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.26 (d, J=8.1 Hz, 1H), 6.95 (d, J=l.9 Hz, 1H), 6.76 (dd, J=8.2, 1.9 Hz, 1H), 4 .80 (d, J=4.5 Hz, 1H), 3.98 (dk, J=13,l, 7.2, 6.4 Hz, 2H), 3.62 (s, 2H), 2, 05-1.93 (m, 1H), 1.92-1.79 (m, 1H), 1.72-1.57 (m, 2H), 1.57-1.38 (m, 2H). LC-MS (Method A): Rt 2.37 min; MS m/z 390.1/392.1 = [M+H]+ (99% @215 nm)

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Example 93.

4-[[2-(4-tert-Butyl-3-hydroxyphenyl)acetyl]amino]-N[3-(hydroxymethyl)tetrahydrofuran-3yl]pyridine-2-carboxamide

Step 1: (4-tert-Butyl-3-methoxyphenyl)methanol

To a stirred solution of 4-tert-butyl-3-methoxybenzoic acid (1.9 g, 9.12 mmol) in THF (20 ml) was added 1 M borane-THF (25.55 ml, 25.55 mmol), and the mixture stirred at 50°C for 1 hour. After cooling to room temperature, the reaction mixture was quenched with methanol (10 ml) and the volatile solvent was removed in vacuo. More methanol (10 ml) was added and volatiles were removed in vacuo. This process was repeated once more to obtain the title compound as a pale yellow oil.

1H NMR (400 MHz, DMSO-a ₆ ) δ 7.14 (d, J=7.9 Hz, 1H), 6.94 (s, 1H), 6.81 (d, J=7.8 Hz, 1H), 5.09 (s, 1H), 4.45 (s, 2H), 3.80 (s, 3H), 1.32 (s, 9H).

Step 2: 1-tert-Butyl-4-(chloromethyl)-2-methoxybenzene

A stirred solution of (4-tert-butyl-3-methoxyphenyl)methanol (step 1) (1.56 g, 8.03 mmol) and DMF (0.59 mL, 8.03 mmol) in DCM (20 mL) was treated with drops of thionyl chloride (1.42 mL, 16.06 mmol) and the mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo and the residue was diluted with EtOAc (10 mL) and washed with saturated NaHCO ₃ (10 mL) . The organic portion was separated, washed with saturated aqueous sodium chloride (2 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound as a yellow oil.

1H NMR (400 MHz, DMSO-a ₆ ) δ 7.21 (d, J=7.9 Hz, 1H), 7.05 (d, J=1.4 Hz, 1H), 6.94 (dd, J=7.9, 1.6 Hz, 1H), 4.72 (s, 2H), 3.82 (s, 3H), 1.33 (s, 9H).

Step 3: 2-(4-tert-Butyl-3-methoxyphenyl)acetonitrile

A solution of 1-tert-butyl-4-(chloromethyl)-2-methoxybenzene (step 2) (1.7 g, 7.99 mmol) in DMF (10 ml) was treated with sodium cyanide (0.78 g, 15.98 mmol ), and the resulting mixture was stirred at room temperature for 8 hours. The mixture was diluted with EtOAc (30 ml) and washed with sat. Sodium carbonate (3x20 ml) and saturated aqueous sodium chloride solution (2x20 ml). The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to give the title compound as a yellow oil.

¹ H NMR (500 MHz, DMSO-a ₆ ) δ 7.22 (d, J=7.9 Hz, 1H), 6.95 (d, J=1.6 Hz, 1H), 6.86 (dd , J=7.9, 1.7 Hz, 1H), 3.96 (s, 2H), 3.82 (s, 3H), 1.32 (s, 9H).

Step 4: 2-(4-tert-Butyl-3-methoxyphenyl)acetic acid

To a solution of 2-(4-tert-butyl-3-methoxyphenyl)acetonitrile (step 3) (1.52 g, 7.48 mmol) H2O (5 ml) was added lithium hydroxide hydrate (1.76 ml, 37.39 mmol ), and this reaction mixture was heated at boiling for 10 hours. After cooling to room temperature, the mixture was acidified with a solution of concentrated HCl. The mixture was extracted with DCM (10 ml) and the combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give the title compound as a pale yellow solid.

¹ H NMR (400 MHz, DMSO-06) δ 12.13 (s, 1H), 7.13 (d, J=7.9 Hz, 1H), 6.87 (d, J=1.6 Hz, 1H), 6.76 (dd,

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J=7.9, 1.7 Hz, 1H), 3.79 (s, 3H), 3.51 (s, 2H), 1.32 (s, 9H).

LC-MS (Method E): Rt 1.14 min; MS m/z 220.9 = [M+H]+ (99% @ 215 nm).

Step 5: Methyl 4-[[2-(4-tert-butyl-3-methoxyphenyl)acetyl]amino]pyridine-2-carboxylate

The title compound was prepared from 2-(4-tert-butyl-3-methoxyphenyl)acetic acid (Step 4) and methyl 4-aminopyridine-2-carboxylate analogously to Example 30, Step 1.

¹ H NMR (500 MHz, DMSO-06) δ 10.78 (s, 1H), 8.55 (d, J=5.5 Hz, 1H), 8.31 (d, J=2.0 Hz, 1H), 7.80 (dd, J=5.5, 2.1 Hz, 1H), 7.16 (d, J=7.9 Hz, 1H), 6.96 (d, J=l.5 Hz, 1H), 6.84 (dd, J=7.9, 1.6 Hz, 1H), 3.87 (s, 3H), 3.81 (s, 3H), 3.66 (s, 2H ), 1.31 (s, 9H).

LC-MS (Method E): Rt 1.19 min; MS m/z 357.0 = [M+H]+ (97% @ 215 nm).

Step 6: 4-[[2-(4-tert-Butyl-3-methoxyphenyl)acetyl]amino]pyridine-2-carboxylic acid

The title compound was prepared from methyl 4-[[2-(4-tert-butyl-3methoxyphenyl)acetyl]amino]pyridine-2-carboxylate (Step 5) and lithium hydroxide hydrate analogously to Example 30, Step 2.

¹ H NMR (500 MHz, DMSO-06) δ 10.87 (s, 1H), 8.54 (d, J=5.6 Hz, 1H), 8.30 (d, J=2.0 Hz, 1H), 7.84 (dd, J=5.6, 2.2 Hz, 1H), 7.16 (d, J=7.9 Hz, 1H), 6.97 (d, J=1.6 Hz, 1H), 6.84 (dd, J=7.9, 1.6 Hz, 1H), 3.81 (s, 3H), 3.68 (s, 2H), 1.31 (s, 9H )

LC-MS (Method E): Rt 1.03 min; MS m/z 343.1 = [M+H]+ (94% @ 215 nm).

Step 7: 4-[[2-(4-tert-Butyl-3-hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid

The title compound was prepared from 4-[[2-(4-tert-butyl-3methoxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (Step 6) and BBr ₃ as in Example 31, Step 1.

1H NMR (500 MHz, DMSO-06) δ 11.12 (s, 1H), 9.32 (s, 1H), 8.60 (d, J=6.0 Hz, 1H), 8.38 (d , J=2.0 Hz, 1H), 7.98 (dd, J=5.9, 2.1 Hz, 1H), 7.08 (d, J=7.9 Hz, 1H), 6.76 (d, J=1.7 Hz, 1H), 6.71-6.66 (m, 1H), 3.62 (s, 2H), 1.32 (s, 9H).

LC-MS (Method E): Rt 0.97 min; MS m/z 329 = [M+H]+ (76% @ 215 nm).

Step 8: 4-[[2-(4-tert-butyl-3-hydroxyphenyl)acetyl]amino]-N-[3 (hydroxymethyl)tetrahydrofuran-3-yl]pyridin-2-carboxamide

The title compound was prepared from 4-[[2-(4-tert-butyl-3hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (Step 7) and (3-aminotetrahydrofuran-3yl)methanol analogously to Example 31, Step 2 .

1H NMR (500 MHz, DMSO^) δ 10.72 (s, 1H), 9.30 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.41 (s, 1H), 8.22 (d, J=2.1 Hz, 1H), 7.82 (dd, J=5.5, 2.1 Hz, 1H), 7.08 (d, J=8.0 Hz, 1H), 6.76 (d, J=1.7 Hz, 1H), 6.68 (dd, J=7.9, 1.6 Hz, 1H), 5.17 (t, J=5 .6 Hz, 1H), 3.90-3.76 (m, 4H), 3.61 (d, J=5.2 Hz, 2H), 3.56 (s, 2H), 2.32 (ddd , J=12.6, 7.6, 5.0 Hz, 1H), 1.98 (dt, J=12.8, 7.8 Hz, 1H), 1.32 (s, 9H).

LC-MS (Method A): Rt 2.91 min; MS m/z 428.3 = [M+H]+ (96% @ 215 nm).

The compounds of the following tabular examples (Table 16) were prepared from 4-[[2-(4-tert-butyl-3hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 93, step 7) analogously to example 93, step 8, replacing (3-aminotetrahydrofuran-3-yl)methanol with the corresponding commercially available amine.

