CZ444399A3 - Xa factor inhibitors with neutral P1 group specificity - Google Patents

Abstract

The present application describes factor Xa inhibitors with a neutral P1 group specificity of Formula I or a pharmaceutically acceptable salt thereof, wherein Ra E can be groups such as methoxy and halo.

Description

Factor Xa inhibitors with neutral P1 group specificity

Technical field

The invention relates generally to novel inhibitors of Factor Xa with neutral P1 group specificity, to pharmaceutical compositions containing them, and to a method for their use as anticoagulants for the treatment and prevention of thromboembolic diseases.

BACKGROUND OF THE INVENTION

WO 96/28427 describes benzamidine anticoagulants of the general formula:

wherein Z ¹ and Z are O, N (R), S or OCH ₂ and the center ring may be phenyl or various heterocycles. The compounds claimed according to the invention do not contain Z ¹ linkers or substitutional features of the above compounds.

WO 95/13155 and PCT International Application US 96/07692 disclose isoxazoline and isoxazole fibrinogen receptor antagonists of the formula:

χ γ where R ¹ can be a basic group, UV can be a six-membered aromatic ring, WX can be differently linear or cyclic and Υ is an oxy group. These all contain a functional group (for example WXC (= O)-)). In contrast, compounds

·· ·· ······· ·· ··

- 2 according to the invention do not contain such acidic functional groups.

EP 0 513 387 describes active oxygen inhibitors which are oxazoles or thiazoles of the general formula:

R ¹ where X is O or S, R ² is preferably hydrogen and both R ¹ and R ³ are substituted cyclic groups wherein at least one group is phenyl. The compounds of the present invention do not correspond to these types of oxazoles or thiazoles.

WO 95/18111 relates to fibrinogenic receptor antagonists containing basic and acidic end groups of the formula:

.7a · ¹ LR ⁼

R '- UV' (R ⁶⁶ ), _R 7 ^{R '} ;

^ (^ Η, Ο ^X R ¹⁰⁾

R ⁸ wherein R ¹ represents a basic moiety, U is an alkylene or heteroatom linker, V may be a heterocycle, and the right-hand moiety of the molecule represents an acidic terminal group. The compounds of the invention do not contain the acidic or basic moiety of WO 95/18111.

In U.S. Patent No. 5,463,071 to Himmelsbach et al. discloses cell aggregation inhibitors which are 5-membered heterocycles of the general formula:

wherein the heterocycle may be aromatic and the groups A-B-C- and F-E-D- are attached to the ring system. A-B-C can be a variety of different substituents, including a basic group attached to an aromatic ring. However, the group F-E-D- should be an acidic functional group that differs from the present invention. Furthermore, the use of the compounds as Factor Xa inhibitors is not disclosed.

Baker et al., In U.S. Patent No. 5,317,103 disclose 5-HT-β antagonists which are indole-substituted five-membered heteroaromatic compounds of the formula:

wherein R ¹ may be pyrrolidine or piperidine and A may be a basic group, including amino and amidino groups. Baker et al. however, it does not teach that A may be a substituted ring system, similar to the system contained in the heteroaromatic compounds of the invention.

Baker et al. in WO 94/02477 disclose 5-HT 2 antagonists which are imidazoles, triazoles or tetrazoles of the general formula:

wherein R ¹ is a nitrogen-containing ring system or a nitrogen-substituted cyclobutane and A may be a basic group, including amino and amidino. But Baker et al. do not disclose that A may be a substituted ring system similar to that contained in the heteroaromatic compounds of the invention.

Tidwell et al. in J. Med. Chem. 1978, 21 (7), 613-623, disclose a series of diarylamidine derivatives, including 3,5-bis (4-amidinophenyl) isoxazole. These compounds were tested against thrombin, trypsin and pancreatic kallikrein.

The compounds of the invention do not include these types of compounds.

• · · · ·

Activated Factor Xa, whose main practical role is the generation of thrombin by the limited proteolysis of prothrombin, plays a major role that links internal and external activation mechanisms in the final general pathway of blood coagulation. Thrombin generation, the final serine protease on the way to generate a fibrin clot from its precursor, is enhanced by formation of a prothrombinase complex (Factor Xa, Factor V, Ca ^2+, and phospholipid). Since it is calculated that a single factor Xa molecule can generate 138 thrombin molecules (Elodi, S., Varadi, K: Optimization of conditions for the catalytic effect of factor IXa-factor VIII Complex: Probable role of the complex in blood amplification Thromb (Res. 1979, 15, 617-629), inhibition of factor Xa may be more effective than inactivating thrombin in disrupting the blood coagulation system.

Therefore, potent and specific inhibitors of factor Xa are needed as potentially valuable therapeutic agents for the treatment of thromboembolic diseases. It is desirable to discover a novel factor of Xa inhibitors.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide novel inhibitors of Factor Xa with neutral PI group specificity, or pharmaceutically acceptable salts or prodrugs thereof.

It is a further object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the invention, or a pharmaceutically acceptable salt or prodrug thereof.

It is another object of the present invention to provide:

a method of treating thromboembolic diseases, comprising administering to the host, in need of such treatment, at least one compound of the present invention or a pharmaceutically acceptable salt or prodrug thereof.

These, and other objects that will become apparent throughout the following description, will be achieved by the inventors' discovery that the compounds of Formula I:

R

I, or a pharmaceutically acceptable salt or prodrug thereof, wherein D, E, M and R are as defined below are potent Factor Xa inhibitors.

[1] In a first embodiment, the present invention provides novel compounds of formula I

or a stereoisomeric or pharmaceutically acceptable salt thereof, wherein;

ring D is phenyl or pyridyl;

E is selected from the group consisting of F, Cl, Br, I, OH, C ₁ _ ₃ alkoxy, SH, C ^ alkyl, S, S (O) R ^3b, S (O) 2 R ^2a, S (0 ) 2NR ² R ^2a , and OCF ₃ ;

R is selected from the group consisting of H, F, Cl, Br, I, OR ^3, SR ^3, CO 2 R ^3, N02, and _{CH2 OR3;}

alternatively, E and R joined to form methylenedioxy or ethylenedioxy;

· · · · · · · · · · · · · · · · · · · · · · · · · · ·

M is selected from:

y z

B aa · »

3 ^e ι »fc f f c c c c c c c 1 1 1 1 1 1 1 1 1 1 1

Z is selected from the group consisting of a bond, C ₄ _ ₄ alkylene, (CH _{2) r} O (CH _{2) r,} (CH _{2) r} NR ³ (CH _{2) r,} (CH _{2) r} C (0) (CH ₂ ) _r , (CH ₂ ) _r C (O) 0 (CH ₂ ) _r , (CH ₂ ) _r OC (O) (CH ₂ ) _r , (CH ₂ ) _r C (O) NR ³ (CH 2) r , (CH 2) r NR ³ (CO) (CH 2) _r , (CH ₂ ) _r OC (O) O (CH ₂ ) _r , (CH ₂ ) _r O C (O) NR ³ (CH ₂ ) _r , (CH ₂₎ ) _r NR ³ C (O) O (CH2) r, (CH 2) r NR ³ C (O) NR ³ (CH 2) _r, (CH _{2) r} s (0) _{p (CH2) r, (CH2) r} SO ₂ NR ³ (CH _{2) r, (CH2) r} ^NR3 SO2 (CH2) r, and (CH 2) r NR ³ SO 2 NR ³ (CH _{2) r,} provided that Z does not form a ring M or group a NN, NO, NS, NCH ₂ N, NCH ₂ O or NCH ₂ S;

R ^1a and R ^1b are independently absent or selected from the group consisting of - (CH ₂ ) _r -R ¹ '-CH = CH-R ¹ NCH ² R ¹ ', OC ¹ R ¹ , SC ¹ R ¹ , NH (CH 2) ₁₂ (CH ₂ ) _t R ^{1 '} , O (CH ₂ ) ₂ (CH ₂ ) _t R ¹ ', and S (CH ₂ ) _t R ¹ ';

alternatively R ^1a and R ^1b , when attached to adjacent carbon atoms, together with the carbon atoms to which they are attached a 5-8 membered saturated, partially saturated or saturated ring substituted with 0-2 R ⁴ and containing 0-2 heteroatoms selected from N, O and S;

alternatively, when Z is C (O) NH and R ^1a is bonded to a ring carbon atom adjacent to Z, then R ^1a is a C (O) group that replaces the amide hydrogen of Z to form a cyclic imide;

R ^{1 is} selected from the group consisting of H, C _1-3 alkyl, F,

Cl, Br, I, -CN, -CHO, (CF ₂ ) _r CF ₃ (CH ₂ ) _r OR ² , NR ² R ^2a , C (O) R ^2c , OC (O) R ² , (CF ² ) r CO ² R ^2c , S (O) p R ^2b , NR ² (CH ₂ ) _r OR ² ,

CH (= NR ^2c) NR ² R ^2a, NR ² C (O) R ^2b, NR ² C (O) NHR ^2b, NR ² C (O) ₂ R ^2a,

OC (O) NR ^2a R ^2b , C (O) NR ² R ^2a , C (O) NR ² (CH 2) r OR ² , SO ² NR ² R ^2a , NR ² SO ² R ^2b , C 3-8 carbocyclic radical substituted with 0-2 R ⁴ and A 5 to 10 membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O and S substituted with 0 to 2 R ⁴ ;

• ·

R ¹ 'is selected from H, CH (CH ² OR ² ) 2, C (O) R ^2c , C (O) NR ² R ^2a ,

S (O) R ^2b , S (O) 2 R ^2b , and SO ² NR ² R ^2a ;

R ² at each occurrence is selected from the group consisting of H, CF _3, C ^ g alkyl, benzyl, C ₃ _G carbocyclic residue substituted with 0-2 R ^4b, and 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O and S substituted with 0-2 R ^4b ;

R ^2a, at each occurrence is selected from the group consisting of H, CF _3, C ^ g alkyl, benzyl, phenethyl, C ₃ _ _g carbocyclic residue substituted with 0-2 R ^4b, and 5-6 membered heterocyclic system containing from 1 to 4 heteroatoms selected from N, O and S substituted with 0-2 R ^4b ;

R ^2b, at each occurrence is selected from the group consisting of CF _3, C _1-4 alkoxy, alkyl, benzyl, C ₃ _G carbocyclic residue substituted with 0-2 R ^4b, and 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O and S substituted with 0-2 R ^4b ;

R ^2c, at each occurrence is selected from the group consisting of CF _3, OH, C-j__ ₄ alkoxy, C £ _G alkyl, benzyl, C ₃ _G carbocyclic residue substituted with 0-2 R ^4b, and 5-6 membered heterocyclic system containing 1 to 4 heteroatoms selected from N, O and S substituted with 0 to 2 R ^4b ;

alternatively, R ² and R ^2a , together with the atom to which they are attached, form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R ^4b and containing 0 to 1 additional heteroatoms selected from the group consisting of N, O and WITH;

R ³ , at each occurrence, is selected from the group consisting of H,

O _1-4 alkyl and phenyl;

• · • ·

R ^3a , at each occurrence, is selected from H,

C ₁ _ ₄ alkyl and phenyl;

R ^3b , at each occurrence, is selected from the group consisting of H,

C ₄ _ ₄ alkyl and phenyl;

R ^2c , at each occurrence, is selected from the group consisting of H,

C _1-4 alkyl and phenyl;

A is selected from the group consisting of:

^{c a} 3-10 carbocyclic residue substituted with 0-2 R ⁴ , and a 5-10 membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O and S, substituted with 0-2 R ⁴ ;

B is selected from: Η, Y and X-Y;

X is selected from the group consisting of C ₁ _ ₄ alkylene,

-CR ² (CR ² R ^2b ) (CH ₂ ) _t -, -C (O) -, - (C = NR ¹ ) -, -CR ² (NR ¹ R ² ) -,

-CR ² (OR ² ) -, -CR ² (SR ² ) -, -C (O) CR ² R ^2a -, -CR ² R ^2a C (O), -S (O) -S (O) pCR ² R ^2a -, -CR ² R ^2a (SO) p -S (O) 2 NR ² -, -NR ² S (O) 2-,

-NR ² S (O) ² CR ² R ^2a -, -CR ² R ^2a S (O) 2 NR ² -, -NR ² S (O) ₂ NR ² -, -C (O) NR ² -, -NR ² C (O) -, -C (O) NR ² CR ² R ^2a -, -NR ² C (O) CR ² R ^2a -, -CR ² R ^2a C (O) NR ² -, -CR ² R ^2a NR ² C (O) -, -NR ² C (O) O-, -OC (O) NR ² -, -NR ² C (O) NR ² -, -NR ² -, -NR ² CR ² R ^2a -, -CR ² R ^2a NR ² -, O, -CR ² R ^2a O and -OCR ² R ^2a -;

Y is selected from a file that includes:

(CH ₂ ) _r NR ² R ^2a , provided that X does not form a bond NN, ON or

An SN, 3-10 carbocyclic residue substituted with 0-2 R ^4a , and a 5-10 membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R ^4a ;

• ·

R ⁴ , at each occurrence, is selected from the group consisting of H, = O, (CH 2) r OR ² , F, Cl, Br, I, C _1-4 alkyl, -CN, NO ₂ , (CH ₂ ) _r NR ² R ^2a, (CH _{2) r} C (O) R ^2c, NR ² C (O) R ^2b, C (O) NR ² R ^2a,

NR ² C (O) NR ² R ^2a, CH (= NR ²⁾ NR ² R ^2a, C (= NS (O) 2 R ⁵⁾ NR ² R ^2a, NHC (= NR ²⁾ NR ² R ^2a, C ( O) NHC (= NR ²⁾ NR ² R ^2a, SO 2 NR ² R ^2a, NR ² SO 2 NR ² R ^2a, NR ² SO 2 -C ₁ _ ₄ alkyl, NR ² SO 2 R ^5, S (O) p R ^5, (CF 2) rCF3, NCH- ^ R ¹ OCH 2 R ¹ ^, R ^ SCR ¹

N (CH ₂ ) ₂ (CH ₂ ) ¹ R ¹ , O (CH ₂ ) ₂ (CH ₂ ) 2 R ¹ , and S (CH 2) ₂ (CH ₂ ) _t R ¹ ';

alternatively one R ⁴ is a 5-6 membered aromatic heterocycle containing 1 to 4 heteroatoms selected from the group consisting of N, O and S;

provided that if B is H, then R ⁴ is other than tetrazole,

C (O) -alkoxy and C (O) NR ² R ^2a ;

R ^4a , at each occurrence, is selected from the group consisting of H, = O, (CH 2) _r OR ² , (CH 2) _r -F, (CH ₂ ) _r -Br, (CH ₂ ) _r -Cl, I,

C ₄ _ ₄ alkyl, CN, N0 _2, (CH _{2) r} NR ² R ^2a, (CH _{2) r} NR ² R ^2b, (CH _{2) r} C (O) R ^2c, NR ² C (0) R ^2b , C (O) NR ² R ^2a , C (O) NH (CH ₂ ) ₂ NR ² R ^2a , NR ² C (O) NR ² R ^2a , CH (= NR ² ) NR ² R ^2a , NHC (= NR ²⁾ NR ² R ^2a,

SO ₂ NR ² R ^2a, NR ² SO 2 NR ² R ^2a, NR ² SO 2 C _L _ ₄ alkyl,

C (O) NHSO ₂ -C ₁ _ ₄ alkyl, NR ² SO 2 R ^5, S (O) p R ^5, and (CF _{2) r} CF _3;

alternatively one R ⁴ is a 5-6 membered aromatic heterocycle containing 1 to 4 heteroatoms selected from the group consisting of N, O and S and substituted with 0 to 1 R ⁵ ;

R ^4b , at each occurrence, is selected from the group consisting of H, = O, (CH 2) r OR ³ , F, Cl, Br, I, C _1-4 alkyl, -CN, NO ₂ , (CH ₂ ) _r NR ³ R ^3a , (CH 2) _r C (O) R ³ , (CH 2) _r C (O) OR ^3c , NR ³ C (O) R ^3a , C (O) NR ³ R ^3a , NR ³ C (O) NR ³ R ^3a, CH (= NR ³⁾ NR ³ R ^3a, NHC (= NR ³⁾ NR ³ R ^3a, SO 2 NR ³ R ^3a, NR ³ SO 2 NR ³ R ^3a, NR ³ SO 2-C-L4 alkyl, NR ³ SO2CF _3, NR ³ SO ₂ -phenyl, S (O) _p CF _3, S (O) _p -C ₁ _ ₄ alkyl, S (O) -phenyl, and (CF _{2) r} CF _3;

• ·

R ⁵ , at each occurrence, is selected from the group consisting of ^CF 3 ', 1-6 and ^3- alkyl, phenyl substituted with 0-2 R 6 and benzyl substituted with 0-2 R 8.

R ⁶ , at each occurrence, is selected from the group consisting of

H, OH, (CH _{2) r} OR ^2, F, Cl, Br, I, C ₁ _ ₄ alkyl, CN, NO ₂ (CH _{2) r} NR ² R ^2a, (CH 2) r C (O) R ^2b, NR ² C (O) R ^2b , NR ² C (O) NR ² R ^2a , CH (= NH) NH 2, NHC (= NH) NH ₂ , SO ₂ NR ² R ^2a , NR ² SO ₂ NR ² R ^2a , and NR ² SO 2 Cl ₁ _ ₄ alkyl;

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

m is selected from 0, 1 and 2;

p is selected from 0, 1 and 2;

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

s is selected from 0, 1 and 2; and t is selected from 0 and 1;

[2] In a preferred embodiment, the present invention provides novel compounds wherein M is selected from the group:

with

Z is selected from the group consisting of (CH ₂ ) _r C (O) (CH ₂ ) _r , (CH ₂ ) _r C (O) 0 (CH ₂ ) _r , (CH ₂ ) _r C (O) NR ³ (CH ₂ ) _r , (CH ₂ ) _r S (O) _p (CH ₂ ) _{r (a} (CH ₂ ) _r SO ₂ NR ³ (CH ₂ ) _r ; and

Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R ^4a ;

phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazole, thiadiazole, triazole,

1,2.3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole,

1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole,

1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole,

1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, benzofuran, benzothiofuran, indole, benzimidazole, benzoxazole, benzthiazole, indazole, benzisoxazole, benzisothiazole, and isoindazole;

- 14 Y may be selected from the following bicyclic heteroaryl ring systems:

S, NH and N.

K is selected from 0, [3] In a more preferred embodiment, the present invention provides novel compounds of formula Ia or 1b:

lb where:

ring D is phenyl or pyridyl;

E is selected from the group consisting of F, Cl, Br and alkoxy;

R is selected from the group consisting of H, F, Cl, Br, OR, and CH ₂ OR ³

M is selected from:

n

- · 15

Β

Z is selected from the group consisting of (CH ₂ ) _r C (O) (CH ₂ ) _r and (CH ₂ ) _r C (O) NR ³ (CH ₂ ) _r ; and

Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R ^4a ;

phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazole, thiadiazole, triazole,

1,2.3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole,

1,3,4-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole,

1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole,

1,2.3-triazole, 1,2,4-triazole, 1,2,5-triazole,

1.3.4- triazole, benzofuran, benzothiofuran, indole, benzimidazole, benzoxazole, benzthiazole, indazole, benzisoxazole, benzisothiazole, and isoindazole;

[4] In an even more preferred embodiment, the present invention provides novel compounds wherein:

ring D is phenyl;

E is selected from the group consisting of F, Cl, Br and OCH ₃ ;

R is selected from H, F, Cl and Br;

M is selected from:

And it is selected from the file:

^{c a} 5-6 carbocyclic residue substituted with 0-2 R ⁴ , and a 5-6 membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O and S, substituted with 0-2 R ⁴ ;

Y is selected from one of the following carbocyclic and hete _v 4 and rocyclic systems which are substituted with 0-2 R, phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, benzimidazolyl, oxadiazole, thiadiazole, triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole,

1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole,

1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole,

1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole and 1,3,4-triazole o

R at each occurrence is selected from the group consisting of H, CF _3, C ₄ _G alkyl, benzyl, C ₅ _G carbocyclic residue substituted with 0-2 R ^41d, and 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N , O and S substituted with 0-2 R ⁴ * ³ ;

and

R, at each occurrence, is selected from a file that includes: · ···· · ··· · ···· · · · · · · · · · · · · · · · · · · ··

- 17 H, CF _3, C _L _G alkyl, benzyl, phenethyl, C ₅ _ _g carbocyclic residue substituted with 0-2 R ^4b, and 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S substituted with 0 up to 2 R ^4b ;

R ^2b, at each occurrence is selected from the group consisting of CF _3, C ₄ _ ₄ alkoxy, C ₄ _G alkyl, benzyl, C ₅ _G carbocyclic residue substituted with 0-2 R ^4b, and 5-6 membered heterocyclic system containing from 1 to 4 heteroatoms selected from N, O and S substituted with 0-2 R ^4b ;

R ^2c , at each occurrence, is selected from the group consisting of

CF _3, OH, C _1-4 alkoxy, C ₁ _G alkyl, benzyl, C ₅ _G carbocyclic residue substituted with 0-2 R ^4b, and 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S substituted with 0 up to 2 R ^4b ;

alternatively, R ² and R ^2a , together with the atom to which they are attached, form a ring selected from imidazolyl, morpholino, piperazinyl, pyridyl and pyrrolidinyl, substituted with 0-2 R ^4b ;

R ⁴ , at each occurrence, is selected from the group consisting of H, = O, OR ² , CH ² OR ² , F, Cl, C 1-4 alkyl, NR ² R ^2a ,

CH ₂ NR ² R ^2a , C (O) R ^2c , CH ₂ C (O) R ^2c , C (O) NR ² R ^2a ,

CH (= NR ²⁾ NR ² R ^2a, C (= NS (0) 2 R ⁵⁾ NR ² R ^2a, SO 2 NR ² R ^2a,

NR ² SO ² -C 1-4 alkyl, S (O) 2 R ⁵ and CF 3, provided that if B is H then R ⁴ is other than tetrazole,

C (O) -alkoxy and C (O) NR ² R ^2a ;

/ 1A v

R 1, at each occurrence, is selected from the group consisting of H, = O, (CH ₂ ) _r OR ² , F, Cl, C 1-4 alkyl, NR ² R ^2a , CH ² NR ² R ^2a , NR ² R ^2b , CH 2 NR ² R ^2b , (CH 2) _r C (O) R ^2c , NR ² C (O) R ^2b ,

C (O) NR ² R ^2a , C (O) NH (CH ₂ ) ₂ NR ² R ^2a , NR ² C (O) NR ² R ^2a ,

SO ₂ NR ² R ^2a , S (O) 2 R ⁵ and CF 3;

- 18 R ^4b , at each occurrence, is selected from the group consisting of H, = O, (CH 2) r OR ³ , F, Cl, alkyl, NR ³ R ^3a , CH 2 NR ³ R ^3a ,

C (O) R ³ , CH ₂ C (O) R ³ , C (O) OR ^3c , C (O) NR ³ R ^3a ,

CH (= NR ³⁾ NR ³ R ^3a, SO 2 NR ³ R ^3a, NR ³ SO 2 -C ₁ _ ₄ alkyl, -NR ³ NR ³ SO2CF3 SO2-phenyl, S (O) ₂ CF _3, S (O) ₂ -C ₁ _ ₄ alkyl and S (O) ₂ -phenyl, CF _3;

[5] In an even more preferred embodiment, the present invention provides novel compounds selected from the group consisting of:

3-Methyl-1-phenyl-lH-pyrazole-5- (N- (2 ¹ aminosulfonyl- [1,1 '] - biphen-4-yl)) carboxyamide;

3-Methyl-1- (2-methoxy) phenyl-1 H -pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide);

3-Methyl-1- (3-methoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide);

3-Methyl-1- (4-methoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] -biphen-4-yl) carboxyamide);

3-Methyl-1- (2-hydroxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide);

3-Methyl-1- (3-hydroxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] -biphen-4-yl) carboxyamide);

3-Methyl-1- (4-hydroxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide);

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (3-fluoro- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide);

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (3-bromo-4- (2 '))

19-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide;

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (3-iodo- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl)) carboxyamide;

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (3-methyl- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide);

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-N-carboxyldimethylamine) phenyl) carboxyamide;

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-N-pyrrolidinocarbonyl) phenyl) carboxyamide;

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-α-methyl-N-pyrrolidino) phenyl) carboxyamide;

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (2'-aminosulfonyl [1,1 '] - biphen-4-yl) carboxyamide);

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-N-pyrrolidinocarbonyl) phenyl) carboxyamide;

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (5- (2-methanesulfonyl) phenyl) pyridin-2-ylcarboxyamide);

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (5-N-pyrrolidinocarbonyl) pyridin-2-ylcarboxyamide);

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (5-N-pyrrolidinocarbonyl) pyridin-2-ylcarboxyamide);

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (5- (2-sulfonamido) phenyl) pyridin-2-ylcarboxyamide);

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5-N- (4 - (- carboxyl-3)

• · • I ·· • • • • · · · • • « • · • · · · · • • • · _> *

hydroxypyrrolidino) phenyl) carboxyamide;

2-Amino-4- (4-methoxyphenyl) -5 - ^[(1 2 aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole;

2-Bromo-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole;

2-Chloro-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole;

2-Chloro-4- (4-phenoxy) -5 - ^[(1 2 aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole;

2-Methoxy-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole;

2-Thiomethyl-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole;

2-Methylsulfoxide-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole;

2-Methylsulfone-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole;

2-Cyano-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole;

2-N, N-Dimethylamino-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole;

2- (1-Pyrrole) -4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole;

3- (4-Methoxyphenyl) -5- [5- (2'-aminosulfonylphenyl-1-yl) pyridine]

9 9 · 9 <4 «* 9 9 9 9 9 9 9 9 9 9 494 494

21-2-yl] aminocarbonyl-5-carbomethoxymethyl-isoxazoline;

3- (4-Methoxyphenyl) -5- [5- (2'-aminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl-5-carboxymethyl-isoxazoline;

3- (4-Methoxyphenyl) -5- [5- (2'-aminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl-5- (N-carbomethoxymethyl) carboxamido methyl isoxazoline;

3- (4-Methoxyphenyl) -5- [5- (2'-aminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl-5- (1,2,4-triazol-1-yl) methyl isoxazoline;

1- (4-Methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] tetrazole;

3-Methyl-1- (4-methoxy-3-chloro) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide);

3-Methyl-1- (4-trifluoromethoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide);

1- (3-Bromophenyl) -3-methyl-1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide;

1- (3-Iodophenyl) -3-methyl-1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide;

1- (3,4-Methylenedioxanphenyl) -3-methyl-1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide;

1- (4-Methoxyphenyl) -3-hydroxylmethylene-1H-pyrazole-5- (4'-pyrrolidinecarbonyl) anilide;

1- (4-Methoxyphenyl) -3-formaldehyde-1H-pyrazole-5- (4'-pyrrolidinecarbonyl) anilide;

· · · · · · · · · · · · · · ·

1- (4-Methoxyphenyl) -5- (4'-pyrrolidinecarbonyl) anilide-3-pyrazolecarboxylic acid;

1- (4-Methoxyphenyl) -3-methylcarboxylate-1H-pyrazole-5- (4'-pyrrolidinecarbonyl) anilide;

1- (4'-Chlorophenyl) -3-methyl-lH-pyrazole-5 - ^[(1 2 aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide;

1- (4'-Chlorophenyl) -3-methyl-1H-pyrazole-5 - [(2'-aminosulfonyl- [1-pyridyl-1'-phenyl] -4-yl) carboxyamide;

1- (3 ', 4'-Dichlorophenyl) -3-methyl-1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1'] - biphen-4-yl) carboxyamide;

1- (3'-Chlorophenyl) -3-methyl-1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide;

2-Amino-4-phenyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole;

2-Chloro-4-phenyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole;

2-Amino-4- [3- (bromo) -4- (fluoro) -phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole;

2-Amino-4- [4-fluorophenyl] -5 - [(2'-aminosulfonyl- [1,1 '] -biphen-4-yl) aminocarbonyl] thiazole;

2-Amino-4- [3-bromophenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole;

2-Chloro-4- [3-bromophenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole;

22 · - .. ·

N - (2'-Aminosulfonyl- [1,1 '] - biphen-4-yl) -1- (4-methoxyphenyl) -3- (methylthio) pyrazole-5-carboxyamide;

1- (4-Methoxyphenyl) -3- (methylsulfonyl) -N- (5- (2'-methylsulfonylphenyl) pyrimid-2-yl) pyrazole-5-carboxyamide;

N- (2'-Aminosulfonyl- [1,1 '] - biphen-4-yl) -1- (4-methoxyphenyl) -3- (methylsulfonyl) -1H-pyrazole-5-carboxyamide;

N- (4-Benzoylpyrrolidno) -1- (4-methoxyphenyl) -3- (methylthio) -1H-pyrazole-5-carboxyamide;

1- (4-Methoxyphenyl) -N- (5- (2'-methylsulfonylphenyl) pyrimid-2-yl) -3- (methylthio) -1H-pyrazole-5-carboxyamide;

N- (4-Benzoylpyrrolodino) -1- (4-methoxyphenyl) -3- (methylsulfonyl) -1H-pyrazole-5-carboxyamide;

N- (2'-Aminosulfonyl- [1,1 '] - biphen-4-yl) -1- (4-methoxyphenyl) -3- (methoxymethyl) -1H-pyrazole-5-carboxyamide;

N- (2'-Aminosulfonyl- [1,1 '] - biphen-4-yl) -1- (4-methoxyphenyl) -3-carbomethoxy-4-pyrazole-5-carboxyamide;

N- (2'-Aminosulfonyl- [1,1 '] - biphen-4-yl) -1- (4-methoxyphenyl) -3- (methylsulfonylmethyl) -1H-pyrazole-5-carboxyamide;

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (5- (2-methanesulfonyl) phenyl) pyrimidin-2-yl) carboxyamide;

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5-N- (4- (N-carboxyl-2-carbomethoxypyrrolidino) phenyl) carboxyamide;

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5-N- (4- (N-carboxyl-3-aminopyrrolidino) phenyl) carboxyamide;

• · ·

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5-N- (4- (N-carboxyl-3-methoxypyrrolidino) phenyl) carboxyamide;

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (5- (2-aminosulfonyl) phenyl) pyridin-2-yl) carboxyamide;

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-amidino) phenyl) carboxyamide;

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (N-pyrrolidino) formylimino) phenyl) carboxyamide;

3-Trifluoromethyl-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl)) -1- (4-methoxyphenyl) pyrrolo [3,4-d] pyrazole-4,6 - (1H, 5H) dione;

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5-carbomethoxy- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl)) carboxyamide;

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5-hydroxymethyl- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl)) carboxyamide;

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N-2-fluoro (4- (N-pyrrolidino) formylimino) phenyl) carboxyamide;

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (N-pyrrolidino) formyl-N - ((2-propyl) methylcarbamoyl) imino) phenyl) carboxyamide;

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (N-pyrrolidino) formyl-N- (methylsulfamoyl) imino) phenyl) carboxyamide;

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N - ((4-amidino) phenyl) methyl) carboxyamide;

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N - ((4- (N-pyrrolidino) formylimino) phenyl) methyl) carboxyamide;

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N - ((1-benzyl) piperidin-4-yl) carboxyamide);

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N - ((1- (pyridin-2-yl) methyl) piperidin-4-yl) carboxyamide;

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (2-methylimidazo-1-yl)) phenyl) carboxyamide;

3-Methyl- (4-methoxy) phenyl-1H-pyrazole-5- (N- {4- (5-methylimidazol-1-yl} phenyl) carboxyamide;

3-Methyl- (4-methoxy) phenyl-1H-pyrazole-5- (N- {4- (4-methylimidazol-1-yl} phenyl) carboxyamide;

3-Trifluoromethyl- (4-methoxy) phenyl-1H-pyrazole-5- (N- {4- (5-carbomethoxyimidazol-1-yl} phenyl) carboxyamide;

3-Trifluoromethyl- (4-methoxy) phenyl-1H-pyrazole-5- (N- {4- (5-carboxyimidazol-1-yl} phenyl) carboxyamide;

1- (4-Methoxyphenyl ¹⁾ -3-hydroxymethyl-lH-pyrazole-5-N- (4 '- (pyrrolidinocarbonyl) phenyl) carboxyamide;

1- (4'-Methoxyphenyl) -3-formaldehyde-1H-pyrazole-5-N- (4 '- (pyrrolidinocarbonyl) phenyl) carboxyamide;

1- (4'-Methoxyphenyl) -5-N- (4 '- (pyrrolidinocarbonyl) anilide) -1H-pyrazol-3-yl-carboxylic acid;

• · ·

- 26 1- (4 ¹ methoxyphenyl) -3-methylcarboxylate-lH-pyrazole-5-N- (4'-pyrrolidinokarbonyl) phenyl) carboxyamide;

1- (4'-Methoxyphenyl) -3-cyanomethyl-1H-pyrazole-5-N- (4'-pyrrolidinocarbonyl) phenyl) carboxyamide;

2- (1 '- (4' ^1- Methoxyphenyl) -5'- (4''-pyrrolidinylon) anilide-1H-pyrazol-3'-yl) acetic acid;

1- (4'-Methoxyphenyl) -3-bromomethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide;

1- (4-Methoxyphenyl ^one) -3-aminomethyl-lH-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide;

1- (4'-Methoxyphenyl) -3- (N-methylsulfonylamino) methyl-1 H -pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide;

1- (4-Methoxyphenyl ¹⁾ -3- (imidazol-l-yl) methyl-lH-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide;

1- (4'-Methoxyphenyl) -3-hydroxylmethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide;

1- (4'-Methoxyphenyl) -3-trifluoroacetylhydroxylmethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide;

1- (4'-Methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'-methylsulfonyl- [1,1 '] - biphen-4-yl) carboxyamide;

1- (4'-Methoxy-2'-hydroxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'-methylsulfonyl- [1,1 '] - biphen-4-yl) carboxyamide;

27 '1- (4'-Methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1'] - biphen-4-yl) carboxyamide;

1- (4-Methoxy ^{1-2'-hydroxycarbonylphenyl)} -3-trifluoromethyl-1H-pyrazole-5-N- (2'-terč.butylaminosulfonyl- [1,1 '] biphen-4-yl) carboxyamide;

1- (4'-Methoxy-2'-hydroxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1.1 ^1] biphen-4-yl) carboxyamide;

1- (4'-Methoxy-2 ¹ -hydroxylmethylfenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide;

1- (4'-Methoxyphenyl) -3-methyl-1H-pyrazole-5-N- (4'-sec-butyl) phenyl) carboxyamide;

1- (4'-Methoxyphenyl) -3-methyl-lH-pyrazole-5-N- (4 ¹ - ^(3-1 '-methyl-3' - pyrazolin-5 '- one-2''- yl) phenyl) carboxyamide;

1- (4'-Methoxyphenyl) -3-methyl-1H-pyrazol-5-N- (4 '- (6''-methylbenzothiazol-2'- ¹ -yl) phenyl) carboxyamide;

1- (4'-Methoxyphenyl) -3-methyl-1H-pyrazole-5-N- (3'-4'-dibromophenyl) carboxyamide;

1- (4'-Methoxyphenyl) -3-methyl-1H-pyrazole-5-N- (4'-n-butyl) phenyl) carboxyamide;

1- (4'-Methoxyphenyl) -3-methyl-1H-pyrazole-5-N- (4 '- (4''-methylpiperidino) phenyl) carboxyamide;

1- (4'-Methoxyphenyl) -3-methyl-1H-pyrazole-5-N- (4 '- (2''-methylimidazol-1''-yl) phenyl) carboxyamide;

• · <

AND

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-carboxy (N-methylimidazo-2-yl) phenyl) carboxyamide);

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-hydroxymethyl (2- (imidazol-2-yl) phenyl))) carboxyamide;

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-hydroxymethyl (2- (1-benzylimidazol-2-yl) phenyl))) carboxyamide;

1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5- (N- (4- (2-carboxy (imidazol-2-yl) phenyl))) carboxyamide;

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (N- (4-methoxyphenyl) amino- (2-thiazolyl) methyl) phenyl))) carboxyamide;

1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5- (N- (4- (2-carboxy (4,5-dihydrothiazol-2-yl) phenyl))) carboxyamide;

1- (4-Methoxyphenyl) -3-trifluoromethyl-lH-pyrazole-5-N-4- (2- (4 ', ^5-dihydro-1 1 ¹ H-imidazol-2'yl) phenyl) carboxyamide;

1- (4-Methoxyphenyl) -3-trifluoromethyl-lH-pyrazole-5-N- (4- (N-2 ¹ aminoethylenkarboxyamid) phenyl) carboxyamide;

1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5- [4- (1,4,5,6-tetrahydropyrimid-2-yl) phenyl] carboxyamide;

1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5- [4- (N-methyl-4,5,6-trihydropyrimid-2-yl) phenyl] carboxyamide;

1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-N-1- (2-fluoro-4-imidazolophenyl) carboxyamide;

1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-N-1- (2-fluoro-4-N-methylimidazolophenyl) carboxyamide;

1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- [4- (4,5-dihydro-1-N-methylimidazo-2-yl) phenyl] carboxyamide;

1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- [4-carbonylguanidine] phenyl] carboxyamide;

1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- [4- (pyrimidin-2-yl) phenyl] carboxyamide;

2- (carboxamido) -4 - [(4-methoxy) phenyl] -5- [(2 ¹ -aminosulfony1- [1,1 '] - biphen-4-yl) carboxyamide] thiazole;

2- (2-Methoxyethylamino) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole;

2- (3-Hydroxypropylamino) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole;

2- (2-Cyanoethylamino) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole;

2- (3-Methoxypropylamino) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole;

2- (N-b-Alanyl) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole;

2- (Isopropylamino) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole;

2- (1,3-Dihydroxy-2-propylamino) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole ;

2 - [(Methoxycarbonyl) methylamino] -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole;

2- (N-Glycyl-4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole;

1 - [(4-Methoxy) phenyl] -3- (ethoxycarbonyl) -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide;

1 - [(4-Methoxy) phenyl] -3- (carboxyamide) -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide;

1 - [(4-Methoxy) phenyl] -3 - [(2-hydroxyethyl) carboxyamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide;

1 - [(4-Methoxy) phenyl] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide-3-hydroxamic acid;

1 - [(4-Methoxy) phenyl] -3- [phenylcarboxyamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide;

1 - [(4-Methoxy) phenyl] -3 - [(3-hydroxypropyl) carboxyamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide;

1 - [(4-Methoxy) phenyl] -3- [3-methylcarboxyamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide;

1 - [(4-Methoxy) phenyl] -3 - [(benzyl) carboxyamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide;

1 - [(4-Methoxy) phenyl] -3 - [(dimethyl) carboxyamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide;

1 - [(4-Methoxy) phenyl] -3 - [(phenylethyl) carboxyamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide;

1 - [(4-Methoxy) phenyl] -3 - [(2-hydroxyphenyl) carboxyamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide;

1 - [(4-Methoxy) phenyl] -3 - [(3-hydroxyphenyl) carboxyamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide;

1 - [(4-Methoxy) phenyl] -3 - [(4-hydroxyphenyl) carboxyamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide;

1 - [(4-Methoxy) phenyl] -3 - [(methoxycarbonyl) amino] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide;

1 - [(4-Methoxy) phenyl] -3-amino-1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide;

1 - [(4-methoxy) phenyl] -3 - [(methoxycarbonyl) -methyl] -1H-pyrazole-5 - ^[(1 2 aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide;

1 - [(4-Methoxy) phenyl] -3 - [(2-hydroxy) ethylamino] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide;

1 - [(4-Methoxy) phenyl] -3- [E-2- (methoxycarbonyl) ethenyl] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide;

1 - [(4-Methoxy) phenyl] -3- [2- (methoxycarbonyl) ethyl] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide;

1 - [(4-Methoxy) phenyl] -3- [E-2- (carboxy) ethenyl] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide;

1 - [(4-Methoxy) phenyl] -3- [2- (carboxy) ethyl] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide;

1 - [(4-Methoxy) phenyl] -3- [E-2- (carboxyamide) ethenyl] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide;

1 - [(4-Methoxy) phenyl] -3- [E-2- (hydroxymethyl) ethenyl] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide;

1 - [(4-Methoxy) phenyl] -3- (hydroxypropyl-1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide;

1 - [(4-Methoxy) phenyl] -3-propyl-1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide;

1 - [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4-cyano-1H-pyrazole-5 - [(2'-methylsulfonyl-3-fluoro- [1,1 '] - biphen-4-yl) carboxyamide;

1 - [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4- (amidino) -1H-pyrazole-5 - [(2'-methylsulfonyl-3-fluoro- [1,1 '] - biphen-4) -yl) carboxyamide;

1 - [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4- (N-hydroxyamidino) -1H-pyrazole-5 - [(2'-methylsulfonyl-3-fluoro- [1,1 '] - biphene) -4-yl) carboxyamide;

1 - [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4- (ethoxycarbonyl) -1H-pyrazole-5 - [(2'-methylsulfonyl-3-fluoro- [1,1 '] - biphen-4) -yl) carboxyamide; and

1 - [(4-Methoxy) phenyl] -3- (trifluoromethyl) -1H-pyrazole-5 - [(2'-methylsulfonyl-3-fluoro- [1,1 '] -biphen-4-yl) carboxyamide-4 -carboxylic acid;

or a pharmaceutically acceptable salt thereof.