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Table 16

Example Structure and name 1NMR LC-MS retention time, [M+HJ+, _He 1HNMR (500 MHz, DMSO-bb) δ 10.74 (s, 1H), 9.31 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.34 (d, J=8.l Hz, 1H), 8.21 (d, J=2.0 Hz, 1H), 7.84 (dd, ng i gt gp J=5.5, 2.2 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 6.77 (d, J=l.6 Hz, 1H), 6.69 TAN (dd, J=8.0, 1.6 Hz, 1H), 4.69 (d, J=5.5 Hz, 1H), 3.61-3.52 (m, ZN), 3.48- 93.1 OH sn, ³ 3.39 (m, 1H), 1.96-1.84 (m, 2H), 1.69-1.58 (m, 2H), 1.32 (s, 9H), 1.32- 4-[2-(4-tert-butyl-3-hydroxyphenyl)acetamido]-M- 1.20 (m, 4H). [(1 S,2 8)-2-hydroxycyclohexyl]pyridine-2- LC-MS (Method A): Rt 3.24 min; MS m/z 426.3 = [M+H]+ (100% @ carboxamide 215 nm) /A ⁰ n 1HNMR (500 MHz, DMSO-bb) δ 10.76 (s, 1H), 9.31 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.44 (d, J=7.6 Hz, 1H), 8.21 (d, J=l.9 Hz, 1H), 7.83 (dd, but υΠΙ", J=5.5, 2.2 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 6.77 (d, J=l.6 Hz, 1H), 6.69 93.2 (dd, J=8.0, 1.7 Hz, 1H), 4.81 (d, J=4.3 Hz, 1H), 4.05-3.93 (m, 2H), 3.56 ( s, 2H), 2.05-1.95 (m, 1H), 1.91-1.80 (m, 1H), 1.74-1.58 (m, 2H), 1.56- 4-[2-(4-tert-butyl-3-hydroxyphenyl)acetamido]-M- 1.42 (m, 2H), 1.32 (s, 9H). [(1 S,2 8)-2-hydroxycyclopentyl]pyridine-2- LC-MS (Method A): Rt 3.12 min; MS m/z 412.3 = [M+H]+ (100% @ carboxamide 215 nm) °Ύ O _n 1HNMR (500 MHz, DMSO-bb) δ 10.77 (s, 1H), 9.30 (s, 1H), 9.01 (s, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.25 (d, J=2.0 Hz, 1H), 7.87 (dd, J=5.5, 2.2 T ⁿ O Hz, 1H), 7.08 (d, J=8.0 Hz, 1H), 6.77 (d, J=l.7 Hz, 1H), 6.69 (dd, J=8.0, 93.3 η XX- VAch he sn™ ³ 1.7 Hz, 1H), 3.87 (dt, J=12.2, 3.8 Hz, 2H), 3.64-3.55 (m, 4H), 2.41-2.33 (m , 2H), 2.08 (ddd, J=13.8, 10.3, 3.9 Hz, 2H), 1.32 (s, 9H). 4-[[2-(4-tert-Butyl-3-hydroxyphenyl)acetyl]amino]-M- LC-MS (Method A): Rt 3.30 min; MS m/z 437.2 = [M+H]+ (98% @ (4-cyanotetrahydropyran-4-yl)pyridin-2-carboxamide 215 nm) A sn ₃ o _n Al U n 1HNMR (500 MHz, DMSO-ab) δ 10.76 (s, 1H), 9.30 (s, 1H), 8.83 (s, and ₃ with Νγγ νΎΧ 1H), 8.52 (d, J=5.5 Hz, 1H), 8.25 (d, J=2.0 Hz, 1H), 7.86 (dd, J=5.5, 2.2 93.4 Ά ⁰ AAn, Hz, 1H), 7.08 (d, J=8.0 Hz, 1H), 6.77 (d, J=l.8 Hz, 1H), 6.69 (dd, J=7.9, Τ pen. OH CHj ³ 1.8 Hz, 1H), 3.57 (s, 2H), 1.73 (s, 6H), 1.33 (s, 9H). 4-[[2-(4-tert-Butyl-3-hydroxyphenyl)acetyl]amino]-X- LC-MS (Method A): Rt 3.41 min; MS m/z 395.2 = [M+H]+ (99% @ (1-cyano-1-methylethyl)pyride in-2-carboxamide 215 nm) ns^ sn ₃ o _n 1HNMR (500 MHz, DMSO-bb) δ 10.74 (s, 1H), 9.30 (s, 1H), 8.48 (d, ac ^ζ γ γγ YT ii J=5.5 Hz, 1H), 8.32 (s, 1H), 8.21 (d, J=2.0 Hz, 1H), 7.83 (dd, J=5.5, 2.2 ^{Μ Γ} %~ ° ΓΑ/λ Hz, 1H), 7.08 (d, J=8.0 Hz, 1H), 6.76 (d, J=l.8 Hz, 1H), 6.69 (dd, J=8.0, 93.5 OH CH ₃ 1.8 Hz, 1H), 3.56 (s, 2H), 3.21 (s, 1H), 1.65 (s, 6H), 1.32 (s, 9H). 4-[[2-(4-tert-Butyl-3-hydroxyphenyl)acetyl]amino]-X- LC-MS (Method A): Rt 3.64 min; MS m/z 394.2 = [M+H]+ (96% @ (1,1-dimethylprop-2-ynyl)pyride in-2-carboxamide 215 nm)

Example 94.

4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-^(1-methyl-1-phenylethyl)pyridine-2-carboxamide

Step 1: 4-[[2-(5-Chloro-2-methoxyphenyl)acetyl]amino]-^(1-methyl-1-phenylethyl)pyridine-2carboxamide

CH ₃

The title compound was prepared from 4-[[2-(5-chloro-2methoxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 8.1, Step 2) and 2-phenylpropan-2amine as in Example 86, Step 7.

Step 2: 4-[[2-(5-Chloro-2-hydroxyphenyl)acetyl]amino]-1-methyl-1-phenylethyl)pyridine-2carboxamide

The title compound was prepared from 4-[[2-(5-chloro-2-methoxyfevil)acetyl]amino]-M-(1

- 181 046966 methyl-1-phenyl-ethyl)pyridine-2-carboxamide (step 1) and BBr3 as in example 3, step 3.

1H NMR (500 MHz, DMSO-d,) δ 10.77 (s, 1H), 9.80 (s, 1H), 8.56 (s, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.10 (d, J=2.0 Hz, 1H), 7.84 (dd, J=5.6, 2.2 Hz, 1H), 7.41-7.37 (m , 2H), 7.33-7.28 (m, 2H), 7.23-7.18 (m, 2H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H), 3.65 (s, 2H), 1.72 (s, 6H).

LC-MS (Method A): Rt 3.88 min; MS m/z 424.2/426.2 = [M+H]+ (99% @ 215 nm)

Biological example 95.

Automated whole-cell voltage clamp assay to detect TMEM16A activity in recombinant cells

Cell culture and preparation.

Thyroid cells (FRT) from Fisher rats stably expressing human TMEM16A (variant TMEM16Aabc; Dr. Luis Galietta, Insituto Giannina, Italy) were cultured in T-75 flasks in Hams F-12 medium modified Coon (Sigma) supplemented with 10% ( v/v) fetal bovine serum, penicillin-streptomycin (10,000 U/ml/10,000 μg/ml), G-418 (750 μg/ml), L-glutamine (2 mM) and sodium bicarbonate solution (7, 5% v/v). At ~90% confluence, cells were harvested for experiments by detachment with a mixture of 2:1 (v/v) Detachin (BMS Biotechnology) and 0.25% (v/v) trypsin-EDTA. Cells were diluted to a density of 3.5-4.5 x 106 cells/ml with medium containing CHO-S-SFM II (Sigma), 25 mM HEPES (Sigma), and soybean trypsin inhibitor (Sigma).

Whole-cell voltage clamp recording.

Whole-cell voltage clamping of FRT-TMEM16A cells was performed using an automated voltage clamp system (Qpatch, Sophion). Briefly, after high-resistance (GΩ) seals were established between the cells and the planar recording array, the patch was ruptured using suction pulses to establish the recording configuration on all cells in the voltage-clamp method.

The following solutions were used in the analysis (all Sigma reagents):

intracellular solution (mM): N-methyl-O-glucamine 130, CaCl ₂ 18.2, MgCl ₂ 1, HEPES 10, EGTA 10, BARTA 20, Mg-ATP 2, pH 7.25, 325 mOsm with sucrose;

extracellular solution (mM): N-methyl-O-glucamine 130, CaCl ₂ 2, MgCl ₂ 1, HEPES 10, pH 7.3, 320 mOsm with sucrose.

The intracellular solution buffers intracellular calcium at levels required to activate ~20% of the maximal current mediated by TMEM16A (EC ₂₀ for calcium ions). Cell voltage clamping was performed at a holding potential of −70 mV, and a combined voltage step (to +70 mV)/ramp (−90 mV to +90 mV) was applied at 0.05 Hz. After a period of ongoing stabilization testing, compounds dissolved in 100% (v/v) DMSO and subsequently diluted in extracellular solution were applied to obtain a cumulative concentration-effect curve. Each concentration of test compound was incubated for 5 minutes before adding the next concentration. Once the final concentration was verified, the supramaximal concentration of either the known active positive modulator or TMEM16A inhibitor, CaCCinhA01 (Del La Fuente et al., 2008), was added to determine the upper and lower limits of the assay.

Compound activity was quantified by measuring the increase in current upon addition of compound and expressing it as a percentage increase in the initial TMEM16A current level. The percentage increase in current was determined for each concentration and the data was plotted as a function of concentration using either Qpatch or Graphpad Prism v6.05 software, providing the concentration that produced 50% of its maximum effect (EC ₅₀ ) and maximum efficiency (percentage increase baseline).

The method for calculating the results is shown in Fig. 1, which shows an example trace from the Qpatch TMEM16A analysis. In fig. 1, I _BL is equal to the base current, I[#1] is equal to the peak current during the concentration of the test compound 1 incubation period, etc.

The TMEM16A peak current at +70 mV was plotted as a function of time during the analysis period. Baseline current ( _IBL ) was measured after a stabilization period. The increase in current for each compound addition was determined by taking the peak current during the incubation period and subtracting the current from the previous recording period and then expressing it as a percentage of the baseline current. For the concentration of test compound 1 in FIG. 1 is:

(I[#i] - IbiAbl) x 100

For each additional concentration tested, the increase in current was determined by subtracting the current from the previous incubation period and normalizing to the baseline value—for test concentration 2 in FIG. 1 is:

(I[#2] - I[#i} / Ibl) x 100

The values for each tested concentration were plotted as a cumulative function of concentration, for example, for test concentration two this would be the sum of the peak changes measured during concentration one plus concentration two.

- 182 046966

The results obtained for example compounds are given in table. 8, from which it can be seen that the compounds of the present invention are capable of significantly increasing the current level of TMEM16A.

Table 17% Potentiation, illustrated with a 3.33 µM solution of test compounds and calculated EC50 values

Example % Potentiation @ 3.33 µM, Average EU ₅₀ , Average (µM) 1 203 0.21 1.1 182 0.56 1.2 170 0.54 1.3 233 0.24 1.4 195 0.40 1.5 149 0.34 1.6 255 0.06 1.7 239 0.15 1.8 300 0.41 1.9 79 4.20 1,Yu 200 0.08 2 262 0.27 2.1 216 0.49 2.2 158 1.61 2.3 203 0.59 2.4 53 2.5 51 1.34 2.6 140 2.91

- 183 046966

2.7 51 8.19 2.8 74 4.55 2.9 148 0.99 2.10 133 0.46 2.11 126 0.43 2.12 111 0.31 2.13 126 0.46 2.14 100 1.78 2.15 163 0.49 2.16 60 4.27 2.17 172 0.27 2.18 118 1.41 2.19 249 0.46 3 287 o,n 3.1a 128 0.18 3.2a 116 0.16 3.3a 91 0.07 3.4a 206 0.14 3.5a 311 0.50 3.6a 546 0.37 3.7a 135 0.28 3.5b 150 0.20 3.6b 205 0.12 3.7b 160 0.18 3.8b 203 0.30 3.9b 144 0.96 3.10b 159 0.46 3.11b 168 0.41 3.12b 143 0.34 3.13b 179 0.25 3.14b 251 0.04 3.15b 127 3.16b 167 0.17 3.17b 227 0.12

- 184 046966

4 96 1.50 4.1 79 2.17 4.2 116 0.66 4.3 151 1.53 4.4 61 4.19 4.5 138 0.70 4.6 53 3.86 4.7 68 4.8 55 2.07 4.9 60 4.66 5 78 0.80 5.1 140 0.87 5.2 63 5.3 152 0.88 5.4 57 5.5 132 0.72 5.6 101 0.15 5.7 131 1.23 5.8 116 0.46 5.9 126 1.13 5.10 78 3.77 5.11 89 0.17 5.12 100 0.76 5.13 94 1.14 5.14 128 0.76 5.15 87 5.16 110 5.17 94 0.65 5.18 79 0.46 5.19 75 1.85 5.20 221 0.57 5.21 172 0.51 5.22 94 5.23 144 1.20

- 185 046966

5.24 189 0.14 5.25 67 5.26 110 1.20 5.27 84 5.29 190 0.86 5.31 145 5.32 285 5.33 49 5.34 185 0.64 5.35 106 0.18 5.36 44 0.06 5.37 117 0.15 5.38 231 0.15 5.39 147 6 162 1.14 7 153 0.65 7.1 241 0.34 7.2 203 0.26 7.3 125 0.20 7.4 52 0.65 7.5 239 0.28 7.6 285 0.10 7.7 234 0.13 7.8 231 0.92 7.9 288 0.23 7.10 218 0.36 7.11 167 0.32 7.12 101 2.11 7.13 212 0.09 7.14 225 0.15 7.15 230 0.05 7.16 354 0.13 8 88 3.02 8.1 155 0.59

- 186 046966

8.2 169 1.96 8.3 238 0.23 9 149 0.23 9.1 77 4.62 9.2 196 0.19 10 250 0.22 AND 76 0.90 12 112 1.76 13 245 1.00 14 58 15 200 0.13 16 63 17 173 1.49 18 405 0.45 19 57 20 111 0.22 21a 99 1.57 21b 164 1.08 22.1 114 22.2 157 0.26 22.3 132 23 93 23.1 150 23.2 87 23.3 59 0.47 23.4 115 23.5 110 23.6 108 23.7 98 23.8 122 23.9 47 23.11 101 23.12 197 0.33 23.13 169 0.57

- 187 046966

23.14 33 23.15 147 1.19 23.16 68 1.40 24 68 25 330 0.37 25.1 393 0.14 26 108 27 90 27.1 52 27.2 300 27.3 166 0.29 28 318 0.40 28.1 68 thirty 113 1.22 30.1 245 0.14 30.2 221 0.18 30.3 100 0.25 30.3a 221 30.4 95 0.75 30.5 63 30.6 80 30.7 124 0.34 30.8 121 0.70 30.9 100 0.47 30.10 265 30.11 125 0.22 30.12 314 30.13 205 0.38 31 223 0.12 31.2 110 0.01 31.3 205 0.21 31.3a 238 0.55 31.4 186 0.02 32 171

- 188 046966

32.1 246 32.2 183 0.34 32.3 288 0.29 32.4 187 0.71 32.5 177 0.59 32.6 153 0.82 32.7 111 0.20 32.8 79 32.9 31 33 245 0.24 34 245 0.09 35 180 0.19 35a 137 0.10 35b 190 0.31 35.1 51 35.2 300 0.61 35.3 144 35.4 138 35.6 53 35.7 97 35.8 250 0.18 35.9 455 0.54 35.10 223 0.28 35.11 107 35.12 158 0.42 35.13 191 0.35 35.14 172 0.27 35.15 158 0.15 35.16 85 0.33 35.17 153 0.15 35.18 147 0.43 35.19 248 0.47 35.20 240 0.42 35.21 200 0.41

- 189 046966

35.22 104 0.22 35.24 120 0.01 35.25 126 0.10 35.26 157 35.27 496 0.33 36 199 0.02 37 352 0.12 38 307 0.05 39 262 0.06 40 153 0.70 40.1 91 0.87 41 38 42 143 0.76 43 174 0.70 44 377 0.05 45 151 46 275 0.25 46a 249 o,n 46b 215 47 237 0.18 47.1 156 1.92 47.2 212 0.23 47.3 237 0.35 48 195 0.10 48.1 185 0.42 49 226 0.68 50 65 51 54 53 184 0.39 54 62 55 114 56 76 57a 285 0.51 57b 162 0.67

- 190 046966

58 217 59 175 60 126 0.35 60.1 60 60.2 169 0.20 61 85 62 99 63 37 64 55 64.1 78 64.2 61 64.3 70 64.4 2 64.5 143 0.45 64.6 0 64.7 83 64.8 97 65 55 65.1 75 0.47 65.2 73 0.48 65.3 33 65.4 10 66 130 67 158 1D0 68 39 69 47 70 138 71 162 71.1 256 0.25 72 53 73 196 0.31 73.1 389 0.28 74 337 0.18 74.1 49

- 191 046966

75 34 76 366 0.22 77 139 0.41 77.1 151 0.54 78 98 0.02 78.1 238 0.05 78.2 86 0.02 79 60 79.1 45 79.2 211 79.3 64 0.24 80 130 81 151 0.37 81.1 108 81.2 103 0.42 81.3 129 0.04 81.4 122 0.04 81.5 74 82 88 0.72 83 6 83.1 159 83.2 41 83.3 16 83.4 58 83.5 185 83.6 248 83.7 147 83.8 35 83.9 18 83.10 62 83.11 13 83.13 -1 83.14 70 83.15 -10

- 192 046966

83.16 60 83.17 8 83.18 16 83.19 28 83.20 9 83.21 70 83.22 85 83.23 -AND 83.24 55 83.25 -8 83.26 95 83.27 -AND 83.28 20 83.29 -9 83.30 93 83.31 78 83.32 -16 85 155 0.35 86 593 0.35 87 332 0.22 88 270 0.24 89 366 0.09 90 219 0.12 92 133 0D1 92.1 151 0.14 92.2 71 0.01 93.1 207 0.05 93.2 220 0.04 93.3 130 0.06 93.4 476 0.07 93.5 136 0.02 94 516 0.34

- 193 046966

Literature.

Accurso FJ, Moss RB, Wilmott RW, Anbar RD, Schaberg AE, Durham TA, Ramsay BW; TIGER-1 Investigator Study Group (2011) Denufosol tetrasodium in patients with cystic fibrosis and normal to mildly impaired lung function. Am J Respir Crit Care Med 183(5):627–634.

Boucher RC (2007) Evidence for airway surface dehydration as the initiating event in CF airway disease. J Intern Med., 261(1):5-16.

Caputo A, Caci E, Ferrera L, Pedemonte N, Barsanti C, Sondo E, Pfeffer U, Ravazzolo R, Zegarra-Moran O & Galietta LJ (2008) TMEM16A, a membrane protein associated with calcium-dependent chloride channel activity. Science, 322(5901):590-594.

Del La Fuente R, Namkung W, Mills A & Verkman AS (2008) Small molecule screen identifies inhibitors of a human intestinal calcium-activated chloride channel. Mol Pharmacol 73(3):758–768.

Kellerman D, Rossi Mospan A, Engels J, Schaberg A, Gorden J & Smiley L (2008) Denufosol: a review of studies with inhaled P2Y(2) agonists that led to Phase 2. Pulm Pharmacol Ther, 21(4):600 -607.

Kunzelmann K & Mall M (2003) Pharmacotherapy of the ion transport defect in cystic fibrosis: role of purinergic receptor agonists and other potential therapeutics. Am J Respir Med 2(4):299–309.

Matsui H, Grubb BR, Tarran R, Randell SH, Gatzy JT, Davis CW and Boucher RC (1998) Evidence for periciliary liquid layer depletion, not abnormal ion composition, in the pathogenesis of cystic fibrosis airways disease. Cell, 95(7):1005-15.

Moss RB (2013) Pitfalls of drug development: lessons learned from trials of denufosol in cystic fibrosis. J Pediatr 162(4):676–680.

Pedemonte N & Galietta LJ (2014) Structure and function of TMEM16 proteins (anoctamins). Physiol Rev 94(2):419–459.

Pezullo AA, Tang XX, Hoegger MJ, Abou Alaiwa MH, Ramachandran S, Moninger TO, Karp PH, Wohlford-Lenan CL, Haagsman HP, van Eijk M, Banfi B, Horswill AR, Stoltz DA, McCray PB Jr, Welsh MJ & Zabner J (2012) Redcued airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung. Nature, 487(7405):109-113.

Yang YD, Cho H, Koo JY, Tak MH, Cho Y, Shim WS, Park SP, Lee J, Lee B, Kim BM, Raouf R, Shin YK & Oh U (2008) TMEM16 confers receptor-activated calcium-dependent chloride conductance. Nature, 455(7217):1210–1215.

Claims (23)