[6] In a second embodiment, the present invention provides novel compounds of formula II:

Or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein

M is selected from:

Z is selected from C (O) CH 2 and C (O) NR ² ;

R ^1a is - (CH ₂ ) J -R ¹ ;

R ¹ 'is selected from the group consisting of H, C 1-3 alkyl, F,

Cl, Br, CH (CH ₂ OR ² ) 2, (CF 2) r CF 3, (CH 2) r OR ² , NR ² R ^2a , S (O) p R ^2b , NR ² (CH 2) r OR ² , NR ² C (O) R ^2b , C (O) NR ² R ^a , C (O) NR ² (CH 2) _r OR ² , and SO ₂ NR ² R ^2a ;

R at each occurrence is selected from the group consisting of H, CF _3, C ₄ _G alkyl, benzyl, C ₃ _G carbocyclic residue substituted with 0-2 ^R4, and 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N , O and S substituted with 0-2 R ⁴ ;

R at each occurrence is selected from the group consisting of H, CF _3, C ₄ _G alkyl, benzyl, phenethyl, C ₃ _G carbocyclic residue substituted with 0-2 ^R4, and 5-6 membered heterocyclic system containing 1-4 heteroatoms selected N, O and S substituted with 0-2 R ⁴ ;

R ^2b, at each occurrence is selected from the group consisting of CF 3, C _1-4 alkoxy, C ₄ _G alkyl, benzyl, C ₃ _G carbocyclic residue substituted with 0-2 ^R4, and 5-6 membered • · · · · · A heterocyclic system containing 1 to 4 heteroatoms selected from N, O and S substituted with 0 to 2 R ⁴ ;

alternatively, R ² and R ^2a , together with the atom to which they are attached, form a 5- or 6-membered saturated, partially saturated or unsaturated ring substituted with 0-2 R ⁴ containing 0 to 1 additional heteroatoms selected from the group consisting of N, O, and S;

R ³ , at each occurrence, is selected from H, C _1-4 alkyl, and phenyl;

A is selected from the group consisting of phenyl, pyridyl, pyrimidyl, and A is substituted with 0-2 R ⁴ ;

B is selected from H and Y;

Y is selected from the group consisting of phenyl, pyridyl,. . 4a tetrazolyl, and morpholmo, and Y is substituted with 0-2 R;

R ⁴ , at each occurrence, is selected from the group consisting of F, Cl, Br, I, C (O) NR ² R ^2a , and (CF ₂ ) _r CF ₃ ;

R ^4a , at each occurrence, is selected from the group consisting of F, Cl, Br, I, C 1-4 alkyl, C (O) NR ² R ^2a , SO ² NR ² R ^2a 'NR ² SO ² -C 1-4 alkyl, S (O) ^pR5, and (CF2) _r CF _3;

R ^5, at each occurrence, is selected from the group consisting of CF _3, C ₄ _G alkyl, phenyl and benzyl;

p is 0,1 and 2; and r is 0, 1, 2a3.

[7] In another preferred embodiment, the present invention provides novel compounds selected from the group consisting of:

3-Methyl-1-phenyl-1H-pyrazole-5- (N- (2-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide);

2-Amino-4-phenyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole; and

2-Chloro-4-phenyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole;

In a third embodiment, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

In a fourth embodiment, the present invention provides a new method of treating or preventing thromboembolic diseases, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

The compounds of the invention may contain asymmetric centers. Compounds of the invention containing asymmetrically substituted atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms are well known in the art. These are, for example, optical resolution of racemic forms or direct synthesis from optically active starting materials. The disclosed compounds may also include many geometric isomers formed on an olefinic bond, a C = N double bond, and the like, and all stable isomers thus derived are within the scope of this invention. The cis and trans optical isomers of the compounds of the present invention are described and can be isolated as mixtures of isomers or as separated isomeric forms. Unless stereochemistry is specifically indicated in a formula or title, it is understood that all chiral are included in the formula or name. • · · · · · · · · · · · · ·

Diastereomeric or racemic forms and all geometric isomeric forms of the structure described.

Substituted herein means that any at least one of the hydrogen atoms attached to the substituent so designated is replaced by a substituent selected from the definition set, provided that the normal valency of such an atom is not exceeded and that the resulting substitution results in a stable compound. When such a substituent is a keto group (i.e., a group = O), then two hydrogen atoms are replaced in that way. Keto substituents are not present on the aromatic moieties.

The present invention also includes all isotopes of the atoms found in the compounds of the invention. Isotopes include atoms having the same atomic number but different mass numbers. Non-limiting examples are hydrogen isotopes, including deuterium and tritium. Carbon isotopes include C-13 and C-14.

If any of the variables (for example R 6) occurs more than once in any component or formula of the compound, its definition is independent at each occurrence. For example, when it is stated that a group is substituted with 0-2 R ⁶ , then said group may be optionally substituted with up to two R ⁶ groups, wherein R 6 is at each occurrence independently selected from the definition of R ⁶ . Combinations of substituents and / or variables are also acceptable, provided that they result in stable compounds.

If the bond to the substituent crosses the bond connecting the two atoms in the ring, then the substituent may be bonded to any ring atom. Unless a substituent is specified for the substituent to the remainder of a compound of the formula, such substituent may be bound by any substituent atom. Combinations of substituents and / or variables are also acceptable, provided that they result in stable compounds.

^L The term 'C ₁ _ ₆ alkyl refers to saturated aliphatic hydrocarbon groups having straight and branched, containing the indicated number of carbon atoms and examples of such groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexenyl. Alkenyl refers to straight or branched chain hydrocarbon chains having one or more unsaturated carbon-carbon bonds and which can occur at any stable point in the entire chain. Examples are ethenyl, propenyl and the like.

The term halogen as used herein refers to fluorine, chlorine, bromine and iodine and the term counterion is used to denote a small, negatively charged residue such as chloride, bromide, hydroxide, acetate, sulfate and the like.

The term carbocycle or carbocyclic radical as used herein refers to any stable 3- to 7-membered monocyclic or 7- to 13-membered bicyclic or tricyclic ring, any of which may be saturated, partially unsaturated or aromatic. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl; [3.3.0] bicyclooctane, [4.3.0] bicyclononane, [4.4.0] bicycodecane (decalin), [2.2.2] bicyclooctane, fluorophenyl, phenyl, naphthyl, indanyl, adamantyl or tetrahydronaphthyl (tetralin).

The term heterocycle or heterocyclic moiety means a stable 5- to 7-membered monocyclic or bicyclic, or 7- to 10-membered bicyclic ring which is saturated, partially unsaturated or aromatic and contains carbon atoms and 1-4 heteroatoms selected from the group consisting of: ·

- 38 including nitrogen, oxygen and sulfur. The term also includes bicyclic groups in which any of the above defined rings is fused to a benzene ring. In such groups, nitrogen and sulfur heteroatoms may be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that will provide a stable structure. The above heterocyclic rings may be substituted on a carbon or nitrogen atom, provided that stable compounds are formed. The nitrogen atom may optionally be quaternized. It is preferred that the total number of sulfur and oxygen atoms be greater than 1 and that these heteroatoms are not adjacent to each other. The term aromatic heterocyclic system refers to a stable 5- to 7-membered monocyclic or bicyclic, or 7- to 10-membered bicyclic ring which is saturated, partially unsaturated or aromatic and contains carbon atoms and 1-4 heteroatoms selected from nitrogen , oxygen and sulfur. It is preferred that the total number of S and O atoms in the aromatic heterocycle be not more than 1.

Examples of the heterocycle include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzthiazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, carbazolyl, 4aH-quinolinyl, carbazolyl, , 2H, 6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, ΙΗ-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,

1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, • · · · · · · · · · · · · · · · · · · · · · · · · ·

- 39 phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyrrolidinyl, pyridyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,

4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl,

1,2.3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,

1,3.4-thiadiazolyl, thiantrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,

1.3.4- triazolyl and xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl, ΙΗ-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl or isatinoyl.

Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

As used herein, "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms which, within the medical range, are suitable for use with tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications. maintaining a reasonable benefit / risk ratio.

The term pharmaceutically acceptable salts as used herein refers to derivatives of the compounds of the invention that are modified by forming their salts with acids or bases. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic salts of basic residues such as amines; or alkali or organic salts of acidic residues such as salts of carboxylic acids and the like. Pharmaceutically acceptable salts include conventional non-toxic salts of quaternary ammonium salts of the parent compounds, for example, from non-toxic inorganic or organic acids. For example, such conventional salts include such inorganic acid derivatives as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and such salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymalein, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic , fumaric, toluenesulfonic, methanesulfonic, ethanesulfonic, oxalic, isethionic and the like.

The pharmaceutically acceptable salts of the present invention can be prepared by synthesis from the parent compound containing a basic or acidic residue by conventional chemical methods. Generally, salts are prepared by reacting the free base or acid with a stoichiometric amount or excess of the desired salt-forming base or acid in water or in an organic solvent or mixtures thereof. Generally, a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is suitable. Suitable salts are listed in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, PA, 1985, p. 1418, incorporated herein by reference.

Prodrug refers to structures formed by covalent attachment of an active parent drug of Formula I to a carrier from which the parent drug is released in vivo when the prodrug is administered to a mammalian subject. Prodrugs of the compounds of formula (I) are prepared by modifying the functional groups present in such drugs so that cleavage of such modifications to form the parent compound occurs by routine manipulation or in vivo. Prodrugs include compounds of formula I wherein:

«·

A hydroxy group, an amino group or a sulfhydryl group attached to another group which, once administered to a mammalian subject, cleaves again to form a free hydroxy group, a free amino group or a free sulfhydryl group. Non-limiting examples of prodrugs include acetates, formates, and benzoates formed on an alcoholic or amine functional group of a compound of Formula I and the like.

By stable compound or stable structure is meant a compound that is robust enough to be retained in isolation to a useful degree of purity from the reaction mixture and formulation into an effective therapeutic agent.

Syntheses

The compounds of the present invention can be prepared by a variety of methods known to those skilled in the art of organic synthesis. The compounds of the invention can be synthesized by methods and synthetic procedures known in the art of organic chemistry as described below. Various variations of the procedures described or described below may also be used. Preferred processes include, but are not limited to, those described below. The reactions are carried out in a suitable solvent against the reactants and materials used and suitable for efficient transformation. It is to be understood that the functional groups present in the molecule are consistent with the proposed transformations. This will sometimes require modification of the synthetic steps or a particular procedure to obtain the desired compound of the invention. It will be appreciated that further considerations in the planning of any synthetic route in the art are based on the reasonable choice of protecting groups for the reactive functional groups present in the compounds of the invention. An authoritative account describing a number of alternatives is given by Greene and Wuts (Protective Groups in Organic Synthesis, Wiley and Sons, 1991). All references are incorporated herein by reference.

99 99

9 9 9 9 9 9 9 • • 9 * 4 4 • 4 444 99 9

9 «4 • 44 4444 44 44

DETAILED DESCRIPTION OF THE INVENTION

Preparation of compounds of formula I with a five membered heterocyclic core

The general procedure for the preparation of compounds of formula I is shown in Scheme 1a-b. Ring M can be N-linked or C-linked to the ring shown in the following scheme as ring D. B 'and protected functional groups can be converted to R, Ba and R ^1a . It will be appreciated that Group E may or may not be protected depending on the requirements of the chemistry used. The compounds can also be prepared by interchanging the sequence of the reaction steps as described in Scheme 1. For the N-linked ring M, the appropriately amino substituted ring D is treated under the conditions described in The Chemistry of Heterocyclic Compounds, Weisberger, A. and Taylor, EC, eds. John Wiley & Sons or as described later in the synthesis section providing the N-linked ring M. Further modification and deprotection is provided by the N-linked ring M, with substituents R, ZAB and R ^1a .

Scheme la

For heterocycle

M bonded through nitrogen

fK /

Z-A-B '

R ^f

For the C-linked five-membered ring M, the above aniline is diazotized with nitrous acid and treated with NaBr to give the heterocyclic bromide. Treatment with η-BuLi followed by DMF provides an aldehyde that can be converted to ring M as described in The Chemistry of Heterocyclic Compounds, by Weisberger, A. and Taylor, EC, edited by John Wiley & Sons or as described later in the synthesis. section. Other precursor functional groups such as acid, cyanide, methyl ketone, etc. can be used to form ring M. Further modifications and deprotection can result in a five-membered ring M substituted with R, ZAB and R ^1a . The corresponding C-linked six-membered ring M can be obtained by converting the above bromide with n-butyllithium and triisopropylborate to give the boronic acid. Suzuka coupling with a suitable heterocyclic bromide, followed by modifications and deprotection affords a C-linked six-membered ring M with the substituents R, ZAB and and R ^1a .

Scheme lb

For carbon-linked heterocycle M

(CO ₂ H, CN, COCH ₃ )

Compounds of the present invention wherein the M-heterocycle is thiazole can be prepared according to the procedures described in Scheme 2. The suitably thickened ring D can be converted to the beta-ketoester in several ways. One preferred method involves transmetallation with an alkyllithium reagent followed by cooling with DMF to give the corresponding aldehyde. Addition of ethyldiazoacetate in the presence of stannous chloride affords the beta-keto ester directly. Other methods are suitable for this conversion, one of which includes

Reformat reaction of the aldehyde followed by oxidation to the beta-ketoester.

Scheme 2

Br nBuLi then DMF

O

! N, CH, CO, R is Sn CH 2, i

1) (EtOCH = CH ₁ SnBu ₃ Pd (PPh ₃ ) 2 Cl 2

2) H ₃ 0NaH. (RO) ₂ CO THF, reflux.

steed

LDA, THF -780C, (RO) ₂ CO

IR (R ^{1, NBS: or} .X 2 -COpR _{Ph (OH) OTs)}

2) R ^{1 and} C (= S) NH ₂

A second preferred method for converting bromide to beta-ketoester involves palladium catalyzed coupling with (ethoxyvinyl) tributyltin followed by acid hydrolysis to give the corresponding acetyl derivative. There are a number of methods for converting an acetyl derivative to a beta-ketoester.

• · ·

• ·

One preferred method involves reacting the acetyl derivative with a dialkyl carbonate in the presence of a base such as sodium hydride or lithium diisopropylamide. The beta-ketoester can be converted to the corresponding thiazole derivatives by bromination with NBS followed by cyclization with a suitable thiourea or thioamide in a solvent such as ethanol or tetrahydrofuran. The method for this one-pot conversion involves treating the beta-ketoester with hydroxytosyloxy iodobenzene in acetonitrile to give the intermediate alpha-tosyloxy-beta-ketoester, followed by the addition of thiourea or thioamide for more efficient cyclization to the corresponding thiazole. Manipulation of this ester group of these thiazoles can then lead to compounds containing a suitable ZAB group. When Z = CONH, standard methods of peptide coupling with a suitable amine, such as reaction of an ester group with an amine-derived aluminum reagent, can be used. If Z = COCH 2, the formation of the acid chloride may be followed by addition of a suitable zinc reagent by standard methods. The R ^{1a group} on the thiazole ring can also be manipulated to provide a variety of different groups. For example, when urea is used as the cyclizing component, 2-aminothiazole is formed. This amino group can be readily diazotized and displaced by a suitable copper halide to give 2-halothiazoles. The halogen atom can be readily displaced by various nucleophiles of carbon, nitrogen, oxygen and sulfur to form a series of alkyl, aryl, heteroatom, and heterocyclic derivatives R ^1a .

The tetrazole compounds of the invention wherein Z is CONH can be prepared as outlined in Scheme 3. The appropriately substituted amine (ED-NH ₂ ) is acylated with ethyloxalyl chloride. The resulting amide can be converted to tetrazole either by the method of Duncia (J. Org. Chem.

1991, 2395-2400) or Thomas (Synthesis 1993, 767-768, 1993). The amide can first be converted to iminoyl chloride and then reacted with NaN ₃ to give 5-carboethoxytetrazole (J. Org. Chem. 1993,

······· ··

58, 32-35 and Bioorg. & Med. Chem. Lett. 1996, 6, 1015-1020). The 5-carboxytetrazole is then coupled with a suitable amine (BANH ₂ ) according to the method described by Weinreb (Tetr. Lett. 1977, 48, 4171-4174). Final deprotection as described below yields the desired product.

The tetrazole compounds of the invention wherein Z is -COse can also be prepared via iminoyl chloride (Chem. Ber. 1961, 94, 1116 and J. Org. Chem. 1976, 41, 1073), using a suitably substituted acyl chloride as the starting material. The ketone linker can be reduced to a compound wherein Z is alkyl.

Scheme 3

Ed-NH ₂

Ct ^ COgEt HN- ^ COsEt cct ch ₂ or ₂ zei, n DE -

Cl

N ₂ CO ₂ Et DE

The tetrazole compounds of the present invention wherein Z is SO ₂ NH-, -S-, -S (O) -, SO ₂ can be prepared as outlined in Scheme 4. An appropriately substituted thiocyanate reacts with sodium azide to form 5-thiotetrazole ( J. Org Chem.

1967, 32, 3580-3592). The thio compound may be alkylated (J. Org. Chem. 1978, 43, 1197-1200) and then oxidized to the sulfoxide or sulfone. The thio compound can be converted to a sulfonyl chloride and then reacted with an amine to produce the desired compound.

sulfonamide. The tetrazole compounds of the invention wherein Z is -O- can be prepared in the same manner as described in Scheme 4 using a suitably substituted isocyanate as a starting material.

Scheme 4

I nh ₂ -ab

N-N

H

N-AB

N-N

AND

The tetrazole compounds of the present invention wherein Z is NH-, -NHCO-, -NHSO ₂ - can be prepared from 5-aminotetrazole, which can be prepared by Smiles rearrangement as outlined in Scheme 5. Thio compound as prepared as described in of Scheme 4 is alkylated with 2-chloroacetamide. The resulting compound was heated to reflux in ethanolic sodium hydroxide to give the corresponding 5-aminotetrazole (Chem. Pharm. Bull. 1991, 39, 3331-3334). The resulting 5-aminotetrazole can then be alkylated or acylated to give the desired products.

• · · · · · ·

Scheme 5

NN de nh ₂

N-N vw *

D-E O

NaOH / EtOH 1, N

N-N

W 'n ^ nh ₂

D-E

The N-linked imidazole ring M can be prepared by the synthetic route outlined in Scheme 6. Alkylation of E-D-NH 2 with 2-bromoethyl acetate followed by treatment with a Gold reagent in the presence of a base such as NaOMe or LDA gives the imidazole ring M.

Scheme 6

e. _d .nh ₂

BrO OEt

The general procedure for preparing the C-linked imidazole ring M is described in Scheme 7. The aldehyde ED-CHO of Scheme 1 can be converted to the cyano compound by treatment with hydroxylamine and then dehydration with POCl ₃ . The amidine can be obtained from the cyano compound by Pinner reaction and then cyclized with an alpha-haloester, ketone or aldehyde to form the imidazole ring M. Alkylation or acylation of the imidazole ring results in further modifications as shown in Scheme 1.

Scheme 7 'D .CHO • tr

CN

NH O

R ^1a

Hal

As shown in Scheme 8, the pyrazole ring M of Formula I, as described in Scheme 1, can be prepared by condensation of an appropriately substituted hydrazine with various diketoesters. Condensations of this type typically result in a mixture of pyrazole regioisomers that can be effectively resolved by silica gel column chromatography. Hydrolysis of the esters followed by coupling with the appropriate amine affords the desired amide intermediate. Various substituents on the pyrazole N1 can then be converted to yield a variety of benzo, heterocyclic and bicyclic compounds.

Scheme 8 ₃ 1a, CO ₂ Et

NHNH ₂

E-D

EtO ₂

N ₃ 1a

AND

R ' ^{and N} ' _N- CO ₂ Et ED ⁺ eD

Column chromatography then with LiOH, THF, water

1. BaNH coupling ₂

1a

2. HCl / MeOH 2. (NH ₄ ) ₂ CO ₃ .

MeOH

D-E

N i

D-E

COOH

When the above methodology is applied to diketoderivatives, a mixture of pyrazole regioisomers is also obtained. These regioisomers can be further converted to compounds of formula I as shown in Scheme 9.

Scheme 9) 1a

YY o

NHNH ₂

N

N ' ^R 1

D-E

E-D

AND

DE ^H W ^a

OMeO

R ^1a = amine or alkyl or aryl

EtO ₂

As in Scheme 8

D-E

R ^1a

Column Chromatography Oxidation, esterification> 1a and / or n 'K _co p N CO ₂ Et

D-E

When ketoimidates are used for condensation with hydrazines, the corresponding pyrazole aminoester regioaducts are obtained (Scheme 9). Conversion of these intermediates to the final compounds of Formula I can be accomplished by protecting the amine function with a suitable protecting group in a manner commonly known to those skilled in the art or by derivatization (such as sulfamide in Scheme 10) and following a general synthetic strategy to prepare the compounds of the invention.

Scheme 10

EtO ₂ C.

Ν NH? »»

D-E

Η;

1 N CO ₂ Et ^Me 2 ^with ° 2Ci.

D-E

Pyridine

MUD

-Λ

NHSO ₂ Me N CO ₂ Et D-E D-E or

As in Scheme 8

MeO ₂ SH

N NHSO ₂ Me ^N ' _N ^ CONHAB

D-E

D-E or

The pyrazole ester intermediate can be further converted to ketones by the cuprate methodology described by Knochel et al. (Scheme 11). Alternatively, the ester can be reduced to either an alcohol or an aldehyde by methods known to those skilled in the art, followed by reductive amination with a suitable amine to an alkylamine or by conversion of the alcohol to a leaving group which can be displaced with a number of nucleophiles to produce intermediates that .

Scheme 11 hydr then acid chloride then

E-D '

ZTlL-cooEt you

AB [HJ

Zn, CuCN, THF

O

AB / RIP fd 3 / N

E-D

-CHO or CH ₂ OH

O - CH ₂ NHAB or CH ₃ SAB or CH ₂ C 4 AB ty

E-D •

Thio compounds such as those described in Scheme 12 can be readily prepared by converting 5-hydroxypyrazole to thiol by treatment with Lawesson's reagent in refluxing toluene.

Scheme 12> 1a

R

Laweson's and J / Lawe & L ^reagents ° D-E

SH Alkyhalid

D-E

Ď-E

Oxidation

D-E O

Xx or

WITH

II

D-E ⁰

ΆΒ

Xy ^ B

N II

D-E θ or--E °

Compounds of the present invention wherein the pyrazole ring M is replaced with 1,2,3-triazole can be prepared as outlined in Scheme 13.

• · • *

- 54 Diagram 13

BANH ₂ coupling

2. HCl / MeOH

3. (NH ₄ ) ₂ CO ₃ , MeoH _R ia

D-E

CH KMnO4 CH (OMe) _2, hydroxy and Ag ₂ O

Ν '

NÍ

D-E

COOH

BANH ₂ coupling

2. HCl / MeOH

3. (NH ₄ ) ₂ CO ₃ , MeoH

D-E

CONHAB

D-E

CONHAB

D-E

CONHAB

Compounds of the present invention wherein ring M is 1,2,4-triazole can be readily obtained by the methodology described by Huisgen et al., (Liebigs Ann. Chem. 1962, 653, 105) by cycloaddition of nitrilimino compounds (derived from triethylamine and chlorhydrazone) and a suitable nitrile dipolarophil as shown in Scheme 14.

Scheme 14

F

D-E

HZCN

EtgN, Benzene

AND

D-E

ZH

This methodology provides a wide variety of 1,2,4-triazole with a number of substitutions at positions 1, 3, and 5. Alternatively,

1,2,4-triazoles can also be prepared by the methodology of Zecchi et al. (Synthesis 1986, 9, 772) via aza Wittig condensation (Scheme 15).

Scheme 15 (Ph) ₃ R > _N

N 2 CO ₂ Me ed-nh

P ^{, c}

JL,

EtO ₂

AND

D-E

1a

R ^1a = alkyl or aryl

Alternatively, 1,2,4-triazoles can also be prepared by the methodology of Sauer et al. (Tetr. Lett. 1968, 325)

by photolysis 16). Scheme 16 cyclic carbonates with suitable nitrile (scheme r13 hv, EtOAc R ^1b CN Rl? V ^N 1 D-E R ^1b = Ester, Alkyl, Aryl ^{R 1a} = Phenyl or ester D-E

In the compounds of the present invention, esters can be converted to amide intermediates by Weinreb methodology (Tetr. Lett. 1977, 48, 4171), i. by condensation of a suitable amine aluminum complex with an ester (Scheme 17).

·· · «

• ·

- 56 Diagram 17

The isoxazoline ring M of formula I wherein the 4 and 5 position is substituted may be prepared as follows

The 1,3-dipolar cycloaddition methodology outlined in Scheme 18. The appropriate benzhydroximinoyoyl chloride or heterocyclic oximinoyl chloride or oxime provides the

1.3-dipolar cycloaddition protocol with appropriate

A 1,2-disubstituted olefin as a dipolarophile mixture of a regioisomer. Separation of the regioisomers by column chromatography followed by a series of reactions as described previously leads to the selected compounds. Optically active isoxazolines can also be obtained by enzymatic resolution into regionomeric esters or by using a suitable chiral auxiliary on dipolarophile as described by Olsson et al. (J. Org. Chem. 1988, 53, 2468).

Scheme 18

E-

x

OH

X = Cl e:, n. ch, or ₂ or X = H NaOCl. CH ₂ Cl

X = H. Cl

1. Hydrolysis

2nd pair NH2-AB

4-carboxamide

3-carboxamide • ·

- 57 *

For compounds of Formula I, where the substrate utilizes a suitably substituted crotonate ester in the cycloaddition procedure described in Scheme 18. Crotonate esters may be obtained from commercial sources or may be obtained from ethyl bromocrotonate by the nucleophilic displacement reactions shown in Scheme 19.

Scheme 19

2 ^r MeOH, CaCO ₃ or tetrazole, triazole, imidazole, NaH / THF

Trisubstituted olefins such as dipolarophiles can be obtained from ethyl propionate by cuprous chemistry (Scheme 20) according to the procedure described by Deslongchamps et al. (Synlett 1994, 660).

Scheme 20 = -CO, Et F, MeCu, RX

R '

COjEt

Compounds of the invention having a 1,3,4-triazole ring M can be readily prepared by the methodology of Moderhack et al. (J. Prakt. Chem. 1996, 338, 169) as shown in Scheme 21.

• · · ·

5f? * - · * · · · · · • · · · · · · ·

Scheme 21 h ₂ n-nh y-CH ₂ OEz 2

O

E-D-NCS then NaOH

HNO-,

HNN Á ν '

AND

D-E

CH (OEt) ₂

N-N

IN

AND

DE • CH (OEt) ₂

BA.

ABBr, NaH

N-N // w

Hydr

NBS then alcohol

CH (OEt) ₂

D-E

N-N

D-E

CO ₂ Et

N-N // V, N — AB

D-E

Hydr.

oxidation of decarboxylation As in Scheme 1 [H] via Weinreb

N-N .OH N D-E X N-N N AND D-E

N-N // V '

DE ⁰

AND

D-E

ΆΒ

X = none or H or an alkyl or heteroatom

This reaction involves condensing the carbazide with a suitably substituted commercially available thioisocyanate to the cyclic thiourea derivatives as described above. Alkylation or nucleophilic displacement reactions on the thionic derivative result in a thio alkyl or aryl intermediate which can be hydrolyzed, oxidized and decarboxylated to a 5-H 2-thio triazole intermediate which can be readily converted to the compounds of the invention. Alternatively, the thionurea intermediate can be oxidized directly to the 2-H triazole, which can be converted to an ester and then subjected to the various reactions mentioned above to give the compounds of the invention.

• · ·

Esters can also be converted to amines by Hoffmann rearrangement and this methodology provides various analogs similar to those mentioned above. The cyclic thionurea intermediate can also be oxidized to the sulfonyl chloride by the methods given in the earlier examples. This again yields the sulfonamides shown in Scheme 22.

Scheme 22

HN-N

CH (OEt) 2 i

D-E

Cl ₂ , AcOH

N-N O .. J / V

Cl

D-E

CH (OEt) ₂

T

N-N

V i

D-E

N-N

N

AND

DE as in Scheme 21 'CO ₂ Et

I i

• nh ₂ t

NN O, JJAO = S ^ _K ,>

BA '.NH

N '

AND

D-E

N-N

Λ

N

AND

D-E

NHCOAB or NHSO ₂ AB

AND

DE nhch ₂ ab

Scheme 23 describes general syntheses of pyrazoles having thio and oxidized sulfur derivatives. The appropriately substituted amine is alkylated with ethyl bromoacetate and then hydrolyzed to the glycine derivative. The preparation of N-nitroso compounds is readily accomplished with sodium nitrite (J. Chem. Soc. 1935, 899). Cyclization to the syndone using acetic anhydride (J. Chem. Soc. 1935, 899) is followed by the introduction of a sulfide unit using the sulfoxide as the solvent and acetyl chloride as the activating agent (Tetr. 1974, 30, 409). Photolytic cleavage of the syndone in the presence of an acetylinic compound results in 1,3,5 trisubstituted pyrazole as a major regioisomer (Chem. Ber. 1979, 112, 1206). This can be converted as described above to final compounds containing sulfide, sulfoxide or sulfone functional groups.

Scheme 23

_ED-NH2

1) BrCH ₂ CO ₂ Me. Et ₃ N

LiOH. THF 3) NaNO ₂ , H ₂ O, ch ₃

NO '^ ed- ° ^{C 2 H} .ch ₃

1) Ac ₂ O hu, HCsCV

S \

'N

E-D Z-A-B E-D

Where V = _N q ₂ sO ₂ NR ₂ or CO ₂ Me or N

Z - A - B E - D

2) Q ₂ SO, AcCl or N

Z-A-B

Scheme 24 shows a possible synthesis of isoxazoles. The substituted benzaldehydes are reacted with hydroxylamine and then chlorinated to give hydroximinoyl chloride according to a known procedure (J. Org. Chem. 1980, 45, 3916). The in situ preparation of nitriloxide with triethylamine and substituted alkyne cycloaddition gives a mixture of regioisomeric isoxazoles as reported by H. Kawakami (Chem. Lett. 1987, 1, 85). The preparation of the disubstituted alkyne is accomplished by nucleophilic attack on an alkynyl anion on an electrophile as reported by Jungheim et al. (J. Org. Chem.

1987, 57, 4007).

Alternatively, the preparation of hydroxiiminoyl chloride of the R ^1a moiety and reaction with an appropriately substituted alkyne provides another series of regioisomeric isoxazoles which are separated by chromatography.

··· · · · ··· * · · · ··· · · · · ·················

Scheme 24

Ε.

cr ^CH0

(1) NH ₂ OH _ν Λ

2) NCS, ^E '

1a CH .CHO

1) NH ₂ OH

2) NCS, Cat

N, A .OH

Cl

Where V = NO ₂ , SO ₂ NR ₂ or CO ₂ Me, a synthetic precursor to -ZAB.

An alternative procedure to prepare only one regioisomer is described in Scheme 25. The protected group is removed from the methylene form V and silylated. Chlorination with carbon tetrachloride or fluorination with difluorodibromomethane under catalysis of triethylborane yields a geminal dihalo compound as described by Sugimotom (Chem. Lett. 1991, 1319). The coupled-mediated conjugate addition-elimination reaction gives the desired alkene, as reported by Harding (J. Org. Chem. 1978, 43,

3874).

Alternatively, acylation with an acid chloride produces a ketone, as reported by Andrews (Tetr. Lett. 1991, 7731), and subsequent reaction with diazomethane affords the enol ether. Each of these compounds can be reacted with hydroximinoyl chloride in the presence of triethylamine to form a regioisomeric isoxazole, as reported by Stevens (Tetr. Lett. 1984, 4587).

• · ·

Scheme 25

X = Cl or F

Y n’a

Y v

Et ₃ N (R ^1a ) ₂ CuLi X ¹ R ^1a

E '.0 ó li> 1a

Where Y = OMe, Cl or F

V = NO ₂ , SO ₂ NR ₂ or CO ₂ Me, a synthetic precursor to -ZAB

If the core substituent R ^1a is CH ₂ Q, the preparation is carried out according to Scheme 26. After treatment with LDA, the starting ketone material is reacted with PhSSO ₂ Ph to give a phenylthiolate compound which is reacted with hydrazine in acetic acid to give a pyrazole derivative. The pyrazole ester is reacted with an amine or aniline (previously treated with AlMe ₃ ) to obtain an amide. Oxidation of the sulfide with mCPBA yields the corresponding sulfone. Removal of the sulfone with a base followed by capture with an electrophile (QX) and treatment with Sml ₂ gave the desired compound after deprotection.

• ·

Preparation 26 nh ₂ / ^Δ

Scheme 27 shows additional preparation methods for R ^1a =

CH ₂ Q or COQ. Protection of the hydroxyl group of hydroxyacetone with a benzyl halide and treatment with base and CO (CO ₂ Et) ₂ gives the tricarbonyl compound. Refluxing with NH ₂ OMe.HCl in pyridine and ethanol in the presence of molecular sieves 3A affords the oxime. Cyclization of the oxime with ED-NHNH ₂ gives the pyrazole, which can be converted to the corresponding amide by reaction with an amine or aniline (previously activated with AlMe ₃ ). Debénzylation by catalytic hydrogenation yields an alcohol. The alcohol is converted to the tosylate with TsCl followed by displacement with the nucleophile to give the desired compound. The alcohol may also be oxidized to the corresponding aldehyde or acid or further converted to an ester or amide.

»· · ·

Scheme 27

HIM

PhCH ₂ Cl

K ₂ CO ₃ acetone

FH

About • · · · · · · · · · · · · · · · · · ·

NaOMe (CO ₂ Et) ₂

Ph

OEt

ED-NHNH ₂

HOAc

E-D '

About N-AB

E-D '

TsCI

Q-H

About N-AB

BzO

BzO.

E-D

About OEt

Preparation of compounds of formula I with a six membered heterocyclic core

Scheme 28 describes the preparation of compounds wherein M is a benzene ring and V is a nitro, a protected sulfonamide or ester group and a precursor of the Z group of Compound I. Group V is introduced to the appropriately substituted phenol by nitration as reported by Poirier et al. (Tetrahedron 1989, 45 (5), 1415), by sulfonylation as reported by Kuznetsov (Akad. Nauk USSR Ser. Khim 1990, 8, 1888) or by carboxylation as reported by Sartori et al. (Synthesis 1988)

10, 763). Bromination with triphenylphosphine and bromine (J. Am. Chem. Soc. 1964, 86, 964) gives the desired bromide. Suzuka coupling with a suitable boronic acid yields the desired substituted pyridine.

Scheme 28

VZ — ED-3 (OH) ₂

2) Pd -,.. / = \ (Ph ₃ P) ₄ Pd _Sr I Br V Na ₂ CO ₃

Schemes 29 to 32 describe the preparation of compounds wherein M is pyridine. Each scheme represents different substitution structures for the pyrimidine ring. In Scheme 29, an appropriately protected aldehyde is subjected to a base-catalyzed condensation with an activated ester to give, after deprotection, the desired aldehyde. Refluxing with ammonium chloride as reported by Dornow and Ische (Chem. Ber. 1956, 89, 876) affords pyridinol which is brominated with POBr 4 (Tjeenk et al. Rec. Trav. Chim 1948, 67, 380) to give the desired 2-bromopyridine. Suzuka coupling with a suitable boronic acid affords the desired substituted pyridine.

Scheme 29

OHC—> RlD

EtOiC

1) NH 2 Cl

2) POBr ₃

Br V _R io

EDB (OH) ₂ (Ph ₃ P) ₄ Pd

Na ₂ CO ₃

IN

D V

Treatment of an appropriately substituted 5-ethoxyoxazole with an alkene as described by Kondrateva et al. (Doc. Akad. Nauk USSR 1965, 164, 816) gives pyridine with the substituent V in the para position. Bromination at position 3 as reported by van der Does and Hertog (Rec. Trav. Khim. Pays-Bas 1965, 84, 951), followed by palladium catalyzed coupling with boronic acid affords the desired substituted pyridine.

Scheme 30

F. ¹

_R ib

Ν — λ Rlb E-D-B (OH) //

3y->, // <\

K-.SO ,.

Br <ph ₃ p) ₄ pd-y = g

Na-iCO

Scheme 31 describes the preparation of a third substitution structure on the pyridine ring. A suitable tricarbonyl compound, which can be prepared by the methods described in Scheme 29, is treated with ammonium chloride to give pyridinol, which is then brominated. Palladium catalyzed coupling provides the desired substituted pyridine.

Scheme 31

EDB (OH) ₂

O

V (Ph ₃ P) ₄ Pd Na ₂ CO ₃ E

N plb • ·

67 Scheme 32 starts from a suitably substituted dicarbonyl compound and reacts with ammonium chloride by the chemical procedure outlined in Schemes 29 and 31. Bromination affords 3-bromopyridine which provides palladium-catalyzed coupling to the desired substituted pyridine.

Scheme 32

-IV,

CHO

O or

1) NH ₄ Cl

E-D-B (OH) //

2) Br ₂ , H ₂ SO ₄

Br

- = <

(Ph ₃ P) ₄ Pd

NčlnCO}

IN

Scheme 33-35 describes the preparation of compounds wherein M is pyridazine. Each scheme represents a different substitution structure for the pyridazine ring. In Scheme 33, the activated ester is reacted with an appropriately substituted α-ketoaldehyde and hydrazine as described by Schmidt and Druey (Helv. Chim. Acta 1954, 37, 134 and 1467). Conversion of pyridazinone to bromide using POBr ₃ and palladium catalyzed coupling affords the desired substituted pyridazine.

Scheme 33

EcO-> Cp.lb ^{+ c =} K

CHO

1) ΝΗ-, ΝΚη

NaOBC * Ν * “MP. ^lb EDB (OH) ·

- NO 2) POBr ₃ (Ph ₃ P) ₄ Pd

Br V Na ₂ CO ₃

E-, jlb

In Scheme 34, glyoxal can react with an activated ketone under basic conditions, and subsequent bromination / dehydrobromination provides the desired ketoaldehyde. Alternatively, the protected ketone can react with activated aldehyde, followed by bromination / dehydrobromination, after removal

Regioisomeric ketoaldehyde yields 68 protecting groups and oxidation. Cyclization as reported by Spiro and Madonia (Ann. Chim. 1958, 48, 1316) with hydrazine followed by palladium-catalyzed coupling affords the desired substituted pyridazine.