1. A compound of general formula (I) or a salt thereof: where R ¹ represents H, CN, C(O)OR ¹² , C1-3alkyl, C2-3alkenyl or C2-3alkynyl, any of the alkyl, alkenyl or alkynyl groups being optionally substituted with one or more substituents selected from fluorine, OR ¹² , N(R ¹² )2, C(O)OR ¹² , C(O)N(R ¹² ) ₂ , C(O)R ¹² and N(R ¹³ )C(O)R ¹² ; wherein each R ¹² and R ¹³ are independently selected from H, C _1-6 alkyl and C _1-6 fluoroalkyl; R ² represents H or C _1-6 alkyl, optionally substituted with OR ¹² ; R ³ represents: C _1-10 αlkyl, C _2-10 alkenyl or C _2-10 alkynyl, any of which is optionally substituted with one or more substituents selected from fluorine, CN, R ¹⁴ , OR ¹⁴ , OR ¹⁵ , N(R ¹⁵ )2, C(O)OR ¹⁵ , C(O)N(R ¹⁵ )2, N(R ¹⁶ )C(O)R ¹⁵ , N(R ¹⁵ )S(O)2R ¹⁴ , N(R ¹⁵ )S(O )2R ¹⁶ and N(R ¹⁵ )C(O)OR ¹⁶ ; or a 3-7 membered carbocyclic or heterocyclic ring system or a 6-10 membered aryl or 5-10 membered heteroaryl ring system, any of which is optionally substituted with one or more substituents independently selected from halogen, CN, C _1-4 alkyl, C _1-4 haloalkyl, OR ¹⁷ and N(R ¹⁷ ) ₂ ; - 194 046966 where R ¹⁴ represents a 6-10 membered aryl or 5-10 membered heteroaryl ring system, or a 3-7 membered carbocyclic or heterocyclic ring system, any of which is optionally substituted with one or more substituents selected from halogen, C1-4alkyl, C1-4haloalkyl, OR ¹⁷ and N(R ¹⁷ )2; where each R ¹⁷ independently represents H, O^alkyl or C1 -4haloalkyl; each R ¹⁵ and R ¹⁶ independently represents H, C _1-6 alkyl or C _1-6 haloalkyl; or R2 and ^R3 , together with the carbon atom to which they are attached, combine to form a 310-membered carbocyclic or heterocyclic ring system, optionally substituted with one or more substituents independently selected from halogen, CN, ^OR9 , N( ^R9 )2, C(O)OR ⁹ , C(O)N(R ⁹ )2, C(O)R ⁹ , N(R ⁹ )C(O)R ⁹ and C _1-4 alkyl, optionally substituted with halogen, OR ⁹ or N(R ⁹ )2; or R ¹ , R ² and R ³ together with the carbon atom to which they are attached combine to form a bridged 5-10 membered carbocyclic or heterocyclic ring system or phenyl, any of which is optionally substituted with one or more substituents selected from halogen, CN , OR ⁹ , N(R ⁹ )2, C(O)OR ⁹ , C(O)N(R ⁹ )2, C(O)R ⁹ , N(R ⁹ )C(O)R ⁹ and C1- 4alkyl, optionally substituted with halogen, OR ⁹ or N(R ⁹ )2; each R ⁹ is independently selected from H, C _1-6 alkyl or C _1-6 haloalkyl; X ¹ represents N; X2 represents CR ⁸ ; R ⁸ represents H, halogen, OH, O(C _1-4 alkyl), CN or NH2; Y represents a bond or straight chain C _1-6 alkylene which is optionally substituted with one or more R ¹⁸ substituents, the two R ¹⁸ substituents being attached to the same or different carbon atoms; wherein each R ¹⁸ independently represents a C _1-3 alkyl or a C _1-3 haloalkyl, in which -CH2- is optionally replaced by -NH- or -O- and where two R ¹⁸ groups can be connected to the atom or atoms to which they attached to form a 3-6 membered carbocyclic or heterocyclic ring system; Z represents -C(O)- or -C(O)NH-; R ⁴ is a 6-14 membered aryl, 5-14 membered heteroaryl or 5-10 membered carbocyclic ring system, any of which is optionally substituted with one or more substituents selected from: halogen, CN, nitro, R ¹⁹ , OR ¹⁹ , OR ⁶ , SR ⁶ , NR ⁶ R ⁷ , C(O)R ⁶ , C(O)R ¹⁹ , C(O)OR ⁶ , C(O)N( R ⁶ )(R ⁷ ), N(R ⁷ )C(O)R ⁶ ; C _1-6 alkyl or O(C _1-6 alkyl), any of which is optionally substituted with one or more substituents independently selected from halogen, CN, nitro, R ¹⁹ , OR ⁶ , SR ⁶ , NR6R ⁷ , C(O) R ⁶ , C(O)OR ⁶ , C(O)N(R ⁶ )(R ⁷ ) and N(R ⁷ )C(O)R ⁶ ; and when R ⁴ is not entirely aromatic, is oxo; where R ¹⁹ represents a 5- or 6-membered aryl or heteroaryl ring system or a 3-7 membered carbocyclic or heterocyclic ring system, any of which is optionally substituted with one or more substituents selected from halogen, C _1-4 alkyl, C _{1 -4} haloalkyl, OH, O(C _1-4 alkyl), O(C _1-4 haloalkyl); R ⁶ represents H, C _1- ^um, C^haloalkpl, benzyl, 3-7 membered carbocyclyl or 3-7 membered heterocyclyl; R ⁷ represents H, C-clcpl or C _1-6 haloalkyl; or R ⁶ and R ⁷ together with the nitrogen atom to which they are attached may form a 4-7 membered heterocyclic ring, optionally containing one or more heteroatoms selected from N, O and S, and optionally substituted with one or more substituents, selected from oxo and halogen; and each of R ^5a and R ^5b independently represents H, C-alcpl or halogen; wherein a heteroaromatic ring or heteroaryl is an aromatic ring system containing from 5 to 14 ring atoms, at least one of which is a heteroatom selected from N, O and S; and wherein the heterocyclic ring or heterocyclyl is a non-aromatic ring system containing from 3 to 10 ring atoms, at least one of which is a heteroatom selected from N, O and S; provided that: when X ² represents CH, Z represents -C(O)-, and Y represents a bond, R ⁴ is not a 5-10 membered heteroaryl ring attached to Y via a nitrogen atom, and where compounds of formula (A) : - 195 046966 or a salt thereof, where R ^1a represents ethyl; R ^2a represents tert-butyl; T, U and Y represent CH, and Z represents N; and R ⁵ is C(O)NHEt, C(O)NH(CH ₂ ) ₂ CH ₃ , C(O)NH(CH ₂ ) ₂ CH ₂ F, C(O)NH(CH ₂ ) ₃ CH ₃ , C(O)NH(CH ₂ ) ₃ CH ₂ F, C(O)NHCH ₂ C=CH or C(O)NHCH ₂ CH=CH ₂ are excluded. 2. A compound according to claim 1 of formula (Iz), where Z represents -C(O)-, and R ^5b represents H: and where R ¹ , R ² , R ³ , R ⁴ , R ^5a , X ¹ , X ² and Y are as defined in claim 1; or a compound of formula (Iy) wherein Z is -C(O)NH- and R ^5b is H: and where R ¹ , R ² , R ³ , R ⁴ , R ^5a , X ¹ , X ² and Y are as defined in claim 1. 3. A compound according to claim 2, wherein the compound is a compound of formula (Iz) and Y is not a bond. 4. A compound according to any one of claims 1 to 3, where R ¹ represents H, CN, ethynyl, methyl, any of which is unsubstituted or substituted with OH. 5. The connection according to any one of claims 1-4, characterized in that R ² represents methyl or ethyl; And R ³ is C _1-4 alkyl, optionally substituted with one or more substituents selected from hydroxyl, methoxy, ethoxy, -C(O)O-(C _1-4 alkyl) and - ^H)C(O)O- (C _1-4 alkyl); or where R ³ represents C1-1oalkyl or C2-3alkynyl, any of which is unsubstituted or substituted with one substituent selected from fluorine, R ¹⁴ , OR ¹⁴ , OR ¹⁵ , C(O)OR ¹⁵ , N(R ¹⁵ )S (O)2R ¹⁶ and N(R ¹⁵ )C(O)OR ¹⁶ ; Where R ¹⁴ is selected from phenyl, pyridyl and a 5- or 6-membered heterocyclic ring; R ¹⁵ is selected from H or C _1-4 alkyl; And R ¹⁶ represents H; or R ³ represents a 3-7 membered carbocyclic or heterocyclic ring system that is unsubstituted or substituted as defined in claim 1; or R ³ is phenyl or pyridyl, either of which is unsubstituted or substituted with one or more substituents selected from OR ¹⁷ and N(R ¹⁷ ) ₂ , where each R ¹⁷ is H or methyl. 6. Connection of claim 5, characterized in that: R ¹ is methyl or CN and R ² and R ³ are both methyl; or R ² and R ³ combine with the carbon atom to which they are attached to form a carbocyclic or heterocyclic ring system, and R ¹ is H, methyl, methyl, substituted OH, CN, ethynyl or C(O)OR ¹² where R ¹² is as defined in paragraph 1. 7. A compound according to any one of claims 1 to 6, characterized in that Y represents -CH ₂ -, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)- or -CH2CH2CH2-, where R ^5a and R ^5b are both H, and/or R ⁴ represents a 6-11 membered aryl group selected from phenyl, naphthyl, indanyl, 1,2,3,4-tetrahydronaphthyl and benzocycloheptanyl, any of which is optionally substituted as defined in claim 1; or R ⁴ represents a 5-1 membered heteroaryl group selected from pyridyl, quinolinyl, - 196 046966 quinoxalinyl, indazolyl, indolyl, benzoxazolyl, dihydrobenzofuranyl, furyl and thienyl, any of which is optionally substituted as defined in claim 1; R ⁴ represents a carbocyclyl group selected from cyclohexyl and adamantyl, either of which is optionally substituted as defined in claim 1; or R ⁴ represents phenyl, optionally substituted with one or more substituents as defined in claim 1; or R ⁴ is a 5-10 membered heteroaryl selected from pyridyl, pyrrolyl, thienyl, furyl, benzoxazolyl, imidazolyl, indolyl or indazolyl, any of which is optionally substituted as defined in claim 1. 8. A compound according to claim 7, wherein R ⁴ is phenyl substituted with an OH group at the 2- or 3- position, and optionally substituted with one or more substituents selected from: halogen, CN, R ¹⁹ , OR ¹⁹ ; OR ⁶ , C(O)OR ⁶ ; C _1-4 alkyl or O(C _1-4 alkyl), any of which is optionally substituted with one or more substituents selected from halogen, CN, R ¹⁹ , OR ⁶ and NR6R ⁷ ; where R ⁶ represents H, C _1-4 alkyl or C _1-4 haloalkyl, or, in the NR ⁶ group, R ⁷ , R ⁶ and R ⁷ are combined with the nitrogen atom to which they are attached to form a 5- or 6- a heterocyclic ring member, optionally containing one or more additional heteroatoms, and optionally substituted with one or more halogen atoms; R ⁷ is as defined in claim 1; And R ¹⁹ represents a 3-6 membered carbocyclyl group or phenyl, any of which is optionally substituted with one or more substituents selected from halogen, methyl and methoxy. 9. A compound according to any one of claims 1 to 8, characterized in that Y represents -CH ₂ -, R ⁴ represents phenyl, and the compound represents a compound of general formula (Ia): where R ¹ , R ² , R ³ , R ^5a , X ¹ and X ² are as defined in paragraph 1; R ¹⁰ represents H, OH, halogen, C1-6alkyl, -O(C1-6alkyl); each R ¹¹ independently represents H, halogen, OH, CN, C1-6alkyl, _{C1-6haloalkyl} , -O( _C1-6alkyl ) or C(O)O-( _C1-6alkyl ); and n is 1 or 2; or a compound of general formula (Id) or (Ie): where R ¹ , R ² and R ³ are as defined in paragraph 1; R ^11a R ^11b R ^11c represents H, halogen, C _1-4 alkyl, C _1-4 haloalkyl or C(O)O(C _1-4 alkyl); is H, halogen, C _1-4 alkyl or C _1-4 haloalkyl; and is H, halogen, CN, C _1-4 alkyl or C _1-4 haloalkyl. 10. A compound according to claim 1, wherein Y is straight C _1-3 alkylene, unsubstituted or substituted with one or more R ¹⁸ substituents, where R ¹⁸ is as defined above, and where two R ¹⁸ substituents may be attached to one or more different carbon atoms. 