Scheme 34 jlD

CHS

CHD

IN

2) Br ₂

1) NaOEt

In Br

NHgNH?

N-N &gt;

E-D V

Analogously to Scheme 34, in Scheme 35, an aldehyde can be reacted with an activated ketone and bromination, dehydrobromination and deprotection to provide the desired diketone. Alternatively, the regioisomeric ketone may be subjected to the same reaction sequence to form an isomeric ketoaldehyde. Reaction with hydrazine followed by palladium catalyzed coupling affords the desired substituted pyridazine.

• ·

·· · ···

Scheme 35

1) NaOEt

2) Br ₂

3) TsOH 1) NaOEt o

Br

ΝΗ, ΝΗ, or

Schemes 36 and 37 describe the preparation of compounds wherein m is pyrimidine. Each scheme represents different substitution structures for the pyrimidine ring. In Scheme 36, condensation with an appropriately substituted acid chloride and activated ester followed by conjugate reduction with tin hydride (Moriya et al., J. Org. Chem. 1986, 51 4708) yields the desired

1,4-dicarbonyl compound. Cyclization with formamidine or substituted amidine followed by bromination affords the desired regioisomeric pyrimidine. Palladium catalyzed coupling affords the desired substituted pyrimidine.

Scheme 36 cioc-p. ^ib

1) NaOEt Xtí-OoC v

2) nSu3SnH ^{EcO2 c} 'AIBN

O, _R 1b

1) formamidine

2) POBr / R 'c Rlb

CHO

EtO ₂ C? <

In _R ib

- ^! HN 2) POBr ₃

5 =?

v · o-- 70 ED-3 (OH) ₂

(Ph ₃ ?) <Pd NcijCO ·} £ ** »

Using similar chemistry, Scheme 37 illustrates how amidine can be condensed with a 1,3-dicarbonyl compound and subsequently brominated at the 5-position (J. Het. Chem. 1973, 10, 153) to give a specific regioisomeric bromopyrimidine.

Palladium catalyzed coupling affords the desired substituted pyrimidine.

Scheme 37 freckles

OHC O

M v

1) formamidine

2) Br,

EDB (OH) ₂ (Ph ₃ P) ₄ Pd

Na ₂ CO ₃

Using the same ketoaldehyde of Scheme 37, cyclization with an appropriately substituted 1,2-diamine (Chimia, 1967, 21, 510) followed by aromatization (Helv. Chim. Acta 1967, 50, 1754) provides a regioisomeric pyrazine mixture as shown in Scheme 38. Bromination of the hydrobromide salt (US Patent No. 2,403,710) yields an intermediate for the palladium catalyzed coupling step as described above.

• · · · · · · · · ·

Scheme 38

OHC O rf plb

V 2) CuO · Cr ₂ O _; . 3) H3r / Br1

- olb r_n-nfr) U '// <^ ‘·

N N

Br V (Ph ₃ ?) ₄ Pd

Na-> CO-,

K N> f

Schemes 39 and 40 describe the preparation of compounds wherein M is 1,2,3-triazine. In Scheme 39, vinyl bromide is subjected to palladium coupling to a molecule containing R ¹¹³ . Alicyclic bromination followed by azide displacement provides the cyclization precursor. Triphenylphosphine-mediated crystallization (J. Org. Chem. 1990, 55, 4724) affords 1-aminopyrazole which is subsequently brominated with

N-bromosuccinimide. The lead tetraacetate-mediated rearrangement described by Neunhoeffer et al. (Ann. 1985, 1732) provides the desired regioisomeric 1,2,3-triazine. Palladium catalyzed coupling provides substituted triazine.

Scheme 39

1) R ^1b CH ₂ Br

3) NaNi

1) NBS

N-N

N 'j »lb

EDB (OH) ₂

2) Pb (OAc) ₄ / == \ Br V (Ph ₃ P) ₄ Pd Na ₂ CO ₃ E-

Rlb

In Scheme 40, the alkene is brominated and the bromide displaced to give the azide regioisomer as in Scheme 39. The same reaction sequence as described above follows and cyclization affords 1-aminopyrazole. Bromination followed by lead tetraacetate-mediated rearrangement gives 1,2,3-triazine. Palladium catalyzed coupling provides additional desirable •

- 72 triazines.

Scheme 40

Ph ₃ P

H-> N ^ N \ V “N 'V' .v

1) NBS

IN

_R 1b ^NaN l 'R _R ib _R lb I) NBS N-N E-D-3 (OH)? . m - 2)? B (OAc) ₄ "\ = / (Ph _{3?) 4} pC - _R xb_ Br V Na ₂ CO ₃ ^e d

N-N c

Schemes 41 and 42 describe the preparation of compounds wherein M is

1,2,4-triazine. In Scheme 41, the nitrile is converted using hydrazine to amidrazone, which is condensed with the α-keto ester to give the triazinone as reported by Paudler and Lee (J. Org. Chem. 1971, 36, 3921). Bromination, as reported by Rykowski and van der Plas (J. Org. Chem. 1987, 52, 71), followed by palladium-catalyzed coupling affords the desired 1,2,4-triazine.

Scheme 41

R ^1b CN nh ₂ nh ₂ (Ph ₃ P) ₄ Pd

Na ₂ CO _{3 R} 1b \ sN

H ₂ N nh ₂

EDB (OH) ₂

0 EtO ₂ C - V Rlb POBr ₃ * Ν N Rlb w Ν N Br v

In Scheme 42, to achieve the opposite regioisomer, the reaction scheme outlined above is modified by substituting the protected α-ketoester. This allows the most nucleophilic nitrogen to attack the ester function to produce opposite regiochemistry. Removal of the protecting group and thermal cyclization yields • · • ·

73 triazinone which is brominated as described above. The palladium catalyzed coupling provides the further desired 1,2,4-triazine.

Scheme 42

EtO

p. ^lp ct:

c c - \ / = ^N , h ₂ n nh ₃

R ^{1b N} "<

N N

YK

Br V

EDB (OH) _{2 R} ib (Ph ₃ P) ₄ Pd Na ₂ CO ₃

2) Ac. HCl

3) Δ

4) POBr ₃

Scheme 43 describes the preparation of compounds wherein M is

1,2,3,4-tetrazine. The lithiation of vinyl bromide, tin transmetallation, palladium catalyzed carbonylation, and hydrazone formation provide a pulp for the subsequent Diels-Alder reaction as reported by Carboni and Lindsey (J. Am. Chem. Soc. 1959, 81, 4342). Treatment with dibenzyl azodicarboxylate followed by catalytic hydrogenation to debenzylate and decarboxylate yields the desired 1,2,3,4-tetrazine after bromination. The palladium catalyzed coupling provides the desired substitution.

Scheme 43

Br

1) nBuLi

2) (nSu) ₃ SnClPd (O), CO) EnNKKK ₂

BnN n

= <

IN

CO ₂ Sr. 1) N

BnO ₂ CN

2) K ₂ , Pd

3) NBS

N-N n'n

Br V

EDB (OH) ₂

NN n 'n (Ph ₃ P) ₄ Pd

Na ₂ CO ₃

IN

E

D

V • ·

·· ··

Preparation of Compounds of Formula I Containing a Bicyclic Core

Schemes 44 and 45 illustrate the preparation of intermediates with a benzopyrazole and indole nucleus useful for the preparation of compounds of Formula I. The starting pyrazole-N-oxide in Scheme 44 can be obtained as described in Chem. Ber. (1926) 35-359. The pyrazole N-oxide can be reduced by any method including triphenylphosphine in refluxing toluene followed by hydrolysis of the nitrile substituent bases to the carboxylic acid to give the benzopyral intermediate, which can be coupled in a conventional manner to yield the compound of formula I.

Scheme 44

The starting indole in Scheme 45 can be obtained by Fischer indole synthesis (Org. Syn. Col. Vol. III 725) from suitably substituted phenylhydrazone and acetophenone. Further processing using synthetic methods involves the introduction of the 3-formyl group by POCl 3 in DMF, the optional protection of the indole NH by the SEM group (TMSCH ₂ CH ₂ OCH ₂ Cl, NaH, DMF) and oxidation of the aldehyde to carboxylic acid ready to convert to compounds Formula I.

• ·

······················

- 75 Scheme 45

Preparation of Group A-B of Formula I

Compounds of the invention wherein B is either a carbocyclic or heterocyclic radical, as defined in Formula 1, are coupled to A as shown generally and specifically in the example of Scheme 46 and Scheme 46, respectively. 47. Both A and B may be substituted with 0-3 R ⁴ . W is defined as a suitably protected nitrogen, for example NO ₂ or NHBOC; protected sulfur such as S-t-Bu or SMOM; or methyl ester. Exchanging bromo-halogen metals in bromo-B with n-butyllithium, cooling with triisopropylborate and acid hydrolysis affords the desired boronic acid, BB (OH) ₂ . The WA-Br subunit may already be bound to ring M prior to the Suzuki coupling reaction. Removal of the protecting group yields the complete subunit.

Scheme 46

B— Br

1) n-BuLi

2) (iPrO) jB

3) HCl

B (OH) ₂

- W-A-B> 0 (0)

Scheme 47 describes a typical example of how the A subunit is prepared for attachment to ring M. 4-Bromaniline is protected

Boc derivative and coupled with 2- (tert-butylamino) sulfonylB-w

A I

Br ·· ·· · · · · · · · ··· ·

- 76 phenylboronic acid under Suzuki conditions. 2- (tert-butylamino) sulfonylphenylboronic acid was prepared according to the method described by Rivero (Bioorg. Med. Chem. Lett. 1994, 189). Removal of the protecting group with TFA provides the aminobifen-4-yl compound. The aminobiphenyl-4-yl is then coupled to the core structures as described below.

Scheme 47

NH-:

NaH (BOC) ₂ O p.

NHBOC

B (OH) ·

Pd (0)

SO, NH-t-Bu

If B is defined as X-Y, the following procedure applies. Groups A and B are either available from commercial sources known in the literature or are readily prepared by adapting standard procedures known to those skilled in organic synthesis. Desired reactive functional groups attached to analogs A and B are either also available from commercial sources known in the literature or are readily prepared by synthesis by adapting standard procedures known to those skilled in the art of synthesis. The table below shows the chemistry required for effective coupling of A to B.

Table A: Preparation of amide, ester, urea, sulfonamide and sulfamide bonds between A and B.

if A contains:

then the reactive substituent Y is:

The following product A-X-Y is obtained:

A-NHR ² as a substituent

C1C (O) -Y

A-NR ² -C (0) -Y · · · · · · · · · · · ·

..... · J. ..::. · · · ···

• · · ........

- 77 secondary NH C1C (O) -Y as part of a ring or chain

A-C (O) -Y

A-OH as a C1C (O) -Y substituent

A-O-C (O) -Y

A-NHR ² as C1C (O) -CR ² R ^2a -Υ A-NR ² -C (O) -CR ² R ^2a -Y substituent secondary NH C1C (0) -CR ² R ^2a -Y AC (0) -CR ² R ^2a -Y as part of a ring or chain

A-OH as C1C (O) -CR ² R ^2a -Y AOC (O) -CR ² R ^2a -Y substituent

^A-NHR2 as a C1C (O) NR ² -Y substituent

A-NR ² -C (O) -nr ² -y secondary NH ¹ C (O) -NR ² -Y AC (O) -NR ² -Y as part of a ring or chain

A-OH as C1C (O) NR ² -Y AOC (O) -NR ² -Y substituent

A-NHR ² as a C ¹ SO ₂ -Y substituent a-nr ² -so ₂ -y secondary NH 1 SO ₂ -Y as part of a ring or chain α-so ₂ -y A-NHR ² as a C ¹ SO ₂ -CR ² R ^2a -Y substituent A-NR ² -SO ₂ -CR ² R ^2a -Y secondary NH ₂ SO ₂ CR ² R ^2a -Y as part of a ring or chain A-SO ₂ -CR ² R ^2a -Y A-NHR ² as a C ₁ SO ² -NR ² -Y substituent a-nr ² -so ₂ -nr ² -y secondary NH 1 SO ₂ NR ² -Y as part of a ring or chain α-so ₂ -nr ² -y A-C (O) C1 HO-Y as as a substituent A-C (O) -O-Y

AC (O) -NR ² -Y

AC (O) C1 NHR ² -Y as a substituent

0 · · · 0 00 0

0 0

A-C (O) Cl secondary NH as part of a circle or strings A-C (O) -Y ACR ² R ^2a -C (O) Cl HO-Y like substituent A-CR ² R ^2a C (O) -O-Y ACR ² R ^2a -C (O) Cl NHR ² -Y as a substituent A-CR ² R ^2a C (O) -NR ² -Y ACR ² R ^2a -C (O) Cl secondary NH as part of a circle or strings A-CR ² R ^2a C (O) -Y aso ₂ ci NHR ² -Y as a substituent α-so ₂ -nr ² -y aso ₂ ci secondary NH as part of a circle or strings α-so ₂ -y ACR ² R ² SO ₂ Cl NHR ² -Y as a substituent A-CR ² R ^2a SO ₂ -NR ² -Y ACR ² R ² SO ₂ Cl secondary NH as part of a circle or strings A-CR ² R ² SO ₂ -Y

• ·

The chemistry of Table A may be performed in aprotic solvents such as chlorinated hydrocarbons, pyridine, benzene or toluene, at temperatures ranging from -20 ° C to the reflux temperature of the solvent, and with or without a trialkylamine base.

Table B: Preparation of ketone bonds between A and B.

if A contains: then reactive substituent Y is: the following product is obtained A-X-Y: A-C (O) Cl BrMg-Y A-C (O) -Y ACR ² R ² C (O) Cl BrMg-Y A-CR ² R ^2a C (O) -Y A-C (O) C1 BrMgCR ² R ^2a -Y AC (O) CR ² R ^2a -Y A-CR ² R ² C (O) Y BrMgCR ² R ^2a -Y A-CR ² R ^2a C (0) CR ² R ^2a -Y

The coupling chemistry of Table B can be accomplished by a number of methods. The Grignard reagent required for Y is prepared from the halogen analog Y in dry ether, dimethoxyethane or tetrahydrofuran at 0 ° C to the reflux temperature of the solvent. The Grignard reagent can be reacted directly under controlled conditions, i.e., low temperature (-20 ° C or lower) and with a large excess of acid chloride or with a catalytic or stoichiometric copper bromide-dimethylsulfide complex in dimethylsulfide as solvent or variants thereof. Other suitable methods include converting the Grignard reagent to a cadmium reagent and coupling according to the invention.

81 of the procedure described by Carson and Prout (Organ. Syn. Col. vol. 3 601, 1955) or by Fe (acac) ₃ mediated coupling according to Fiandanese et al. (Tetr. Lett. 1984, 4805) or by coupling mediated by divalent manganese catalysis (Cahiez and Laboue, Tetr. Lett. 1992, 33 (31), 4437).

Table C: Preparation of ether and thioether bonds between A and B

if A contains: then reactive substituent Y is: the following product is obtained A-X-Y: A-OH Br-Y A-O-Y ACR ² R ^2a -OH Br-Y ACR ² R ² OY A-OH BrCR ² R ^2a -Y A-OCR ² R ^2a -Y A-SH Br-Y A-S-Y A-CR ² R ^2a -SH Br-Y A-CR ² R ² SY A-SH Br-CR ² R ^2a -Y A-SCR ² R ^2a -Y

The ether and thioether bonds of Table C can be prepared by reacting the two components in a polar aprotic solvent such as acetone, dimethylformamide or dimethyl sulfoxide in the presence of a base such as potassium carbonate, sodium hydride or potassium tert-butoxide at a temperature ranging from ambient to reflux. flow • ·

• · • • · · · • • • • • · • · • • · • · • • · · · • • • • • • ) _ · ·

of the solvent used.

Table D: Preparation C. -SO- and -SO ₂ - bonds from thioethers of the table if the starting material is: and is oxidized by Alumina (wet) / Oxone to form: and is oxidized with m-chloroperbenzoic acid to form: A-S-Y A-S (O) -Y α-so ₂ -y A-CR ² R ² SY A-CR ² R ² S (O) -Y A-CR ² R ² SO ₂ -Υ A-SCR ² R ^2a -Y AS (0) CR ² R ^2a -Y A-SO ₂ CR ² R ^2a -Y

The thioethers of Table C serve as a conventional starting material for the preparation of the sulfoxide and sulfone analogs of Table D. The combination of wet alumina and oxone provides reliable reactants for the oxidation of thioether to sulfoxide, as reported by Greenhalgh (Syn. Lett., 235, 1992). The sulfone can be prepared according to the method described by Satoh (Chem. Lett.,

381, 1992) using m-chloroperbenzoic acid.

The invention is illustrated by the following examples, which are illustrative only and in no way limit the scope of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The abbreviations used in the examples are defined as follows: ° C for degrees Celsius, d for doublet, dd for doublet of doublets, equiv for equivalent or equivalents, ESMS for electron mass spectroscopy, H for hydrogen or hydrogen, hours for hour or hours, g for gram or grams, m for multiplet, M for molar, mg for milligram or milligrams, MHz for megahertz, min for minute or minutes, ml for milliliter or milliliters, nmr or NMR for nuclear magnetic spectroscopy noodles, t for triplet, TLC for thin layer chromatography, BOP for benzotriazol-1-yloxy-tris (duimethylamino) phosphonium hexafluorophosphate, DMAP for dimethylaminopyridine, DME for dimethoxyethane, EDAC for 1- (3-dimethylaminopropyl) -3- ethyl carbodiimide, LAH for lithium aluminum hydride, NBS for N-bromosuccinimide, PyBrop for bromo-tris-pyrrolidinophosphonium hexafluorophosphate, TBAF for tetrabutylammonium fluoride, TBS-C1 for t-butyldimethylsilyl chloride and TEA for triethylamine.

Example 1

3-Methyl-1-phenyl-1H-pyrazole-5- (N-2'-aminosulfonyl- [1,1 '] -biphen-4-yl)) carboxyamide

Ethyl 2-N- (methoxy) imino-4-oxopentanoate: A mixture of ethyl pentanoate-2,4-dione (24.5 g, 154.9 mmol) and methoxyamine hydrogen chloride (13.58 g, 162.6 mmol) in ethanol (100 mL) was allowed to stand over activated 3 A molecular sieves (75 g) at ambient temperature for 18 hours. Following removal of the molecular sieves by filtration, dichloromethane is added and the reaction mixture is filtered. The solution was evaporated and the residue was subjected to a silica gel column. The title compound was isolated in homogeneous form eluting with 5: 1 hexane: ethyl acetate to give 9.09 g of product.

Ethyl 3-methyl-1-phenyl-1H-pyrazolecarboxylate: Ethyl 2-N- (methoxy) imino-4-oxopentanoate (0.5 g, 2.67 mmol) and phenylhydrazine (0.58 g, 5.35 mmol) in Acetic acid (10 mL) and 2-methoxyethanol (5 mL) were heated at 105 ° C for 5 ° C. · · · · · · · · · · · · · · · · · ·

- 84 hours. The reaction mixture was evaporated, dissolved in ethyl acetate and washed with 0.2 N HCl and then with water. The solution was dried (Na ₂ SO ₄ ), evaporated and the residue was worked up on a silica gel column. Elution with a 10: 1 to 5: 1 gradient of hexane: ethyl acetate gave 160 mg of ethyl 3-methyl-1-phenyl-ΙΗ-pyrazolecarboxylate; LRMS (M + H) &lt; + & gt ^; m / z: 231.

3-Methyl-1-phenyl-1H-pyrazole-5- (N- (2'-N-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl)) carboxyamide: To 0 ° C 4- ( 2- (N-tert-butylaminosulfonyl) phenyl) aniline (0.22 g, 0.73 mmol) in dichloromethane (10 mL) was added a solution of trimethylaluminum (2.0 M in hexane, 5 eq, 1.75 mL). ). The mixture was stirred for 15 minutes and then ethyl 3-methyl-1-phenyl-1H-pyrazolecarboxylate (0.16 g, 0.69 mmol) in dichloromethane (5 mL) was added. The reaction mixture was allowed to warm to ambient temperature and stirred for 18 hours. The mixture was carefully cooled with water and then diluted with ethyl acetate and the layers were separated, dried and evaporated. The residue was worked up on a silica gel column and the title compound was isolated by gradient elution with 3: 1 to 1: 1 hexane: ethyl acetate. There was thus obtained 150 mg of 3-methyl-1-phenyl-1H-pyrazole-5- (N- (4- (2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl)) carboxyamide; HRMS ( M + H) ⁺ calcd m / z 489.196038, found 489.194346.

3-Methyl-1-phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl)) carboxyamide: 150 mg solution of 3-methyl-1-phenyl- 1 H -pyrazole-5- (N- (4- (2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide) in trifluoroacetic acid (15 mL) was heated at reflux for 1 hour. The mixture was evaporated, taken up in ethyl acetate and washed with 1 N sodium hydroxide solution.The organic solution was dried and evaporated to give 140 mg of the product Further purification of 3-methyl-1-phenyl-1H-pyrazole-5- (N- (4 - (2'-Aminosulfonyl- [1,1 '] - biphen-4-yl)) carboxyamide was performed by HPLC using a gradient elution of water: acetonitrile with 0.05% acetic acid on a C18 reverse phase column (60 A) HRMS (M + H) ⁺ calcd m / z: 433.133438, found: 433.131005.

Example 2

3-Methyl-1- (2-methoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide)

This compound was prepared by the same methodology as described in Example 1, substituting phenylhydrazine

2-methoxyphenylhydrazine.HCl. There was thus obtained 3-methyl-1- (2-methoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; HRMS (M + H)); ⁺ calculated m / z: 463.144002, found: 463.144162.

Example 3

3-Methyl-1- (3-methoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide)

This compound was prepared using the same methodology as described in Example 1, substituting phenylhydrazine with 3-methoxyphenylhydrazine.HCl. There was thus obtained 3-methyl-1- (3methoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; HRMS (M + H)); ⁺ calculated m / z: 463.144002, found: 463.144301.

Example 4

3-Methyl-1- (4-methoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide)

This compound was prepared by the same methodology as described in Example 1, substituting phenylhydrazine

4-methoxyphenylhydrazine.HCl. There was thus obtained 3-methyl-1- (4-methoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; HRMS (M + H)); ⁺ calculated m / z: 463.144002, found: 463.141980.

- 8V

Example 5

3-Methyl-1- (2-hydroxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] -biphen-4-yl) carboxyamide)

The product of Example 2,3-methyl-1- (2-methoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] -biphen-4-yl) carboxyamide) (0.245 g, 0.53 mmol) of v-dichloromethane (20 mL) was cooled to 0 ° C and a solution of boron tribromide in dichloromethane (1.0 M, 6 equivalents, 3.2 mL) was added. The reaction mixture was evaporated and the residue was applied to a small plug of silica gel and eluted with ethyl acetate.The ethyl acetate solution was dried and evaporated This material was purified by HPLC using an elution gradient of water: acetonitrile with 0.05% trifluoroacetic acid to C18 reverse phase column (60 A) to give the title compound HRMS (M + H) ⁺ calculated m / z: 449.128352, found: 449.129006.

Example 6

3-Methyl-1- (3-hydroxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide)

The product of Example 3, 3-methyl-1- (3-methoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] -biphen-4-yl) carboxyamide) was treated in the same manner as described in Example 5 to give the title compound: HRMS (M + H) ⁺ calcd m / z: 449.128352, found: 449.127620.

Example 7

3-Methyl-1- (4-hydroxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide

The product of Example 4, 3-methyl-1- (4-methoxy) phenyl-1H.

- 87 pyrazole-5- (Ν- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide was treated in the same manner as described in Example 5 to give the title compound; HRMS (M + H) ⁺ calcd m / z: 449, 128352, found: 449.127304.

Example 8

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (3-fluoro- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide)

3-Methyl-1- (4-methoxyphenyl) -ΙΗ-pyrazolecarboxylic acid: A mixture of ethyl 3-methyl-1- (4-methoxyphenyl) -1H-pyrazolecarboxylate (0.01997 mol, 5.197 g) and potassium hydroxide (3.362 g, 3.0 eq) in ethanol (70 mL) was stirred at ambient temperature for 5 hours. The solvent was removed in vacuo and the residue was taken up in water. Then the mixture was extracted with methylene chloride (3x) to remove unreacted starting material. The aqueous layer was acidified to pH 3 by dropwise addition at 0 ° C conc. HCl and an acid precipitate is obtained. The solid was collected by filtration and sucked dry for several hours. 4.23 g of pure product (91%) are obtained; mp 161.8 ° C.

2-Fluoro-4- (2-aminosulfonylphenyl) aniline: Mixture

2-fluoro-4-bromoaniline (0.01 mol, 2.51 g), boronic acid (2.57 g, 1.0 eq), sodium carbonate (3.18 g, 3.0 eq) and tetrakis (triphenylphosphine) palladium (0) (0.23 g, 0.02 eq) in tetrahydrofuran (100 mL) and water (50 mL) was stirred at ambient temperature for 30 minutes while nitrogen was bubbled through the mixture to remove oxygen. The reaction mixture was then heated at reflux for 18 hours. The reaction mixture was filtered through celite to remove the catalyst and washed with tetrahydrofuran (50 mL). The filtrate was evaporated in vacuo and the residue taken up in water and extracted with ethyl acetate (3x); ethyl acetate extracts were washed with brine, dried (MgSO ₄₎ and evaporated. The residue was purified by silica gel flash chromatography (150 g)

88 eluting with 2.5: 1 hexane: ethyl acetate to give 1.976 g of pure product (61%).

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (3-fluoro-4- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl)) carboxyamide: K solution

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazolecarboxylic acid (0.001 mol, 0.232 g) in dry acetonitrile (10 mL) was added thionyl chloride (0.3 mL, 4.0 eq). The reaction mixture was heated at 50 ° C for 1 hour and then allowed to cool to ambient temperature and stirred for 1 hour. The solvent and excess thionyl chloride were removed in vacuo and the residue was pumped to dryness for several hours.

To this dry residue was added a mixture of 2-fluoro-4 - ((2-N-tert-butylsulfonylamido) phenylaniline (0.322 g, 1.0 eq) and triethylamine (0.14 mL, 1.0 eq; 0 eq for the HCl salt) in dry methylene chloride (10 mL) The reaction mixture was stirred at room temperature for 2 hours The reaction mixture was evaporated and purified by silica gel flash chromatography (50 g) eluting with 3: 1 hexane: ethyl acetate and 0.301 g of pure product with tert-butylsulfonamide (56%) is obtained.

This product was treated with trifluoroacetic acid at 55 ° C for 2 hours to remove the sulfonamide protecting group and purified by reverse phase HPLC to afford 0.287 g of pure product (86%); HRMS (M + H) ⁺ for the title compound calculated 481.134581, found 481.133650.

Example 9

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (3-bromo-4- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide)

2-Bromo-4- (2-aminosulfonylphenyl) aniline: This compound was prepared as described for 2-fluoro-4- (2-aminosulfonylphenyl) aniline as described in Example 8, starting from.

2,4-dibromaniline to replace 2-fluoro-4-bromoaniline.

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (3-bromo-4- (2'-aminosulfonyl- [1,1 '] - biphenyl-4-yl)) carboxyamide: This is: the compound was prepared in the same manner as described in Example 8 by coupling with 2-bromo-4 - ((2-N-t-butylsulfonamido) phenyl) aniline to replace 2-fluoro-4 - ((2-N-t-butylsulfonamido) The title compound is obtained as a pure product after purification by reverse phase HPLC: HRMS (M + H) ⁺ calcd 541.054513, found 541.055540.

Example 10

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (3-iodo- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide)

2-Iodo-4- (2-aminosulfonylphenyl) aniline: This compound was prepared as described for 2-fluoro-4- (2-aminosulfonylphenyl) aniline as described in Example 8, starting from

2-iodoaniline to replace 2-fluoro-4-bromoaniline.

3- methyl-l- (4-methoxyphenyl) -lH-pyrazole-5- (N- (3-iodo- (2'-aminosulfonyl- [1.1 ^1] -biphenyl-4-yl) carboxyamide: This compound is prepared in the same manner as described in Example 8 by coupling with 2-iodo-4 - ((2-N-tert-butylsulfonamido) phenyl) aniline to replace 2-fluoro-4 - ((2-N-tert-butylsulfonamido) phenyl) The title compound is obtained as a pure product after purification by reverse phase HPLC: HRMS (M + H) ⁺ calcd 589.040654, found 589.039223.

Example 11

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (3-methyl- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide)

2-Methyl-4- (2-aminosulphonylphenyl) aniline: This compound is a 2-methyl-4- (2-aminosulfonylphenyl) aniline. · · · ··· ··· · · · · · · · · · ··· · · ···

90 prepared according to the method described for 2-fluoro-4- (2-aminosulfonylphenyl) aniline as described in Example 8, starting from

2-methyl-4-bromoaniline to replace 2-fluoro-4-bromoaniline.

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (3-methyl- (2'-aminosulfonyl- [1,1 '] - biphenyl-4-yl)) carboxyamide: prepared in the same manner as described in Example 8 by coupling with 2-methyl-4 - ((2-N-tert-butylsulfonamido) phenyl) aniline to replace 2-fluoro-4 - ((2-N-tert-butylsulfonamido) phenyl) The title compound is obtained as a pure product after purification by reverse phase HPLC: HRMS (M + H) ⁺ calcd 477.159652, found 477.159337.

Example 12

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-N-carboxyldimethylamino) phenyl) carboxyamide

4- (N-Carboxyldimethylamine) aniline: A two-fold excess of pure dimethylamine (ca. 0.73 g) was added to a 0 ° C solution of p-nitrobenzoyl chloride (1.5 g, 8.1 mmol) in dichloromethane (50 mL). The reaction mixture was evaporated to dryness and the residue was dissolved in ethyl acetate. This solution was washed with 1 N hydrochloric acid solution and brine, then evaporated to give

4- (carboxyldimethylamine) nitrobenzene.

This material was reduced under an atmosphere of hydrogen gas (3.515 kg / cm ² ) in methanol (100 mL) in the presence of 10% palladium on carbon catalyst (100 mg). After two hours the reduction is complete; the reaction was purged with nitrogen gas and the catalyst was removed through a pad of celite. The solvent was evaporated to give the title compound.

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-N-carboxyldimethylamino) phenyl) carboxyamide: This compound was prepared in the same manner as described in Example 8 by coupling with · Jl

4- (N-carboxyldimethylamine) aniline to replace it

2-fluoro-4 - ((2-N-tert-butylsulfonamido) phenyl) aniline and then omitting the deprotection step with trifluoroacetic acid. The title compound is obtained as a pure product after purification by reverse phase HPLC; HRMS (M + H) ⁺ calcd 379.177016, found 379.176235.

Example 13

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-N-pyrrolidinocarbonyl) phenyl) carboxyamide

4- (N-Pyrrolidinocarbonyl) aniline: A two-fold excess of pure pyrrolidine (1.15 g, 16.2 mmol) was added to a 0 ° C solution of p-nitrobenzoyl chloride (1.5 g, 8.1 mmol) in dichloromethane (50 mL). ). The reaction mixture was evaporated to dryness and the residue was dissolved in ethyl acetate. This solution was washed with 1 N hydrochloric acid solution and brine, then evaporated to give

4- (N-pyrrolidinocarbonyl) nitrobenzene.

This material was reduced under an atmosphere of hydrogen gas (3.515 kg / cm ² ) in methanol (100 mL) in the presence of 10% palladium on carbon catalyst (100 mg). After two hours the reduction is complete; the reaction was purged with nitrogen gas and the catalyst was removed through a pad of celite. The solvent was evaporated to give the title compound.

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-N-pyrrolidinocarbonyl) phenyl) carboxyamide: This compound was prepared in the same manner as described in Example 8 by coupling with

4- (N-pyrrolidinocarbonyl) aniline to replace it

2-fluoro-4 - ((2-N-tert-butylsulfonamido) phenyl) aniline and then omitting the deprotection step with trifluoroacetic acid. The title compound is obtained as a pure product after purification by reverse phase HPLC; HRMS (M + H) ⁺ calculated 404.184841, found 404.182119.

- 92 Example 14

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-α-methyl-N-pyrrolidino) phenyl) carboxyamide

4- (α-N-pyrrolidino) methylaniline: To pyrrolidine (0.67 g, 0.79 mL, 9.4 mmol) in chloroform (50 mL) was added

4-nitrobenzyl bromide (2.03 g, 9.4 mmol) and sodium carbonate (2 g). The reaction mixture was heated at reflux for 2 hours and then stirred at ambient temperature for 18 hours. Water was added to the reaction mixture and the layers were separated. The chloroform layer was evaporated to give 1.55 g of the N-alkylation product; LRMS (M + H) &lt; + & gt ^; m / z:

207.2.

Reduction of the nitro group of the material prepared above was accomplished by stirring this material with stannous chloride dihydrate (8.5 g, 37.6 mmol) in ethanol (50 mL) at ambient temperature for 18 hours. The reaction mixture was diluted with 1 N sodium hydroxide solution and extracted with ethyl acetate (3x). The extracts were washed with brine, dried and evaporated to give 1.23 g

4- (α-pyrrolidino) methylanilone; LRMS (M + H) &lt; + & gt ^; m / z: 177.2.

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-a-methyl-N-pyrrolidino) phenyl) carboxyamide: A mixture of 3-methyl-1- (4-methoxyphenyl) -1H -pyrazolecarboxylic acids (100 mg, 0.43 mmol),

4- (α-N-pyrrolidino) methylaniline (76 mg, 0.43 mmol) in dimethylformamide (3 mL) was cooled to 0 ° C. Add N-methylmorpholine. The reaction mixture was thawed at ambient temperature and stirred for 18 hours. The reaction mixture was diluted with 1 N sodium hydroxide and then extracted with ethyl acetate.

The extracts were washed with brine, dried and evaporated. This material was purified by HPLC using a gradient elution of water: acetonitrile with 0.05% trifluoroacetic acid in reverse phase on a C18 (60 A) column to give the title compound (70 mg); LRMS (M + H) &lt; + & gt ^; m / z: 391.2.

• ·

93 Example 15

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole) -5- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide

3-Trifluoromethyl-5-methyl-1- (4-methoxyphenyl) -1H-pyrazole: A mixture of 1,1,1-trifluoro-2,4-pentanedione (0.02 mol, 2.4 ml) and

4-methoxyphenyl hydrazine.HCl (4.54 g, 1.3 eq.) Was heated at reflux for 6 hours. The reaction mixture was evaporated and purified by silica gel flash chromatography (400 g) eluting with 4: 1 hexane-ethyl acetate to give 4.5 g of pure product.

3-Trifluoromethyl-5-hydroxymethyl-1- (4-methoxyphenyl) -1H-pyrazole: A mixture of 3-trifluoromethyl-5-methyl-1- (4-methoxyphenyl) -1H-pyrazole (0.01756 mol, 4.5 g), N-bromosuccinimide (3.439 g, 1.1 eq.) and AIBN (0.1 g) in carbon tetrachloride (100 mL) were refluxed for 18 hours. The reaction mixture was filtered through celite to remove solid impurities and washed with carbon tetrachloride (100 mL). The filtrate was evaporated and purified by silica gel flash chromatography (400 g) eluting with hexane / ethyl acetate 4: 1 to give 3.826 g of pure product (65%).

This material was treated with calcium carbonate (2.637 g,

1.5 eq) in dioxane (80 mL) and water (20 mL) at 55-60 ° C for 18 hours. The reaction mixture was evaporated and purified by silica gel flash chromatography (400 g) eluting with hexane / ethyl acetate 4: 1 to give 1.198 g of pure product (39%). Recrystallization from benzene / hexane gave an analytically pure sample; mp 79.0 ° C; CHNF: Theory% C 52.95,% H 4.07,% N 10.29,% F 20.94; Found% C 52.88,% H 3.98,% N 10.11,% F 20.62.

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5-carboxylic acid: To a solution of 3-trifluoromethyl-5-hydroxymethyl-1- (4-trifluoromethyl-5-hydroxymethyl-1-). * CA «· CA CA * CA CA

94-methoxyphenyl) -1H-pyrazole (4.400 mmol, 1.198 g) in acetonitrile (20 mL) and water (20 mL) was added at 0 ° C sodium periodate (1.977, 2.1 eq) and several crystals ruthenium chloride. The reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was filtered through celite to remove white solid impurities and the filter cake was washed with a 1: 1 mixture of acetonitrile and water. The filtrate was evaporated in vacuo and the residue taken up in water. The aqueous layer was acidified (pH 3) by the addition of conc. HCl at 0 ° C and then extracted with ethyl acetate (3x); The ethyl acetate extracts were washed with brine, dried (MgS0 ₄₎ and evaporation gave 1.13 g of pure product (90%).

3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole) -5- (N- ^(2-N-1 terč.butylaminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide: To 300 mg 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5-carboxylic acid (1.05 mmol) in dichloromethane (10 mL) at 0 ° C was added a solution of oxalyl chloride in dichloromethane (2 M,

1.5 equivalents, 1.58 mmol, 0.8 mL) and a drop of dimethylformamide. After 4 hours the reaction is complete, the solvent is evaporated and the acid chloride is transferred to the next reaction.

The material prepared above was dissolved in dichloromethane (20 mL) and then added to the 0 ° C solution over 15-20 minutes.

4- (2-N-tert-butylaminosulfonyl) phenyl) aniline (1.2 equivalents, 1.25 mmol, 0.365 g), pyridine (10 equivalents,

12.5 mmol, 0.99 g, 1.0 mL) and N, N-dimethylaminopyridine (1.2 equivalents, 1.25 mmol, 0.155 g) in dichloromethane (20 mL). The reaction mixture was maintained at 0 ° C until thin layer chromatography indicated that all of the starting acid chloride was consumed. The reaction mixture was evaporated and the residue was suspended in a 1N hydrochloric acid solution. The suspension is extracted with ethyl acetate; the extracts were washed with 1N hydrochloric acid solution (2x), then dried and evaporated. There was thus obtained 660 mg of the desired product; LRMS (M + Na) &lt; + & gt ^; m / z: 594.5.

V 44 44 • 4 · * 4 • 4 4 4 · 4 4 4 4 • V 4 4 · · 4 44

95-3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole) -5- (N- (2'aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide): 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole) -5- (N- (2'-N-terc.butylaminosulfonyl- [1.1 ^1] biphen-4-yl) carboxyamide (0.66 g) was dissolved in acetic trifluoroacetic acid (20 ml) and heated at reflux for 30 minutes The reaction mixture was evaporated and then dissolved in ethyl acetate and washed with 1 N sodium hydroxide solution (2x) and brine. 48 g of crude product This material was purified to analytical purity by first flash chromatography on silica gel, eluting with hexane / ethyl acetate 2: 1, followed by recrystallization of the homogeneous product from chloroform, to give 0.262 g of the title compound; CHNSF:% C 55.81,% H 3.718,% N 10.85,% S 6.218,%

F, 11.03; Found% C 56.02,% H 3.77,% N 10.51,% S 5.84,% F 11.29.

Example 16

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole) -5- (Ν- (4-N-pyrrolidinocarbonyl) phenyl) carboxyamide

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole) -5- (Ν- (4-N-pyrrolidinocarbonyl) phenyl) carboxyamide: 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5 The carboxylic acid (500 mg) was dissolved in anhydrous CH ₂ Cl ₂ (25 mL) with thionyl chloride (0.257 mL). The mixture was stirred at ambient temperature for 24 hours. The volatiles were removed under reduced pressure and the solution was dried in vacuo. 4- (N-pyrrolidinocarbonyl) aniline (0.369 g) was dissolved in anhydrous CH ₂ Cl ₂ (30 mL) and cooled to 0 ° C.

Anhydrous pyridine (1.43 mL) and DMAP (0.259 g) were added and the mixture was stirred for 15 minutes. The prepared acid chloride was dissolved in anhydrous CH ₂ C1 ₂ (5 mL) and added dropwise to the reaction mixture. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was concentrated in vacuo. Purification was performed on silica gel using ethyl acetate / hexanes (1: 1) as eluent to give 325 mg (95% purity, HPLC). LRMS (M + H) ⁺ = 459 ^< 23 ^H 21 ^N 4 ° 3 ^F 3 ^{1 HRMS} P ^{ro C} 23 ^H 21 ^N 4 ° 3 ^F 3 (M + H) ⁺ calculated

458.156576, found 458.156478. ¹ H NMR (CDCl ₃ ) δ 1.85-1.99 (m, 4H), 3.41 (t, 2H, J = 6.23 Hz), 3.63 (t, 2H, J = 6.59) Hz), 3.85 (s, 3H), 6.99 (d, 2H, J = 6.95 Hz), 7.31 (s, 1H), 7.31 (s, 4H), 7.42 (s) d, 2H, J = 6.59 Hz), 8.42 (s, 1H).

Example 17

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole) -5- (N- (5- (2-methanesulfonyl) phenyl) pyridin-2-yl) carboxyamide

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole) -5- (N- (5- (2-methanesulfonyl) phenyl) pyridin-2-yl) carboxyamide: This material was prepared according to the procedures described in Example 15 except that during the coupling step 4- (2-N-t-butylaminosulfonyl) phenyl) aniline is replaced by 2-amino-5- (2-N-t-butylaminosulfonyl) phenyl) pyridine. Purification by HPLC using a gradient elution of water / acetonitrile with 0.05% trifluoroacetic acid using reverse phase C18 (60 A) gave a pure sample of the title compound; LRMS (M + H) &lt; + & gt ^; m / z: 517, (M + Na) &lt; + & gt ^; m / z: 539.

Example 18

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole) -5- (Ν- (5-N-pyrrolidinocarbonyl) pyridin-2-yl) carboxyamide

2-Amino-5- (N-pyrrolidinocarbonyl) pyridine: A mixture of aminonicotinic acid (2.26 g, 16.4 mmol) and pyrrolidine (1.16 g, 16.4 mmol) in dimethylformamide (20 mL) is cooled to 0 Deň: 32 ° C. To this mixture was added N-methylmorpholine (3.31 g, 32.7 mmol) and HBTU (6.2 g, 16.4 mmol). The reaction mixture was allowed to cool to ambient temperature and stirred for 18 hours. The reaction mixture was diluted with 1 N sodium hydroxide and extracted with ethyl acetate. The product is purified by flash chromatography using 10%.

97 methanol in chloroform as eluent; 1.65 g of product is isolated; LRMS (M + H) &lt; + & gt ^; m / z: 192.

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole) -5- (N- (5-N-pyrrolidinocarbonyl) pyridin-2-yl) carboxyamide: This material was prepared according to the procedures described in Example 15 except that during the in the coupling step, replace 4- (2-N-t-butylaminosulfonyl) phenyl) aniline with 2-amino-5- (N-pyrrolidinocarbonyl) pyridine. Purification by HPLC using a gradient elution of water / acetonitrile with 0.05% trifluoroacetic acid using reverse phase C18 (60 A) gave a pure sample of the title compound; LRMS (M + H) ⁺ m / z: 517; (M + Na) ⁺ m / z: 460.2.

Example 19

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole) -5- (N- (5-N-pyrrolidinocarbonyl) pyridin-2-yl) carboxyamide:

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole) -5- (N- (5-N-pyrrolidinocarbonyl) pyridin-2-yl) carboxyamide: To a solution of 3-methyl-1- (4-methoxyphenyl) -ΙΗ -pyrazolecarboxylic acid (1.02 g, 4.4 mmol) in dichloromethane (20 mL) at 0 ° C 4.4 mL of a 2 M solution of oxalyl chloride in dichloromethane was then added drop of dimethylformamide. After 2 hours the solvent was removed to give 1.12 g of the acid chloride. This material was carried on to the next step without purification.

To 2-amino-5- (N-pyrrolidinocarbonyl) pyridine (0.4 g, 2.1 mmol) with triethylamine (0.3 g, 3.0 mmol) in dichloromethane (40 mL) was added dichloromethane solution (10 mL). of the acid chloride prepared above (0.5 g, 2.0 mmol). The reaction mixture was allowed to melt at ambient temperature and evaporated. The product was isolated by flash chromatography with 10% chloroform in methanol. HPLC purification using a gradient elution of water and water mixtures.

98% acetonitrile with 0.05% trifluoroacetic acid using a C18 reverse phase column (60 A) gave a pure sample of the title compound; HRMS (M + H) ⁺ calculated m / z: 405.180090, found: 405.180328.

Example 20

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (5- (2sulfonamido) phenyl) pyridin-2-yl) carboxyamide:

This compound was prepared by the methodology described in Example 19 except that 2-amino-5- (2- (N-tert-butylsulfonylamido) phenyl) pyridine was used in the coupling step instead of 2-amino-5- (N-pyrrolidinocarbonyl) pyridine. . The resulting product was stirred in trifluoroacetic acid (20 mL) for 18 hours and the solvent was removed by distillation under reduced pressure.

Purification of the crude by HPLC using a gradient elution of water / acetonitrile with 0.05% trifluoroacetic acid using a C18 reverse phase column (60 A) gave a pure sample of the title compound; HRMS (M + H) ⁺ calculated m / z: 464.139251, found: 464.138485.

Example 21

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5-N- (4- (N-carboxyl-3-hydroxypyrrolidino) phenyl) carboxyamide

4- (N-Carboxyl-3-tert-butyldimethylsilyloxypyrrolidino) aniline:

To 3-hydroxypyrrolidine hydrogen chloride (1.63 g, 14.9 mmol) and triethylamine (1.51 g, 14.9 mmol) in dichloromethane (50 mL) at 0 ° C was added a solution of p-nitrobenzoyl chloride (2.5 g, 12.4 mmol) in dichloromethane (50 mL). The reaction mixture was evaporated to dryness and the residue was dissolved in ethyl acetate. This solution was washed with 1 N hydrochloric acid and brine, then dried and evaporated to give 2.22 g of product; LRMS (M + H) &lt; + & gt ^; m / z:

237.

• • •

- 99 Tetrahydrofuran solution (75 mL) of the material prepared above (2.2 g, 9.4 mmol), tert-butyldimethylsilyl chloride (1.54 g, 10.2 mmol) and imidazole (0.89 g, 13.0 mmol) is cooled to 0 ° C and stirred for 72 hours. The reaction mixture was filtered and evaporated. The residue was dissolved in ethyl acetate and washed with water and brine, dried and evaporated. Flash chromatography using hexane / ethyl acetate 2: 1 gave 2.07 g of pure product; LRMS (M + H) &lt; + & gt ^; m / z: 351.

The material prepared above (2.07 g) was reduced under an atmosphere of hydrogen gas (3.515 kg / cm ² ) in methanol (100 mL) in the presence of 10% palladium on carbon catalyst (200 mg). After two hours the reduction is complete; the reaction mixture was purged with nitrogen and the catalyst was removed by filtration through a pad of celite. The solvent was evaporated to give 1.75 g of 4- (N-carboxyl-3-tert-butyldimethylsilyloxypyrrolidino) aniline; LRMS (M + H) &lt; + & gt ^; m / z: 321.

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5-N- (4- (N-carboxyl-3-hydroxypyrrolidino) phenyl) carboxyamide

This compound was prepared by the methodology described in Example 19 except that 4- (N-carboxyl-3-tert-butyldimethylsilyloxopyrrolidine) aniline was used in the coupling step instead of 2-amino-5- (N-pyrrolidinocarbonyl) pyridine. The tert-butyldimethylsilyl protecting group is removed by treatment with two equivalents of tetrabutylammonium fluoride in tetrahydrofuran. The solvent was evaporated, the residue was dissolved in ethyl acetate and washed with water.

After drying and solvent removal, the crude product was purified by HPLC using a gradient elution of water / acetonitrile with 0.05% trifluoroacetic acid using a C18 reverse phase column (60 Å) to give a pure sample of the title compound; HRMS (M + H) ⁺ calculated m / z: 420.179756, found: 420.175589.

• ·

- ιού

Example 22

2-Amino-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole

1- (4-Methoxyphenyl) -1 '- (4-bromophenyl) aminocarbonyl acetone · 4-Methoxyacetophenone (3.00 g, 19.97 mmol) was dissolved in 60 mL of THF followed by addition of LDA (2.0 M in THF (10.0 mL, 20 mmol) and stirring at room temperature for 1 hour. 4-Bromophenyl isocyanate (3.95 g, 19.97 mmol) was added and the reaction was stirred at room temperature overnight. The solution was acidified with 10% HCl and diluted with 300 mL EtOAc. The solution was washed with brine (300 mL), dried over MgSO ₄ , filtered through a pad of silica gel and the volatiles removed in vacuo. The product was recrystallized from hot diethyl ether (3.08 g, 44%).

2-Amino-4- (4-methoxyphenyl) -5- (4-bromophenyl) thiazole: 1- (4-Methoxyphenyl) -1 '- (4-bromophenyl) aminocarbonyl acetone (3.08 g, 8.84 mmol) and hydroxy (tosyloxy) iodobenzene (3.46 g, 8.84 mmol) was combined with 100 mL acetonitrile and refluxed for 45 min, followed by the addition of thiourea (0.673 g, 8.84 mmol) and refluxing 4. clock. The volatiles were removed in vacuo and the residue was triturated from hot MeOH (1.68 g, 47%) MS (NH ₃ -DCI) 404.0 (M + H) ⁺ .

2-Amino-4- (4-methoxyphenyl) -5 - [(2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole: 2-amino-4- (4-methoxyphenyl) -5- (4-bromophenyl) thiazole (1.68 g, 4.15 mmol), sodium carbonate (0.88 g, 8.31 mmol), tetrabutylammonium bromide (0.134 g, 0.415 mmol) and 2- (tert. butylaminosulfonyl) phenyl boronic acid (1.50 g, 5.82 mmol) was combined in a solution containing a 1: 1: 4 mixture of benzene, acetonitrile and water and degassed with N ₂ for 15 minutes. After flushing with N ₂ , tetracytriphenylphosphine palladium (0) was added and the reaction mixture was heated to reflux overnight. The solution was diluted with EtOAc, placed

ΙΟΙ into a separatory funnel and wash three times with 150 ml of brine each time. The organic phase was dried over MgSO ₄ , filtered through a pad of silica gel and the volatiles removed in vacuo. The residue was dissolved in a minimum amount of hot CHCl ₃ , the product was triturated with Et ₂ O and isolated (1.59 g, 71.3%) by vacuum filtration. MS (NH ₃ -DCI) 537.2 (M + H) ⁺ .

2-Amino-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] -biphen-4-yl) aminocarbonyl] thiazole: 2-amino-4- (4-methoxyphenyl) - 5 - [(2 ^L tert-Butylaminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole was dissolved in 20 mL of TFA and refluxed for 1 hour. Volatiles were removed in vacuo and the title compound was purified by preparative HPLC. MS (NH _{3 -} DCI)

481.1 (M + H) &lt; + & gt ^; .

Example 23

2-Bromo-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] -biphen-4-yl) aminocarbonyl] thiazole

Methyl 3- (methoxyphenyl) -3-oxopropionate: Bis- (trimethylsilyl) amine (158.2 mL, 0.750 mmol) was dissolved in 150 mL of THF and cooled to -78 ° C using a dry ice / acetone bath. N-butyllithium (2.5 M in hexane, 300 mL, 0.750 mol) was introduced through a cannula and the mixture was stirred at this temperature for 20 minutes. 4-Methoxyacetophenone (51.20 g, 0.340 mol) was added and the mixture was stirred at -78 ° C for 3 hours. Dimethyl carbonate (87.0 mL, 1.02 mol) was added via cannula and the system was stirred overnight at room temperature. The solution was acidified with 10% HCl, diluted with 1 L of EtOAc and washed three times with 400 mL of 10% HCl. The organic phase was dried over MgSO ₄ , filtered through a pad of silica gel and the volatiles were removed in vacuo. The title compound was obtained as a viscous brown oil (65.09 g, 91.7%) MS (NH ₃ -DCI) 347.9 (M + H) ⁺ .

2-Amino-4- (4-methoxyphenyl) -5- (carbomethoxy) thiazole: Methyl

- 102 ·· - ··

The 3- (methoxyphenyl) -3-oxopropionate (33.34 g, 95.75 mmol) and hydroxy (tosyl) iodobenzene (37.55 g, 95.75 mmol) were combined in 350 mL acetonitrile and heated to reflux. 45 minutes followed by the addition of thiourea (7.29 g, 95.75 mmol) and refluxing for 2 hours. The volatiles were removed in vacuo and the residue was dissolved in EtOAc / hexane 50/50 and filtered and passed through a pad of silica gel. Once the impurities eluted, the product was obtained by eluting with 100% EtOAc and removing the volatiles in vacuo. The title compound was obtained as a brownish solid (38.52 g, 75%) MS (NH ₃ -DCI) 254.2 (M + H) ⁺ .

2-Bromo-4- (4-methoxyphenyl) -5- (4-bromophenyl) thiazole: Copper (II) bromide (11.42 g, 51.17 mmol) and tert-butyl nitrite (6.93 mL, 58.6 mmol) were added. The reaction mixture was combined in 75 mL of acetonitrile and heated to reflux until gas evolution ceased. To the acetonitrile solution was added 2-amino-4- (4-methoxyphenyl) -5- (4-bromophenyl) thiazole (12.3 g, 46.55 mmol) and the mixture was heated to reflux until gas evolution ceased. The solution was diluted with 300 mL EtOAc and washed repeatedly with 250 mL saturated Na ₂ CO ₃ solution. The organic phase was dried over MgSO ₄ , filtered through a pad of silica gel and the volatiles removed in vacuo. The residue was purified by preparative HPLC to give the title compound as a brown solid, 8.95 g (57%) M (NH ₃ -DCI) 328.0 (M + H) ⁺ .

2-Bromo-4- (4-methoxyphenyl) -5 - [(2'-tert-butylaminosulfonyl- [1,1 ¹ ] -biphen-4-yl) aminocarbonyl] thiazole: To a solution of (2 ^1- tert-butylaminosulfonyl- [1.1 ^1] biphen-4-yl) amine (2.57 g, 8.47 mmol) in 50 mL of methylene chloride at 25 ° C was added trimethylaluminum (12.7 mL of a 2.0 M solution in toluene , 25.41 mmol). The resulting solution was stirred until no gas evolution was observed (about 25 minutes). To this solution was added 2-bromo-4- (4-methoxyphenyl) -5- (4-bromophenyl) thiazole (2.94 g,

9.31 mmol) and the mixture was stirred at reflux for 2 hours. The solution was cooled with saturated NH ₄ Cl, diluted with 200 mL EtOAc and washed

- ΙΟ *?

with twice 200 ml of brine. Dry the organic phase over MgSO ₄ , filter through a pad of silica gel and remove the volatiles in vacuo to give the title compound as a gold solid (5.0 g, 98%) MS (NH 4 -DCI) 600.3 (M + H) &lt; + & gt ^; .

2-Bromo-4- (4-methoxyphenyl) -5- ^[(1 2 aminosulfonyl- [1,1 '] biphen-4-yl) aminocarbonyl] thiazole: Deprotection with trifluoroacetic acid used in the last step of Example 1 with 2- bromo-4- (4-methoxyphenyl) -5 - [(2'-tert-butylaminosulfonyl- [1,1 '] -biphen-4-yl) aminocarbonyl] thiazole (1.00 g, 1.66 mmol) yields the title compound. This was isolated as a white solid by preparative HPLC, MS (ESI) 543.8 (M + H) ⁺ .

Example 24

2-Chloro-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] -biphen-4-yl) aminocarbonyl] thiazole

Using methods similar to Example 2 except that CuCl ₂ is used in diazotization instead of CuBr ₂ and halogenation of 2-amino-4- (4-methoxyphenyl) -5- (4-bromophenyl) thiazole yields the corresponding 2-chloro- 4- (4-methoxyphenyl) -5- (4-bromophenyl) thiazole. The final product, 2-chloro-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] -biphen-4-yl) aminocarbonyl] thiazole, was isolated by preparative HPLC as a white solid; MS (NH 4 -DCI) 500.3 (M + H) ⁺ .

Example 25

2-Chloro-4- (4-phenoxy) -5 - [(2'-aminosulfonyl- [1,1 '] -biphen-4-yl) aminocarbonyl] thiazole

2-Chloro-4- (4-phenoxy) -5 - [(2'-aminosulfonyl- [1,1 '] -biphen-4-yl) aminocarbonyl] thiazole: 2-chloro-4- (4-methoxyphenyl) - 5 [(2'-Aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole (0.40 g, 0.8 mmol) was dissolved in 5 mL of CH ₂ Cl ₂ and cooled to • 9 9 9 9 9 9 9 9 9 9 9 9 9 9

9 9 9 9 9

9 9 9 · 99 9 · ···

- 104 0 C, followed by addition BC1 ₃ (1.0 M solution in CH ₂ C1 ₂ / 4.8 ml

4.8 mmol) and then stirred at room temperature for 72 hours. The solution was cooled with 10% HCl and the volatiles were removed in vacuo. The title compound was purified by preparative HPLC, MS (NH ₃ -DCI) 485.9 (M + H) ⁺ .

Example 26

2-Methoxy-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole

2-Methoxy-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole: 2-chloro-4- (4-methoxyphenyl) - 5 ^[(1 2 aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole (0.120 g, 0.240 mmol) and sodium methoxide (0.10 g, 2.0 mmol) was dissolved in 20 ml methanol and heated to reflux; the reaction mixture was monitored by TLC. The title compound is isolated as a white solid by preparative HPLC MS (ESI)

518.0 (M + Na) &lt; + & gt ^; .

Example 27

2-Thiomethyl-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole

2-Thiomethyl-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole: 2-chloro-4- (4-methoxyphenyl) - 5 [(2'-Aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole (0.700 g, 1.4 mmol) and sodium thiomethoxide (0.490 g, 7.0 mmol) were heated to reflux. in 50 ml THF and the reaction was monitored by TLC (ca. 4 hours). The volatiles were removed in vacuo and the title compound was purified by preparative HPLC, MS (ESI) 534.0 (M + H) ⁺ .

Examples 28 and 29 fl fll fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl

- 105 • fl

2-Methylsulfoxide-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole and 2-methylsulfone-4- (4-methoxyphenyl) - 5 - [(2'-Aminosulfonyl- [1,1 '] -biphen-4-yl) aminocarbonyl] thiazole

2-thiomethyl-4- (4-methoxyphenyl) -5 - ^[(1 2 aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole (0.54 g, 1.05 mmol) and Oxone ^R (1.94 g, 3.16 mmol) was dissolved in 300 mL of 50/50 methanol / water and stirred at room temperature for 72 hours. The solution was diluted with 400 mL EtOAc and washed three times with 200 mL brine. The organic phase was dried over MgSO ₄ , filtered through a pad of silica gel and the volatiles were removed in vacuo and the residue was purified by preparative HPLC. Both compounds of Examples 28 and 29 are obtained after HPLC purification.

2-Methylsulfoxide-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole MS (ESI) 527.9 (M + H) ) ⁺ .

2-Methylsulfone-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] -biphen-4-yl) aminocarbonyl] thiazole MS (ESI) 543.9 (M + H) ⁺ .

Example 30

2-Cyano-4- (4-methoxyphenyl) -5 - ^[(1 2 aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole

2-Cyano-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole: 2-methylsulfone-4- (4-methoxyphenyl) -5- [(2'-Aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole (0.500 g, 0.920 mmol) and sodium cyanide (0.225 g, 4.60 mmol) were combined in 35 mL DMF and the mixture was stirred at room temperature overnight and then heated at 70 ° C for several hours. Dissolve the solution in 300 mL of EtOAc and wash three times with 200 mL of brine, dry over MgSO ₄ .

Filter through a pad of silica gel and remove the volatiles in vacuo. The title compound was isolated as a white solid by preparative HPLC MS (ESI) 490.9 (M + H) ⁺ .

Example 31

2-N, N-Dimethylamino-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole

2-N, N-Dimethylamino-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole: 2-chloro-4- (4-methoxyphenyl) ) -5 - [(2'-Aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole (0.200 g, 0.4 mmol) and dimethylamine (40% solution in water, 1.00 mL, 2.00 mmol) was stirred at room temperature in 50 mL THF overnight. Volatiles were removed in vacuo and the title compound was purified by preparative HPLC, MS (ESI) 509.0 (M + H) ⁺ .

Example 32

2- (1-Pyrrole) -4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] biphen-4-yl) aminocarbonyl] thiazole

2- (1-Pyrrole) -4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] biphen-4-yl) aminocarbonyl] thiazole: 2-amino-4- (4- methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole (0.050 g, 0.104 mmol) and 2,5-dimethoxytetrahydrofuran (0.015 mL, 0.114 mmol) were heated at reflux in 20 ml acetic acid for 1 hour. The volatiles were removed in vacuo and the title compound was purified by preparative HPLC, MS (ESI) 531.0 (M + H) ⁺ .

Example 33

3- (4-Methoxyphenyl) -5- [5- (2'-aminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl-5-carbomethoxymethyl-isoxazoline

4-Methoxybenzaldehyde oxime: 4-Methoxybenzaldehyde (10.0 g, 73.4 mmol) was dissolved in 20 mL ethanol. A solution of hydroxyamine hydrochloride (6.38 g, 91.8 mmol) in 50 mL H ₂ O was then added, followed by a solution of sodium acetate (12.1 g, 146.8 mmol) in 50 mL H ₂ O. The mixture was stirred at room temperature under N ₂ for 12 hours. The ethanol was removed in vacuo and the aqueous mixture was extracted with EtOAc. The EtOAc solution was washed with brine, dried over MgSO ₄ and concentrated to give 12.8 g of a pale yellow oil. 1 H NMR showed to be 80% pure (92% yield). This material was carried on to the next step without further purification. (CDC1 _3): δ 2.15 (s, 1H); 3.83 (s, 3H); 6.92 (d, 2 H); 7.50 (d, 2 H); 10 (S, 1 H).

3- (4-Methoxyphenyl) -5-carbomethoxy-methyl-isoxazolin-5-ylcarboxylic acid: 4-Methoxybenzaldehyde oxime (5.00 g, 33.1 mmol) and itaconic acid monomethyl ester (5.72 g, 39.7 mmol) together with 200 ml of THF. To the above mixture, bleach (84 mL of a 0.67 M aqueous solution) was added dropwise at room temperature. The reaction mixture was then stirred at room temperature under N ₂ for 12 hours. THF was removed in vacuo. The aqueous mixture was acidified with aqueous HCl and extracted with EtOAc. The EtOAc solution was washed with brine, dried over MgSO ₄ , concentrated and chromatographed with 10 to 30% MeOH in CH ₂ Cl ₂ on silica gel to give 5.58 g of the desired product (58%). 1 H NMR (DMSO-d 6): δ 3.08 (m, 2H); 3.61 (s, 3H); 3.55-3.87 (m, 2 H); 3.80 (s, 3H); 7.00 (d. 2H); 7.61 (d, 2 H).

3- (4-Methoxyphenyl) -5-N- [2'-tert-butylaminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl-5-carbomethoxymethyl-isoxazoline:

3- (4-Methoxyphenyl) -5-carbomethoxymethylisoxazolin-5-ylcarboxylic acid (1.89 g, 6.44 mmol) was heated to reflux with 100 mL acetonitrile and 4.70 mL (64.4 mmol) thionyl chloride for 1 hour under N ₂ . The solvent was removed in vacuo. Remaining thionyl chloride was removed by addition of toluene and then evaporated to dryness. The solid formed was

1ΓΓ8 dissolved in 100 ml CH ₂ C1 ₂ and treated with 2-amino-5 - [(2'-terč.butylaminosulfonyl) phenyl] pyridine (1.57 g, 5.15 mmol) followed by N, N-dimethylpyridine (0 , 94 g, 7.73 mmol). Stir the reaction mixture at room temperature and complete the reaction within 30 minutes. The mixture was diluted with CH ₂ C1 ₂ and washed with water and brine. It was then dried over MgSO ₄ and concentrated. The crude mixture is chromatographed on silica gel, eluting with methylene chloride / ethyl acetate (9: 1) to give 2.55 g of the desired product (68%). MS (ES ⁺ ) 581.1 (M + H); 603.1 (M + Na).

3- (4-Methoxyphenyl) -5-N- [2-aminosulfonylphenyl ¹ yl) pyridin-2-yl] aminocarbonyl-5-carbomethoxymethyl-isoxazoline: 3- (4-Methoxyphenyl) -5-N- [2 ¹ -tert-Butylaminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl-5-carbomethoxymethyl-isoxazoline (1.26 g, 2.17 mmol) was dissolved in 15 mL of TFA and stirred at room temperature under N ₂ for 22 hours. TFA was removed in vacuo and the crude product was purified by chromatography (on silica gel, eluting with ethyl acetate and 5% methanol in CH ₂ Cl ₂ ) to give 1.10 g of the desired product (97%). MS (ES +) 525.0 (M + H); 547.0 (M + Na).

Example 34

3- (4-Methoxyphenyl) -5- [5- (2'-aminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl-5-carboxymethyl-isoxazoline

3- (4-Methoxyphenyl) -5-N- [2'-aminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl-5-carbomethoxymethyl-isoxazoline (0.95 g, 1.78 mmol) was dissolved in 20 mL ml THF. Aqueous LiOH (2.3 mL of 1M solution) was added. The mixture was stirred at room temperature under N ₂ for 1.5 hours. THF was removed in vacuo, the residue was diluted with H ₂ O and extracted with EtOAc. The aqueous mixture was acidified with HCl and extracted with EtOAc. The EtOAc solution was washed with brine, dried over MgSO ₄ and concentrated to a pale yellow foam (0.85 g, 94%). MS (ES ⁺ ) 511.0 (M + H) 533.0. (M + Na).

- 109 Example 35

3- (4-Methoxyphenyl) -5- [5- (2'-aminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl-5- (N-carbomethoxymethyl) carboxamidomethyl-isoxazoline

3- (4-Methoxyphenyl) -5- [5- (2'-aminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl-5-carboxymethyl-isoxazoline (0.20 g, 0.39 mmol) was dissolved in 20 mL EtOAc and 5 mL DMF. To this mixture was added methyl glycine ester hydrochloride (49.0 mg, 0.039 mmol), TBTU (0.13 g, 0.39 mmol) and Et 2 N (0.16 mL, 1.17 mmol). The mixture was stirred at room temperature under nitrogen for 22 hours. The mixture was then diluted and extracted with EtOAc. The EtOAc solution was washed with brine, dried over MgSO ₄ , concentrated and chromatographed with 5% MeOH in CH ₂ Cl ₂ on silica gel to afford 0.11 g of the desired product (49%). MS (ES ⁺ ) 582.0 (M + H); 604.0, (M + Na).

Example 36

3- (4-Methoxyphenyl) -5- [5- (2'-aminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl-5- (1,2,4-triazol-1-yl) methylisoxazoline

3- (4-Methoxyphenyl) -5- (1,2,4-triazol-1-yl) methyl-isoxazolin-5-ylcarboxylic acid: 1,2,4-Tetrazole (5.04 g, 73.0 mmol) and K2CO3 (11.23 g, 81.3 mmol) was added together to 100 mL THF. Then methyl 2- (bromomethyl) acrylate (13.0 g, 72.6 mmol) was added. The mixture was stirred at room temperature under N _{2 for} 4 hours. The mixture was poured into water and extracted with EtOAc. The combined organic solution was washed with brine, dried over MgSO ₄ and concentrated to give 8.38 g of methyl 2- (1,2,4-triazol-1-ylmethyl) acrylate

4-Methoxybenzaldehyde oxime (1.63 g, 10.8 mmol) and methyl

2- (1,2,4-triazol-1-ylmethyl) acrylate (1.50 g, 8.97 mmol) was added.

- ιϊο added together in 100 ml CH ₂ C1 _2nd To the above mixture, bleach (23 mL of a 0.67 M aqueous solution) was added dropwise at room temperature. The reaction mixture was then stirred at room temperature under N ₂ for 12 hours. The mixture was diluted with CH 2 Cl 2 and washed with water and brine. It was then dried over MgSO ₄ , concentrated and chromatographed with 30-100% EtOAc in CH ₂ Cl ₂ on silica gel to give 1.81 g of the desired product (66%).

The above ester (1.81 g) was dissolved in 25 mL THF and aqueous LiOH (7.2 mL 1 M solution) was added. The mixture was stirred at room temperature under N ₂ for 0.5 h. THF was removed in vacuo. The aqueous mixture was diluted with H ₂ O and extracted with EtOAc. The resulting aqueous solution was acidified and then extracted with EtOAc. The resulting white precipitate was filtered and dried (1.30 g). ¹ H NMR (DMSO-d 6): δ (q, 2H); 3.78 (s, 3H); 4.74 (q, 2 H); 6.98 (d, 2 H); 7.53 (d, 2 H); 7.92 (s, 1 H); 8.51 (s, 1 H); 13.75 (s, 1 H).

3- (4-Methoxyphenyl) -5-N - [(2'-tert-butylaminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl-5- (1,2,4-triazol-1-yl) methylisoxazoline: 3- (4-Methoxyphenyl) -5- (1,2,4-triazol-1-yl) methyl) -isoxazolin-5-ylcarboxylic acid (0.30 g, 1.03 mmol) was heated to reflux with 20 ml of acetonitrile and 0.75 ml (10.3 mmol) of thionyl chloride under N ₂ for 1 hour. The solvent was removed in vacuo. Remaining thionyl chloride was removed by addition of toluene and then evaporated to dryness. The resulting solid was dissolved in 20 ml CH ₂ C1 ₂ and treated with

2-amino-5 - [(2'-tert-butylaminosulfonyl) phenyl] pyridine (0.25 g, 0.82 mmol) followed by N, N-dimethylpyridine (0.15 g, 1.24 mmol). Stir the reaction mixture at room temperature and complete the reaction in less than 30 minutes. The mixture was diluted with CH ₂ C1 ₂ and washed with water and brine. It was then dried over MgSO ₄ and concentrated. The crude product is chromatographed on silica gel, eluting with a mixture of methylene chloride and ethyl acetate (30-100%) to give 0.31 g of the desired product (51%). MS (ES &lt; + &gt;) 590.2, (M + H); 612.1.

- 111 3- (4-Methoxyphenyl) -5-N- [2'-aminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl-5- (1,2,4-triazol-1-yl) methyl isoxazoline :

3- (4-Methoxyphenyl) -5-N- [2'-tert-butylaminosulfonylphenyl-1-yl) pyridin-yl] aminocarbonyl-5- (1,2,4-triazol-1-yl) methyl isoxazoline (0 (24 g, 0.41 mmol) was dissolved in 5 mL of TFA and stirred at room temperature under N ₂ for 12 hours. TFA was removed in vacuo and the crude product was purified by silica gel chromatography eluting with ethyl acetate to give 0.19 g of the desired product (87%). MS (ES ⁺ ) 534.0 (M + H) &lt; + &gt;; 556.0 (M + Na).

Example 37

1- (4-Methoxyphenyl) -5- ^[(1 2 aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] tetrazole

1- (4-Methoxyphenyl) -5-carboethoxy-tetrazole: 4-methoxyaniline (20.0 g, 0.16 mol) and triethylamine (26.3 mL, 0.19 mol) was dissolved in CH ₂ C1 ₂ (200 ml) then oxalyl chloride (18.1 ml, 0.16 mol) was added dropwise. The mixture was stirred at room temperature under N ₂ for 15 minutes. The mixture was then diluted with CH ₂ C1 ₂ and washed with water and brine. The CH ₂ Cl ₂ solution was dried over MgSO ₄ and concentrated to a brownish solid (34.7 g, 96%). MS (DCI-NH ₃ ) 224, (M + H); 241 (M + NH _4).

The above amide (34.0 g, 0.15 mol) was heated to reflux for 20 hours with a solution of triphenylphosphine (56.6 g, 0.22 mol) in 500 mL CCl ₄ (the solution was stirred at 0 ° C for 15 min.) before adding the amide). The reaction mixture was cooled and hexane was added. The precipitate was filtered off. Concentrate the filtrate to a solid. This was dissolved in 400 mL of CH ₃ CN and NaN ₃ (10.0 g, 0.15 mol) was added. The mixture was stirred at room temperature under N ₂ for 12 hours. The solvent was evaporated. The solid was removed in EtOAc and washed with water and brine. It was then dried over MgSO ₄ and concentrated and chromatographed on silica gel (eluting with CH ₂ Cl ₂ ) to give 27.7 g of the desired product (58%). MS (DCI-NH ₃ ) 249, (M + H), 266 (M + NH ₄ ) ⁺ .

• ·

- 112 1- (4-Methoxyphenyl) -5 - [(2 ¹ -terč.butylaminosulfonyl [1,1 '] biphen-4-yl) aminocarbonyl] tetrazole: 2'-onyl terč.Butylaminosulf 4-amino- [1 1 '] - Biphen-4-yl (1.84 g, 6.04 mmol) was dissolved in 100 mL of anhydrous CH ₂ Cl ₂ and trimethylaluminum (15.2 mL of a 2.0 M solution in heptane) was added slowly. The mixture was stirred at room temperature under N ₂ for 15 minutes and 1- (4-methoxyphenyl) -5-carboethoxy-tetrazole (1.50 g, 6.04 mmol) was added. The reaction mixture was stirred at room temperature under N ₂ for 18 hours. The reaction mixture was carefully quenched with 0.1 N aqueous HCl. Then diluted with CH ₂ C1 ₂ and washed with water and brine. The organic solution was dried over MgSO ₄ , concentrated, and chromatographed on silica gel (10% EtOAc / CH ₂ Cl ₂ ) to give 1.20 g of the desired product (39%). MS (ESI) 507.0 (M + H) &lt; + & gt ^; .

1- (4-Methoxyphenyl) -5 - [(2'-aminosulfonyl [1,1 '] - biphen-4-yl) aminocarbonyl] tetrazole: 1- (4-Methoxyphenyl) -5 - [(2'-tert. butylaminosulfonyl] tetrazole (1.20 g, 2.37 mmol) was dissolved in 10 mL of TFA and the mixture was heated under reflux for 1 hour under N. The TFA was removed in vacuo and the crude material was purified by reverse phase HPLC to yield 0.30 g. 12 g of the desired product (11%) MS (ESI) 451.0 (M + H) ⁺ .

Example 38

3-Methyl-1- (4-methoxy-3-chloro) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide)

This compound was prepared by the same methodology as described in Example 1 except that the phenylhydrazine was replaced

4-methoxy-3-chlorophenylhydrazine. HCl. Thus it is obtained

3-methyl-1- (4-trifluoromethyl) phenyl-1H-pyrazole-5- (N- (4- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide); HRMS (M + H) ⁺ calculated m / z: 497.1050, found: 497.1045.

Example 39 • ·

- 113 3-methyl-l- (4-trifluoromethoxy) phenyl-lH-pyrazole-5- (N- (2 ¹ aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide

This compound was prepared by the same methodology as described in Example 1 except that the phenylhydrazine was replaced

4-trifluoromethoxyphenylhydrazine. HCl. Thus it is obtained

3-methyl-1- (4-trifluoromethyl) phenyl-lH-pyrazole-5- (N- (2'-aminosulfonyl- [1.1 ^1] biphen-4-yl) carboxyamide; HRMS (M ⁺ H) calculated m / z: 517.1170, found: 517.1176.

Example 40

1- (3-Bromophenyl) -3-methyl-1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide

This compound was prepared by the same methodology as described in Example 1 except that the phenylhydrazine was replaced with 3-bromophenylhydrazine. HCl. There was thus obtained 1- (3-bromophenyl) -3-methyl-lH-pyrazole-5 - ^[(1 2 aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; HRMS (M + H) ⁺ calcd m / z: 511.043949, found: 511.043295.

Example 41

1- (3-iodophenyl) -3-methyl-lH-pyrazole-5 - ^[(1 2 aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide

This compound was prepared by the same methodology as described in Example 1 except that phenylhydrazine was replaced with 3-iodophenylhydrazine. HCl. There was thus obtained 1- (3-iodophenyl) -3-methyl-1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; HRMS (M + H) ⁺ calcd m / z: 559.030090; found 559.027878.

Example 42 • ·

• ·

114

1- (3,4-Methylenedioxanphenyl) -3-methyl-1H-pyrazole-5 - [(2 ^L aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide

This compound was prepared using the same methodology as described in Example 1 except that the phenylhydrazine was replaced with 3,4-methylenedioxanphenylhydrazine. HCl. There was thus obtained 1- (3,4-methylenedioxanphenyl) -3-methyl-1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; HRMS (M + H) ⁺ calcd m / z: 477.123267; found: 477.124553.

Example 43

1- (4-Methoxyphenyl) -3-hydroxylmethylene-1H-pyrazole-5- (4 'pyrrolidinocarbonyl) anilide

1- (4-Methoxyphenyl) -3-hydroxylmethylene-1H-pyrazole-5-ethylcarboxylate: To a solution of 1- (4-methoxyphenyl) -3-methyl-1H-pyrazole-5-ethylcarboxylate (1.58 g, 7.1 mmol) in CCl ₄ (250 mL) was added NBS (1.5 g, 8.5 mmol) and benzoyl peroxide (73 mg, 4 mmol) and the mixture was degassed and then charged with nitrogen. The mixture was heated under reflux for 18 hours under nitrogen then cooled to room temperature, diluted with CH ₂ Cl ₂ (100 mL), washed with 10% NaOH (20 mL x 3), water (20 mL x 3), and brine (10 mL x 2) and dried over MgSO ₄ . Filtration and concentration gave the crude bromide (2.4 g). To a solution of the crude bromide in aqueous DMSO (75%, 40 mL) was added Cu ₂ O (1.5 g, 10.5 mmol) and the mixture was stirred at 60 ° C for 2 hours. The mixture was filtered to remove excess Cu ₂ O and the filtrate was extracted with ethyl ether. The ether layer was washed with brine (10 mL x 5) and dried over MgSO ₄ . Filtration and concentration followed by purification by flash chromatography with EtOAc-CH ₂ Cl ₂ (1: 1) gave 1- (4-methoxyphenyl) -3-hydroxymethylmethylene-1H-pyrazole-5-ethylcarboxylate (1.5 g, 81%) . LRMS (M + H) &lt; + & gt ^; m / z: 277.

• · • ·

115

1- (4-Methoxyphenyl) -3-hydroxylmethylen-lH-pyrazole-5- (4'pyrrolidinkarbonyl) anilide: To a solution of 4- (4'pyrrolidinkarbonyl) aniline (390 mg, 2.05 mmol) in CH ₂ C1 ₂ (20 mL) was added at 0 ° C with AlMe ₃ (2M in hexanes, 3 mmol). The mixture was stirred for 15 minutes at room temperature and then a solution of 1- (4-methoxyphenyl) -3-hydroxylmethylen-lH-pyrazole-5-ethylkarboxylátu (560 mg, 2.05 mmol) in CH ₂ C1 ₂ (5 mL) and the resulting mixture was stirred overnight. Cool the mixture with water (5 mL) and filter through a pad of celite to remove Al (OH) ₃ . The filtrate was washed with water and brine and dried over MgSO ₄ . Filtration and concentration followed by purification by flash chromatography with EtOAc-CH ₂ Cl ₂ to give 1- (4-methoxyphenyl) -3-hydroxylmethylen-lH-pyrazole-5- (4'-pyrrolidinocarbonyl) anilide (570 mg, 67% yield) . EMS (M + Na) ⁺ m / z 443. HRMS (M + H) calcd m / z: 420.1798, found 420.1771.