11. A compound according to claim 1, wherein R ⁴ represents a 6-11 membered aryl group selected from phenyl, naphthyl, indanyl, 1,2,3,4-tetrahydronaphthyl and benzocycloheptanyl, each of which is unsubstituted or substituted as defined in paragraph 1. - 197 046966 12. A compound according to claim 1, selected from: N-tert-butyl-4-[[2-(2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (compound 1); N(1-adamantyl)-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (compound 1.3); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl|amino|-H-(3-methoxy-1.1-dimethylpropyl)pyridine-2carboxamide (compound 1.4); 4-[[2-(5-chloro-2-hydroxy(()enyl)acetyl|amino|-H-(1-methylcyclobutyl)pyridine-2-carboxamide (compound 1.6); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-(1-methylcyclohexyl)pyridine-2-carboxamide (compound 1.7); tert-butyl-N-[3-[[4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carbonyl]amino]-3methyl-butyl]carbamate (compound 1.8); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-cyclohexylpyridine-2-carboxamide (compound 1.10); N-tert-butyl-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (compound 3); N(1,1-dimethylpropyl)-4-[[2-(4-fluoro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (compound 3.1a); N tert-butyl-4-[[2-(4-fluoro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (compound 3.2a); N tert-butyl-4-[[2-(2-chloro-6-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (compound 3.3a); 4-[[2-(4-bromo-5-chloro-2-hydroxyphenyl)acetyl]amino]-N-tert-butylpyridine-2-carboxamide (compound 3.4a); 4-[[2-(5-tert-butyl-2-hydroxyphenyl)acetyl]amino]-N-(1-cyanocyclobutyl)pyridine-2carboxamide (compound 3.5a); 4-[[2-(5-tert-butyl-2-hydroxyphenyl)acetyl]amino]-N-(1-methylcyclobutyl)pyridine-2carboxamide (compound 3.6a); N-tert-butyl-4-[2-(2,5-dibromo-3-fluoro-6-hydroxyphenyl)acetamido]pyridine-2-carboxamide (compound 3.7a); N tert-butyl-4-[[2-[2-hydroxy-5-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (compound 3.5b); N-tert-butyl-4-[[2-(4-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (compound 3.6b); N tert-butyl-4-[[2-[2-hydroxy-4-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (compound 3.7b); N-tert-butyl-4-[[2-(2-hydroxy-5-methoxyphenyl)acetyl]amino]pyridine-2-carboxamide (compound 3.8b); N-tert-butyl-4-[(6-hydroxyindan-1-carbonyl)amino]pyridine-2-carboxamide (compound 3.9b); N-tert-butyl-4-[(7-hydroxyindan-1-carbonyl)amino]pyridine-2-carboxamide (compound 3.10b); N-tert-butyl-4-[[2-(2,5-dibromo-3-chloro-6-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (compound 3.11b); N-tert-butyl-4-[[2-(3-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (compound 3.12b); N-tert-butyl-4-[[2-(2-fluoro-5-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (compound 3.13b); N-tert-butyl-4-[[2-(4-chloro-3-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (compound 3.14b); N-tert-butyl-4-[[2-(2-chloro-3-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (compound 3.15b); N-tert-butyl-4-[[2-(2-chloro-5-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (compound 3.16b); N-tert-butyl-4-[[2-(3-chloro-5-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (compound 3.17b); N tert-butyl-4-[[2-(2-thienyl)acetyl]amino]pyridine-2-carboxamide (compound 5); 4-[[2-(2-adamantyl)acetyl]amino]-N-tert-butylpyridine-2-carboxamide (compound 5.1); N tert-butyl-4-[[2-(4-fluoro-2-methoxyphenyl)acetyl]amino]pyridine-2-carboxamide (compound 5.2); N tert-butyl-4-[[2-(5-chloro-2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (compound 5.3); N tert-butyl-4-[[2-(2-furyl)acetyl]amino]pyridine-2-carboxamide (compound 5.4); N tert-butyl-4-[[2-(3-chlorophenyl)acetyl]amino]pyridine-2-carboxamide (compound 5.5); N tert-butyl-4-[[2-(1H-indol-3-yl)acetyl]amino]pyridine-2-carboxamide (compound 5.6); N tert-butyl-4-[[2-(o-tolyl)acetyl]amino]pyridine-2-carboxamide (compound 5.7); N tert-butyl-4-[[2-(3,4-dichlorophenyl)acetyl]amino]pyridine-2-carboxamide (compound 5.8); - 198 046966 >tert-butyl-4-[[2-(3-fluorophenyl)acetyl]amino]pyrvdine-2-carboxamide (compound 5.9); No. tert-butyl-4-[[2-(5-chloro-2-methoxyphenyl)acetyl]amino]pyrvdine-2-carboxamvd (compound 5.10); N tert-butyl-4-[[2-(p-tolyl)acetyl]amino]pyrvdine-2-carboxamvd (compound 5.11); ^tert-butyl-4-[[2-(2-(|)tor(|)enyl)acetyl|amino|pyridine-2-carboxamide (compound 5.12); N tert-butyl-4-[[2-(4-fluorophenyl)acetyl]amino]pyrvdine-2-carboxamide (compound 5.13); N tert-butyl-4-[[2-(m-tolyl)acetyl]amino]pyridine-2-carboxamide (compound 5.14); 4-[[2-(1.3-benzoxazol-6-yl)acetyl|amino|^-tert-butylpyridine-2-carboxamide (compound 5.15); N tert-butyl-4-[[2-(2-chloro-3-pyridyl)acetyl]amino]pyridine-2-carboxamide (compound 5.16); ^tert-butyl-4-[[2-(2.6-dichloro(|)enyl)acetyl|amino|pyridine-2-carboxamide (compound 5.17); >1ret-butyl-4-[[2-(4-chloro-3-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (compound 5.18); N-tert-butyl-4-[[2-(3,5-dichlorophenyl)acetyl]amino]pyridine-2-carboxamide (compound 5.19); N-tert-butyl-4-[[2-(2-chlorophenyl)acetyl]amino]pyridine-2-carboxamide (compound 5.20); N-tert-butyl-4-[[2-(3-chloro-4-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (compound 5.21); N-tert-butyl-4-(indan-1-carbonylamino)pyridine-2-carboxamide (compound 5.22); N-tert-butyl-4-[(2-quinoxalin-6-ylacetyl)amino]pyridine-2-carboxamide (compound 5.23); N-tert-butyl-4-[[2-(2-naphthyl)acetyl]amino]pyridine-2-carboxamide (compound 5.24); >tert-butyl-4-(2,3-dihydrobenzofuran-3-carbonylamino)pyridine-2-carboxamide (compound 5.25); N-tert-butyl-4-(6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-carbonylamino)pyridine-2-carboxamide (compound 5.26); N-tert-butyl-4-(tetralin-1-carbonylamino)pyridine-2-carboxamide (compound 5.27); N-tert-butyl-4-[[2-(6-quinolyl)acetyl]amino]pyridine-2-carboxamide (compound 5.29); N-tert-butyl-4-[[1-(3-chlorophenyl)cyclopropanecarbonyl]amino]pyridine-2-carboxamide (compound 5.31); N-tert-butyl-4-[[2-(2,3-dihydro-1,4-benzodioxin-6-yl)acetyl]amino]pyridine-2-carboxamide (compound 5.32); N-(1,1-dimethylprop-2-ynyl)-4-[(2-isochroman-1-ylacetyl)amino]pyridin-2-carboxamide (compound 5.33); 4-[[2-(4,4-difluorocyclohexyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (compound 5.34); N-(1,1-dimethylprop-2-ynyl)-4-[[2-[4-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (compound 5.35); N-(1,1-dimethylprop-2-ynyl)-4-[[2-[3-(trifluoromethyl)-1H-pyrazol-4-yl]acetyl]amino]pyridine-2carboxamide (compound 5.36); N-(1,1-dimethylprop-2-ynyl)-4-[[2-[3-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (compound 5.37); N-(1,1-dimethylprop-2-ynyl)-4-[[2-[2-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (compound 5.38); 4-[[2-(2,3-dihydro-1,4-benzoxazin-4-yl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2carboxamide (compound 5.39); N-tert-butyl-4-[[2-(5-cyano-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (compound 6); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-(1,1-dimethylbutyl)pyridine-2-carboxamide (compound 7.2); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-(1,1,2-trimethylpropyl)pyridine-2-carboxamide (compound 7.6); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-isopropylpyridine-2-carboxamide (compound 7.7); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-(4-methyltetrahydropyran-4-yl)pyridin-2carboxamide (compound 7.9); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-tetrahydropyran-4-ylpyridin-2-carboxamide (compound 7.11); 4-[2-(5-chloro-2-hydroxyphenyl)acetamido]-N-[(1s,4s)-4-hydroxycyclohexyl]pyridine-2carboxamide (compound 7.12); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-sec-butylpyridine-2-carboxamide (compound 7.13); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-(2-hydroxy-1,1,2-trimethylpropyl)pyridine-2carboxamide (compound 7.14); N-(3-bicyclo[1.1.1]pentanyl)-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2carboxamide (compound 7.15); - 199 046966 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-(1-cyanocyclobutyl)pyridine-2-carboxamide (compound 7.16); tert-butyl-3-[[4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2carbonyl]amino]piperidine-1-carboxylate (compound 8.1); tert-butyl-(1r,5s,6s)-6-{4-[2-(5-chloro-2-hydroxyphenyl)acetamido]pyridin-2-amido}-3azabicyclo[3.1.0]hexane-3-carboxylate ( connection 8.3); 4-[[2-(5-x.tor-2-hydroxy(|)enyl)acetyl|amino|-H-(1,1-dimethylpropyl)pyridine-2-carboxamide (compound 9.2); N tert-butyl-4-[[2-(5-tert-butyl-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (compound 10); methyl 3-[2-[[2-(tert-butylcarbamoyl)-4-pyridyl]amino]-2-oxoethyl]-4-hydroxybenzoate (compound 13); N tert-butyl-4-[[2-(2-hydroxy-5-methylphenyl)acetyl]amino]pyridine-2-carboxamide (compound 15); N tert-butyl-4-[[2-(3-hydroxy-2-pyridyl)acetyl]amino]pyridine-2-carboxamide (compound 19); X-tert-butyl-4-[[2-(5-fluoro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (compound 20); N-tert-butyl-4-[[(1C) or (^)-indan-1-carbonyl]amino]pyridine-2-carboxamide (compound 21a); N-tert-butyl-4-[[(1C) or (^)-indan-1-carbonyl]amino]pyridine-2-carboxamide (compound 21b); N-tert-butyl-4-[(2-phenylacetyl)amino]pyridine-2-carboxamide (compound 22); 4-(3,3-dimethylbutanoylamino)-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (compound 22.1); 4-[(2-cyclopentylacetyl)amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (compound 22.2); 4-[[2-(3-chloro-4-pyridyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (compound 22.3); 4-[[2-(4-chlorophenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide (compound 23); 4-[[2-(3-chlorophenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide (compound 23.1); 4-[[2-(2-chloro-5-fluorophenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide (compound 23.2); N-tert-butyl-4-(indan-2-carbonylamino)pyridine-2-carboxamide (compound 23.3); N tert-butyl-4-[[2-[2-(difluoromethoxy)phenyl]acetyl]amino]pyridine-2-carboxamide (compound 23.4); N tert-butyl-4-[[2-[2-(difluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (compound 23.5); N-tert-butyl-4-[[2-(3,4-difluorophenyl)acetyl]amino]pyridine-2-carboxamide (compound 23.6); N-tert-butyl-4-[[2-(3,5-difluorophenyl)acetyl]amino]pyridine-2-carboxamide (compound 23.7); N tert-butyl-4-[[2-(2,3-difluorophenyl)acetyl]amino]pyridine-2-carboxamide (compound 23.8); 4-[[2-(2-chlorophenyl)acetyl]amino]-H-tetrahydropyran-4-ylpyridin-2-carboxamide (compound 23.9); N(1-cyanocyclobutyl)-4-[[2-(6-quinolyl)acetyl]amino]pyridine-2-carboxamide (compound 23.11); N tert-butyl-4-[[2-[2-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (compound 23.12); 4-[[2-(2-bromophenyl)acetyl]amino]-N-tert-butylpyridine-2-carboxamide (compound 