Example 44

1- (4-Methoxyphenyl) -3-formaldehyde-1H-pyrazole-5- (4'-pyrrolidinecarbonyl) anilide

To a solution of 1- (4-methoxyphenyl) -3-hydroxylmethylene-1H-pyrazole-5- (4'-pyrrolidinocarbonyl) anilide (140 mg, 0.33 mmol) in THF (20 mL) was added MnO ₂ (435 mg, 15 eq.) The mixture was heated at reflux for 12 hours. The mixture was filtered to remove excess MnO ₂ and the filtrate was concentrated to afford 1- (4-methoxyphenyl) -3-formaldehyde-1H-pyrazole-5- (4'-pyrrolidino carbonyl) anilide as a solid in almost quantitative yield. LRMS (M + H) &lt; + & gt ^; m / z: 419.

Example 45

1- (4-Methoxyphenyl) -5- (4 -pyrrolidinokarbonyl ¹⁾ anilide-3-pyrazolecarboxylic acid

To a solution of AgNO ₃ (34 mg, 0.2 mmol) in H ₂ O (0.5 mL) was added ·

• · 4 4 · 4 4 4 · 44 4

4444 4 · «444

4 4444 4 4 4 444 444 · 4 4 4 4 4 4 44 444 4444 44 44

- 116 NaOH (16 mg, 0.4 mmol) and then a solution of 1- (4-methoxyphenyl) -3-formaldehyde-1H-pyrazole-5- (4'-pyrrolidinocarbonyl) anilide (42 mg, 0.1 mmol) in MeOH (0.5 mL). The mixture was stirred at room temperature for 30 minutes and then carefully acidified with conc. HCl (35 μΐ) to pH of about 2 and concentration to give a residue which is purified by flash chromatography to give 1- (4-methoxyphenyl) -5- (4'-pyrrolidinocarbonyl) anilide-3-pyrazolecarboxylic acid (25 mg, 58 %) ESMS (M + Na) &lt; + & gt ^; m / z: 456.9.

Example 46

1- (4-Methoxyphenyl) -3-methylcarboxylate-1H-pyrazole-5- (4 'pyrrolidinocarbonyl) anilide

To a solution of 1- (4-Methoxyphenyl) -3-formaldehyde-lH-pyrazole-5- ⁽¹ 4 -pyrrolidinkarbonyl) anilide (42 mg, 0.1 mmol) in MeOH (1 mL) was added KCN (7.8 mg , 0.12 mmol), HOAc (7.2 mg, 0.12 mmol) and MnO ₂ (120 mg, 0.83 mmol) and the resulting mixture was stirred at room temperature for 12 hours. The mixture was diluted with EtOAC (50 mL), washed with water (10 mL x 3) and brine, and dried over MgSO ₄ . The solution was filtered, concentrated, and purified by flash chromatography with EtOAC to give 1- (4-methoxyphenyl) -3-methylcarboxylate-1H-pyrazole-5- (4'-pyrrolidinocarbonyl) anilide (38 mg, 85% yield). ESMS (M + Na) &lt; + & gt ^; m / z: 471.

Example 47

1- (4'-Chlorophenyl) -3-methyl-1H-pyrazole-5 - [(2'-aminosulfonyl [1,1 '] - biphen-4-yl) carboxyamide

This compound was prepared by the same methodology as described in Example 1 except that the phenylhydrazine was replaced with 4-chlorophenylhydrazine. HCl. Thus it is obtained

1- (4'-chlorophenyl) -3-methyl-1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; HRMS (M + H) @ ⁺ 9

117 calcd m / z: 467.094465; found: 467.093532.

Example 48

1- (4'-Chlorophenyl) -3-methyl-1H-pyrazole-5 - [(2'-aminosulfonyl [1-pyridyl-1'-phenyl] -4-yl) carboxyamide

This compound was prepared by the same methodology as described in Example 8 except that the phenylhydrazine was replaced with 4-chlorophenylhydrazine. HCl and 2-amino-5- (2-N-t-butylaminosulfonylphenyl) pyridine were used in the coupling step. There was thus obtained the title compound; HRMS (M + H) ⁺ : calcd 468.08914; found 468.088873.

Example 49

1- (3 ^1, 4'-dichlorophenyl) -3-methyl-lH-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide

This compound was prepared by the same methodology as described in Example 1 except that the phenylhydrazine was replaced with 3,4-dichlorophenylhydrazine. HCl. There was thus obtained the title compound; HRMS (M + H) ⁺ : calcd 501.05553; found 501.053920.

Example 50

1- (3'-Chlorophenyl) -3-methyl-1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide

This compound was prepared by the same methodology as described in Example 1 except that the phenylhydrazine was replaced with 3-chlorophenylhydrazine. HCl. There was thus obtained the title compound; HRMS (M + H) ⁺ : calcd 467.094465; found 467.091517.

• ·

I · · · · I · 4

I · · ·

118 Example 51

^2-Amino-4 '-phenyl-5- [(2' aminosulfonyl- [1,1 '] biphen-4-yl) aminocarbonyl] thiazole

2-Amino-4-phenyl-5-carboethoxythiazole: To ethyl solution

3-phenyl-3-oxopropionate (5.0 g, 26.0 mmol) in 100 mL of acetonitrile was added hydroxy (tosyloxy) iodobenzene (11.2 g,

28.6 mmol). The resulting suspension was stirred at 65 ° C for 1 hour, whereupon the reaction mixture became a homogeneous solution. Thiourea (2.2 g, 28.6 mmol) was then added and stirring was continued at 65 ° C for 2 hours. The mixture was cooled and concentrated and the residue taken up in ethyl acetate, washed with saturated aqueous Na ₂ CO ₃ and brine, dried (MgSO ₄ ) and concentrated. The residue was triturated with ethyl ether to give 4.9 g (70%) of the title compound as a yellow solid. NMR (CDC1 ₃₎ d 7.65 (m, 2H), 7.39 (m, 3H), 5.98 (broad s, 2H), 4.18 (q, 2H), 1.22 (t, 3H ).

2-Amino-4-phenyl-5 - [(2'-tert-butylaminosulfonyl- [1,1 '] -biphen-4-yl) aminocarbonyl] thiazole: To a solution of (2'-tert-butylaminosulfonyl- [1,1']] -biphen-4-yl) amine (0.68 g, 2.22 mmol) in 15 mL of methylene chloride was added dropwise at 25 ° C with trimethylaluminum (3.3 mL of a 2.0 M solution in toluene, 6.68 mmol). ). The resulting solution was stirred until gas evolution was observed (about 15 minutes). To this solution was added 2-amino-4-phenyl-5-carboethoxythiazole (0.30 g, 1.11 mmol) in 5 mL of methylene chloride. The resulting solution was stirred at 40 ° C for 16 hours and then cooled to 25 ° C followed by addition of saturated aqueous NH ₄ Cl solution. After dilution with ethyl acetate, the organic layer was washed with 10% aqueous HCl, saturated aqueous NaHCO ₃ and brine, dried (MgSO ₄ ), and concentrated in vacuo. The residue was purified by flash chromatography (eluting with 1: 1 hexanes / ethyl acetate) to give 0.3 g (54%) of the title compound as a solid. MS (ESI) 507.1 (M + H) &lt; + & gt ^; .

• · · ·

119 · 2-Amino-4-phenyl-5 - ^[(1 2 aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole A solution of 2-amino-4-phenyl-5 - [(2 tert-Butylaminosulfonyl- [1,1 '] -biphen-4-yl) aminocarbonyl] thiazole (80 mg, 0.16 mmol) in 3 mL of trifluoroacetic acid was stirred at reflux for 20 minutes and then cooled to room temperature. and concentrated in vacuo. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with a H ₂ O / CH ₃ CN gradient with 0.05% TFA) and lyophilized to give 50 mg (71%) of the title compound as a white powder. MS (ESI) 451.0 (M + H) &lt; + & gt ^; .

Example 52

2-Chloro-4-phenyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole

2-Chloro-4-phenyl-5 - [(2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole: To a solution of copper (II) chloride (54 mg, 0.4 mmol) in T-Butyl nitrite (42 mg, 0.4 mmol) was added to 5 mL acetonitrile. The mixture was heated to 80 ° C and then 2-amino-4-phenyl-5- [2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole (200 mg, 0) was added. , 4 mmol). Stirring is continued for 1 hour at 80 ° C with evolution of gas. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 10% aqueous HCl, saturated NaHCO ₃ and brine, dried (MgSO ₄ ) and concentrated to give 0.2 g (95%) of the title compound which was used without further cleaning. MS (ESI) 526.1 / 528.0 (M + H) &lt; + & gt ^; .

2-Chloro-4-phenyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole: 2-Chloro-4-phenyl-5 - [(2'terc) solution Butylaminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole (100 mg, 0.19 mmol) in 5 mL of trifluoroacetic acid was stirred at reflux for 20 minutes and then cooled to room temperature and concentrate in vacuo. The residue was purified by HPLC (C18 reverse phase column, eluting with a H ₂ O / CH ₃ CN gradient with 0.5% TFA) and lyophilized to give 50 mg (56%).

120 of the title compound as a white powder. MS (ESI) 469.9 / 471.9 (M + H) &lt; + & gt ^; .

Example 53

2-Amino-4- [3- (bromo) -4- (fluoro) -phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole:

Methyl 3- [3- (bromo) -4- (fluoro) -phenyl] -3-oxopropionate: To a suspension of sodium hydride (1.1 g of a 60% suspension in mineral oil, washed with hexane, 27.6 mmol) in 50 mL tetrahydrofuran was added dimethyl carbonate (2.3 mL, 27.6 mmol) and 3'-bromo-4'-fluoroacetophenone (3.0 g, 13.8 mmol). The resulting suspension was stirred at 65 ° C for 1 hour and then cooled to room temperature. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by chromatography (eluting with hexane / ethyl acetate 3: 1) to give 1.0 g (26%) of the title compound. ¹ H NMR (CDCl ₃ ) (keto tautomer data) δ 8.15 (dd, 1H), 7.87 (m, 1H), 7.2 (m, 1H), 3.95 (s, 2H), 3.73 (s, 3H).

2-Amino-4- [3- (bromo) -4- (fluoro) phenyl] -5-carbomethoxythiazole: Following the procedure described in Example 51, methyl 3- [3- (bromo) -4- (fluoro) phenyl] - 3-Oxopropionate (1.0 g, 3.66 mmol) was converted to 0.6 g of the title compound. 1 H NMR (CDCl ₃ ) δ 7.97 (m, 1H), 7.90 (broad s, 2H), 7.68 (m, 2H), 3.61 (s, 3H).

2-Amino-4- [3- (bromo) -4- (fluoro) phenyl] -5- [2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole: The procedure described in of Example 51, 2-amino-4- [3- (bromo) -4- (fluoro) phenyl] -5-carbomethoxythiazole (0.25 g, 0.75 mmol) was converted to the title compound as a white powder, followed by HPLC purification. ¹ H NMR (CDCl 3) δ 9.95 (s, 1H), 7.98 (d, 1H), 7.94 (dd, 1H), 7.65-7.55 (m, 3H), 7 50 (d, 2H); 7.36 (m,

1H), 7.30-7.25 (m, 3H), 7.18 (s, 2H). MS (ESI) 546.9 / 548.8 (M + H) &lt; + & gt ^; .

• · · · · · · · · · · ·

121 Example 54

2-Amino-4- [4-fluorophenyl] -5 - ^[(1 2 aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole

Following the procedure described in Example 51, 4'-fluoroacetophenone is converted to the title compound, 2-amino-4- [4-fluorophenyl] -5- [2'-aminosulfonyl- [1,1 '] - biphen-4- yl) aminocarbonyl] thiazole. ¹ H NMR (CDCl ₃ ) δ (9.82 (s, 1H), 7.98 (d, 1H), 7.65-7.60 (m, 2H), 7.58-7.52 (m, 4H), 7.25 (m, 3H);

7.20-7.13 (m, 4H). MS (ESI) 468.9 (M + H) &lt; + & gt ^; .

Example 55

2-Amino-4- [3-bromophenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole

Following the procedure described in Example 51, 3'-bromoacetophenone is converted to the title compound, 2-amino-4- [3-bromophenyl] -5- [2'-aminosulfonyl- [1,1 '] - biphen-4- yl) aminocarbonyl] thiazole. ¹ H NMR (CDCl ₃ ) δ (9.95 (s, 1H), 7.98 (d, 1H), 7.81 (s, 1H), 7.60-7.22 (m, 4H), 7 18 (broad s, 2H), 5.4 (broad S, 2H) MS (ESI) 528.8 / 530.8 (M + H) ⁺ .

Example 56

2-Chloro-4- [3-bromophenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole

Following the procedure described in Example 52, 2-amino-4- [3-bromophenyl] -5 - [(2'-tert-butylaminosulfonyl- [1,1 '] -biphen-4-yl) aminocarbonyl] thiazole was converted to the title compound. of the title, 2-chloro-4- [3-bromophenyl] -5- [2'-aminosulfonyl- [1,1 '] biphen-4-yl) aminocarbonyl] thiazole. MS (ESI) 547.9 / 549.8 (M + H) &lt; + &gt;

122 · * • • • • • • • •

Example 57

N- (2'-Aminosulfonyl- [1,1 '] - biphen-4-yl) -1- (4-methoxyphenyl) -3- (methylthio) pyrazole-5-carboxyamide

Ethyl N- (4-methoxyphenyl) glycine: To a solution of p-anisidine (15.00 g, 122 mmol) in DMF (100 mL) under N _{2 is} added ethyl bromoacetate (23.50 g, 141 mmol) and 14.95 g (141 mmol). of anhydrous sodium carbonate. The mixture was heated at 70 ° C for 16 hours and then cooled to room temperature. Water (500 mL) was added and the mixture was stirred vigorously until a precipitate formed. The solid was collected and washed with 100 mL of water, dried in vacuo to give 19.59 g (88%) of the title compound as a gray solid.

¹ H NMR (CDCl ₃ ): δ 6.81 (d, J = 8.8, 2H); 6.579 (d, J = 8.8, 2H; 4.24 (q, J = 7.0, 2H); 4.10 (s, 1H); 3.86 (s, 2H); 3.75 (S) 1.28 (t, J = 7.0, 3H).

N- (4-Methoxyphenyl) glycine: To a solution of 19.59 g (108 mmol) of ethyl N- (4-methoxyphenyl) glycine in 100 ml of THF is added under N ₂ 5.44 g (130 mmol) of lithium hydroxide monodyrate in 25 ml. ml of water. After 15 hours, the volume of the mixture was reduced in vacuo to 1/2 of the original volume and then acidified to pH 3 with concentrated hydrochloric acid and a precipitate formed. The solid was collected and washed with 100 mL of water and then dried in vacuo to give 9.92 g (51%) of the title compound as an off-white solid. - @ 1 HNMR (CDCl _3): δ 6.68 (d, J = 8.8, 2H); 6.49 (d, J = 8.8, 2H); 3.73 (s, 2 H); 3.64 (s, 3H); 2.49 (broad S, 2H).

N- (4-Methoxyphenyl) -N-nitrosoglycine: Sodium nitrite (3.97 g, 57.5 mmol) in 10 mL of water was added to a suspension of N- (4-methoxyphenyl) glycine (9.92 g, 54.7 mmol) in 50 ml of water under nitrogen. The mixture was then stirred at room temperature for about 6 hours until the solution was clear. The solution was acidified to pH 3 with concentrated hydrochloric acid and a precipitate formed. The solid was collected and washed with 50 ml of water and then dried.

123 desired compounds such as

7.17 (d, J = 8.8, 2H);

, 3.56 (s, 3H), 2.29 to 11.50 g (100% ¹ 1 HNMR (CDCl _3):?

2H); 4.30 (s, 2H in vacuo and white solid 6.70 (d, J (broad s, afford. = 8.8, liazole: N- (4-methoxyphenyl) 3I)) was dissolved in 100 mL ° C after for 14 hours, poured into 300 ml of ice to decompose the excess LUT sruje give 10.50 g 4R (CDC1 _3): δ 7.65 (d), 6.63 (s, 1H), 3.91 (s ,

1- (4-Methoxyphenyl) -4-oxy-1,2,3-oxa-N-nitrosoglycine (11.50 g, 54.7 mM acetic acid and heated to 70) The reaction mixture was cooled and then water. After stirring for 30 ml: acetic anhydride, the reaction mixture was filtered (100%) of a clear thick oil. N 1 J = 9.2, 2H), 7.08 (d, J = 9.2, 2H 3 H). MS (NH ₃ -CI m / z 193.3 (M + H) ⁺ ).

1- (3-Cyanophenyl) -4-oxy-5-methylthio-1,2,3-oxadiazole:

1- (4-methoxyphenyl) -4-oxy-1,2,3-oxadiazole (2.03 g, 10.6 mmol) was dissolved in 26 mL of dry DMSO and cooled to 0 ° C.

Carefully add acetyl chloride (1.66 g, 21.1 mmol) under a liquid layer under N ₂ . The reaction mixture was stirred at room temperature for 14 hours. Then the reaction mixture was diluted with 10 mL of Et ₂ O and washed twice with 25 mL of saturated aqueous NaHCO ₃ and then three times with 25 mL of water to remove DMF. The organic extract was dried with MgSO ₄ and concentrated in vacuo to give 1.83 g of a red solid which was used without further purification. MS (NH ₃ --Cl) m / z 239.2 (M + H) ⁺ .

Methyl 1- (4-methoxyphenyl) -3-methylthio-pyrazole-5-carboxylate: Crude 1- (4-methoxyphenyl) -4-oxy-5-methylthio-1,2,3-oxadiazole (1,83 g, 7 , 68 mmol) and methyl propiolate (6.45 g, 76.8 mmol) were dissolved in 10 mL of CH ₂ Cl ₂ and the quartz reaction vessel was purged with N ₂ . The reaction mixture is irradiated in a Rayonet RPR-100 photochemical reactor for 14 hours. The crude product was concentrated in vacuo and then chromatographed with 20% EtOAc / hexanes on silica gel to give 1.06 g (49%) of a yellow solid. ¹ H NMR (CDCl ₃ ): δ 7.33 (d, J = 8.8, 2H); 6,95 · · · ,95 ,95 ,95 ,95 ,95 ,95 ,95 ,95 ,95 ,95 ,95 ,95 ,95 ,95

124 (d, J = 8.8, 2H); 6.89 (s, 1H); 3.85 (s, 3H); 3.78 (s, 3H);

2.55 (s, 3H). MS (NH ₃ --Cl) m / z 279.2 (M + H) ⁺ .

N- (2'-tert-Butylaminosulfonyl- [1,1 '] - biphen-4-yl) -1- (4-methoxyphenyl) -3-methylthiopyrazole-5-carboxyamide: Trimethyl aluminum (1.4 ml, 2.0 M in heptane, 2.8 mmol) was added to 2'-tert-butylaminosulfonyl-4-amino- [1,1 '] biphen-4-yl (215 mg, 0.7 mmol) in CH ₂ Cl _{2 2} (5 mL). After stirring at room temperature under N ₂ for 75 minutes, a solution of methyl 1- (4-methoxyphenyl) -3-methylthiopyrazyl-5-carboxylate (197 mg, 0.71 mmol) in CH ₂ Cl ₂ (2 mL) was added and the resulting solution was stirred for 70 hours. The reaction mixture was cooled by the slow addition of 1 M HCl, diluted with H ₂ O and extracted into CH ₂ Cl ₂ . The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was chromatographed on silica gel (30-40% EtOAc / hexanes) to give the desired product (357 mg, 92%). ¹ H NMR (CDCl ₃ ): δ 8.14 (d, 1H, J = 7.7),

7.50 (m, 9H), 7.27 (m, 1H), 7.01 (d, 2H, J = 8.8), 6.83 (s,

1H), 3.87 (s, 3H), 3.57 (s, 1H), 2.59 (s, 3H), 1.01 (s, 9H).

N- ⁽¹ 2 aminosulfonyl- [1,1 '] - biphen-4-yl) -1- (4-methoxyphenyl) -3-methylthio-pyrazole-5-carboxamide: N- (2'-terč.butylaminosulfonyl- [1,1 '] - Biphen-4-yl) -1- (4-methoxyphenyl) -3-methylthiopyrazole-5-carboxyamide (328 mg, 0.60 mmol) was stirred in TFA (5 mL) for 17 h . The solvent was evaporated and the crude product was chromatographed on silica gel (50% EtOAc / hexanes) to give a yellow solid (267 mg, 91%). ¹ H NMR (CDCl ₃ ): δ 10.62 (s, 1H), 7.98 (dd, 1H, J = 7.7, J '= 1.5), 7.62 (d, 2H, J = 8.8), 7.55 (m, 2H), 7.30 (m, 5H), 7.22 (s, 2H), 6.98 (m,

3H), 3.76 (S, 3H), 2.51 (s, 3H).

Example 58

1- (4-Methoxyphenyl) -3- (methylsulfonyl) -N- (5- (2'-methylsulfonylphenyl) pyrimid-2-yl) pyrazole-5-carboxyamide

2-Methylthiophenylboronic acid: 2-Bromothioanisole (29.0 g, • · · ·

143 mmol) was dissolved in dry THF (400 mL) and cooled to -75 ° C. Triisopropyl borate (46 mL, 199 mmol) was then added over 35 minutes. The cold bath was removed and the reaction mixture was stirred at room temperature for 16 hours. The resulting solution was cooled in an ice bath and 6 M HCl (100 mL) was added. The mixture was stirred at room temperature for 5 hours and concentrated to approximately half the original volume. The concentrated solution was partitioned between Et ₂ O and water. The organic layer was extracted with 2M NaOH, then acidified again with 6 M HCl and extracted several times into Et ₂ O. The EtO ₂ washings were dried over Na ₂ SO ₄ , filtered and evaporated to give a beige solid (20.4 g, 85%). ¹ H NMR (CDCl 3): δ 8.01 (dd, 1H, J = 7.3, J '= 1.4), 7.53 (dd, 1H, J = 7.7, J' = 1 1), 7.43 (td, 1H, J =

7.3, J '= 1.8), 7.34 (td, 1H, J = 7.3, J' = 1.5), 6.22 (s,

2H), 2.50 (s, 3H).

2- [Bis (tert-butoxycarbonyl) amino] -5-bromopyrimidine: Sodium hydride (5.06 g, 60%, 127 mmol) was added in 2 portions to 2-amino-5-bromopyrimidine (10.0 g, 57 mmol) in dry THF (500 mL) at 0 ° C. The mixture was stirred for 30 minutes and di-tert-butyl dicarbonate (27.6 g 126 mmol) was added. The resulting mixture was heated at reflux for 17 hours, cooled carefully with water and concentrated. The concentrated mixture was diluted with EtOAc and extracted with water. The combined aqueous layers were extracted with EtOAc.

All organic layers were combined, dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was chromatographed on silica gel (10-15% EtOAc / hexanes) to give the desired product (15.48 g, 72%). ¹ H NMR (CDCl ₃ ): δ 8.78 (s, 2H), 1.47 (s, 18H).

2- [Bis (tert-butoxycarbonyl) amino] -5- (2'-methylthiophenyl) pyrimidine 2- [Bis (tetrabutoxycarbonyl) amino] -bromopyrimidine (2.00 g, 5.3 mmol) was dissolved in benzene (130 mL). Add 2-methylthiophenylboronic acid (2.24 g, 13.3 mmol), aqueous sodium carbonate (13 mL, 2.0 M, 26 mmol), tetrabutylammonium bromide (86 mg, 0.26 mmol) and bis (triphenylphosphine) palladium. (II) chloride (190 mg, 0.27 mmol) and the resulting mixture was first vacuumed and then vacuumed

126

purged with argon and refluxed for 17 hours. The cooled mixture was diluted with EtOAc and water. The layer was separated and the organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product is chromatographed on silica gel (50% EtOAc / hexanes), evaporated and chromatographed a second time on silica gel (30-50% EtOAc / hexanes to give the desired product (2.13 g, 96%). ^Χ NMR (CDCl ₃₎ ): δ 8.81 (s, 2H), 7.41 (m, 2H), 7.25 (m, 2H), 2.39 (s, 3H), 1.49 (s, 18H).

2- [Bis (tert-butoxycarbonyl) amino] -5- (2 ¹ -methylsulfonylfenyl) pyrimidine: 2- [Bis (tert-butoxycarbonyl) amino] -5- (2 ¹ -methylthiofenyl) pyrimidine (2.13 g, 5 , 1 mmol) was dissolved in MeOH (20 mL) and cooled to 0 ° C. In a separate beaker, prepare an Oxone solution (5.49 g) by diluting to 27 ml with water. Part of this solution (17 mL, 5.6 mmol) was removed and adjusted to pH 4.2 with saturated Na ₃ PO ₄ solution (4.7 mL). This mixture was added to the reaction mixture and stirred at room temperature for 23 hours. The resulting mixture was diluted with water and extracted with CHCl ₃ . The organics were combined, washed with water and brine, dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was chromatographed on silica gel (50-100% EtOAc / hexanes) to give the sulfone (1.28 g, 56%). 4 NMR (CDCl ₃ ): δ 8.81 (s, 2H), 8.28 (dd, 1H, J = 7.6, J '= 1.4), 7.72 (m, 2H), 7, 39 (dd, 1H, J = 7.3, J 1 =

1.4), 2.76 (s, 3H), 1.50 (s, 18H).

2-Amino-5- (2'-methylsulfonylphenyl) pyrimidine hydrochloride:

2- [Bis (tert-butoxycarbonyl) amino] -5- (2'-methylsulfonylphenyl) pyrimidine (1.28 g, 2.8 mmol) was suspended in a mixture of HCl and dioxane (10 mL, 4.0 M) and stirred at 20 hours at room temperature. The resulting mixture was triturated with Et ₂ O and filtered to give a white solid (772 mg, 95%). ¹ H NMR (CDCl ₃ + few MeOD drops): δ 8.53 (s, 2H), 8.22 (dd, 1H, J = 7.7,

J '= 1.8), 7.77 (m, 2H), 7.40 (dd, 1H, J = 7.4, J' = 1.5),

2.94 (s, 3H).

127

Methyl 1- (4-methoxyphenyl) -3-methylsulfonyl-pyrazole-5-carboxylate M-CPBA (1.18 g, 57-86%, 3.9 mmol) was added to methyl 1- (4-methoxyphenyl) -3 methyl thiopyrazole-5-carboxylate (434 mg, 1.6 mmol) in CH ₂ Cl ₂ (40 mL) and stirred at room temperature for 24 hours. Additional m-CPBA (600 mg, 57-86%, 1.9 mmol) was added and the mixture was stirred for 2.5 days. The reaction mixture was extracted with saturated Na ₂ SO ₃ and saturated NaHCO ₃ . The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was chromatographed on silica gel (40% EtOAc / hexane) to give the desired product (416 mg, 86%). @ 1 HNMR (CDCl _3): δ 7.46 (s,

1H), 7.36 (d, 2H, J = 8.8), 6.99 (d, 2H, J = 8.8), 3.87 (s,

3H), 3.84 (s, 3H), 3.26 (s, 3H).

1- (4-Methoxyphenyl) -3-methylsulfonyl-pyrazole-5-carboxylic acid: Lithium hydroxide solution (1.3 mL, 1.0 M, 1.3 mmol) was added to the suspension of methyl 1- (4-methoxyphenyl) 3-methylsulfonylpyrazole-5-carboxylate (272 mg, 0.78 mmol) in MeOH (10 mL) and stirred at room temperature for 17 hours. The mixture was concentrated and partitioned between EtOAc and H ₂ 0. The organic extracts were removed and the aqueous extract was acidified with 1 M HCl and extracted twice with EtOAc. The organic extracts from this extraction were combined, dried over Na ₂ SO ₄ , filtered and evaporated to give the product (266 mg). - @ 1 HNMR (CDCl ₃ + few drops MeOD): δ 7.45 (s, 1H), 7.38 (d, 2H, J = 9.2), 6.96 (d,

2H, J = 9.2), 3.86 (s, 3H), 3.25 (s, 3H).

1- (4-Methoxyphenyl) -3- (methylsulfonyl) -N- (5- (2'-methylsulfonylphenyl) pyrimid-2-yl) pyrazole-5-carboxyamide: Oxalyl chloride (120 μΐ, 1.4 mmol) and dry DMF (2 drops) were added at room temperature to 1- (4-methoxyphenyl) -3-methylsulphonylpyrazole by 5-carboxylic acid (262 mg, 0.88 mmol) in dry CH ₂ C1 ₂ (5 mL) and stirred for 2 hours below N ₂ . The solution was evaporated and placed briefly under high vacuum and re-dissolve in CH ₂ C1 _2nd This solution was added over a few minutes to a mixture of 2-amino-5- (2'-methylsulfonylphenyl) pyrimidine hydrochloride (253 mg, 0.89 mmol) and

- 128

Of 4-dimethylaminopyridine (270 mg, 2.2 mmol) in CH 2 Cl 2 (3 mL). The resulting solution was stirred at room temperature under N ₂ for 23 hours, diluted with CH ₂ Cl ₂ , extracted with H ₂ O, dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was chromatographed on silica gel (75-100% EtOAc / hexanes) to give an off-white solid, which was taken up in toluene and filtered to give pure product (191 mg, 41%). ¹ H NMR (CDCl ₃ ): δ 8.65 (s, 2H), 8.62 (s, 1H), 8.24 (d, 1H, J = 7.0), 7.71 (m, 2H) 7.47 (d, 2H, J = 8.8), 7.39 (s, 1H), 7.33 (d, 1H, J = 6.6), 6.98 (d, 2H, J = 8.8), 3.85 (s, 3H), 3.30 (s, 3H), 2.80 (s, 3H).

Example 59

N- ⁽¹ 2 aminosulfonyl- [1,1 '] - biphen-4-yl) -1- (4-methoxyphenyl) -3- (methylsulfonyl) -lH-pyrazole-5-carboxamide

N- (2 ¹ -terč.Butylaminosulfonyl- [1,1 '] - biphen-4-yl) -1- (4-methoxyphenyl) -3- (methylsulfonyl) -lH-pyrazole-5-carboxamide: Trimethyl aluminum (930 μί, 2.0 M in heptane, 1.86 mmol) was added to 2'-tert-butylaminosulfonyl-4-amino- [1,1 '] - biphen-4-yl (142 mg, 0.47 mmol) in CH ₂ Cl ₂ (5 mL). The mixture was stirred at room temperature under N _{2 for} 60 minutes, a solution of methyl 1- (4-methoxyphenyl) -3-methylsulfonylpyrazole-5-carboxylate (145 mg, 0.47 mmol) in CH ₂ Cl ₂ (2 mL) was added and the resulting solution was stirred for 51 hours. The reaction mixture was carefully cooled by dropwise addition of 0.1 M HCl, diluted with water and extracted twice into CH ₂ Cl ₂ . The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give the desired product (277 mg, 100%).

¹ H NMR (CDCl ₃ ): δ 8.21 (bs, 1H), 8.16 (dd, 1H, J = 7.6, J '= 1.1), 7.57 (m, 3H), 7 46 (m, 5H), 7.39 (s, 1 H), 7.27 (d, 1 H,

J = 7.3), 6.99 (d, 2H, J = 8.8), 3.86 (s, 3H), 3.31 (s, 3H), 1.03 (S, 9H).

N- ⁽¹ 2 aminosulfonyl- [1,1 '] biphen-4-yl) -1- (4-methoxyphenyl) -3- (methylsulfonyl) -lH-pyrazole-5-carboxamide:

N- (2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl) -1- (4 •)

- 129

-methoxyphenyl) -3- (methylsulfonyl) -1H-pyrazole-5-carboxyamide (274 mg, 0.47 mmol) was stirred in TFA (5 mL) for 74 hours. The solvent was evaporated. The crude product was recrystallized from CHCl ₃ to give a white solid (236 mg, 95%). ¹ H NMR (CDCl ₃ + few drops MeOD): δ 8.13 (d, 1H, J = 7.7), 7.67 (d, 2H, J = 8.4), 7.59 (t, 1H J = 6.3), 7.46 (m, 6H), 7.32 (d, 1H, J = 8.5), 7.00 (d, 2H, J = 9.2), 3.86 (s, 3H), 3.31 (s, 3H).

Example 60

N- (4-Benzoylpyrrolidine) -1- (4-methoxyphenyl) -3- (methylthio) -1H-pyrazole-5-carboxyamide

1- (4-Methoxyphenyl) -3-methylthio-1H-pyrazole-5-carboxylic acid: A solution of lithium hydroxide (4.5 mL, 1.0 M, 4.5 mmol) was added to a suspension of methyl 1- (4- methoxyphenyl) -3-methylthio-1H-pyrazole-5-carboxylate (840 mg, 3.0 mmol) in MeOH (30 mL) and stirred at room temperature for 21 hours. The resulting mixture was concentrated and partitioned between EtOAc and H ₂ O. The organic layer was removed and the aqueous layer was acidified with 1 M HCl and extracted twice with EtOAc. The combined organic extracts were dried over Na ₂ SO ₄ , filtered and evaporated to give a clear product (784 mg, 98%). ¹ H NMR (CDCl ₃ ): δ 7.33 (d, 2H, J = 8.4),

6.97 (s, 1H), 6.95 (d, 2H, J = 8.4), 3.85 (s, 3H), 2.55 (s,

3H).

N- (4-Benzoylpyrrolidine) -1- (4-methoxyphenyl) -3- (methylthio) -1H-pyrazole-5-carboxyamide: Oxalyl chloride (140 μΐ, 1.6 mmol) and dry DMF (2 drops) are added at at room temperature to 1- (4-methoxyphenyl) -3- (methylthio) -lH-pyrazole-5-carboxylic acid (275 mg, 1.0 mmol) in dry CH ₂ C1 ₂ (8 mL) and stirred for 100 minutes under N ₂ . The solution was evaporated and briefly subjected to high vacuum and redissolved in CH ₂ C1 ₂ (8 mL) and add (4-aminobenzoyl) pyrrolidine (198 mg, 1.0 mmol) then 4-dimethylaminopyridine (190 mg, 1.6 mmol). The resultant mixture is stirred with stirring. at room temperature for 17 hours, diluted with CH ₂ Cl ₂ and extracted with H ₂ O. The aqueous extract was extracted with CH ₂ Cl ₂ , and the combined organic extracts were extracted with brine. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was chromatographed on silica gel (75-100% EtOAc / hexanes) to give the desired product (464 mg, 100%).

1 H-NMR (CDCl ₃ ): δ 7.91 (bs, 1H), 7.44 (s, 4H), 7.39 (d, 2H, J = 8.8), 6.97 (d, 2H) J = 8.8), 6.83 (s, 1H), 3.84 (s, 3H), 3.62 (t, 2H, J = 6.6), 3.42 (t, 2H, J) = 6.6), 2.57 (s, 3H), 1.91 (m, 4H).

Example 61

1- (4-Methoxyphenyl) -N- (5- (2'-methylsulfonylphenyl) -pyrimid-2-yl) -3- (methylthio) -1H-pyrazole-5-carboxyamide

1- (4-Methoxyphenol) -N- (5- (2'-methylsulfonylphenyl) pyrimid-2-yl) -3- (methylthio) -1H-pyrazole-5-carboxyamide: Trimethyl aluminum (1.5 mL, 2, 0 M in heptane, 3.0 mmol) was added to 2-amino-5- (2'-methylsulfonylphenyl) pyrimidine hydrochloride (208 mg, 0.73 mmol) in CH ₂ Cl ₂ (5 mL). Stir the mixture at room temperature under N ₂ for 75 min, add a solution of methyl 1- (4-methoxyphenyl) -3-methylthio-1H-pyrazole-5-carboxylate (203 mg, 0.73 mmol) in CH ₂ Cl ₂ (2 mL) and the resulting solution was stirred for 70 hours. The mixture was cooled cautiously by the dropwise addition of 1 M HCl, diluted with HCl and extracted into CH ₂ C1 _2nd The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was chromatographed on silica gel (50-100% EtOAc / hexanes) to give the desired product (101 mg, 28%). This material was combined with 19 mg of the second reaction product and purified by preparative HPLC on a C18 reverse phase column

(30-100% MeCN / H ₂ O / 0.5% TFA) to give a white powder (111 mg) ¹ H NMR (CDC1 _3): δ 8.67 (with, J = 2H), 8.24 9.1), 7.33 (d, (d, 1H, J = 7.3), 1H, J = 8.4), 7.71 6.96 (m, 2H) 7.44 (d, 2H,, (d, 2H, J = 9.2), 6.86 (with, 1H), 3.84 (with, 3H), 2.79 (S, 3H),

2.59 (s, 3H).

• ·

131 Example 62

N- (4-Benzoylpyrrolidine) -1- (4-methoxyphenyl) -3- (methylsulfonyl) -1H-pyrazole-5-carboxyamide

N- (4-Benzoylpyrrolidine) -1- (4-methoxyphenyl) -3- (methylsulfonyl) -1H-pyrazole-5-carboxyamide: N- (4-benzoylpyrrolidine) -1- (4-methoxyphenyl) -3- (methylthio) 1 H -pyrazole-5-carboxyamide (200 mg, 0.46 mmol) was dissolved in MeOH (6 mL). A solution of Oxone (561 mg, 0.91 mmol) in H ₂ O (3 mL) was added and the resulting mixture was stirred at room temperature under Ar for 17 h. The reaction mixture was diluted with H ₂ O and extracted twice with CHCl ₃ . The combined organic extracts were dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was purified by preparative HPLC on a C-18 reverse phase column (10-70% MeCN / H ₂ O / 0.5% TFA) to give a white powder (200 mg, 93%). ¹ H NMR (CDCl ₃ ): δ 8.98 (s, 1H), 7.52 (s, 1H),

7.39 (m, 6H), 6.95 (d, 2H, J = 8.8), 3.84 (s, 3H), 3.65 (t,

2H, J = 6.6), 3.41 (t, 2H, J = 6.2), 3.28 (s, 3H), 1.93 (m,

4H).

Example 63

N- ⁽¹ 2 aminosulfonyl- [1,1 '] - biphen-4-yl) -1- (4-methoxyphenyl) -3- (methoxymethyl) -lH-pyrazole-5-carboxamide

Ethyl 3- (bromomethyl) -1- (4-methoxyphenyl) -1H-pyrazole-5-carboxylate and ethyl 3- (dibromomethyl) -1- (4-methoxyphenyl) -1H-pyrazole-5-carboxylate: Ethyl 1- ( 4-methoxyphenyl) -3-methyl-lH-pyrazole-5-carboxylate (2.00 g, 7.83 mmol) was dissolved in 30 ml CC1 ₄ and N-bromosuccinimide (3.06 g, 17.2 mmol ) and benzoyl peroxide (0.02 g, 0.08 mmol). The reaction mixture was heated for 48 hours and then cooled to room temperature. The succinimide was filtered off and the solvent was evaporated. The reaction mixture was chromatographed on silica gel (20% EtOAc / hexanes) to give 0.94 g (36%) of the monobromide. ¹ 1 HNMR (CDCl _3): δ 7.34 (d, J = »4 4"> · 4 4 »4 * 4 C 44" 4 4 · 4

4444 4 4 4 * · 4 • · 444 4 · 4 · 44 4 44

4 4

44 444 4444 »

132

8.8, 2H); 7.06 (s, 1H); 6.96 (d, J = 8.8, 2H); 4.53 (s, 2 H); 4.24 (q, J = 7.0, 2H); 3.85 (s, 3H); 1.27 (t, J = 7.0, 3H). Dibromide (0.34 g, 10%) was also isolated. ¹ H NMR (CDCl ₃ ): δ 7.34 (d, J = 9.1, 2H); 7.31 (s, 1H); 6.96 (d,

J = 9.1, 2H); 6.73 (s, 1H); 4.26 (q, J = 7.0, 2H); 3.85 (s, 3H); 1.29 (t, J = 7.0, 3H).

1- (4-Methoxyphenyl) -3- (methoxymethyl) -1H-pyrazole-5-carboxylic acid: Ethyl 3- (bromomethyl) -1- (4-methoxyphenyl) -1H-pyrazole-5-carboxylate (0.50 g) (1.47 mmol) was dissolved in 12 mL of 0.5 NaOMe in methanol and heated at reflux for 14 h. The reaction mixture was cooled and reduced to 1/10 of the original volume. The reaction mixture was dissolved in 20 mL of water and extracted with EtOAc. The aqueous mixture was acidified with 1 N HCl and extracted with EtOAc to give 0.236 g (61%) of the desired product. A mixture of ethyl and methyl esters (about 0.05 g) was found in the first EtOAc extract. ¹ H NMR (CDCl 3): δ 7.32 (d, J =

8.8, 2H); 7.11 (s, 1H); 6.94 (d, J = 8.8, 2H); 4.54 (s, 2 H);

3.85 (s, 3H); 3.44 (s, 3H).

N- (2'-tert-Butylaminosulfonyl- [1,1 '] - biphen-4-yl) -1- (4-methoxyphenyl) -3- (methoxymethyl) -1H-pyrazole-5-carboxyamide: Oxalyl chloride (460 mg, 3.6 mmol) and dry DMF (2 drops) were added at room temperature to 1- (4-methoxyphenyl) -3- (methoxymethyl) -1H-pyrazole-5-carboxylic acid (236 mg, 0.90 mmol) ) in dry CH ₂ Cl ₂ (5 mL) and stirred for 2 hours under N ₂ . The resulting solution was evaporated and placed under high vacuum for a short time and redissolved in CH ₂ Cl ₂ (2 mL). This solution was added over a few minutes to a mixture of tert-butylaminosulfonyl-4-amino- [1,1 '] -biphen-4-yl (288 mg, 0.945 mmol) in 5 mL of CH ₂ Cl ₂ . The resulting solution was stirred at room temperature under N ₂ for 23 hours, diluted with CH ₂ Cl ₂ , extracted with H ₂ O, dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was chromatographed on silica gel (30% EtOAc / hexanes) to give a white solid (110 mg, 22%). MS (ESI) mlz 571.0 (M + Na) ⁺ .

133

N- (2'-Aminosulfonyl- [1,1 '] -biphen-4-yl) -1- (4-methoxyphenyl) -3- (methoxymethyl) -1H-pyrazole-5-carboxyamide: N- (2' - tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl) -1- (4-methoxyphenyl) -3- (methoxymethyl) -1H-pyrazole-5-carboxyamide (110 mg, 0.20 mmol) was dissolved in 5 ml of TFA and stirred at room temperature for 16 hours. The solvent was removed and the product was purified by preparative HPLC on a C-18 reverse phase column (10-90% MeCN / H ₂ O / 0.05% TFA) to give a white powder (94 mg, 95%).

¹ H NMR (CDCl ₃ ): δ 8.15 (d, J = 8.1, 1H); 7.73 (br s, 1H);

7.53 (m, 4H); 7.43 (m, 4 H); 7.32 (d, J = 7.3, IH); 7.01 (s,

1H); 6.96 (d, J = 9.2, 2H); 4.59 (s, 2 H); 4.26 (brs, 2H);

3.86 (s, 3H); 3.49 (s, 3H). HRMS m / z 493.1546 (M + H) &lt; + & gt ^; .

Example 64

N- (2'-Aminosulfonyl- [1,1 '] - biphen-4-yl) -1- (4-methoxyphenyl) -3-carbomethoxy-py-pyrazole-5-carboxyamide

3-Formyl 1- (4-methoxyphenyl) -1H-pyrazole-5-carboxylic acid: Ethyl 3- (dibromomethyl) -1- (4-methoxyphenyl) -1H-pyrazole-5-carboxylate (0.34 g, 0.813 mmol) was dissolved in 2 mL THF and lithium hydroxide (34 mg, 0.816 mmol) dissolved in 0.5 mL water was added to the methanolic solution. The mixture was stirred at room temperature for 16 hours and the solvent was evaporated and the residue was dissolved in 10 ml of water, acidified with 1 N HCl and extracted with EtOAc to give 66 mg (33%) of the desired product. ^{Χ Η} NMR (CDC1 _3): δ 10.06 (s, 1H); 7.56 (s, 1 H); 7.40 (d, J = 9.1, 2H); 7.01 (d, J = 9.1, 2H); 4.54 (s, 2 H); 3.88 (s, 3H).

N- (2'-tert-Butylaminosulfonyl- [1,1 '] -biphen-4-yl) -3-formyl-1- (4-methoxyphenyl) -1H-pyrazole-5-carboxyamide: Oxalyl chloride (20 mL) and dry DMF (2 drops) was added at room temperature to 3-formyl 1- (4-methoxyphenyl) -1H-pyrazole-5-carboxylic acid (66 mg, 0.25 mmol) in dry CH ₂ Cl ₂ (5 ° C ₎ . (Ml) and mix. 2 hours under N ₂ . The resulting solution was evaporated and placed under high vacuum for a short time and redissolved in CH ₂ Cl ₂ (2 mL). This solution was added over a few minutes to a mixture of 2'-tert-butylaminosulfonyl-4-amino- [1,1 '] - biphen-4-yl (51 mg, 0.17 mmol) in 2 mL of CH ₂ Cl ₂ .

The resulting solution was stirred at room temperature under N ₂ for 23 hours, diluted with CH ₂ Cl ₂ , extracted with H ₂ O, dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was chromatographed on silica gel (30% EtOAc / hexanes) to give a white solid (16.2 mg, 11%). ¹ H NMR (CDCl 3): δ 10.09 (s, 1H); 8.16 (d,

J = 8.1, 1H); 7.77 (br s, 1H); 7.56 (m, 3H); 7.49 (m, 4H);

7.40 (m, IH); 7.25 (m, 2 H); 7.04 (d, J = 8.8, 2H); 3.89 (s,

3H); 3.61 (brs, 1H); 1.02 (s, 9H).

N- (2 ¹ -terč.Butylaminosulfonyl- [1,1 '] - biphen-4-yl) -3-carbomethoxy-1- (4-methoxyphenyl) -lH-pyrazole-5-carboxamide N- (2'- tert-Butylaminosulfonyl- [1,1 '] - biphen-4-yl) -3-formyl-1- (4-methoxyphenyl) -1H-pyrazole-5-carboxyamide (16.2 mg, 0.03 mmol), KCN (6.9 mg,

0.11 mmol), activated manganese dioxide (100 mg) and acetic acid (1.7 μΐ, 0.03 mmol) are dissolved / suspended in 1 ml of methanol and stirred at room temperature for 24 hours. The reaction mixture was filtered through celite and evaporated to 14 mg (82%) of the desired product. 1 H NMR (CDCl 3): δ 8.16 (d, J = 8.1, 1H);

7.67 (br. S, 1H); 7.53 (m, 3H); 7.48 (m, 4H); 7.27 (m, 2 H);

7.02 (d, J = 8.8, 2H); 3.99 (s, 3H); 3.87 (s, 3H); 1.02 (s,

9H).

N- ⁽¹ 2 aminosulfonyl- [1,1 '] - biphen-4-yl) -3-carbomethoxy-1- (4-methoxyphenyl) -lH-pyrazole-5-carboxamide: N- (2'-tert. Butylaminosulfonyl- [1,1 '] - biphen-4-yl) -3-carbomethoxy-1- (4-methoxyphenyl) -1H-pyrazole-5-carboxyamide (14 mg, 0.02 mmol) was dissolved in 2 mL of TFA and stirred at room temperature for 16 hours. The solvent was removed and the product was purified by preparative HPLC on a C-18 reverse phase column (10-90% MeCN / H ₂ O / 0.05% TFA to give a yellow powder (9 mg, 81%).

¹ H NMR (CDCl 3): δ 8.16 (d, J = 8.1, 1H); 7.67 (br. S, 1H);

135

7.50 (m, 11H); 7.31 (d, J = 7.0, 1H); 7.00 (d, J = 8.8, 2H); 4.59 (s, 2 H); 4.20 (brs, 2H); 3.99 (s, 3H); 3.87 (s, 3H). HRMS m / z 507.1260 (M + H) &lt; + & gt ^; .

Example 65

N- (2'-tert-Aminosulfonyl- [1,1 '] - biphen-4-yl) -1- (4-methoxyphenyl) -3- (methylsulfonylmethyl) -1H-pyrazole-5-carboxyamide

Ethyl 1- (4-methoxyphenyl) -3- (methylsulfonylmethyl) -1H-pyrazole-5-carboxylate: Ethyl 3- (bromomethyl) -1- (4-methoxyphenyl) -1H-pyrazole-5-carboxylate (0.4440 g, 1 , 31 mmol) was dissolved in 10 mL of THF with potassium thiomethoxide (0.248 g, 2.88 mmol) and the mixture was heated under reflux for 14 hours. The reaction mixture was cooled and reduced to 1/10 of the original volume. The reaction mixture was dissolved in 20 mL of water and extracted with EtOAc and oxidized with air for 24 hours to give 0.358 g of crude material. The product was purified by preparative reverse phase C-18 HPLC (10-90% MeCN / H ₂ O / 0.05% TFA) to give 47 mg of a white powder (11%) of the desired product. ¹ H NMR (CDCl ₃ ): δ 7.32 (d, J = 8.8, 2H); 7.18 (s, 1 H); 6.97 (d, J = 8.8, 2H);

4.37 (s, 2 H); 4.25 (q, J = 7.1, 2H); 3.86 (s, 3H); 1.28 (t, J = 7.1, 3H).

N- (2'-tert-Butylaminosulfonyl- [1,1 '] - biphen-4-yl) -1- (4-methoxyphenyl) -3- (methylsulfonylmethyl) -1H-pyrazole-5-carboxyamide: Trimethyl aluminum (0 , 41 mL, 2.0 M in heptane, 0.83 mmol) was added to 2 ¹ -terč.butylaminosulfonyl-4-amino- [1.1 ^1] biphen-4-yl (50.6 mg, 0.166 mmol) in CH ₂ Cl ₂ (5 mL). Stir the mixture at room temperature under N ₂ for 75 minutes, add a solution of ethyl 1- (4-methoxyphenyl) -3- (methylsulfonylmethyl) -1H-pyrazole-5-carboxylate (47 mg, 0.139 mmol) in CH ₂ Cl _{2 2} (2 ml) and the resulting solution was stirred for 70 hours. The reaction mixture was carefully cooled by dropwise addition of 1 M HCl, diluted with H ₂ O, and extracted into CH ₂ Cl ₂ . The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was purified by preparative HPLC

136 on C-18 reverse phase column (10-90% MeCN / H ₂ O / 0.05% TFA) to give the desired product (80 mg, 100%). @ 1 HNMR (CDCl _3): δ

8.16 (d, J = 8.1, IH); 7.76 (br s, 1H); 7.49 (m, 8H); 7.27 (m, IH); 7.08 (m, IH); 7.01 (d, J = 8.8, 2H); 4.41 (s, 2 H);

3.87 (s, 3H); 2.96 (s, 3H); 1.02 (ε, 9H).

N- (2'-Aminosulfonyl- [1,1 '] - biphen-4-yl) -1- (4-methoxyphenyl) -3- (methylsulfonylmethyl) -1H-pyrazole-5-carboxyamide: N- (2'ter) Butylaminosulfonyl- [1,1 '] - biphen-4-yl) -1- (4-methoxyphenyl) -3- (methylsulfonylmethyl) -1H-pyrazole-5-carboxyamide (80 mg,

0.15 mmol) was dissolved in 2 mL TFA and stirred at room temperature for 16 hours. The solvent was removed and the residue was purified by preparative reverse phase C-18 HPLC (10-90% MeCN / H ₂ O / 0.5% TFA) to give a white powder (47 mg, 58%). ^{Χ Η} NMR (CDC1 _3): δ 8.16 (d, J = 8.1, 1H); 8.06 (brs,

1H); 7.60 (m, 4H); 7.44 (m, 4H); 7.33 (m, IH); 7.09 (br s,

1H); 7.01 (d, J = 9.1, 2H); 4.43 (s, 2 H); 4.38 (br d, 2H);

3.87 (s, 3H); 2.97 (s, 3H). HRMS m / z 541.1137 (d + H) ⁺ .

Example 66

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (5- (2-methanesulfonyl) phenyl) pyrimidin-2-yl) carboxyamide

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (5- (2-methanesulfonyl) phenyl) pyrimidin-2-yl) carboxyamide: This material was prepared according to the procedure described in Example 15 with except that during the coupling step, 4- (2-N-tert-butylaminosulfonyl) phenyl) aniline is replaced by 2-amino-5- (2-methanesulfonyl) phenyl) pyrimidine. Purification by HPLC utilizes a gradient elution of water: acetonitrile with 0.5% trifluoroacetic acid on a reverse phase C18 (60 A) column to give a clear sample of the title compound; HRMS (M + H) ⁺ calcd m / z: 518.110986, found 518.108715.

Example 67 • ·

- 137

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5-N- (4- (N-carboxyl-2-carbomethoxypyrrolidine) phenyl) carboxyamide

N- (4-Nitrobenzoyl) -2-carbomethoxypyrrolidine: K

2-carbomethoxypyrrolidine (d, 1-proline methyl ester, 1.64 g, 12.7 mmol) with pyridine (10.1 g, 12.7 mmol) in CH ₂ Cl ₂ (100 mL) at 0 ° C is added after dropwise 4-nitrobenzoyl chloride (2.36 g, 12.7 mmol) in CH ₂ C1 _2nd The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was evaporated and flash chromatographed on silica gel, eluting with a gradient of 2: 1 hexane: EtAc to 1: 2 hexane: EtOAc. Thus, 1.3 g of the title compound is isolated; LRMS (M + H) &lt; + & gt ^; m / z = 279.

N- (4-Aminobenzoyl) -2-carbomethoxypyrrolidine:

N- (4-nitrobenzoyl) -2-carbomethoxypyrrolidine (0.54 g, 1.94 mmol) in MeOH (50 mL) with 10% Pd-C (0.10 g) was shaken under an atmosphere of H ₂ gas (3.515 kg) / cm ² ) for 4 hours.

Filter the reaction mixture through a pad of Celite ^R and evaporate to give 0.41 g of aniline; LRMS (M + H) &lt; + & gt ^; m / z = 249.

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5-N- (4- (N-carboxyl-2-carbomethoxypyrrolidine) phenyl) carboxyamide: This compound was prepared according to the methodology described in Example 19 except that in the coupling step, N- (4-aminobenzoyl) -2-carbomethoxypyrrolidine was used in place of 2-amino-5- (N-pyrrolidinecarbonyl) pyridine. The solvent was evaporated, the residue was dissolved in ethyl acetate and washed with water. After drying and removal of the solvent, the crude product was purified by HPLC using a gradient elution of water: acetonitrile with 0.5% trifluoroacetic acid on a reverse phase C18 (60 A) column to give a clear solution of the title compound; mp 46 ° C, HRMS (M + H) ⁺ calcd m / z: 462.190320, found 462.188795.

• · <

138

Example 68

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5-N- (4- (N-carboxyl-3-aminopyrrolidine) phenyl) carboxyamide

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5-N- (4- (N-carboxyl-3azidopyrrolidin) phenyl) carboxyamide: K 3-methyl-1- (4-methoxyphenyl) -1H-pyrazole -5-N- (4- (N-carboxyl-3-hydroxypyrrolidine) phenyl) carboxyamide (prepared in Example 21, 0.14 g, 0.33 mmol) with Et 2 N (0.05 g, 0.5 mmol) ) in CH ₂ Cl ₂ was added methanesulfonyl chloride (0.057 g, 0.05 mmol). After 18 hours the reaction was complete. The mixture was evaporated, dissolved in EtOAc, washed with 1 N HCl, dried and evaporated. There was thus obtained 0.21 g of methanesulfonate; LRMS (M-SO ₂ CH ₃ ) ⁺ m / z = 403.

The methanesulfonate prepared above (0.17 g, 0.35 mmol) and sodium azide (0.11 g, 1.76 mmol) in DMF (10 mL) were heated at 60 ° C for 4 hours. Brine was added to the cooled reaction mixture, and the suspension was extracted with EtOAc (3x).

The combined extracts were washed with water (5x), dried (MgSO ₄₎ and evaporated to give 0.10 g of the azide; LRMS (MN2) ^& _lt ; ^{+ &gt;} m / z = 418.

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5-N- (4- (N-carboxyl-3-aminopyrrolidine) phenyl) carboxyamide: Azide prepared above (0.10 g, 0.22 mmol) in MeOH (20 mL with 10% Pd-C was stirred under H ₂ (1 atm). After 2 h, the reaction was purged with N ₂ , filtered through a pad of Celite ^R and evaporated. The crude product was purified by HPLC using gradient elution with a mixture of water and acetonitrile with 0.05% trifluoroacetic acid on a C18 (60 A) reverse phase column to give a clear sample of the title compound, mp 133.4 ° C HRMS (M + H) ⁺ calculated m / from: 420.203565, found: 420.203373.

Example 69

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5-N- (4- (N-carboxyl-3)

(methoxypyrrolidin) phenyl) carboxyamide

4- (N-carboxyl-3-methoxypyrrolidine) aniline: K

3-hydroxypyrrolidine hydrogen chloride (1.63 g, 14.9 mmol) and triethylamine (1.51 g, 14.9 mmol) in dichloromethane (50 mL) at 0 ° C was added a solution of p-nitrobenzoyl chloride (2.5 g) , 12.4 mmol) in dichloromethane (50 mL). The reaction mixture was evaporated to dryness and the residue was dissolved in ethyl acetate. This solution was washed with 1 N hydrochloric acid and brine, then dried and evaporated to give 2.22 g of product; LRMS (M + H) &lt; + & gt ^; m / z:

237.

To a suspension of NaH (0.16 g 60% suspension in mineral oil, 6.89 mmol) in THF (30 mL) was added dropwise a solution of the hydroxy compound prepared above (0.65 g, 2.75 mmol) in THF (10 mL). ). The reaction mixture was cooled to 0 ° C and methyl iodide (0.43 g, 3.03 mmol) was added. The reaction mixture was stirred at ambient temperature for 24 hours. The reaction mixture was diluted with Et ₂ O and washed with 0.5 N NH 4 Cl and brine, then dried and evaporated to give methyl ether (0.47 g); LRMS (M + H) &lt; + & gt ^; m / z = 251.

Methyl ether (0.42 g, 1.68 mmol) in MeOH (50 mL) with 10% Pd-C (0.05 g) was stirred under an atmosphere of H ₂ gas (1 atm) for 3 hours. Rinse the reaction with N ₂ , filter through a pad of Celite ^R and evaporate to give 0.28 g of aniline;

LRMS (M + H) &lt; + & gt ^; m / z = 221.

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5-N- (4- (N-carboxyl-3methoxypyrrolidine) phenyl) carboxyamide: This compound was prepared according to the methodology described in Example 19 except that in the coupling step using 4- (N-carboxyl-3-methoxypyrrolidino) aniline instead of 2-amino-5- (N-pyrrolidinecarbonyl) pyridine. The solvent was evaporated, the residue was dissolved in ethyl acetate and washed with water. After drying and removal of the solvent, the crude product is purified by HPLC using a gradient of 0.05% water: acetonitrile gradient

140 trifluoroacetic acid on C18 (60 A) reverse phase column to give a clear solution of the title compound; mp 40.2 ° C, HRMS (M + H) ⁺ calculated m / z: 434.195406, found 434.194469.

Example 70

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (5- (2-aminosulfonyl) phenyl) pyridin-2-yl) carboxyamide

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (5- (2-aminosulfonyl) phenyl) pyridin-2-yl) carboxyamide: This material was prepared according to the procedure described in Example 15 with except that during the coupling step, 4- (2-N-t-butylaminosulfonyl) phenyl) aniline is replaced by 2-amino-5- (2-N-t-butylaminosulfonyl) phenyl) pyridine. The tert-butylsulfonamide group is removed by heating the coupling product at room temperature in TFA for 1 hour and then removing the TFA by distillation in vacuo. Purification of the final product by HPLC utilizes a gradient elution of water: acetonitrile with 0.5% trifluoroacetic acid on a reverse phase C18 (60 A) column to give a clear sample of the title compound; HRMS (M + H) ⁺ calcd m / z: 518.110986, found 518.112930.

Example 71

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-amidino) phenyl) carboxyamide. TFA

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-cyano) phenyl) carboxyamide: To 3-trifluoromethyl-5-methyl-1- (4-methoxyphenyl) -ΙΗ-pyrazole (Example 15, 0.6 g, 2.1 mmol) in CH ₂ Cl ₂ at 0 ° C was added oxalyl chloride in CH ₂ Cl ₂ (2 M solution, 1.6 mL,

3.15 mmol) followed by a few drops of DMF. The reaction mixture was allowed to warm to ambient temperature and stirred for 18 hours. The reaction mixture was heated to 50 ° C. · ·· · «····· · · ··

141 pumped off for several hours to remove the last HCl residue. The acid chloride was combined with p-aminobenzonitrile (0.3 g, 2.52 mmol) and DMAP (0.77 g, 6.3 mmol) in CH ₂ C1 ₂ (40 ml) and stirred at ambient temperature for 18 hours. The reaction mixture was evaporated and partitioned between 1 N HCl and EtOAc. The EtOAc layer was dried and evaporated to give 0.79 g of crude product. Further purification was performed by MPLC with a 200 g flash silica gel column, eluting with 3: 1 hexane: EtOAc and collecting 25 mL fractions. 45 g of the desired nitrile are obtained from fractions 30 to 65; 188.2, HRMS (M + H) ⁺ calculated m / z: 386.09081, found: 386.098101.

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (O-methyl) formimino) phenyl) carboxyamide. HCl: An anhydrous HCl gas stream was passed through a solution of 3-trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (cyano) phenyl) carboxyamide) (255 mg, 0.58 mmol) in dry MeOAc (25 mL) and dry MeOH (5 mL) at 0 ° C until saturation The mixture was allowed to stand for 18 hours at 10 ° C, then a tightly closed vessel was opened and the solvent was removed by distillation in vacuo. is repeatedly distilled with dry Et ₂ O and then pumped for several hours to remove the last HCl residue.

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-amidino) phenyl) carboxyamide. TFA: The imidate (0.58 mmol) prepared above was dissolved in dry MeOH (10 mL) and (NH ₄ ) ₂ CO ₃ (0.32 g, 3.33 mmol) was added. The mixture was stirred at ambient temperature for 18 hours and then evaporated to dryness. Purification of the final product was performed by HPLC using a gradient elution of water: acetonitrile with 0.05% trifluoroacetic acid on a C18 (60 A) reverse phase column to give a clear sample of the title compound; mp 232.5, HRMS (M + H) ⁺ calcd m / z 404.133435, found 404.132331.

Example 72 • ·

- 142

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (N-pyrrolidin) formylimino) phenyl) carboxyamide. TFA

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (N-pyrrolidin) formylimino) phenyl) carboxyamide. TFA: 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (0-methyl) formimino) phenyl) carboxyamide. The HCl (Example 71, 0.58 mmol) prepared above was dissolved in dry MeOH (10 mL) and pyrrolidine (0.12 g, 1.74 mmol) was added. The mixture was stirred at ambient temperature for 18 hours, then evaporated to dryness. Purification of the final product was performed by HPLC using a gradient of water: acetonitrile with 0.5% trifluoroacetic acid in reverse phase on a C18 (60 A) column to give a clear sample of the title compound; mp 89.5, HRMS (M + H) ⁺ calculated m / z: 458.180385, found 458.183032.

Example 73

3-Trifluoromethyl-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl)) -1- (4-methoxyphenyl) pyrrolo [3,4-d] pyrazole-4,6 - (1H, 5H) -dione

1.1.1-Trifluoroacetaldehyde-N- (4-methoxyphenyl) hydrazone: A mixture of ethyl 1,1,1-trifluoroacetaldehyde hemiacetal (4.2 g, 34.17 mmol) and 4-methoxyphenylhydrazine. HCl (4.97 g, 28.48 mmol) in EtOH (100 mL) was heated to reflux and cooled to room temperature once all components were dissolved. The reaction mixture was evaporated to dryness to give 5.34 g of a dark oil which was used in the next step without further purification; LRMS (M + H) &lt; + & gt ^; m / z = 219.2.

1.1.1-Trifluoroacetoyl bromide-N- (4-methoxyphenyl) hydrazone: To the dark oil prepared above (0.87 g, 4 mmol) in DMF (25 mL) was added N-bromosuccinimide (O, O) in portions at 0 ° C. 72 g, mmol). The reaction was complete in 2 hours (TLC, 3: 1 hexane: EtOAc). The reaction mixture was diluted with brine and extracted

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 The extracts were washed with brine (5x), dried (MgSO 4) and evaporated to give 0.69 g of the product as a dark oil. This material was used without further purification.

4- (2-N-t-butylaminosulfonyl) phenyl) bromo-maleimide: Bromo-maleic anhydride (0.29 g, 1.65 mmol) was added to 4- (2-N-t-butylaminosulfonyl) phenyl) aniline (0.5 g, 1.65 mmol) in THF (10 mL). After 1 hour, the solution was cooled to 0 ° C and N-methylmorpholine (0.2 g, 1.98 mmol) was added followed by isobutyl chloroformate (0.27 g, 1.98 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred for 18 hours. The reaction mixture was evaporated, dissolved in EtOAc, washed with 1 N HCl, dried and evaporated. The product was further purified by MPLC using a 200 g flash silica gel column eluting with 3: 1 hexane: EtOAc and collecting 25 mL fractions. The desired product (0.39 g) was isolated from fraction 35-65; HRMS (M + H) ⁺ calcd m / z: 462.024890, found: 462.025783.

3-Trifluoromethyl-5- (N- (2'-Nt-butylaminosulfonyl- [1,1 '] - bifen-4-yl)) - 1- (4-methoxyphenyl) pyrrolo [3,4-d] pyrazole-4 6- (1H, 5H) -dione: A mixture of 1,1,1-trifluoroacetyl bromide-N- (4-methoxyphenyl) hydrazone (0.68 g, 2.29 mmol) and 4- (2-N-tert. butylaminosulfonyl) phenyl) bromomaleimide (0.2 g, 0.4 mmol) with Et ₃ N (0.35 g, 3.45 mmol) in toluene was heated at reflux for 3 h. The reaction mixture was diluted with EtOAc, washed with 1 N HCl, dried (MgSO ₄ ) and evaporated to give 0.35 g of crude product. The product was isolated by MPLC eluting the crude material from a flash silica gel column (200 g) with 3: 1 hexane: EtOAc and collecting 251 fractions. Fraction 33-58 gives 0.15 g of pure material; mp 196.1 ° C, HRMS (M + H) ⁺ calculated m / z: 653.165176, found: 653.16600.

3-Trifluoromethyl-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl)) -1- (4-methoxyphenyl) pyrrolo [3,4-d] pyrazole-4, 6- (1H, 5H) -dione: The product from above (0.15 g, 0.25 mmol) was heated at reflux for 1 hour. The reaction cools »»

144 and evaporation gave 0.14 g of crude material. The product was isolated using MPLC eluting the crude material from a flash silica gel column (200 g) with 2: 1 hexane: EtOAc and collecting 25 mL fractions. Fractions 55-90 are combined and triturated with a little Et ₂ O. By this method 0.06 g of pure material; mp 210.7 ° C, HRMS (M + H) ⁺ m / z: 543.09002, found: 543.097942.

Example 74

3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5-carbomethoxy (N- (2 ¹ aminosulfonyl- [1,1 '] biphen-4-yl)) carboxyamide and EXAMPLE 75

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5-hydroxymethyl- (N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl)) carboxyamide

Preparation of a mixture of 3-trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5-carbomethoxy- (N- (2'-N-tert-butylaminosulfonyl- [1,1 '] -biphen-4-yl)) carboxyamide and 3 - Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5-hydroxymethyl- (N- (2'-N-tert-butylaminosulfonyl- [1,1 '] -biphen-4-yl)) carboxyamide: 3- Trifluoromethyl-5- (N- (2'-N-tert-butylaminosulfonyl- [1,1 '] -Toifen-4-yl)) -1- (4-methoxyphenyl) pyrrolo [3,4-d] pyrazole-4 6- (1H, 5H) -dione (0.37 g, 0.62 mmol) in AcCN (30 mL) was added dropwise at 0 ° C to a solution of NaBH ₄ (0.096 g, 2.48 mmol) in MeOH (20 mL). The reaction was complete in less than 1 hour (TLC, 3: 1 hexane: EtOAc).

The mixture was evaporated, dissolved in EtOAc and washed with 1 N HCl. The organic layer was dried and evaporated to give a mixture of the title compounds (0.37 g). This mixture was separated by MPLC using a 400 g flash silica gel column eluting with 2: 1 hexane: EtOAc; 25 ml of eluent fraction were collected.

3-Trifluoromethyl-1- (4-methoxyphenyl) -ΙΗ-pyrazole-5-carbomethoxy- (N- (2'-N-tert-butylaminosulfonyl-145)) was isolated from fractions 50-66. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

[1,1 '] - biphen-4-yl)) carboxyamide (0.15 g); HRMS (M + Na) ⁺ calculated m / z: 653.165761, found: 653.164400.

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5-hydroxymethyl- (N- (2'-N-tert-butylaminosulfonyl- [1,1 '] - biphen-4) was isolated from fractions 69-100. -yl) carboxyamide (0.12 g); HRMS (M + Na) ⁺ calculated m / z: 625.170847, found 625.169900.

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5-carbomethoxy- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl)) carboxyamide: Product from fractions 50- 66 (0.15 g) was heated to reflux in TFA for 1 hour. The reaction was cooled and evaporated to give 0.14 g of crude material. Purification of the final HPLC product using a gradient elution of water: acetonitrile with 0.05% trichloroacetic acid on a C18 reverse phase column (60 A) gave a pure sample of Example 74; mp 233.3 ° C, HRMS (M + H) ⁺ calculated m / z: 575.121216, found: 575.120500.

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5-hydroxymethyl- (N- (2-aminosulfonyl- [1,1 '] -bifen-4-yl)) carboxyamide: Product from fractions 69-100 (0.12 g) was heated at reflux for 1 hour. The reaction was cooled and evaporated to give 0.11 g of crude material. Purification of the final product by HPLC using a gradient elution of water: acetonitrile with 0.05% trifluoroacetic acid in reverse phase with a C18 (60 A) column gave a pure sample of Example 75; mp 115.4 ° C, HRMS (M + H) ⁺ calculated m / z: 547.126302, found:

547.124400.

Example 76

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N-2-fluoro (4- (N-pyrrolidino) formylimino) phenyl) carboxyamide. TFA

3-Fluoro-4-nitrobenzamide: 3-fluoro-4-nitrobenzoic acid (5.0 g, 27 mmol) and SOCl ₂ (6.42 g, 54 mmol) with a few drops

146

DMF in benzene (100 mL) was heated at reflux for 3 hours. The reaction mixture was evaporated to dryness, then evaporated several times with Et ₂ O to give 5.56 g of pure material.

The acid chloride prepared above was dissolved in EtOAc (50 mL) and added dropwise to a 0 ° C biphasic mixture of EtOAc (150 mL) and concentrated NH 4 OH (100 mL). After 30 minutes, the layers were separated, the aqueous layer was saturated with NaCl and extracted with EtOAc. The combined organic extracts were dried and evaporated to give 4.85 g of benzamide; LRMS / ES ^- (MH) m / z = 182.9.

3-Fluoro-4-aminobenzonitrile: To 0 ° C EtOAc (150 mL) solution

3- fluoro-4-nitrobenzamide (4.85 g, 26.4 mmol) and Et ^ N (5.34 g, 52.8 mmol) was added dropwise a CH ₂ C1 ₂ (50 mL) solution of 1.1 1-trichloroacetyl chloride (5.28 g, 29.04 mmol). The reaction was complete in 2 hours (TLC, 1: 1 hexane: EtOAc) and then the mixture was washed with 1 N HCl, dried (MgSO ₄ ) and evaporated to give 4.1 g of the corresponding nitrile.

The 4-nitrobenzonitrile derivative prepared above (4.1 g, 24.7 mmol) in EtOH / water (80 mL / 40 mL) was heated to reflux with powdered iron 8.3 g, 148 mmol) and NH ₄ Cl (0). , 83 g, 15.3 mmol) for 2 hours. The reaction mixture was filtered and evaporated to dryness. The residue was dissolved in EtOAc, washed with brine and dried (MgSO ₄ ) to give 2.68 product; LRMS (M + H) &lt; + & gt ^; m / z = 137.0. The product was further purified by MPLC on a 360 g flash silica gel column eluting with 3: 1 hexane: EtOAc; 25 ml fractions were collected. Fractions 128-195 gave 1.32 g of pure product.

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (2-fluoro-4-cyano) phenyl) carboxyamide: To 3-trifluoromethyl-5-methyl-1- (4-methoxyphenyl) 1 H-pyrazole (Example 15, 1.13 g, 3.95 mmol) in CH ₂ Cl ₂ (100 mL) was added at 0 ° C oxalyl chloride in CH ₂ Cl ₂ (2 M solution, 2.96 mL, 5 mL). , 93 mmol) and then a few drops of DMF. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. It is then evaporated and drained for a period of time.

147 hours to remove the last HCl residue.

The acid chloride was combined with 3-fluoro-4-aminobenzonitrile (0.59 g, 4.35 mmol) and DMAP (1.45 g, 11.85 mmol) in CH ₂ C1 ₂ (100 ml) and stirred at neighborhood 18 hours. The reaction mixture was evaporated and partitioned between 1 N HCl and EtOAc. The EtOAc layer was dried and evaporated to give 0.79 g of crude product. Further purification was performed by MPLC with a 360 g flash silica gel column eluting with 4: 1 hexane-EtOAc and collecting 25 mL fractions.

0.83 g of the desired nitrile was obtained from fractions 91-133; mp 160.6, LRMS (M + H) ⁺ m / z = 405.0.

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (2-fluoro-4- (O-methyl) formimino) phenyl) carboxyamide. HCl: An anhydrous HCl gas stream was passed through a solution of 3-trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-cyano) phenyl) carboxyamide (0.83 g, 2.05 mmol) in dry MeOAc (50 mL) and dry MeOH (10 mL) at 0 ° C until saturation. After standing for 18 hours at 10 ° C, the sealed vessel is opened and the solvent is removed by vacuum distillation. The residue was repeatedly evaporated with dry Et ₂ O and then pumped for several hours to remove the HCl residue.

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (2-fluoro-4- (N-pyrrolidino) formylimino) phenyl) carboxyamide. TFA: 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (2-fluoro-4- (0-methyl) formimino) phenyl) carboxyamide. The HCl (2.05 mmol) prepared above was dissolved in dry MeOH (15 mL) and pyrrolidine (0.44 g, 6.15 mmol) was added. The mixture was stirred at ambient temperature for 18 hours and then evaporated to dryness. Purification of the final HPLC product using a gradient elution of water / acetonitrile with 0.05% trifluoroacetic acid in reverse phase on a C18 (60 A) column gave a pure sample of the title compound, mp 61.8 ° C, HRMS (M + H) ⁺ calcd m / z: 476.170963, found: 476.170693.

148

·· ······· · ·

Example 77

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (N-pyrrolidino) formyl-N - ((2-propyl) methylcarbamoyl) imino) phenyl) carboxyamide

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (N-pyrrolidine) formyl-N - ((2-propyl) methylcarbamoyl) imino) phenyl) carboxyamide: K 3- trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (N-pyrrolidine) formylimino) phenyl) carboxyamide. TFA (Example 72, 0.311 g) was added with 1 N NaOH (25 mL) and the resulting suspension was extracted with CH ₂ Cl ₂ (2 x 35 mL). The organic extracts were dried and evaporated to give 0.18 g (0.39 mmol) of the free base. The free base was redissolved in CH ₂ Cl ₂ (20 mL) and cooled to 0 ° C and then Et ₃ N (0.08 g, 0.78 mmol) was added. 4.4 ml (0.44 mmol) of a 0.1 N solution of isobutyl chloroformate (0.01 mol [1.3 ml] of pure isobutyl chloroformate in 100 ml of CH ₂ Cl ₂ are added dropwise to the cooled solution and the mixture is stirred at 0 ° The reaction mixture was evaporated and partitioned between EtOAc and 1 N HCl The EtOAc layer was dried and evaporated to give 0.10 g of crude material, which was further purified by MPLC using 200 g of flash silica gel and eluting with 2 90.1 ° C, HRMS (M + H) ⁺ calcd m / z: 558.2345, found: 558: 1 hexane: EtOAc 25 mL fractions were collected and 40-80 fractions were collected from 40-80 fractions. , 2334.

Example 78

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (N-pyrrolidino) formyl-N- (methanesulfamoyl) imino) phenyl) carboxyamide

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (N-pyrrolidino) formyl-N- (methanesulfamoyl) imino) phenyl) carboxyamide

To 3-trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (N-pyrrolidin) formylimino) phenyl) carboxyamide. TFA

149 (Example 72, 0.332 g) was added with 1 N NaOH (25 mL) and the resulting suspension was extracted with CH ₂ Cl ₂ (2 x 35 mL). The organic extracts were dried and evaporated to give 0.18 g (0.39 mmol) of the free base. The free base was redissolved in CH ₂ Cl ₂ (25 mL) and cooled to 0 ° C before DMAP (0.095 g, 0.78 mmol) was added. To the cooled solution was added dropwise 4.2 mL (0.42 mmol) of a 0.1 N solution of methanesulfonyl chloride (0.01 mol [0.78 mL] of pure methanesulfonyl chloride in 100 mL of CH ₂ Cl ₂ ) and the mixture was stirred at 0 ° C for 48 hours. The reaction mixture was evaporated and partitioned between EtOAc and 1 N HCl. The EtOAc layer was dried and evaporated to give 0.11 g of crude material. This was further purified by MPLC using 200 g of flash silica gel eluting with 2: 1 hexane: EtOAc. 25 ml of fraction were collected and 0.050 g of pure product was isolated from fractions 81-130; mp 117.2 ° C, HRMS (M + H) ⁺ m / z found: 558.2334.

Example 79

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N - ((4-amidino) phenyl) methyl) carboxyamide. TFA α-Amino-4-cyanotoluene: A mixture of 4-cyanobenzyl bromide (3 g, 15.3 mmol) and NaN ₃ (1.99 g, 30.6 mmol) in DMF (20 mL) was stirred at ambient temperature for 18 h. hours. The reaction mixture was diluted with brine and extracted with EtOAc. The organic extracts were washed with brine (5x), dried (MgSO ₄₎ and evaporated to give 1.87 g of the benzylic azide product.

The benzyl azide (1.87 g, 11.84 mmol) and SnCl ₂ .H ₂ O (7.25 g, 32.2 mmol) in MeOH (50 mL) was stirred at ambient temperature for 18 hours. The solution was evaporated to dryness and then the residue was dissolved in 1 N NaOH and extracted with EtOAc. The EtOAc layer was washed with brine, dried and evaporated to give 0.83 g of α-amino-4-cyanotoluene.