23.13); N-tert-butyl-4-[[2-(2-cyanophenyl)acetyl]amino]pyridine-2-carboxamide (compound 23.14); 4-[[2-(2-chlorophenyl)acetyl]amino]-H-(4-cyanotetrahydropyran-4-yl)pyridin-2-carboxamide (compound 23.15); N(4-cyanonotetrahydropyran-4-yl)-4-[[2-(6-quinolyl)acetyl]amino]pyridin-2-carboxamide (compound 23.16); 4-[[2-(2-chloro-5-methoxyphenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide (compound 24); N-(3-bicyclo[1.1.1]pentanyl)-4-[[2-(5-tert-butyl-2-hydroxyphenyl)acetyl] amino]pyridine-2 carboxamide (compound 25); 4-[[2-(5-tert-butyl-2-hydroxyphenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridin-2carboxamide (compound 25.1); N tert-butyl-4-[[2-(2-hydroxy-5-phenyl-phenyl)acetyl]amino]pyridine-2-carboxamide (compound 26); N tert-butyl-4-[[2-[5-chloro-2-hydroxy-4-(pyrrolidin-1-ylmethyl)phenyl]acetyl]amino]pyridine-2carboxamide (compound 27); No. tert-butyl-4-[[2-[4-[(tert-butylamine)methyl]-5-chloro-2-hydroxyphenyl]acetyl]amino]pyridine-2 - 200 046966 carboxamide (compound 27.1); N tert-butyl-4-[[2-[5-chloro-2-hydroxy-4-(morpholinomethyl)phenyl]acetyl]amino]pyridine-2carboxamide (compound 27.2); N-tert-butyl-4-[[2-[5-chloro-4-[(3,3-di(()torpyrrolidin-1-yl)methyl|-2hydroxyphenyl]acetyl]amino]pyridine-2-carboxamide ( connection 27.3); Cht-butyl-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-5-fluoro-pyridine-2-carboxamide (compound 28); Cht-butyl-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-3-fluoro-pyridine-2-carboxamide (compound 28.1); 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(1-cyanocyclobutyl)iridine-2-carboxamide (compound 30); 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(1,1-dimethylproi-2-inyl)iridine-2-carboxamide (compound 30.1); 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(4-fluoro-1-bicyclo[2.1.1]hexanyl)iridine-2-carboxamide (compound 30.2); 4-[[2-(2-chlorophenyl)acetyl]amino]-H-(1-cyclopropyl-1-methylethyl)pyridine-2-carboxamide (compound 30.3); 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(1-cyano-1-methylethyl)iridine-2-carboxamide (compound 30.3a); 4-[[2-(2-chlorophenyl)acetyl]amino]-H-(1-methyl-3-bicyclo[1.1.1]pentanyl)pyridine-2-carboxamide (compound 30.4); 4-[[2-(2-chlorophenyl)acetyl]amino]-H-(1-cyano-3-bicyclo[1.1.1]pentanyl)pyridine-2-carboxamide (compound 30.5); 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(2,2-difluorocyclopropyl)iridine-2-carboxamide (compound 30.6); 4-[[2-(2-chlorophenyl)acetyl]amino]-N-(1-cyanocycloproyl)iridine-2-carboxamide (compound 30.7); 4-[[2-(2-chlorophenyl)acetyl]amino]-H-(1-methylcyclopropyl)pyridine-2-carboxamide (compound 30.8); 4-[[2-(2-chlorophenyl)acetyl]amino]-H-(3-fluoro-1-bicyclo[1.1.1]pentanyl)pyridine-2-carboxamide (compound 30.9); 4-[[2-(2-chlorophenyl)acetyl]amino]-H-(2-fluoro-1,1-dimethylethyl)pyridine-2-carboxamide (compound 30.10); 4-[[2-(2-chlorophenyl)acetyl]amino]-H-(4-ethynyltetrahydropyran-4-yl)pyridin-2-carboxamide (compound 30.11); 4-[[2-(2-chlorophenyl)acetyl]amino]-H-(1-cyanocyclopentyl)pyridine-2-carboxamide (compound 30.12); 4-[[2-(2-chlorophenyl)acetyl]amino]-H-(2,2-difluoro-1,1-dimethylethyl)pyridine-2-carboxamide (compound 30.13); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-H-(4-cyanotetrahydropyran-4-yl)pyridin-2carboxamide (compound 31); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-(1-ethynylcycloientyl)iridine-2-carboxamide (compound 31.2); 4-[2-(5-chloro-2-hydroxyphenyl)acetamido]-N-[(H^)-2-hydroxycyclohexyl]iridine-2carboxamide (compound 31.3); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-[(^^)-2-hydroxycyclohexyl]iridine-2carboxamide or 4-[[2-(5-chloro-2-hydroxyphenyl) )acetyl]amino]-N-[(1R,2R)-2hydroxycyclohexyl]pyridine-2-carboxamide (compound 31.3a); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-H-(4-ethynyltetrahydropyran-4-yl)pyridin-2carboxamide (compound 31.4); X[(6-amino-2-pyridyl)methyl]-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2carboxamide (compound 32); 12-[[4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carbonyl]amino]dodecanoic acid (compound 32.1); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-(3-iridylmethyl)iridine-2-carboxamide (compound 32.2); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-(2-iridylmethyl)iridine-2-carboxamide (compound 32.3); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-(4-iridylmethyl)iridine-2-carboxamide (compound 32.4); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-[(2-hydroxyphenyl)methyl]iridine-2-carboxamide (compound 32.5); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-(1,1-dimethyl-2-morpholinoethyl)iridin-2 - 201 046966 carboxamide (compound 32.6); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-(2-hydroxy-1,1-dimethylethyl)pyridine-2carboxamide (compound 32.7); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-(3,3-difluoro-4-piperidyl)pyridine-2-carboxamide (compound 32.8); 4-[[2-(5-chloro-2-hydroxy(|)enyl)ace'tyl|amino|-H-(1H-imidazol-2-yl)pyridin-2-carboxamide (compound 32.9); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-[(1R,2R)-2-hydroxycyclopentyl]pyridine-2carboxamide (compound 33); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-(1-cyano-1-methylethyl)pyridine-2-carboxamide (compound 34); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-[3-(hydroxymethyl)tetrahydrofuran-3yl]pyridin-2-carboxamide (compound 35); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-[(3R)-3 -(hydroxymethyl)tetrahydrofuran-3yl]pyridin-2-carboxamide or 4-[[2-(5 -chloro-2-hydroxyphenyl)acetyl]amino]-N-[(3S)-3(hydroxymethyl)tetrahydrofuran-3-yl]pyridin-2-carboxamide (compound 35a); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-[(3R)-3-(hydroxymethyl)tetrahydrofuran-3yl]pyridin-2-carboxamide or 4-[[2-(5 -chloro-2-hydroxyphenyl)acetyl]amino]-N-[(3S)-3(hydroxymethyl)tetrahydrofuran-3-yl]pyridin-2-carboxamide (compound 35b); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-(4-hydroxy-4-methylcyclohexyl)pyridine-2carboxamide in the form of a 6:4 mixture of stereoisomers (compound 35.1); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-[O2g)-2-(hydroxymethyl)cyclohexyl]pyridine-2carboxamide (compound 35.2); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-[O3g)-3-hydroxycyclopentyl]pyridine-2carboxamide (compound 35.3); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-[2-hydroxy-1-(hydroxymethyl)-1methylethyl]pyridine-2-carboxamide (compound 35.4); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-(3-hydroxycyclohexyl)pyridine-2-carboxamide as a mixture of stereoisomers (compound 35.6); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-(3-phenoxypropyl)pyridine-2-carboxamide (compound 35.7); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-(1-methylcyclopropyl)pyridine-2-carboxamide (compound 35.8); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-[1-methyl-1-(2-pyridyl)ethyl]pyridine-2carboxamide (compound 35.9); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-(3-phenylpropyl)pyridine-2-carboxamide (compound 35.10); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-[2-hydroxy-1-(2-pyridyl)ethyl]pyridine-2carboxamide (compound 35.11); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-[(5-methoxy-2-pyridyl)methyl]pyridine-2carboxamide (compound 35.12); Ethyl 3-[[4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carbonyl]amino]-3methylbutanoate (compound 35.13); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-(3-hydroxy-1,1-dimethylpropyl)pyridine-2carboxamide (compound 35.14); >benzyl-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (compound 35.15); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-phenylpyridine-2-carboxamide (compound 35.16); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-[(^^)-2-hydroxycyclopentyl]pyridine-2carboxamide (compound 35.17); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-[(N^)-2-hydroxycyclopentyl]pyridine-2carboxamide (compound 35.18); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-[(1S,2R)-2-hydroxycyclopentyl]pyridine-2carboxamide (compound 35.19); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-(1-ethynylcyclohexyl)pyridine-2-carboxamide (compound 35.24); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-[1-(hydroxymethyl)cyclobutyl]pyridine-2carboxamide (compound 35.25); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-[3-(hydroxymethyl)oxetan-3-yl]pyridin-2carboxamide (compound 35.26); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-(1-cyano-2-methoxy-1-methylethyl)pyridine-2carboxamide (compound 35.27); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-[(1-hydroxycyclobutyl)methyl]pyridine-2 - 202 046966 carboxamide (compound 35.28); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (compound 36); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-(1-cyano-1,2-dimethylpropyl)pyridine-2carboxamide (compound 37); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-(1-methylcyclopentyl)pyridine-2-carboxamide (compound 38); N(4-tert-butylcyclohexyl)-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (compound 39); N tert-butyl-4-[[2-(2-chloro-3-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (compound 40); N tert-butyl-4-[[2-(2-chloro-5-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (compound 40.1); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-[4-(2-hydroxyethyl)tetrahydropyran-4yl]pyridin-2-carboxamide (compound 42); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-[1,1-dimethyl-3-(2,2,2trifluoroethylamine)propyl]pyridine-2-carboxamide (compound 43); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-(4-fluoro-1-bicyclo[2.1.1]hexanyl)pyridine-2carboxamide (compound 44); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-[3-(2,2-dimethylpropanoylamine)-1,1dimethylpropyl]pyridine-2-carboxamide (compound 45); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-(1-cyano-2-hydroxy-1-methylethyl)pyridine-2carboxamide (compound 46); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-[(I)-1-cyano-2-hydroxy-1-methylethyl]pyridine-2carboxamide (compound 46a); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-H-[(N)-1-cyano-2-hydroxy-1-methylethyl]pyridine-2carboxamide (compound 46b); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-H-(3-cyanotetrahydrofuran-3-yl)pyridin-2carboxamide (compound 47); methyl 2-[4-[[4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2carbonyl]amino]tetrahydropyran-4-yl]acetate (compound 47.1); methyl 