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N - ((4150)

cyano) phenyl) methyl) carboxyamide: To 3-trifluoromethyl-5-methyl-1- (4-methoxyphenyl)-1,4-pyrazole (Example 15, 0.4 g, 1.4 mmol) and N-methylmorpholine (0.156 g, Isobutyl chloroformate (0.21 g, 1.54 mmol) was added at 0 ° C in CH ₂ Cl ₂ (30 mL). The reaction mixture was stirred at 0 ° C for 30 min and 0.203 g of N 1 -amino-4-cyanotoluene (1.54 mmol) in CH ₂ Cl ₂ (8 mL) was added. After 18 hours, the reaction mixture was washed with 1 N HCl and 1 N NaOH, dried and evaporated to give 0.54 g of crude material. Further purification was performed by MPLC with a column of 200 g of flash silica gel, eluting with 2: 1 hexane: EtOAc and collecting 25 mL fractions. 0.32 g of the desired nitrile is obtained from fractions 61-120; mp 197.5 ° C, LRMS (M + H) ⁺ m / z = 401.0.

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N - ((2-fluoro-4- (O-methyl) formimino) phenyl) methyl) carboxyamide. HCl: A stream of anhydrous HCl gas is passed through a solution of 3-trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N - ((4-cyano) phenyl) methyl) carboxyamide (0.32 g, 0.8 mmol) in dry MeOAc (25 mL) and dry MeOH (5 mL) until the solution is saturated.

After standing for 18 hours at 10 ° C, the sealed vessel is opened and the solvent is removed by vacuum distillation. The residue was repeatedly evaporated with dry Et ₂ O, then pumped for several hours to remove the last HCl residue.

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N - ((4-amidino) phenyl) methyl) carboxyamide. TFA: The imidate (0.4 mmol) prepared above was dissolved in dry MeOH (15 mL) and (NH ₄ ) ₂ CO ₃ (0.192 g, 2.0 mmol) was added. The mixture was stirred at ambient temperature for 18 hours and then evaporated to dryness. Purification of the final product by HPLC using a gradient elution of water: acetonitrile with 0.05% trifluoroacetic acid in reverse phase on a C18 (60 A) column gave a pure sample of the title compound; mp 131.4 ° C, HRMS (M + H) ⁺ found m / z: 418.1478.

Example 80 • ·

- 151

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N - ((4- (N-pyrrolidino) formylimino) phenyl) methyl) carboxyamide. TFA

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N - ((4- (N-pyrrolidino) formylimino) phenyl) methyl) carboxyamide. TFA: 3-trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N - ((4- (0-methyl) formimino) phenyl) methyl) carboxyamide. The HCl (Example 79, 0.4 mmol) prepared above was dissolved in dry MeOH (15 mL) and pyrrolidine (0.09 g, 1.2 mmol) was added. The mixture was stirred at ambient temperature for 18 hours, then evaporated to dryness. Purification of the final product was by HPLC using a gradient elution of water: acetonitrile with 0.05% trifluoroacetic acid in reverse phase on a C18 (60 A) column to give a pure sample of the title compound: LRMS (M + H) ⁺ m / from: 472.3.

Example 81

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N - ((1-benzyl) piperidin-4-yl) carboxyamide) TFA

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- ((1-benzyl) piperidin-4-yl) carboxyamide) TFA: K 3-Trifluoromethyl-5-methyl-1- (4 -methoxyphenyl) -ΙΗ-pyrazole (Example 15, 2.86 g 10 mmol) and N-methylmorpholine (1.01 g, 10 mmol) in THF (50 mL) at 0 ° C was added isobutyl chloroformate (1.36 g) The reaction mixture was stirred at 0 ° C for 30 min and 1.90 g of 1-benzyl-4-aminopiperidine (10 mmol) was added, and after 18 hours the reaction mixture was evaporated to dryness and dissolved in 1 N NaOH and then extracted with EtOAc, the EtOAc layer was washed with brine and then dried and evaporated to give 4.36 g of crude material, recrystallization with n-butyl chloride to give 1.16 g of the product, mp 120.8 ° C.

Dissolve 0.10 g of the sample in Et ₂ O and add TFA to form

- 152

TFA salt. Trituration with Et ₂ O and n-butyl chloride afforded 0.015 g of pure product; mp 175.6 ° C, HRMS (M + H) ⁺ calculated m / z: 459.200, found: 459.199.

Example 82

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- ((1- (pyridin-2-yl) methyl) piperidin-4-yl) carboxyamide) TFA

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (piperidin-4-yl) carboxyamide) HCl: To a solution of 3-trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5 - (N- ((benzyl) piperidin-4-yl) carboxyamide Example 81, 1.06 g, 2.31 mmol) in CH ₂ Cl ₂ (40 mL) was added 1-chloroethyl chloroformate (0.5 g, 3, The reaction mixture was stirred for 2 hours and then evaporated to dryness, the residue was dissolved in MeOH (50 mL) and heated at reflux for 1 hour.

LRMS (M + H) &lt; + & gt ^; m / z: 369.2.

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- ((1- (pyridin-2-yl) methyl) piperidin-4-yl) carboxyamide) TFA: K 3-Trifluoromethyl-1 - (4-methoxyphenyl) -1H-pyrazole-5- (N- (piperidin-4-yl) carboxyamide) HCl (0.21 g) and K ₂ CO ₃ (θ ' ^{3 in AcOH} (20 mL) were added picolyl chloride (0.16 g) The reaction mixture was stirred at ambient temperature for 18 hours, diluted with water and extracted with EtOAC (3x), dried (MgSO ₄ ) and evaporated to give 0.29 g of crude product. final product was performed by HPLC using a gradient elution method of water: acetonitrile with 0.05% trifluoroacetic acid in reverse phase on a C18 (60 A) column to give a pure sample of the title compound LRMS (M + H) ⁺ m / from: 460.3.

Example 83

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (2153) ········

(methylimidazo-1-yl) phenyl) carboxyamide. TFA

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (2-methylimidazo-1-yl) phenyl) carboxyamide) TFA: A mixture of 3-trifluoromethyl-5-methyl-1- ( 4-methoxyphenyl) -1H-pyrazole (Example 15, 0.20 g, 0.7 mmol), BOP (0.44 g, 1 mmol), Et 2 N (0.1 g, 1 mmol) and 1- ( 4-Aminophenyl) -2-methylimidazole (0.17 g, 1 mmol) in DMF (20 mL) was heated at 50-55 ° C for 1 hour, then cooled to room temperature and stirred for 18 hours. Dilute with water and extract with EtOAc.

The EtOAc extracts were washed with water (5x), dried (MgSO ₄ ) and evaporated. Purification of the final HPLC product using a gradient elution of water / acetonitrile with 0.05% trifluoroacetic acid on a C18 (60 A) column gave a pure sample of the title compound; mp 103.7 ° C, HRMS (M + H) ⁺ m / z: 442.188.

Example 84

3-Methyl- (4-methoxy) phenyl-1H-pyrazole-5- (N- {4- (5-methyl-imidazol-1-yl} phenyl) carboxyamide and Example 85

3-Methyl- (4-methoxy) phenyl-1H-pyrazole-5- (N- {4- (5-methyl-imidazol-1-yl} phenyl) carboxyamide,

N- (4-nitrophenyl) -5-methylimidazole: A solution of p-nitrofluorobenzene (2 g, 14 mmol) in DMF (20 mL) was treated with potassium carbonate (8 g, 58 mmol) and 4-methylimidazole (1.2 g). , 14 mmol). The mixture was heated under reflux for 18 hours, the reaction mixture was cooled and concentrated under reduced pressure. The residue was treated with water and the mixture was extracted with ethyl acetate and dried over magnesium sulfate. The organic layer was concentrated and the residue was purified by flash chromatography (methanol / methylene chloride, 0.5: 9.5) to give 1.8 g (62%).

- 154

p-nitro-4 (S) -methylimidazol-1-yl as a 7: 1 mixture of regioisomers).

N- (4-aminophenyl) -5-methylimidazole: Reduction in MeOH: TFA (9.5: 0.5) with 0.1 eq. Pd / C (10%) at 3.867 kg / cm ² at ambient temperature for 20 hours followed by filtration through celite gave 1.4 g (93%) of p-amino-4 (S) -methylimidazol-1-yl.

Preparation of a mixture of 3-methyl- (4-methoxy) phenyl-1H-pyrazole-5- (N- {4- (5-methylimidazol-1-yl} phenyl) carboxyamide and 3-methyl- (4-methoxy) phenyl-1H-pyrazole -5- (N- {4- (4-methyl-imidazol-1-yl} phenyl) carboxyamide: A solution of 3-methyl-1- (4-methoxyphenyl) -1H-pyrazolecarboxylic acid (200 mg, 0.8 mmol) in acetonitrile (5 mL) was treated with an excess of thionyl chloride and the resulting mixture was heated at reflux for 2 h, then cooled, concentrated, dissolved in methylene chloride (5 mL) and treated with DMAP (0.22 mg, 1 mL). 8 mmol) and N- (4-aminophenyl) -5-methylimidazole (131 mg, 0.7 mmol) The reaction mixture is stirred at ambient temperature for 18 hours, the residue is treated with water and the mixture is extracted with ethyl acetate and dried The organic layer was concentrated and the residue was purified by flash chromatography (methanol / methylene chloride, 0.5: 9.5) to give a mixture of 3-methyl- (4-methoxy) phenyl-1H-pyrazole-5- ( N- {4- (5-methylimidazol-1-yl} phenyl) carboxyamide and 3-methyl- (4-methoxy) phenyl-1H- pyrazole-5- (N- {4- (4-methylimidazol-1-yl} phenyl) carboxyamide. The final products were purified by normal phase HPLC eluting with solvent A (hexane) and solvent B (ethanol) using 80% A and 20% B and eluting at 7.5 ml / min.

Example 84: 3-Methyl- (4-methoxy) phenyl-1H-pyrazole-5- (N- {4- (5-methylimidazol-1-yl} phenyl) carboxyamide: ¹ H NMR (CDCl 3):

2.19 (s, 3H), 2.38 (s, 3H), 3.85 (s, 3H), 6.76 (s, 1H), 6.97 (m, 2H), 7.14 (m 1 H, 7.25 (m, 2H), 7.39 (m, 2H), 7.50 (s,

1H), 7.71 (m, 2H), 8.05 (s, 1H).

• ·

- 155 · · 155 155 155 155 155 155 155 155

- · * · * * • * * * * φ φ φ

Example 85: 3-Methyl- (4-methoxy) phenyl-1H-pyrazole-5- (4- {4- (4-methylimidazol-1-yl} phenyl) carboxyamide: 1 H NMR (CDCl ₃ ): 2, 31 (s, 3H), 2.36 (s, 3H), 3.83 (s, 3H), 6.71 (s, 1H), 6.94 (m, 3H), 7.26 (m, 2H) 7.39 (m, 2H), 7.58 (m, 2H), 7.92 (s, 1H), 8.23 (s, 1H).

Example 86

3-Trifluoromethyl- (4-methoxy) phenyl-1H-pyrazole-5- (N- {4- (5-carbomethoxyimidazol-1-yl) phenyl) carboxyamide

Butyl glyoxyl (4-nitroanilino) imine: A solution of p-nitroaniline (6.3 g, 53.4 mmol) in ethyl alcohol (50 mL) was treated with n-butylgluoxylate (8 g, 53.8 mmol). After stirring for 18 hours, the reaction mixture was concentrated under reduced pressure. The residue was treated with water and the mixture was extracted with ethyl acetate and dried over magnesium sulfate. The organic layer was concentrated to give the title compound in almost quantitative yield, which was used without further purification.

4-Amino- (5- (carbomethoxy) imidazol-1-yl) benzene: To a solution of butyl glyoxyl (4-nitroanilino) imine (1.6 g, 6.9 mmol) in methanol (10 mL) is added potassium carbonate ( 1,9 g,

13.9 mmol) and tosylmethyl isocyanate (2.3 g, 11.8 mmol). The solution was stirred for 1 hour at room temperature and then the solvent was evaporated under reduced pressure. The residue was treated with saturated sodium chloride solution and extracted with methylene chloride. The organic extract was concentrated and triturated with methanol. The precipitate was collected and dried to give intermediate 4-nitro- (5- (carbomethoxy) imidazol-1-yl) benzene (1.5 g, 94%). MS (ES) m / z (rel intensity), 249 (M &lt; + &gt;, 100).

Reduction to 4-amino- (5- (carbomethoxy) imidazol-1-yl) benzene was carried out according to the procedure described in Examples 84 and 85; MS (ES) m / z (rel intensity), 219 (M &lt; + &gt;, 100).

- 156

3-Trifluoromethyl- (4-methoxy) phenyl-1H-pyrazole-5- (N- {4- (5-carbomethoxy-imidazol-1-yl} phenyl) carboxyamide: Solution

4-amino- (5- (carbomethoxy) imidazol-1-yl) benzene (152 mg, 0.7 mmol) was coupled with 3-trifluoromethyl (4-methoxy) phenyl-1H-pyrazole-5-carbonyl chloride (205 mg) (0.7 mmol) according to the procedure described in Examples 84 and 85. Purification by flash chromatography (methanol / methylene chloride, 1: 9) yielded

3-Trifluoromethyl- (4-methoxy) phenyl-1H-pyrazole-5- (N- {4- (5-carbomethoxyimidazo-1-yl) phenyl) carboxyamide (70 mg, 20%); MS (ES) m / z (rel intensity) 486 (M &lt; + &gt;, 100).

Example 87

3-Trifluoromethyl- (4-methoxy) phenyl-1H-pyrazole-5- (N- {4- (5-carboxyimidazol-1-yl} phenyl) carboxyamide

3-Trifluoromethyl- (4-methoxy) phenyl-1H-pyrazole-5- (N- {4- (5-carboxyimidazol-1-yl} phenyl) carboxyamide): 3-Trifluoromethyl- (4-methoxy) phenyl-1H-pyrazole -5- (N- {4- (5-carbomethoxyimidazol-1-yl} phenyl) carboxyamide (147 mg, 0.3 mmol) was suspended in a 4: 1 mixture of THF and water and treated with LiOH (37 mg, 0 The reaction mixture was stirred at room temperature for 1 hour, neutralized with 1 N HCl, extracted with ethyl acetate, dried over MgSO _4, and concentrated to give the acid.The final product was purified by reverse phase HPLC. Vydec C-18 column eluting with solvent mixture A (water: TFA, 99.5: 0.5) and solvent mixture B (acetonitrile: water: TFA, 90: 9.5: 0.5) using a gradient starting from from A at 100% and change over 60 minutes to B at 100%; MS (ES) m / z rel intensity), 471.9 (M +, 100).

Examples 88-90

Crude acid, 3-trifluoromethyl- (4-methoxy) phenyl-1H-pyrazole-5- (N- {4- (5-carboxyimidazol-1-yl} phenyl) carboxyamide,

- 157 -.........

Dissolve in acetonitrile, treat with excess thionyl chloride and heat at reflux for 2 hours. The solvent was removed under reduced pressure. Coupling with the amines specified below was carried out according to the procedure described in Examples 84 and 85 to give the compounds of Examples 88 to 90. The final products were purified by reverse phase HPLC on Vydec ^R on column C-18 eluting with solvent mixture A (water: TFA, 99.5: 0.5) and solvent mixture B (acetonitrile: water: TFA, 90: 9.5: 0.5), using a gradient starting from A at 100% and changing to B at 100% over 60 minutes Examples 88 to 90 of trifluoroacetic acid salt are obtained.

Example 88: 3-Trifluoromethyl- (4-methoxy) phenyl-1H-pyrazole-5- (N- {4- (5-N-methylcarbamidimidazol-1-yl} phenyl) carboxyamide: Preparation using excess N-methylamine.HCl 1 H NMR (CDCl ₃ ): 2.89 (d, J = 4.7 Hz, 3H), 6.13 (m, 1H), 6.98 (d, 1H);

J = 9.1 Hz, 3H), 7.15 (d, J = 8.8 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H), 7.48 (m, 3H) , 7.59 (s, 1H), 8.79 (s, 1H).

Example 89: 3-Trifluoromethyl- (4-methoxy) phenyl-1H-pyrazole-5- (N- {4- (5-carbamidimidazol-1-yl} phenyl) carboxyamide: Prepared by saturating a 0 ° C CH ₂ Cl ₂ solution acid chloride with NH ₃ gas: MS (ES) m / z (rel intensity), 468.9 (M +, 100).

Example 90: 3-Trifluoromethyl- (4-methoxy) phenyl-1H-pyrazole-5- (N- {4- (5-methylsulfonylcarbamide-1-imidazole} phenyl) carboxyamide Prepared using methanesulfonamide as the amine component; MS ( ES) m / z (rel intensity), 546.9 (M +, 100).

Example 91

1- (4'-Methoxyphenyl) -3-hydroxylmethyl-1H-pyrazole-5-N- (4'-pyrrolidinocarbonyl) phenyl) carboxyamide

1- (4'-Methoxyphenyl) -3-hydroxylmethyl-1H-pyrazole-5-ethyl

158 carboxylate: To a solution of 1- (4'-methoxyphenyl) -3-methyl-py-pyrazole-5-ethylcarboxylate (1.58 g, 7.1 mmol) in CCl ₄ (250 mL) was added NBS (1.5 mL). g, 8.5 mmol) and benzoyl peroxide (73 mg, 4 mmol%). The mixture was degassed and charged with nitrogen, refluxed under nitrogen for 18 hours, and then cooled to room temperature. The mixture was diluted with CH ₂ Cl ₂ (100 mL), washed with 10% NaOH (20 mL x 3), water (20 mL x 3) and brine (10 mL x 2), and dried over MgSO ₄ . Filtration and concentration gave crude 1- (4'-methoxyphenyl) -3-bromomethyl-1H-pyrazole-5-ethylcarboxylate (2.4 g). To a solution of the crude in aqueous DMSO (75%, 40 mL) was added Cu ₂ O (1.5 g, 10.5 mmol) and the mixture was stirred at 60 ° C for 2 hours. The mixture was filtered to remove Cu ₂ O and the filtrate was extracted with ethyl ether. The ether layer was washed with brine (10 mL x 5) and dried over MgSO ₄ . Filtration and concentration followed by purification by silica gel column chromatography with EtOAc / CH ₂ Cl ₂ (1: 1) gave the title compound (1.5 g, 81% yield). ESMS (M + H) &lt; + & gt ^; m / z: 277.

1- (4-Methoxyphenyl ¹⁾ -3-hydroxylmethyl-lH-pyrazole-5-N- (4'-pyrrolidinocarbonyl) phenyl) carboxyamide: To a solution of 4- (pyrrolidinyl-one) aniline (390 mg, 2.05 mmol) in CH ₂ Cl ₂ (20 mL) at 0 ° C was added AlMe 2 (2 M in hexane, 3 mmol). The mixture was stirred at room temperature for 15 minutes and then a solution of 1- (4'-methoxyphenyl) -3-hydroxymethylene-lH-pyrazole-5ethylkarboxylátu (560 mg, 2.05 mmol) in CH ₂ C1 ₂ (5 mL).

The resulting mixture was stirred overnight, cooled with water (5 mL) and filtered through a pad of celite to remove Al (OH) ₃ . The filtrate was washed with water and brine and dried over MgSO ₄ . Filtration, concentration and purification by silica gel column chromatography with solvent gradient (CH ₂ Cl ₂ - EtOAc) gave the title compound (570 mg, 67% yield). ESMS (M + Na) ⁺ m / z: 443. HRMS (M + H) ⁺ calculated m / z: 420.1798, found: 420.1771.

Example 92 · · · · · · · · · ·

- £ 5

1- (4'-Methoxyphenyl) -3-formaldehyde-1H-pyrazole-5-N- (4 '- (pyrrolidinocarbonyl) phenyl) carboxyamide

To a solution of 1- (4-methoxyphenyl) -3-hydroxylmethyl-1H-pyrazole-5-N- (4'-pyrrolidinocarbonyl) phenyl) carboxyamide 6 (140 mg, 0.33 mmol) in THF (20 mL) was added MnO ₂ (435 mg, 4.95 mmol) and the resulting mixture was heated to reflux for 12 hours. The mixture was filtered to remove excess MnO ₂ and the filtrate was concentrated to give Example 92 (100%) as a white solid. ESMS (M + H) &lt; + & gt ^; m / z: 419.

Example 93

1- (4'-Methoxyphenyl) -5-N- (4 '- (pyrrolidinocarbonyl) anilide) -1H-pyrazol-3-yl-carboxylic acid

1- (4'-Methoxyphenyl) -5-N- (4 '- (pyrrolidinocarbonyl) anilide) -1H-pyrazol-3-yl-carboxylic acid: To a solution of AgNO ₃ (34 mg, 0.2 mmol) in H ₂ 0 (0.5 mL) was added at 0 ° C NaOH (16 mg, 0.4 mmol), and a solution of 1- (4'-methoxyphenyl) -3-formaldehyde-1H-pyrazole-5-N - ((4 1-pyrrolidinocarbonyl) phenyl) carboxyamide (Example 92, 42 mg, 0.1 mmol) in MeOH (0.5 mL). The mixture was stirred at room temperature for 30 minutes and then carefully acidified with conc. hydrochloric acid (35 mL) to pH 2 and concentration gave a residue which was purified by silica gel column chromatography with solvent gradient (CH ₂ Cl ₂ : EtOAc) to give the title compound (25 mg, 58%). ESMS (M + Na) &lt; + & gt ^; m / z 456.9.

Example 94

1- (4'-Methoxyphenyl) -3-methylcarboxylate-1H-pyrazole-5-N- (4'-pyrrolidinocarbonyl) phenyl) carboxyamide

1- (4'-Methoxyphenyl) -3-methylcarboxylate-1H-pyrazole-5-N- (4 ')

-pyrrolidinocarbonyl) phenyl) carboxyamide: To a solution of 1- (4'-methoxyphenyl) -3-formaldehyde-1H-pyrazole-5-N- (4'-pyrrolidinocarbonyl) phenyl) carboxyamide (Example 92, 42 mg, 0.1 mmol) ) in MeOH (1 mL) was added KCN (7.8 mg, 0.12 mmol), HOAc (7.2 mg, 0.12 mmol) and MnO ₂ (120 mg, 0.83 mmol) and the resulting mixture was Stir at room temperature for 12 hours. The mixture was diluted with EtOAc (50 mL), washed with water (10 mL x 3) and brine, and dried over MgSO ₄ . The solution was filtered, concentrated and purified by silica gel column chromatography with EtOAc to give the title compound (38 mg, 85% yield). ESMS (M + Na) &lt; + & gt ^; m / z 471.

Example 95

1- (4'-Methoxyphenyl) -3-cyanomethyl-1H-pyrazole-5-N- (4'-pyrrolidinocarbonyl) phenyl) carboxyamide

1- (4'-Methoxyphenyl) -3-cyanomethyl-1H-pyrazole-5-N- (4'-pyrrolidinocarbonyl) phenyl) carboxyamide: To a solution of 1- (4'-methoxyphenyl) -3- (hydroxylmethyl-1H-pyrazole) -5-N - ((4'-pyrrolidinocarbonyl) phenyl) carboxyamide (120 mg, 0.29 mmol) in CH ₂ Cl ₂ (15 mL) was added MsCl (48 mg, 0.43 mmol) and Et ₃ N ( 44 mg, 0.43 mmol) The mixture was stirred at room temperature for 2 hours and then concentrated The solution of the residue in DMF (3 mL) was treated with NaCN (43 mg, 0.87 mmol) and stirred for 16 hours EtOAc (50 mL) and water (5 mL) were added to the reaction mixture, and the EtOAc layer was washed with brine (10 mL x 5), dried over MgSO ₄ , concentrated, and purified by TLC on silica gel eluting with EtOAc to give the compound. title title (57 mg, 46%) ESMS (M + Na) ⁺ m / z 430.

Example 96

2- (1 '- (4' methoxyphenyl) -5 ¹ - (4 ¹ '-pyrrolidinokarbonyl) ^{anilide-lH-pyrazol-3-1-yl)} acetic acid

2- (1 '- (4' '- Methoxyphenyl) -5' - (4 '' - pyrrolidinocarbonyl) anilide - 161

-1H-pyrazol-3'-yl) acetic acid: To 1- (4'-methoxyphenyl) -3-cyanomethyl-1H-pyrazole-5-N - ((4'-pyrrolidinocarbonyl) phenyl) carboxyamide (27 mg, 0.063) mmol) was added 6 N HCl (1 mL) and the resulting mixture was stirred at 75 ° C for 16 hours. The mixture was extracted with EtOAc and the organic layer was dried over MgSO ₄ , concentrated and purified by silica gel TLC eluting with 20% MeOH in EtOAc to give the title compound (2 mg, 7%). MS (ES -) (MH) ^&lt; ^{+ &gt;} m / z: 447.

Example 97

1- (4'-Methoxyphenyl) -3, -bromomethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide:

1- (4'-Methoxyphenyl) -3-hydroxylmethyl-1H-pyrazole-5-N- (2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide: To a solution of 4- (2 tert -Butylaminosulfonylphenyl) aniline (1.33 g, 4.3 mmol) in CH ₂ Cl ₂ (40 mL) was added at 0 ° C with AlMe ₃ (2 M in hexane, 6.5 mmol). The mixture was stirred at room temperature for 30 minutes and a solution of 1- (4 ¹ methoxyphenyl) -3-hydroxylmethyl-lH-pyrazole-5-ethylkarboxylátu (1.09 g, 3.95 mmol) in CH ₂ C1 ₂ (5 ml) and the resulting mixture was heated at reflux for 6 hours and cooled with water (5 ml). The mixture was filtered through a pad of Celite and the filtrate was washed with water and brine and dried over MgSO ₄ . Filtration, concentration and purification by silica gel column chromatography with solvent gradient (CH ₂ Cl ₂ : EtOAc to 10% MeOH / EtOAc) gave the title compound (1.8 g, 85%). ESMS (M + H) &lt; + & gt ^; m / z: 535.

1- (4'-Methoxyphenyl) -3-bromomethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide: To a solution of 1- (4'- methoxyphenyl) -3-hydroxylmethyl-1H-pyrazole-5-N- (2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide (880 mg, 2.49 mmol) in CH ₂ Cl ₂ (100 mL) was added PBr 4 (675 mg, 2.49 mmol). The resulting mixture was stirred at room temperature for 2 hours and concentrated. The residue was treated with TFA (10 mL), heated.

162 at reflux for 2 hours and then concentrated. The residue was dissolved in EtOAc (50 mL) and water (5 mL). The EtOAc layer was washed with brine (10 mL), dried over MgSO ₄ , concentrated and purified by solvent gradient column chromatography (hexane: EtOAc) to give the title compound (800 mg,

%). ESMS (M + H) &lt; + & gt ^; m / z: 541/543.

Example 98

1- (4'-Methoxyphenyl) -3-aminomethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide

1- (4'-methoxyphenyl) - 3-aminomethyl-lH-pyrazole-5-N- (2'-aminosulfonyl- [1.1 ^1] biphen-4-yl) carboxyamide: To a solution of 1- (4 '- methoxyphenyl) -3-bromomethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] -biphen-4-yl) carboxyamide (140 mg, 0.259 mmol) in a solvent mixture (EtOH / CH ₃ CN / H ₂ O = 10: 5: 1, 20 mL) was added NaN ₃ (50.5 mg, 0.776 mmol). The mixture was heated for 16 hours and the resulting solution was cooled to room temperature. To the above solution was added a solution of SnCl ₂ · 2H ₂ O (350 mg, 1.55 mmol) in MeOH (4 mL), and the resulting mixture was stirred at room temperature for 2 hours. The mixture was neutralized with 1 N NaOH to pH 8-9 and extracted with EtOAc. The EtOAc layer was concentrated and purified by TLC on silica gel eluting with 20% MeOH in CH ₂ Cl ₂ to give the title compound (126 mg, ca. 100%). ESMS (M + H) &lt; + & gt ^; m / z: 478.1.

Example 99

1- (4'-Methoxyphenyl) -3- (N-methylsulfonylamino) methyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide

1- (4'-Methoxyphenyl) -3- (N-methylsulfonylamino) methyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide: To solution 1 - (4'-Methoxyphenyl) -3-aminomethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide (15 mg, 0.031) ·

- 16? * Mmol) in CH ₂ Cl ₂ (1 mL) was added MsCl (3.6 mg, 0.035 mmol) and Et 2 N (4.7 mg, 0.047 mmol). The mixture was stirred at room temperature for 2 hours, then concentrated and purified by TLC on silica gel eluting with EtOAc-CH ₂ Cl ₂ (1: 1) to give the title compound (12 mg, 70%). HRMS (M + H) ⁺ calculated m / z: 556.1324, found: 556.1320.

Example 100

1- (4'-Methoxyphenyl) -3- (imidazol-1-yl) methyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide

1- (4'-Methoxyphenyl) -3- (imidazol-1-yl) methyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide: K of a solution of 1- (4'-methoxyphenyl) -3-bromomethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] -biphen-4-yl) carboxyamide (30 mg, 0.055 mmol) in CH ₂ Cl ₂ (2 mL) was added imidazole (12 mg, 0.176 mmol) and the resulting mixture was stirred at room temperature for 8 hours. The mixture was concentrated and purified by TLC on silica gel eluting with

CH ₂ Cl ₂ / EtOAc (1: 3) to give the title compound.

ESMS (M + Na) &lt; + & gt ^; m / z: 528.5.

Example 101

1- (4'-Methoxyphenyl) -3-hydroxylmethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide and Example 102

1- (4'-Methoxyphenyl) -3-trifluoroacetylhydroxylmethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide

Preparation of a mixture of 1- (4'-methoxyphenyl) -3-hydroxylmethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide and 1- (4'- methoxyphenyl) -3-trifluoroacetylhydroxylmethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide

- 164

To 1- (4 ¹ methoxyphenyl) -3-hydroxylmethyl-lH-pyrazole-5-N- (2'-terc.butylaminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide (40 mg, 0.075 mmol 25% TFA in CH ₂ Cl ₂ (6 mL) was added and the mixture was stirred at room temperature for 20 hours. The mixture was concentrated and purified by preparative HPLC to give Example 101:

1- (4'-Methoxyphenyl) -3-hydroxylmethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide (8 mg, 22%):

ESMS (M + H) ⁺ m / z: 479 and the compound of Example 102: 1- (4'-methoxyphenyl) -3-trifluoroacetylhydroxylmethyl-1H-pyrazole-5 -N- (2'-aminosulfonyl- [1,1 '] 1-Biphen-4-yl) carboxyamide 18 mg, 42%); ESMS (M + H) &lt; + & gt ^; m / z: 575.

Example 103

1- (4'-Methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'-methylsulfonyl- [1,1 '] -biphen-4-yl) carboxyamide

N - (4'-methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-5-methylpyrazole: To a solution of 2-bromo-5-methoxyphenylmethylcarboxylate (4.9 g, 20 mmol) in DMF (25 mL) was added 3- methyl 5-trifluoromethylimidazole (3.0 g, 20 mmol), CuBr (1 g, 7 mmol) and K ₂ CO ₃ (2.76 <3, 20 mmol). The mixture was stirred at 110 ° C for 18 hours and diluted with EtOAc (150 mL). The mixture was filtered through a pad of Celite and the filtrate was washed with water and brine (10 mL x 5) and dried over MgSO ₄ . Filtration, concentration and purification by column chromatography on silica gel of a mixture of hexane and CH ₂ Cl ₂ (1: 1) gave N - (4'-methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-5-methylpyrazole (3.17 g, 51%). ESMS (M + H) &lt; + & gt ^; m / z: 315.

N- (4'-methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-carboxylic acid: To a solution of N- (4'-methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-5- methylpyrazole (2.54 g, 8.09 mmol) in CC1 ₄ (150 mL) is added NBS (2.88 g, 16.18 mmol), benzoyl peroxide (31 mg, 0.12 mmol) and AIBN (123 mg, 0,44 • ·

- 163 ¹ mmol) and the mixture was degassed and then filled with nitrogen. The mixture was heated to reflux under nitrogen for 24 hours, cooled to 0 ° C and filtered. The filtrate was concentrated to give a crude oil. To a solution of the crude oil in CH 2 Cl 2 (50 mL) and water (20 mL) was added KMnO ₄ (1.8 g, 11.4 mmol). The mixture was stirred at 95 ° C for 1.5 hours and cooled to room temperature. A solution of Na ₂ SO ₃ (5 g in 15 mL water) and NaHCO ₃ (5.5 g in 30 mL water) was added and the resulting mixture was filtered through a pad of celite. The filtrate was extracted with ether and the aqueous layer was carefully acidified with conc. HCl to pH 2 and extracted with EtOAc. The EtOAc layer was washed with brine (10 mL) and dried over MgSO ₄ . filtration and concentration gave N - (4'-methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-carboxylic acid (1.2 g, 43.1%). ESMS (M + H) &lt; + & gt ^; m / z: 345.

1- (4'-Methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'-methylsulfonyl- [1,1 '] - biphen-4-yl) carboxyamide To a solution of IN- (4'-methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-carboxylic acid (344 mg, 1 mmol) in DMF (5 mL) was added PyBrop (559 mg, 1.2 mmol) and the mixture was stirred at room temperature for 30 minutes. It will be added

N, N-diisopropylethylamine (288 mg, 2.5 mmol) and the resulting mixture was stirred for 10 min before a solution of 4- (2'-methylsulfonylphenyl) aniline (265 mg, 1 mmol) was added. The resulting mixture was stirred at 90 ° C for 16 h, diluted with EtOAc (100 mL), washed with 1 N HCl (20 mL x 2), 10% NaHCO ₃ (20 mL x 2), water (10 mL). ) and brine (20 mL x 4), dried over MgSO ₄ and concentrated. The residue was dissolved in CH ₂ C1 ₂ (20 mL) and treated with DOWAX (1 g) for 30 minutes. The mixture was filtered and the filtrate was purified by column chroamtografii gradient solvents (CH ₂ C1 ₂₎ to give the title compound (430 mg, 73%). ESMS (M + H) &lt; + & gt ^; m / z: 592.

Example 104

1- (4'-Methoxy-2'-hydroxycarbonylphenyl) -3-trifluoromethyl-1H

-pyrazole-5-N- (2'-methylsulfonyl- [1,1 '] -biphen-4-yl) carboxyamide To a solution of 1- (4'-methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-1H- pyrazole-5-N- (2'-methylsulfonyl- [1,1 '] - biphen-4-yl) carboxyamide (250 mg, 0.49 mmol) in MeOH (10 mL) was added aqueous NaOH (0.39 g in 5 ml of water) and the mixture was stirred at room temperature for 16 hours. It was then extracted with ether, and the resulting aqueous solution was carefully acidified with conc. HCl to pH 2 and extracted with EtOAc. The EtOAc layer was dried over MgSO ₄ , concentrated, and purified by silica gel column chromatography with EtOAc to give the title compound (110 mg, 50%) as a white solid. ESMS (M + H) &lt; + & gt ^; m / z: 578.

Example 105

1- (4'-Methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide To a solution of IN- (4'-methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-carboxylic acid (344 mg, 1 mmol) in DMF (5 mL) was added PyBrop (559 mg, 1.2 mmol) and the mixture was stirred at room temperature for 30 minutes. N, N-diisopropylethylamine (288 mg, 2.5 mmol) was added and the resulting mixture was stirred for 10 min before 4- (2'-tert-butylaminosulfonylphenyl) aniline hydrochloride salt (358 mg, 1 mmol) was added. The resulting mixture was stirred at 90 ° C for 16 h and cooled with EtOAc (100 mL). The mixture was washed with 1 N HCl (20 mL x 2), 10% NaHCO ₃ (20 mL x 2), water (10 mL) and brine (20 mL x 4), dried over MgSO _4, and concentrated. The residue was dissolved in CH 2 Cl 2 (20 mL) and treated with DOWEX (1 g) for 30 minutes and filtered. The filtrate was purified by silica gel column chromatography with gradient solvents (CH ₂ Cl ₂ : EtOAc) to give 1- (4'-methoxy-2'methoxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'-tert-butyl). Butylaminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide 550 mg, 85%) ESMS (M + H) ⁺ m / z: 649.

1- (4'-Methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'-tert-butylaminosulfonyl- [1,1 '] -biphen-4-yl) -17- TFA (5 mL) was added and the mixture was concentrated and purified by TLC silica gel eluting with 10% EtOAc in CH ₂ Cl ₂ to give the title compound (160 mg, 87%). ESMS (M + H) &lt; + & gt ^; m / z: 593.

Example 106

1- (4'-Methoxy-2'-hydroxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'-tert-butylaminosulfonyl- [1,1 '] -biphenyl) carboxyamide

To a solution of 1- (4'-methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'-tert-butylaminosulfonyl- [1,1 '] -biphen-4-yl) carboxyamide (350 mg, 0.54 mmol) in MeOH (5 mL) was added aqueous NaOH (90 mg in 5 mL water) and the mixture was stirred at room temperature for 16 hours. After extraction with ether, the resulting aqueous solution was carefully acidified with conc. HCl to pH 2 and extracted with EtOAc. The EtOAc layer was dried over MgSO ₄ . concentrate and purify by silica gel column chromatography with EtOAc to give the title compound (210 mg, 61.3%) as a white solid. ESMS (M + H) &lt; + & gt ^; m / z: 635.

Example 107

1- (4'-Methoxy-2'-hydroxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] -biphen-4-yl) carboxyamide

To 1- (4'-methoxy-2'-hydroxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'-tert-butylaminosulfonyl- [1,1 '] -biphen-4-yl) carboxyamide ( 210 mg (0.33 mmol) of TFA (5 mL) was added and the resulting solution was heated at reflux for 1 h. The mixture was concentrated and purified by TLC silica gel eluting with 10% MeOH in EtOAc to give the title compound (190 mg, 99%). ESMS (M + H) &lt; + & gt ^; m / z: 579.

Example 108 • · 4 »« · 4

16 &apos; 1- (4'-Methoxy-2 ' -hydroxylmethylphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2 ' -aminosulfonyl- [1,1 &apos;] biphen-4-yl) carboxyamide

To a solution of 1- (4'-methoxy-2'-hydroxylmethylphenyl) -3-trifluoromethyl-ΙΗ-pyrazole-5-N- (2'-aminosulfonylphenyl) phenyl) carboxyamide (210 mg, 0.36 mmol) in THF (5 ml) was added at 0 ° C

N, N-diisopropylethylamine (62 mg, 0.54 mmol) and isopropyl chloroformate (freshly distilled, 46 mg, 0.38 mmol) and the resulting mixture was stirred at room temperature for 1.5 hours. NaBH ₄ (30 mg, 0.79 mmol) was added and the mixture was stirred for 1 hour. The reaction was cooled with 1 N HCl and stirred for 30 minutes. The mixture was diluted with EtOAc and the organic layer was washed with water and brine, dried over Na ₂ SO ₄ and purified by TLC on silica gel eluting with EtOAc to give the title compound (75 mg, 37%). ESMS (M + Na) &lt; + & gt ^; m / z: 586.9.

Examples 109 to 115

IN- (4 ¹ methoxyphenyl) -3-methylpyrazole-5-yl) ethylcarboxylate: To a solution of 4-methoxyphenylhydrazine (8.65 g, 50 mmol) in HOAc (300 mL) at 80 ° C was added oxime (ethyl 2- Of N- (methoxy) imino-4-oxopentanoate (see Example 1), 6 g, 32 mmol) and the mixture was refluxed for 18 h and concentrated. Dissolve the residue in EtOAc (300 mL), wash with 10% NaOH (100 mL), water (100 mL x 2) and brine (20 mL x 2), dry over MgSO ₄ , concentrate and purify by silica gel chromatography CH ₂ Cl ₂ gave partially pure product which was recrystallized in hexane to give the title compound (10.5 g, 80%). ESMS (M + H) &lt; + & gt ^; m / z: 261.