4-[[4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2carbonyl]amino]tetrahydropyran-4-carboxylate (compound 47.2); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-(3-cyanooxetan-3-yl)pyridin-2-carboxamide (compound 47.3); 4-[[2-(5-fluoro-2-hydroxyphenyl)acetyl]amino]-N-(1-methylcyclobutyl)pyridine-2-carboxamide (compound 48); N(4-cyanonotetrahydropyran-4-yl)-4-[[2-(5-fluoro-2-hydroxyphenyl)acetyl]amino]pyridine-2carboxamide (compound 48.1); N[3-(tert-butylamine)-1,1-dimethyl-3-oxopropyl]-4-[[2-(5-chloro-2hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (compound 49); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-[3-(methanesulfonamido)-1,1dimethylpropyl]pyridine-2-carboxamide (compound 50); N(3-acetamido-1,1-dimethylpropyl)-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2carboxamide (compound 51); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-[4-(hydroxymethyl)tetrahydropyran-4yl]pyridin-2-carboxamide (compound 53); No. tert-butyl-4-[[2-[3-(1-hydroxyethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (compound 54); N-tert-butyl-5-chloro-4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (compound 55); N tert-butyl-4-[[2-[5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl]acetyl]amino]pyridine-2carboxamide (compound 56); N tert-butyl-4-[[(I) or (N)-4-chloro-7-hydroxyindan-1-carbonyl]amino]pyridine-2-carboxamide (compound 57a); N tert-butyl-4-[[(H) or (N)-4-chloro-7-hydroxyindan-1-carbonyl]amino]pyridine-2-carboxamide (compound 57b); N tert-butyl-4-[[2-(2-cyclopropylphenyl)acetyl]amino]pyridine-2-carboxamide (compound 58); 4-[[2-(3-bromo-5-chloro-2-hydroxyphenyl)acetyl]amino]-N-tert-butylpyridine-2-carboxamide (compound 59); N(4-fluoro-1-bicyclo[2.1.1]hexanyl)-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (compound 60); N(1-cyano-2-hydroxy-1-methylethyl)-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (compound 60.1); - 203 046966 No. (1,1-dimethylprop-2-ynyl)-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (compound 60.2); N tert-butyl-4-[[2-(5-chloro-2-hydroxy-3-isopropylphenyl)acetyl]amino]pyridine-2-carboxamide (compound 61); N tert-butyl-4-[[2-[5-chloro-2-hydroxy-3-(1-methoxyethyl)phenyl]acetyl]amino]pyridine-2carboxamide (compound 62); 4-[[2-(6-quinolyl)acetyl]amino]-H-tetrahydropyran-4-yl-pyridin-2-carboxamide (compound 63); 4-(benzylcarbamoylamine)-N-tert-butylpyridine-2-carboxamide (compound 64); N-tert-butyl-4-(cyclohexylmethylcarbamoylamine)pyridine-2-carboxamide (compound 64.1); N-tert-butyl-4-(2-phenylethylcarbamoylamine)pyridine-2-carboxamide (compound 64.2); N-tert-butyl-4-[[(N)-1-phenylethyl]carbamoylamino]pyridine-2-carboxamide (compound 64.3); N tert-butyl-4-[[(U)-1-phenylethyl]carbamoylamino]pyridine-2-carboxamide (compound 64.4); N-tert-butyl-4-[(2-chlorophenyl)methylcarbamoylamino]pyridine-2-carboxamide (compound 64.5); N-tert-butyl-4-[(3-chlorophenyl)methylcarbamoylamino]pyridine-2-carboxamide (compound 64.7); N-tert-butyl-4-[(4-chlorophenyl)methylcarbamoylamino]pyridine-2-carboxamide (compound 64.8); N-tert-butyl-4-[(2-hydroxyphenyl)carbamoylamino]pyridine-2-carboxamide (compound 65); No. tert-butyl-4-[(2-methoxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide (compound 65.1) ; No. tert-butyl-4-[(2-hydroxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide (compound 65.2) ; No. tert-butyl-4-[(3-hydroxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide (compound 65.3) ; No. tert-butyl-4-[(4-hydroxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide (compound 65.4) ; N tert-butyl-4-[[2-[2-hydroxy-5-(1-hydroxyethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (compound 66); N tert-butyl-4-[[2-[2-hydroxy-5-[1-(2,2,2-trifluoroethylamine)ethyl]phenyl]acetyl]amino]pyridine-2carboxamide (compound 67); N tert-butyl-4-[[2-[3-(cyanomethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (compound 68); N tert-butyl-4-[[2-[3-(methoxymethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (compound 69); N tert-butyl-4-[[2-[2-hydroxy-5-(morpholinomethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (compound 70); 4-[[2-(5-fluoro-2-hydroxyphenyl)acetyl]amino]-H-[3-(hydroxymethyl)tetrahydrofuran-3yl]pyridine-2-carboxamide (compound 72); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-[1-(hydroxymethyl)-2-methoxy-1methylethyl]pyridine-2-carboxamide (compound 73); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-(1,1-dimethylbut-2-ynyl)pyridine-2-carboxamide (compound 73.1); N tert-butyl-4-[[2-[2-hydroxy-5-(3-hydroxypropyl)phenyl]acetyl]amino]pyridine-2-carboxamide (compound 75); 4-[[2-(5-chloro-4-fluoro-2-hydroxyphenyl)acetyl]amino]-N(1-methylcyclobutyl)pyridine-2carboxamide (compound 76); 4-[[2-(2,5-difluorophenyl)acetyl]amino]-H-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (compound 77); 4-[[2-(2,5-difluorophenyl)acetyl]amino]-H-(4-fluoro-1-bicyclo[2.1.1]hexanyl)pyridine-2carboxamide (compound 77.1); 4-[[2-(4-chloro-2-hydroxyphenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (compound 78); N(1,1-dimethylprop-2-ynyl)-4-[[2-[2-hydroxy-4-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2carboxamide (compound 78.1); N(1,1-dimethylprop-2-ynyl)-4-[[2-[2-hydroxy-5-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2carboxamide (compound 78.2); 4-[(2-chroman-4-ylacetyl)amino]-N-(1,1-dimethylprop-2-ynyl)pyridin-2-carboxamide (compound 79); N(1,1-dimethylprop-2-ynyl)-4-[[2-(1-isopropyl-3,5-dimethylpyrazol-4-yl)acetyl]amino]pyridine2-carboxamide (compound 79.1); N(1,1-dimethylprop-2-ynyl)-4-[[2-(III-indazol-4-yl)acetyl]amino]pyridine-2-carboxamide (compound 79.2); N(1,1-dimethylprop-2-ynyl)-4-[[2-(III-indol-7-yl)acetyl]amino]pyridine-2-carboxamide (compound 79.3); N(1-cyano-1-methylethyl)-4-[[2-(5-fluoro-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide - 204 046966 (connection 81); >(1-cyano-2-hydroxy-1-methylethyl)-4-[[2-(5-fluoro-2-hydroxyphenyl)acetyl]amino]pyridine-2carboxamide (compound 81.1); 4-[[2-(5-fluoro-2-hydroxyphenyl)acetyl]amino]-N-isopropyl-pyridine-2-carboxamide (compound 81.2); H-(1.1-dimethylprop-2-ynyl)-4-[[2-(5-(()tor-2-hydroxy(()enyl)acetyl|amino|pyridine-2-carboxamide (compound 81.3); >(4-fluoro-1-bicyclo[2.1.1]hexanyl)-4-[[2-(5-fluoro-2-hydroxyphenyl)acetyl]amino]pyridine-2carboxamide (compound 81.4); 4-[[2-(5-fluoro-2-hydroxyphenyl)acetyl]amino]-N-[1-(hydroxymethyl)cyclobutyl]pyridine-2carboxamide (compound 81.5); N-(1-cyano-1-methylethyl)-4-(thiophene-3-carbonylamino)pyridine-2-carboxamide (compound 83); N-(1-cyano-1-methylethyl)-4-[(2-cyclohexylacetyl)amino]pyridine-2-carboxamide (compound 83.1); N-(1-cyano-1-methylethyl)-4-(cyclohexanecarbonylamino)pyridine-2-carboxamide (compound 83.2); N-(1-cyano-1-methylethyl)-4-[(3,3-difluorocyclopentanecarbonyl)amino]pyridine-2-carboxamide (compound 83.3); N-(1-cyano-1-methylethyl)-4-[(1-methylcyclopentanecarbonyl)amino]pyridine-2-carboxamide (compound 83.4); N-(1-cyano-1-methylethyl)-4-(3-cyclohexylpropanoylamine)pyridine-2-carboxamide (compound 83.5); 4-(2-{bicyclo[2.2.1]heptan-2-yl}acetamido)-H-(1-cyano-1-methylethyl)pyridine-2-carboxamide (compound 83.6); N-(1-cyano-1-methylethyl)-4-[[2-(1-methylcyclohexyl)acetyl]amino]pyridine-2-carboxamide (compound 83.7); >[2-[(1-cyano-1-methylethyl)carbamoyl]-4-pyridyl]-2-cyclopropyl-pyrimidine-5-carboxamide (compound 83.8); >[2-[(1-cyano-1-methylethyl)carbamoyl]-4-pyridyl]-3-isobutylisoxazole-5-carboxamide (compound 83.9); N-(1-cyano-1-methylethyl)-4-[[2-(4,4-difluorocyclohexyl)acetyl]amino]pyridine-2-carboxamide (compound 83.10); 4-[(1-benzylcyclopropanecarbonyl)amino]-N-(1-cyano-1-methylethyl)pyridine-2-carboxamide (compound 83.11); N-(1-cyano-1-methylethyl)-4-[3-(2-methoxy-4-pyridyl)propanoylamino]pyridine-2-carboxamide (compound 83.13); 4-[(5-tert-butyl-2-methylpyrazole-3-carbonyl)amino]-N-(1-cyano-1-methylethyl)pyridine-2carboxamide (compound 83.14); N-(1-cyano-1-methylethyl)-4-[(2-pyrazol-1-ylbenzoyl)amino]pyridin-2-carboxamide (compound 83.15); >[2-[(1-cyano-1-methylethyl)carbamoyl]-4-pyridyl]-6-(trifluoromethyl)pyridine-2-carboxamide (compound 83.16); N-[2-[(1-cyano-1-methylethyl)carbamoyl]-4-pyridyl]-3-oxo-4H-1,4-benzoxazine-7-carboxamide (compound 83.17); >[2-[(1-cyano-1-methylethyl)carbamoyl]-4-pyridyl]-1-ethylindole-2-carboxamide (compound 83.18); N-(1-cyano-1-methylethyl)-4-[[2-(2,2,2-trifluoroethyl)pyrazole-3-carbonyl]amino]pyridine-2carboxamide (compound 83.19); >[2-[(1-cyano-1-methylethyl)carbamoyl]-4-pyridyl]-3-phenylisoxazole-4-carboxamide (compound 83.20); 4-[(1-benzylpyrazole-4-carbonyl)amino]-N-(1-cyano-1-methylethyl)pyridine-2-carboxamide (compound 83.21); N-(1-cyano-1-methylethyl)-4-[(2-methyl-5-phenylpyrazole-3-carbonyl)amino]pyridine-2-carboxamide (compound 83.22); N-(1-cyano-1-methylethyl)-4-[[2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoyl]amino]pyridine-2carboxamide (compound 83.23); N-(1-cyano-1-methylethyl)-4-[(3-methyl-1-phenylpyrazole-4-carbonyl)amino]pyridine-2-carboxamide (compound 83.24); >[2-[(1-cyano-1-methylethyl)carbamoyl]-4-pyridyl]-2-phenoxypyridine-3-carboxamide (compound 83.25); N-(1-cyano-1-methylethyl)-4-[[2,5-dimethyl-1-(2-thienylmethyl)pyrrole-3-carbonyl]amino]pyridine-2carboxamide (compound 83.26); >[2-[(1-cyano-1-methylethyl)carbamoyl]-4-pyridyl]-5-(2-methoxyphenyl)isoxazole-3-carboxamide - 205 046966 (connection 83.27); N[2-[(1-cyano-1-methylethyl)carbamoyl]-4-pyrrvdyl]-4-methyl-2-phenylthiazol-5-carboxamvd (compound 83.28); 4-[(4-acetamidobenzoyl)amino|-H-(1-cyano-1-methylethyl)pyridine-2-carboxamide (compound 83.29) ; N-[2-[(1-cyano-1-methylethyl)carbamoyl]-4-pyridyl]-1,3-benzothiazol-7-carboxamide (compound 83.30); N-(1-cyano-1-methylethyl)-4-[3-(4-fluorophenyl)butanoylamino]pyridine-2-carboxamide (compound 83.31); H-[2-[(1-cyano-1-methylethyl)carbamoyl|-4-pyridyl|-1-methyl-2-oxoquinoline-3-carboxamide (compound 83.32); N-tert-butyl-3-[[2-(2-hydroxycyclohexyl)acetyl]amino]benzamide (compound 84); 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl|amino|-H-[1-cyano-2-methoxy-1(methoxymethyl)ethyl]pyridine-2-carboxamide (compound 86); 4-[[2-(3-amino-4-tert-butylphenyl)acetyl]amino]-N-tert-butylpyridine-2-carboxamide (compound 87); 4-[[2-(2-amino-4-tert-butylphenyl)acetyl]amino]-N-tert-butylpyridine-2-carboxamide (compound 88); N-tert-butyl-4-[[2-(4-tert-butyl-3-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (compound 89); N-tert-butyl-4-[[2-(4-tert-butyl-2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (compound 90); N-tert-butyl-4-[[2-(4-tert-butyl-2-fluoro-5-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (compound 91); 4-[[2-(4-chloro-3-hydroxyphenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridin-2carboxamide (compound 92); 4-[[2-(4-chloro-3-hydroxifenyl)acetyl| amino| -N-(1-cyano-1-methylethyl)pyridine-2-carboxamide (compound 92.1); 4-[[2-(4-chloro-3-hydroxyphenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (compound 92.2); 4-[[2-(4-chloro-3-hydroxyphenyl)acetyl]amino]-N-[(1s,2s)-2-hydroxycyclopentyl]pyridine-2carboxamide (compound 92.3); 4-[[2-(4-tert-butyl-3-hydroxyphenyl)acetyl]amino]-N-[3-(hydroxymethyl)tetrahydrofuran-3yl|pyridine-2-carboxamide (compound 93); 4-[[2-(4-tert-butyl-3-hydroxyphenyl)acetyl]amino]-N-[(2S)-2-hydroxycyclohexyl]pyridine-2carboxamide (compound 93.1); 4-[[2-(4-tert-butyl-3-hydroxyphenyl)acetyl]amino]-N-[(2S)-2-hydroxycyclopentyl]pyridine-2carboxamide (compound 93.2); 4-[[2-(4-tert-butyl-3-hydroxyphenyl)acetyl]amino]-N-(4-cyanonotetrahydropyran-4-yl)pyridin-2carboxamide (compound 93.3); 4-[[2-(4-tert-butyl-3-hydroxyphenyl)acetyl]amino]-N-(1-cyano-1-methylethyl)pyridine-2carboxamide (compound 93.4); 4-[[2-(4-tert-butyl-3-hydroxyphenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2carboxamide (compound 93.5); And 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N-(1-methyl-1-phenylethyl)pyridine-2-carboxamide (compound 94); and salts of any of the above. 13. The compound according to claim 1, which is H-tert-butyl-4-[[2-(5-chloro-2hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (compound 3) or a salt thereof. 14. The compound according to claim 1, which is 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N[(3R)-3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridin-2 -carboxamide or 4-[[2-(5-chloro-2hydroxyphenyl)acetyl]amino]-N-[(3S)-3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridin-2-carboxamide (compound 35a) or its salt. 15. The compound according to claim 1, which is 4-[[2-(5-chloro-2-hydroxyphenyl)acetyl]amino]-N(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (compound 36 ) or its salt. 16. The compound according to claim 1, which is H-(1.1-dimethylprop-2-ynyl)-4-[[2-[3(trifluoromethyl)-1H-pyrazol-4-yl]acetyl]amino]pyridin-2- carboxamide (compound 5.36) or its salt. 17. A method for producing a compound of general formula (I), in which Z represents -C(O)- according to any one of claims 1 to 16, including: A) introducing into the reaction a compound of formula (II): - 206 046966 R ² R ¹ O R ^5b nh ₂ R ^5a (P) where R ¹ , R ² , R ³ , R ^5a , R ^5b , X ¹ and X ² are as defined in paragraph 1; with a compound of formula (III): where R ⁴ and Y are as defined in claim 1; in the presence of a condensing agent; or B) reacting a compound of formula (II) with an acid chloride of an acid of formula (IV): where R ⁴ and Y are as defined in claim 1; to obtain a compound of formula (I) wherein Z is -C(O)-. 18. A method for producing a compound of formula (I), in which Z represents -C(O)NH and Y represents -^^alkylene- according to any one of claims 1 to 16, comprising: introducing into the reaction a compound of formula (II) where R ¹ , R ² , R ³ , R ^5a R ^5b , X ¹ and X ² are as defined in paragraph 1, with a compound of formula (XIV): O=C=NY ¹ -R ⁴ (xiv) where R ⁴ is as defined in claim 1, and Y ¹ is -CH ₂ - or -CH ₂ CH ₂ -, to obtain a compound of formula (I), in which Z represents C(O)NH and Y represents -^^alkylene. 19. Method for preparing the compound of formula (Id): where R ^11a represents Cl and R ^11b represents H, according to any one of claims 1 to 16, including: introducing into the reaction a compound of formula (II) where R ¹ , R ² , R ³ , R ^5a R ^5b , X ¹ and X ² are as defined in paragraph 1, with 5-chloro-2(3H)-benzofuranone, which has the structure: - 207 046966 to obtain a compound of formula (Id) in which R ^11a represents Cl and R ^11b represents H. 20. A method for producing a compound of formula (I), where Z represents -C(O)-, according to any one of claims 1 to 16, including: A) introducing into the reaction a compound of formula (X): O R ^5b II I n X .Zh t » ⁰ _R 5a (X) where X ¹ , X ² , Y, R ⁴ , R ^5a and R ^5b are as defined in paragraph 1; with a compound of formula (VII): R ¹ R ^r T'NH ₂ R ^{3 2} (VII) where R ¹ , R ² and R ³ are as defined in paragraph 1; or B) reacting a compound of formula (XV): where X ¹ , X ² , Y, R ⁴ , R ^5a and R ^5b are as defined in claim 1, and R ²² represents halogen; with an amine of formula (VII) as defined above and carbon monoxide in the presence of a phosphorus ligand and a palladium catalyst to produce a compound of formula (I) in which Z is -C(O)-. 21. A pharmaceutical composition containing a compound according to any one of claims 1 to 16 and a pharmaceutically acceptable excipient. 22. A method of treating or preventing diseases and pathological conditions affected by modulation of TMEM16A, selected from respiratory diseases and pathological conditions, dry mouth (xerostomia), intestinal hypermobility, cholestasis and ocular diseases, the method comprising administering to a patient in need of such treatment, an effective amount of a compound of general formula (I): or a salt thereof, wherein R ¹ is H, CN, C(O)OR ¹² , C1-3alkyl, C2-3alkenyl or C2-3alkynyl, any of the alkyl, alkenyl or alkynyl groups being optionally substituted with one or more substituents selected from fluorine, OR ¹² , N(R ¹² )2, C(O)OR ¹² , C(O)N(R ¹² ) ₂ , C(O)R ¹² and N(R ¹³ )C(O)R ¹² ; wherein each R ¹² and R ¹³ are independently selected from H, C _1-6 alkyl and C _1-6 fluoroalkyl. R ² represents H or C _1-6 alkyl, optionally substituted with OR ¹² ; - 208 046966 R ³ represents: C _1-10 alkyl, C _2-1 oalkenyl or C _2-10 alkynyl, any of which is optionally substituted with one or more substituents selected from fluorine, CN, R ¹⁴ , OR ¹⁴ , OR ¹⁵ , N(R ¹⁵ ) 2 , C(O)OR ¹⁵ , C(O)N(R ¹⁵ )2, N(R ¹⁶ )C(O)R ¹⁵ , N(R ¹⁵ )S(O)2R ¹⁴ , N(R ¹⁵ )S(O )2R ¹⁶ and N(R ¹⁵ )C(O)OR ¹⁶ ; or a 3-7 membered carbocyclic or heterocyclic ring system or a 6-10 membered aryl or 5-10 membered heteroaryl ring system, any of which is optionally substituted with one or more substituents independently selected from halogen, CN, C _1-4 alkyl, C _1-4 haloalkyl, OR ¹⁷ and N(R ¹⁷ ) ₂ ; where R ¹⁴ represents a 6-10 membered aryl or 5-10 membered heteroaryl ring system, or a 3-7 membered carbocyclic or heterocyclic ring system, any of which is optionally substituted with one or more substituents selected from halogen, C1-4alkyl , C1-4haloalkyl, OR ¹⁷ and N(R ¹⁷ )2; wherein each R ¹⁷ independently represents H, C _-4 alkyl or C1 _-4 haloalkyl; R ¹⁵ and R ¹⁶ are each independently H, ClClkyl or Clhaloalkyl; or ^R2 and ^R3 , together with the carbon atom to which they are attached, combine to form a 310-membered carbocyclic or heterocyclic ring system, optionally substituted with one or more substituents independently selected from halogen, CN, ^OR9 , N( ^R9 )2 , C(O)OR ⁹ , C(O)N(R ⁹ )2, C(O)R ⁹ , N(R ⁹ )C(O)R ⁹ and C-4alkyl, optionally substituted with halogen, OR ⁹ or N (R ⁹ )2; or R ¹ , R ² and R ³ together with the carbon atom to which they are attached combine to form a bridged 5-10 membered carbocyclic or heterocyclic ring system or phenyl, any of which is optionally substituted with one or more substituents selected from halogen, CN , OR ⁹ , N(R ⁹ )2, C(O)OR ⁹ , C(O)N(R ⁹ )2, C(O)R ⁹ , N(R ⁹ )C(O)R ⁹ and C _{1 -4} alkyl, optionally substituted with halogen, OR ⁹ or N(R ⁹ )2; each R ⁹ is independently selected from H, C _1-6 alkyl or C _1-6 haloalkyl; X ¹ represents N; X ² represents CR ⁸ ; R ⁸ represents H, halogen, OH, OXL, CN or NH2; Y is a straight chain bond or C^alkylene which is optionally substituted with one or more R ¹⁸ substituents, the two R ¹⁸ substituents being attached to the same or different carbon atoms; wherein each R ¹⁸ is independently C _-3 alkyl or C _1-3 haloalkyl, in which -CH2- is optionally replaced by -NH- or -O- and wherein two R ¹⁸ groups can be combined with the atom or atoms to which they are attached , with the formation of a 3-6-membered carbocyclic or heterocyclic ring system; Z represents -C(O)- or -C(O)NH-; R ⁴ is a 6-14 membered aryl, 5-14 membered heteroaryl or 5-10 membered carbocyclic ring system, any of which is optionally substituted with one or more substituents selected from: halogen, CN, nitro, R ¹⁹ , OR ¹⁹ , OR ⁶ , SR ⁶ , NR ⁶ R ⁷ , C(O)R ⁶ , C(O)R ¹⁹ , C(O)OR ⁶ , C(O)N( R ⁶ )(R ⁷ ), N(R ⁷ )C(O)R ⁶ ; C-alkyl or O(C _1-6 alkyl), any of which is optionally substituted with one or more substituents independently selected from halogen, CN, nitro, R ¹⁹ , OR ⁶ , SR ⁶ , NR6R ⁷ , C(O)R ⁶ , C(O)OR ⁶ , C(O)N(R ⁶ )(R ⁷ ) and N(R ⁷ )C(O)R ⁶ ; and when R ⁴ is not entirely aromatic, is oxo; where R ¹⁹ represents a 5- or 6-membered aryl or heteroaryl ring system or a 3-7 membered carbocyclic or heterocyclic ring system, any of which is optionally substituted with one or more substituents selected from halogen, C _1-4 alkyl, C _{1 -4} haloalkyl, OH, O(C _1-4 alkyl), O(C _1-4 haloalkyl); R ⁶ represents H, C _1- ^km, C-dalogenalkyl, benzyl, 3-7 membered carbocyclyl or 3-7 membered heterocyclyl; R ⁷ represents H, C-alkyl or C _1-6 haloalkyl; or R ⁶ and R ⁷ together with the nitrogen atom to which they are attached may form a 4-7 membered heterocyclic ring, optionally containing one or more heteroatoms selected from N, O and S, and optionally substituted with one or more substituents, selected from oxo and halogen; and each of R ^5a and R ^5b independently represents H, C^alkyl or halogen; wherein a heteroaromatic ring or heteroaryl is an aromatic ring system comprising 5-14 ring atoms, at least one of which is a heteroatom selected from N, O and S; and, wherein the heterocyclic ring or heterocyclyl is a non-aromatic ring system comprising 3-10 ring atoms, at least one of which is a heteroatom selected from N, O and S. - 209 046966 23. The method according to claim 22, where the respiratory diseases and pathological conditions are selected from cystic fibrosis, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, bronchiectasis, including non-cystic fibrosis, asthma and primary ciliary dyskinesia; where dry mouth is a result of Sjögren's syndrome, radiation therapy and xerogenic drugs; where intestinal hypermobility is associated with gastric dyspepsia, gastroparesis, chronic constipation and irritable bowel syndrome; wherein the eye disease is dry eye disease.