N - (4'-Methoxyphenyl) -3-methylpyrazol-5-yl) carboxylic acid: A solution of N - (4'-methoxyphenyl) -3-methylpyrazol-5-yl) ethoxycarboxylate (5.9 g, 22.7 mmol) ) in THF (50 mL) was treated at room temperature with 1 N NaOH (50 mL) for 24 h. The aqueous layer of the mixture was carefully acidified with conc. HCl to pH

169 · 2 and extracted with EtOAc. The EtOAc layer was dried, concentrated, and purified by column chromatography with gradient solvents (CH ₂ Cl ₂ : EtOAc) to give the title compound (3.7 g, 66.3%). ESMS (MH) ^&lt; ^{+ &gt;} m / z: 245.

Preparation of Examples 109-115 via library: To a solution of 1N- (4'-methoxyphenyl) -3-methylpyrazol-5-yl) carboxylic acid (450 mg, 1.94 mmol) in CH ₃ CN (30 mL) was added SOCl ₂ (1.4 g,

11.6 mmol). The resulting mixture was heated at reflux for 1.5 hours and then concentrated. A solution of the residue in THF (38 mL) was divided into portions and added to a solution of anilines or amines (0.1 mmol / sample / well) and DMAP (12.4 mg / well) in THF (1 mL / well) at 96 mL. well polyphiltronic filter plates. The 96 well polyphiltronic filter plate containing the reaction mixtures was shaken at room temperature for 2 days. To each well in the well was added a suspension of DOWEX (0.2 g) in CH ₂ Cl ₂ (0.4 mL) and the resulting mixtures were shaken for one hour. The mixtures were filtered and the filtrates were carefully collected and dried under vacuum to give a library.

Example 109

1- (4'-Methoxyphenyl) -3-methyl-1H-pyrazole-5-N- (4'-sec-butyl) phenyl) carboxyamide: ESMS (M + H) ⁺ m / z: 404.

Example 110

1- (4'-Methoxyphenyl) -3-methyl-lH-pyrazole-5-N- (4 '- (3' -methyl-3 ¹¹ -pyrazoline-5 '- one-2''- yl) phenyl ) carboxyamide: ESMS (M + H) &lt; + & gt ^; m / z 364.

Example 111

1- (4'-Methoxyphenyl) -3-methyl-1H-pyrazole-5-N- (4 '- (6' ¹ -methylbenzothiazol-2 '' - yl) phenyl) carboxyamide: ESMS (M + H) ⁺ m / from: 455.

· E> 4 · · 4 4 4 4 4

- 170 Example 112

1- (4'-Methoxyphenyl) -3-methyl-1H-pyrazole-5-N- (3 ', 4'-dibromophenyl) carboxyamide: ESMS (M + H) ⁺ m / z: 364;

Example 113

1- (4'-Methoxyphenyl) -3-methyl-1H-pyrazole-5-N- (4'-n-butyl) phenyl) carboxyamide: ESMS (M + H) ⁺ m / z: 464;

Example 114

1- (4'-Methoxyphenyl) -3-methyl-1H-pyrazole-5-N- (4 '- (4''- methylpiperidino) phenyl) carboxyamide: ESMS (M + H) ⁺ m / z: 405.

Example 115

1- (4'-Methoxyphenyl) -3-methyl-lH-pyrazole-5-N- (4 ¹ - ^{(2-methylimidazol-1 1} 1 '-yl) phenyl) carboxyamide: ESMS (M + H) ⁺ m / from: 388.

Example 116

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-carboxy (N-methylimidazo-2-yl) phenyl) carboxyamide)

Part A. To 4-nitro-1- (2'-N-methylimidazoyl) benzene (0.58 g, 2.51 mmol) prepared from 4-nitrobenzoyl chloride and 1-methylimidazole by the method of Regel, E et al., Liebigs Ann. Chem. (1977) 145, ethanol (50 mL), trifluoroacetic acid (1 mL) and 10% palladium on carbon (60 mg) were added. The mixture is hydrogenated in a Parr apparatus at 2.812 kg / cm ² for 0.5 hour. The reaction mixture was filtered and concentrated. The aniline salt obtained was dissolved in water and extracted with ether. The aqueous layer was basified with 1 N NaOH, extracted with ethyl acetate and dried (MgSO ₄ ) and evaporated to give 0.35 g (70%) of the aniline MS (AP +) 202.1 (M + H) ⁺ .

* ·

- 171 -

Part Β. To 1- (4-methoxyphenyl) -3-trifluoromethyl-lH-pyrazole-5-carboxylic acid (0.25 g, 0.87 mmol) in CH ₂ C1 ₂ (15 mL) was added oxalyl chloride (0.1 mL, 1.14 mmol) and a few drops of DMF. The reaction mixture was stirred for 24 hours and then concentrated. Aniline from Part A (0.175 g, 0.87 mmol), DMAP (0.27 g, 2.2 mmol) and fresh CH ₂ Cl ₂ (20 mL) were then added to the acyl chloride and the reaction mixture was stirred for 24 hours. The mixture was concentrated and the residue was dissolved in EtOAc (10 mL) and TFA (0.1 mL), concentrated and purified by reverse phase HPLC to give 60 mg (11%) of the title compound; ¹ H NMR (DMSO-d 6) δ 10.97 (s, 1H), 8.30 (d, j = 8.0 Hz, 2H), 7.80 (d, j = 8.80 Hz, 2H), 7.63 (d, j = 10.2 Hz, 2H), 7.48 (d, j = 9.20 Hz, 2H), 7.22 (s, 1H), 7.07 (d, j = 8) 80 Hz, 2H), 3.98 (s, 3H), 3.82 (s, 3H) ppm; HRMS (M + H) ⁺ C ₂₃ H ₁₉ F ₃ N ₅ O ₃ 470.1443.

Example 117

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-hydroxymethyl (2- (imidazol-2-yl) phenyl))) carboxyamide and Example 118

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-hydroxymethyl (2- (1-benzylimidazol-2-yl) phenyl))) carboxyamide and Example 119

1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5- (N- (4- (2-carboxy (imidazol-2-yl) phenyl))) carboxyamide

Part A: K -nitro-1- (2'-N-benzylimidazolyl) benzene (0.47 g, 1.53 mmol) prepared from 4-nitrobenzoyl chloride and 1-benzimidazole according to the method of Regel, E. et al. Liebigs Ann. Chem. (1977) 145, EtOAc (15 mL) and stannous chloride (0.86 g, 3.80 mmol) were added. The reaction mixture was heated to 909 ° C

The mixture was refluxed for 2 hours and then stirred at room temperature for 18 hours. An additional 0.3 g of stannous chloride was added and the reaction mixture was stirred for 3 hours, cooled to 0 ° C, then 6 M NaOH and extracted with EtOAc and dried (Na ₂ SO ₄ ) to give 0.4 g (95%) of an orange solid. MS (M + H) &lt; + & gt ^; 278.2 (AP &lt; + &gt;)

Part B: The benzylic compound of Part A (0.229 g, 0.4 mmol) was hydrogenated on a Parr apparatus in EtOH (30 mL) and TFA (0.5 mL) with 30 mg of 10% Pd / C at 2.812 kg / cm ^2. for 0.5 hour. The reaction mixture was filtered and concentrated and purified by reference phase HPLC to give the title compound above.

MS (M + H) &lt; + & gt ^; 278.2 (AP &lt; + &gt;).

Example 117: 5.3 mg (2.2%) ¹ H NMR (DMSO-d 6) δ: 10.75 (s, 1H), 7.66 (d, J = 8.40 Hz, 2H), 55 m + d, J = 6.60 Hz, 3H), 7.45 (d, J = 9.10 Hz, 2H), 7.40 (d, J = 8.40 Hz, 2H), 7.05 (d, J = 8.80 Hz, 2H), 6.55 (brd S, 2H), 6.00 (d, J = 4.0 Hz, 1H), 3.81 (3H, s) ppm. HRMS calcd for (M + H) ⁺ C ₂₂ H _ig F ₃ N ₅ O ₃ 458.1437.

Example 118: 73 mg (25%) ¹ H NMR (DMSO-d 6) δ: 10.76 (s, 1H), 7.69 (s, 1H), 7.64 (d, J = 1.90 Hz, 1H), 7.63 (d, J = 8.80Hz,

2H), 7.55 (s, 1H), 7.34 (d, J = 5.80Hz, 2H), 7.32 (m, 5H),

7.19 (brd, 1H), 7.10 (dd, J = 2.20, 5.80 Hz, 2H), 7.06 (d,

J = 9.20 Hz, 2H), 6.24 (s, 1H), 5.38 (d, J = 3.70 Hz, 2H), 3.81 (s, 3H) ppm; HRMS (M + H) ⁺ for C ₂₉ H ₂₅ F ₃ N ₅ O ₃ 548.1923.

Example 119: 15 mg (6.2%) ¹ H NMR (DMSO-d 6) δ: 10.99 (s, 1H), 8.56 (d, J = 8.50 Hz, 2H), 7.84 ( d, J = 8.80 Hz, 2H), 7.64 (s,

1H), 7.48 (d, J = 8.80Hz, 2H), 7.41 (s, 2H), 7.31 (m, 1H),

7.07 (m + d, J = 8.80Hz, 3H), 3.82 (s, 3H) ppm; HRMS (M + H) ⁺ for ^C 22 ^H 17 ^F 3 ^N 5 ° 3 456.1271.

Example 120

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N-4- (N- (4-73)).

• • • • 4 • 4

(methoxyphenyl) amino- (2-thiazolyl) methyl) phenyl)) carboxyamide and Example 121

1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5- (N- (4- (2-carboxy- (4,5-dihyrothiazol-2-yl) phenyl))) carboxyamide

Part A: p-Aminobenzaldehyde (135 mg, 1.11 mmol) and TEA (0.155 mL, 1.11 mmol) were added to 3-trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5-carboxylic acid chloride acid (0.34 g, 1.11 mmol) in CH ₂ Cl 2 (10 mL). The reaction mixture was stirred for 18 hours and then concentrated. Purification by silica gel chromatography using 2: 1 hexanes / ethyl acetate as t

0.16 g (37%) of a pale yellow solid was obtained.

MS (ESI) (M + H) &lt; + & gt ^; 388.1.

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (N- (4-methoxyphenyl) amino- (2-thiazolyl) methyl) phenyl))) carboxyamide:

Part Β: To thiazole (0.1 mL, 1.43 mmol) in THF (6 mL) cooled to -40 ° C was added n-BuLi (0.6 mL, 1.43 mmol) and the mixture was stirred for 1 h. 5 hours. To the aldehyde from Part A (0.14 g, 0.36 mmol) in benzene (10 mL) and MeOH (5 mL) were added 4A molecular sieves and p-anisidine (44 mg, 0.36 mmol) and the mixture was heated at reflux for 15 minutes. The mixture was filtered and concentrated to give the imine. To the imine in THF (5 mL) at -78 ° C was added a thiazole anion via cannula. The reaction mixture was stirred at 0 ° C for 0.5 h and then cooled with 1 M KHSO ₄ (0.4 mL). The product was extracted with EtOAc and dried (MgSO ₄ ). Purification by silica gel chromatography using hexanes / EtOAc 1: 2 gave 0.113 g (54%) of the title compound; MS (M + H) &lt; ⁺ &gt; 578.1; NMR (CDCl 3) δ: 7.74 (d, J = 3.30 Hz, 1H), 7.50 (d, J = 15.4 Hz, 2H), 7.41 (brd s, 5H), 7.27 (d, J = 3.30Hz,

1H), 7.12 (s, 1H), 7.01 (d, J = 9.20 Hz, 2H), 6.74 (d, J = 8.80 Hz, 2H), 6.59 (d, J = 8.80 Hz, 2H), 5.71 (d, J = 3.60 Hz, 1H),

4.56 (d, J = 3.60 Hz, 1H), 3.85 (s, 3H), 3.71 (s, 3H) ppm.

• ·

17 * 4 • * 1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5- (N- (4- (2-carboxy- (4,5-dihyrothiazol-2-yl) phenyl))) carboxyamide Part C: To the product of Part B (98 mg, 0.17 mmol) in acetonitrile (10 mL) at 0 ° C was added cerito ammonium nitrate (0.185 g, 0.34 mmol) in water (10 mL). The reaction mixture was stirred for 10 minutes and then concentrated. The residue was dissolved in EtOAc and washed with aqueous sodium bisulfite and dried (MgSO ₄ ). The product was purified by silica gel column chromatography, reverse phase HPLC and lyophilization to give the title compound (10 mg, 12%). ¹ H NMR (CDCl ₃ ) δ: 8.54 (d, J = 8.80 Hz, 2H), 8.09 (d, J = 2.90 Hz, 1H), 7.73 (d, J = 3) 30 Hz, 1H), 7.66 (s, 1H), 7.59 (d, J = 8.80 Hz, 2H), 7.48 (d, J = 8.80 Hz, 2H), 7, 19 (s, 1H), 7.05 (d, J = 9.20 Hz, 2H),

3.88 (s, 3H) ppm; MS (M + H) &lt; + & gt ^; 473.2 (AP +).

Example 122

1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-N-4- (2- (4 ',

5'-dihydro-1'H-imidazol-2'yl) phenyl) carboxyamide and Example 123

1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (4- (N-2'-aminoethylenecarboxyamide) phenyl) carboxyamide

To trimethylaluminum (1.2 mL, 2 M in heptane) cooled to 0 ° C was added ethylenediamine (57 mg, 0.95 mmol) and the mixture was stirred for 15 minutes. Then, a suspension of previously prepared ethyl 3-trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-carboxyphenyl) carboxyamide (0.2 g, 0.47 mmol)) in toluene (10 mL) was added. ml).

The reaction was heated at 50 ° C for a total of 9 hours and then at room temperature for 18 hours. The reaction was cooled with ice water, filtered and concentrated. The aqueous layer was extracted with CH ₂ Cl ₂ , which was then extracted with 1 N HCl. The acidic layer is basified

175

and extracted with EtOAc and dried (MgSO ₄ ). Purification by reverse phase HPLC and freeze-drying afforded 56 mg (22%) of imidazoline (Example 122) and 7 mg (3%) of the ring-opened amide (Example 123).

Example 122: For imidazoline: ¹ H NMR (DMSO-d 6) δ: 11.10 (s, 1H), 10.40 (s, 1H), 7.91 (d, J = 3.60 Hz, 4H), 7.64 (s, 1H), 7.48 (d, J = 8.80 Hz, 2H), 7.07 (d, J = 9.20 Hz, 2H), 3.99 (s, 4H), 3.82 (s, 3H) ppm; MS (ESI) 430.2 (M + H) &lt; + & gt ^; .

Example 123: For amide: ¹ H NMR (DMSO-d 6) δ: 10.88 (s, 1H), 8.59 (t, J = 5.50 Hz, 1H), 7.87 (d, J = 8) 80 Hz, 2H), 7.79 (m, 2H), 7.75 (d, J = 8.80 Hz, 2H), 7.61 (s, 1H), 7.47 (d, J = 9) 2 Hz, 2H), 7.06 (d, J = 8.80 Hz, 2H), 3.82 (s, 3H), 3.51 (q, J = 5.50 Hz, 2H), 2, 98 (q, J = 5.90Hz, 2H) ppm; MS (ESI) 448.2 (M + H) &lt; + & gt ^; .

Example 124

1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5- [4- (1,4,5,6-tetrahydro-pyrimid-2-yl) -phenyl] carboxyamide

Ethyl 3-trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-carboxyphenyl) carboxyamide (0.2 g, 0.48 mmol) and 1,3-diaminopropane (70 mg, Purification by reverse-phase HPLC and freeze-drying gave 20 mg (7.5%). ¹ H NMR (DMSO-d 6) δ: 11.0 (s, 1H), 10.3 (s, 1H), 7.86 (d, J = 8.80Hz, 2H), 7.72 (d,

J = 8.80 Hz, 2H), 7.63 (s, 1H), 7.48 (d, J = 9.20 Hz, 2H), 7.06 (d, J = 9.20 Hz, 2H) 3.82 (s, 3H), 3.40 (m, 4H), 1.96 (t, 2H); HRMS calcd for C ₂ ^H 2 ^F 3 ^N 2 l 5 ° 2 ^{η9 1θ ζ θ η} ° 444.1646.

Example 125

1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5- [4- (N-methyl-4,5,6-trihydro-pyrimid-2-yl) -phenyl] carboxyamide

176 Ethyl 3-trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-carboxyphenyl) carboxyamide (0.2 g, 0.48 mmol) and N-methyl-1,3 -propanediamine (0.1 mL, 0.95 mmol) was coupled as described above by purification by reverse phase HPLC and drying

by freezing yield 58 mg (21%) . ! _Η NMR (DMSO-d6) δ: 9.70 (with, 1H), 7.85 (d, J = 8.80Hz, 2H). 7.62 (d, J = 9,20 Hz 2H), 7.55 (with, 1H), 7.47 (d, J = 9.20 Hz, 2H), 7.07 (d, J = 9.20 Hz, 2H), 3.82 (with, 3H), 3.57 (t, J = 5.50) Hz, 2H), 3.39 (m, 2H), 2.97 (with, 3H), 2.05 (t, J = 5.50 Hz) 2H) ppm.

Example 126

1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-N-1- (2-fluoro-4-imadazolophenyl) carboxyamide

Part A: To 3-fluoro-4-nitrobenzoic acid (2.81 g, 15 mmol) in CH ₂ Cl ₂ (75 mL) was added oxalyl chloride (1.72 mL, 19.7 mmol) and a few drops of DMF. The reaction mixture was stirred for 6 hours, stripped and ethanol was added. After 18 hours, the ethanol was removed and EtOAc (30 mL) and stannous chloride (13.7 g, 61 mmol) were added. The reaction mixture was heated at reflux for 2 hours, cooled and saturated NaHCO ₃ was added. Extraction with EtOAc and drying (MgSO ₄ ) gave 2.7 g (97%) of the aniline.

Part Β: To 1- (4-methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-carboxylic acid (0.21 g, 0.73 mmol) in CH ₂ Cl ₂ (15 mL) was added oxalyl chloride (0, 08 mL, 0.95 mmol) and a few drops of DMF. The reaction mixture was stirred for 24 hours and then concentrated.

The acid chloride, DMAP 0.27 g, 2.20 mmol) and the aniline from Part A (134 mg, 0.73 mmol) were combined in fresh CH ₂ Cl ₂ and stirred for 18 hours. The reaction mixture was washed with 1 N HCl, saturated NaHCO 3, brine, and dried (MgSO ₄ ). Purification by silica gel chromatography using hexanes / EtOAc 1: 1 as eluent gave 254 mg (79.6%) ¹ H NMR (CDCl ₃ ) δ 8.44 (t, J = 8.10 Hz, 1H), 7 89 (d, J = 3.30 Hz, 1H); 7.84 (d, J = 9.60 Hz);

17% (1H), 7.77 (dd, J = 11, 40, 1.50 Hz, 1H), 7.46 (d, J = 9.10 Hz,

2H), 7.20 (s, 1H), 7.04 (d, J = 8.80 Hz, 2H), 4.39 (q, J = 7.0 Hz, 2H), 3.88 (s, 3H), 1.41 (t, J = 6.90 Hz, 3H) ppm.

Part C: To trimethylaluminum (0.57 mL, 2 H in heptane) cooled to 0 ° C was added ethylenediamine (27.6 mg, 0.46 mmol) and the mixture was stirred for 15 minutes. Add a suspension of ethyl 3-trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-carboxy-2-fluorophenyl) carboxyamide (0.1 g, 0.23 mmol) in toluene ( The reaction mixture was heated at 50 ° C for 18 hours and then cooled with ice water, filtered and concentrated The aqueous layer was extracted with CH ₂ Cl ₂ from which it was then extracted with 1 N HCl. extract with EtOAc and dry (MgSO ₄ ) Purification by reverse phase HPLC and lyophilization gave 26 mg (20%) ¹ H NMR (DMSO-d 6) δ 10.80 (s, 1H), 10.55 (s 1 H, 8.10 (t, J = 8.06 Hz, 1H), 7.93 (dd, J = 11.0, 1.5 Hz, 1H), 7.80 (d, J = 8, 79 Hz, 1H), 7.64 (s, 1H), 7.47 (d, J = 9.15 Hz, 2H), 7.06 (d, J = 8.80 Hz, 2H), 4.01 (s, 4H), 3.81 (s, 3H) ppm; HRMS for ^C 21 ^H 18 ^F 4 ° 2 ^N 5 ^found 488.1393.

Example 127

1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-N-1- (2-fluoro-4-N-methyl-imidazolophenyl) carboxyamide

N-methylethylenediamine (52 mg, 0.71 mmol) and ethyl-3-trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-carboxy-2-fluorophenyl) carboxyamide) (150 mg, Purification by reverse phase HPLC and lyophilization gave 54 mg (27%). 1 H NMR (DMSO-d 6) δ (S, 1H), 8.03 ( t, J = 8.10 Hz, 1H), 7.74 (dd, J = 11.0, 1.5 Hz, 1H), 7.63 (s, 1H), 7.56 (d, J = 9) 90 Hz, 1H), 7.47 (d, J = 8.80 Hz, 2H), 7.05 (d, J = 8.80 Hz, 2H), 4.06 (m, 2H), 3, 95 (m, 2H), 3.80 (s, 3H), 3.08 (s, 3H) ppm MS (ESI) 462.3 (M + H) ⁺ Analysis calculated for C ₂₂ H ₁₉ F ₄ N ₅ O ₂ (TFA) 1.4 (H ₂ O) C: 46.1 H: 3.53 N:

178 _ ·

10.96, found C: 46.68 H: 3.29 N: 10.91.

Example 128

1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- [4- (4,5-dihydro-1-N-methyl-imidazo-2-yl) phenyl] carboxyamide and Example 129

1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- [4-carbonylguanidine] phenyl] carboxyamide

Part A: To a dichloromethane solution (50 mL) of N-4'-methoxyphenyl-3-trifluoromethylpyrazole-5-carboxylic acid (2 g, 6.99 mmol) was added oxalyl chloride (1.36 g, 10.48 mmol) and several drops of DMF. The reaction mixture was stirred at room temperature for 3 hours, then evaporated and the pale yellow solid was redissolved in dichloromethane (50 mL). To this was added methyl 4-aminobenzoate (1 g, 6.99 mmol) and DMAP (2.1 g, 17.47 mmol). The reaction mixture was stirred at room temperature overnight, cooled with dilute HCl (50 mL), the organics extracted with ethyl acetate (2 x 100 mL), dried (MgSO ₄ ) and evaporated to give a yellow solid. Purification of the crude coupled product by silica gel flash chromatography (hexane: ethyl acetate 7: 3) afforded the desired coupled precursor as colorless crystals (1.9 g). LRMS (ESI) mlz 420.0 (100). @ ¹ H NMR (CDCl3): .delta.8.019 (d, J = 8.8, 2H); 7.617 (s 1H); 7.480 (m, 4H); 7.158 (s, 1 H); 7.03 (d, J = 8.8, 2H); 3.90 (s, 3H); 3.87 (s, 3H) ppm.

1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- [4- (4,5-dihydro-1H-methyl-imidazo-2-yl) phenyl] carboxyamide: Part B: Product from part A (0.2 g, 0.048 mmol) in dichloromethane (50 mL) was treated with N1-methylethylenediamine (0.071 g, 0.099 mmol) followed by trimethylaluminum (1.23 mL, 2.45 mmol). The reaction mixture was stirred at room temperature overnight and

179 was then cooled with dilute HCl (5 mL). The product was concentrated in vacuo and purified by preparative HPLC (acetonitrile / water, 2% TFA). Lyophilization gave colorless crystals (0.167 g) of the desired product. LRMS (ESI) m / z 444.2 (100). HRMS: (M + H) ⁺ calcd 444.1647, found 444.1644. ¹ H NMR (DMSO-d 6) δ 11.07 (s, 1H); 10.12 (s, 1 H); 7.88 (d, J = 8.8, 2H); 7.71 (d, J = 8.8, 2H); 7.63 (s, 1 H); 7.47 (m, 2 H); 7.06 (m, 2 H); 4.05 (m. 2H); 3.89 (m, 2 H); 3.82 (s, 3H); 3.09 (s, 3H) ppm.

1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- [4-carbonylguanidine) phenyl] carboxyamide: Part C: The product of Part A (150 mg, 0.358 mmol) was subjected to the standard Weinreb methodology described from above with guanidine hydrochloride (103 mg, 1.074 mmol) and trimethylaluminum (103 mg, 1.432 mmol) in dichloromethane (10 mL). The mixture was stirred at ambient temperature for 18 hours and quenched with 1 N hydrochloric acid (5 mL). The slurry was basified (pH 9, saturated sodium bicarbonate). The organic phases were extracted with dichloromethane (3 x 100 mL) and dried (Na ₂ SO ₄ ). Evaporation of the solvent followed by purification by reverse phase preparative HPLC and lyophilization afforded the desired acylguanidyl compound as colorless crystals. LRMS (ESI) m / z 447.2 (100); HRMS (M + H) ⁺ 447.1392 (calc.) 447.1391 (found); ¹ H NMR (DMSO) δ: 11.20 (s, 1H); 11.0 (s, 1 H); 8.33 (brd, 4H); 7.98 (d, J = 8.79, 2H); 7.88 (d, J = 8.79, 2H); 7.64 (s, 1 H);

7.48 (d, J = 8.79, 2H); 7.07 (d, J = 9.16, 2H); 3.82 (s, 3H) ppm.

• · • ·

- 180 ..-

Example 130

1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- [4- (pyrimidin-2-yl) phenyl] carboxyamide

Part A: Standard Suzuka coupling of 4-trifluoromethylphenylboronic acid (0.88 g, 3.77 mmol) and 2-bromopyrimidine (0.5 g, 3.144 mmol) yields the coupled product (0.47 g). LRMS (ESI) m / z 268.1 (100); ¹ H NMR (CDCl 3) δ: 8.82 (d, J = 5.1, 2H); 8.52 (d, J = 8.8, 2H); 7.96 (brd, IH); 7.73 (d, J = 8.8, 2H);

7.23 (t, J = 4.8, 1H) ppm; Hydrolysis of this compound with 1 N NaOH / EtOH (1: 1, 10 mL) for 18 hours, followed by purification using flash chromatography (4: 1 hexanes: ethyl acetate) afforded the desired anilinopyrimidyl precursor (0.24 g). LRMS (NH-Cl) m / z 172.2 (100); ¹ HNMR (CDCl ₃ ) δ: 8.73 (d, J = 5.1, 2H); 8.28 (m, 2 H); 7.06 (t,

J = 5.1 (1H); 6.76 (m, 2 H); 3.94 (brd, 2H) ppm.

1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- [4- (pyrimidin-2-yl) phenyl] carboxyamide: Part B: Standard DMAP (0.23 g, 1.92 mmol) coupling of the compound obtained in Part A (0.13 g, 0.77 mmol) with trifluoromethylpyrazolic acid chloride (0.22 g, 0.77 mmol carboxylic acid) obtained previously gave the desired coupled product which was purified by flash chromatography on silica gel ( hexane / ethyl acetate,

1: 1) to give the title compound as colorless crystals (0.14 g). LRMS (ESI) m / z 440.1 (100); HRMS (M + H) ⁺ 440.1334 (calc.) 440.1333 (found); ¹ HNMR (DMSO-D6) δ:

10.89 (s, 1H); 8.88 (d, J = 4.8, 2H); 8.39 (d, J = 8.8, 2H):

7.82 (d, J = 8.4, 2H); 7.61 (s, 1H); 7.48 (d, J = 8.8, 2H); 7.43 (t, J = 4.7) , 1H): 7.07 (d, J = 9.2, 2H): 3.82 (s, 3H) ppm.

Example 131

2- (Carboxyamide) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] -biphen-4-yl) carboxyamide] thiazole

- 17 f · «- ··

2-Bromo-4 - [(4-methoxy) phenyl] -5- (methoxycarbonyl) thiazole. A mixture of copper (I) bromide (11.43 g, 51.2 mmol) and tert-butyl nitrite (6.0 g, 58.2 mmol) in 200 mL of acetonitrile was stirred at 80 ° C until gas evolution ceased (about 30 minutes). To this solution was added 2-amino-4 - [(4-methoxy) phenyl] -5- (methoxycarbonyl) thiazole (12.3 g, 46.55 mmol) in 100 mL acetonitrile. The solution was stirred at 80 ° C until gas evolution ceased (about 1 hour). The mixture was cooled, diluted with saturated aqueous Na ₂ CO ₃ and then filtered through a pad of celite. The filtrate was diluted with ethyl acetate and the organic layer was washed with saturated aqueous Na ₂ CO ₃ , dried (MgSO ₄ ) and concentrated to give 8.95 g (59%) of the title compound which was used without further purification. LRMS (ES &lt; + &gt;): 328 (M + H) &lt; + & gt ^; .

2-Bromo-4 - [(4-methoxy) phenyl] thiazole-5-carboxylic acid. To a solution of 2-bromo-4 - [(4-methoxy) phenyl] -5- (methoxycarbonyl) thiazole (6.24 g, 19.74 mmol) in 20 mL of methanol and 20 mL of water was added lithium hydroxide monohydrate (0, 91 g, 21.7 mmol). The mixture was stirred at ambient temperature for 1 hour, then additional lithium hydroxide monohydrate (0.91 g, 21.7 mmol) was added. The mixture was stirred for an additional hour, the volatiles were removed in vacuo and the residue was cooled with 10% aqueous HCl. The mixture was extracted with ethyl acetate and the organics were washed with brine, dried (MgSO ₄ ) and concentrated. The residue was recrystallized from chloroform-hexane to give 2.2 g (37%) of the title compound as a white solid. LRMS (ES -): 303 (MH) -.

2-tert-Butylcarboxyamido-4 - [(4-methoxy) phenyl] thiazole-5-carboxylic acid. To a solution of 2-bromo-4 - [(4-methoxy) phenyl] thiazole-5-carboxylic acid (2.0 g, 6.36 mmol) was added t-butyllithium (12.3 mL) dropwise at -78 ° C. 1.7 M solution in hexanes, 21.0 mmol). The reaction mixture was stirred for 15 minutes and then tert-butyl isocyanate was added dropwise. The cooling bath was removed and the reaction mixture was stirred while heating to temperature

- 182 'room for 18 hours. The reaction was cooled with 10% aqueous HCl and then diluted with ethyl acetate. The organic layer was washed with brine, dried (MgSO ₄ ) and concentrated to give 0.9 g (43%) of the title compound which was used without further purification. LRMS (ES -): 332.9 (MH) '.

2- (tert-Butylcarboxyamide) -4 - [(4-methoxy) phenyl] -5 - [(2 '- (tert-butylamino) sulfonyl- [1,1'] - biphen-4-yl) carboxyamide] thiazole. To a solution of 2- (tert-butylamino) carbonyl-4 - [(4-methoxy) phenyl] thiazole-5-carboxylic acid (0.50 g, 1.49 mmol) in 10 mL of methylene chloride was added oxalyl chloride (0.16 mL). (1.86 mmol) and three drops of dimethylformamide. the reaction mixture was stirred at ambient temperature for 4 hours and then the volatiles were removed in vacuo. The residue was dissolved in 10 mL of methylene chloride and then 4-dimethylaminopyridine (0.36 g, 2.99 mmol) was added. The mixture was stirred at ambient temperature for 15 minutes and then 2 '- (tert-butylamino) sulfonyl- [1,1'] -biphen-4-ylamine (0.38 g, 1.24 mmol) was added. The reaction mixture was stirred for 24 hours. The reaction mixture was diluted with ethyl acetate, washed sequentially with 10% aqueous HCl, saturated NaHCO ₃ and brine, dried (MgSO ₄ ) and concentrated to give 0.69 g (75%) of the title compound which was used without further purification. LRMS (ES +): 643.4 (M + Na) &lt; + & gt ^; .

2- (tert-Butylcarboxyamide) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole.

2- (tert-Butylcarboxyamide) -4 - [(4-methoxy) phenyl] -5 - [(2 '- (tert-butylamino) sulfonyl- [1,1'] - biphen-4-yl) carboxyamide] thiazole solution (0.69 g, 1.11 mmol) in 5 mL of trifluoroacetic acid was stirred at 80 ° C for 1 h and then cooled and concentrated in vacuo. The residue was purified by preparative HPLC (reverse phase C18 column, eluting with a gradient of H 2 O / CH ₃ CN with 0.5% TFA) and lyophilized to afford 0.34 g (53%) of the title compound as a white powder. LRMS (ES):

565.1 (M + H) &lt; + & gt ^; .

• · «<

•

183

2- (Carboxyamide) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole. A solution of 2- (terč.butylkarboxyamid) -4- [(4-methoxy) phenyl] -5- [(2-amino ¹⁾ sulfonyl- [1,1 '] biphen-4-yl) carboxyamide] thiazole (70 mg, ,

0.10 mmol) in 20 mL trifluoroacetic acid was stirred at 80 ° C for 24 h and then cooled and concentrated in vacuo. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilized to give 20 mg (32%) of the title compound as a white powder. LRMS (ES +): 508.8 (M + H) &lt; + & gt ^; .

Example 132

2- (2-Methoxyethylamino) -4 - [(4-methoxy) phenyl] -5- [2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole

To a solution of 2-bromo-4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole (25 mg, 0.046 mmol) in 3 mL of acetonitrile was added 2-methoxyethylamine (0.04 mL, 0.46 mmol). The resulting solution was stirred at 60 ° C for 18 hours, then cooled, filtered through a small pad of silica gel and concentrated in vacuo. The residue was purified by preparative HPLC (C18 reverse phase column, gradient elution)

H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilization gave 10 mg (41%) of the title compound as a white powder. LRMS (ES):

538.9 (M + H) &lt; + & gt ^; .

Example 133

2- (3-Hydroxypropylamino) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole

To a solution of 2-bromo-4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole (50 mg, 0.092 mmol) in 3 ml of acetonitrile was added 3-hydroxypropylamine (0.5 ml)

- 184 ’-i • ··» ·

5.5 mmol). The resulting solution was stirred at 60 ° C for 18 hours and then cooled, filtered through a small pad of silica gel and concentrated in vacuo. The residue was purified by preparative HPLC (reverse phase C18 column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilized to afford 19 mg (37%) of the title compound as a white powder. LRMS (ES +): 538.9 (M + H) &lt; + & gt ^; .

Example 134

2- (2-cyanoethyl) -4 - [(4-methoxy) phenyl] -5 - ^[(1 2 aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole

To a solution of 2-bromo-4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole (80 mg, 0.15 mmol) ) in 3 ml of acetonitrile is added 3-aminopropionitrile (0.11 ml,

1.5 mmol). The resulting solution was stirred at 60 ° C for 48 hours and then cooled, filtered through a small pad of silica gel and concentrated in vacuo. The residue was purified by preparative HPLC (reverse phase C18 column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilized to give 35 mg (41%) of the title compound as a white powder. LRMS (ES +): 534.2 (M + H) &lt; + & gt ^; .

Example 135

2- (3-Methoxypropylamino) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole

To a solution of 2-bromo-4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole (80 mg, 0.15 mmol) ) in 3 ml of acetonitrile is added 3-methoxypropylamine (0.15 ml,

1.5 mmol). The resulting solution was stirred at 60 ° C for 18 hours and then cooled, filtered through a small pad of silica gel and concentrated in vacuo. The residue was purified by preparative HPLC (reverse phase C18 column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilized to afford 25 mg (31%) of the title compound as a white powder. LRMS (ES +): 552.8 (M + H) &lt; + & gt ^; .

• · • ·

- 189

Example 136

2- (Ν-β-Alanyl) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole

2- (2- (Methoxycarbonyl) ethylamino) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole.

To a solution of 2-bromo-4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole (80 mg, 0.15 mmol) 3) 3-Aminopropionate hydrochloride (0.20 mL, 1.5 mmol) and N, N-diisopropylethylamine (0.26 mL, 1.5 mmol) were added in 3 mL acetonitrile. The resulting solution was stirred at 60 ° C for 48 hours and then cooled, filtered through a small pad of silica gel and concentrated in vacuo. The residue was purified by preparative HPLC (reverse phase C18 column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilized to afford 45 mg (55%) of the title compound as a white powder. LRMS (ES +): 567.2 (M + H) &lt; + & gt ^; .

2- (Ν-β-Alanyl) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole. To a solution of 2- (2- (methoxycarbonyl) ethylamino) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole ( 38 mg, 0.066 mmol) in 2 mL tetrahydrofuran and 2 mL water was added lithium hydroxide monohydrate (5 mg, 0.13 mmol). The resulting solution was stirred at ambient temperature for 18 hours and then concentrated in vacuo. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilized to afford 32 mg (88%) of the title compound as a white powder. LRMS (ES -): 665.0 (M-H + TFA).

Example 137

2- (Isopropylamino) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] -biphen-4-yl) carboxyamide] thiazole

186 To a solution of 2-bromo-4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole (80 mg, 0.15) mmol) in 3 mL of acetonitrile was added isopropylamine (0.13 mL,

1.5 mmol). The resulting solution was stirred at 60 ° C for 72 hours and then cooled, filtered through a small pad of silica gel and concentrated in vacuo. The residue was purified by preparative HPLC (reverse phase C18 column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilized to afford 28 mg (37%) of the title compound as a white powder. LRMS (ES +): 523.1 (M + H) &lt; + & gt ^; .

Example 138

2- (1,3-Dihydroxy-2-propylamino) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole

To a solution of 2-bromo-4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole (80 mg, 0.15 mmol) 1) 1,3-dihydroxy-2-aminopropane (0.13 g, 1.5 mmol) was added in 3 mL acetonitrile. The resulting solution was stirred at 60 ° C for 72 hours and then at 75 ° C for an additional 24 hours. The reaction mixture was cooled, filtered through a small pad of silica gel, and concentrated in vacuo. The residue was purified by preparative HPLC (reverse phase C18 column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilized to afford 30 mg (37%) of the title compound as a white powder. LRMS (ES +): 555.1 (M + H) &lt; + & gt ^; .

Example 139

2 - [(Methoxycarbonyl) methylamino] -4 - [(methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole

To a solution of 2-bromo-4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole (80 mg, 0.15 mmol) ) in 3 ml of acetonitrile was added glycine methyl ester hydrochloride (0.18 g, 1.5 mmol) and N, N-diisopropylethylamine (0.26).

187 ml, 1.5 mmol). The resulting solution was stirred at 60 ° C for 72 hours and then at 75 ° C for an additional 24 hours. The reaction mixture was cooled, filtered through a small pad of silica gel, and concentrated in vacuo. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilized to afford 40 mg (37%) of the title compound as a white powder. LRMS (ES +): 553.0 (M + H) &lt; + & gt ^; .

Example 140

2- (N-Glycyl) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole

To a solution of 2- (2- (methoxycarbonyl) methylamino) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole ( 27 mg, 0.049 mmol) in 2 mL tetrahydrofuran and 2 mL water were added lithium hydroxide monohydrate (4 mg, 0.098 mmol). The resulting solution was stirred at ambient temperature for 18 hours and then concentrated in vacuo. The residue was purified by preparative HPLC (reverse phase C18 column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilized to afford 16 mg (61%) of the title compound as a white powder. LRMS (ES -): 536.8 (M + H) &lt; + & gt ^; .

Example 141

1 - [(4-Methoxy) phenyl] -3- (ethoxycarbonyl) -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide

1 - [(4-Methoxy) phenyl] -3,5-dimethylpyrazole. To a solution of 4-methoxyphenylhydrazine hydrochloride (118.7 g, 0.68 mmol) in 300 mL glacial acetic acid was added 2,4-pentanedione (68.0 g, 0.68 mol). The resulting solution was stirred at 100 ° C for 18 hours and then concentrated in vacuo. The residue was dissolved in ethyl acetate, filtered through a pad of silica gel to give 131 g (95%) of the title compound.

- 188 in the title, which is used without further purification. LRMS (NH ₄ -CI): 203.3 (M + H) ⁺ .

1 - [(4-Methoxy) phenyl] pyrazole-3,5-dicarboxylic acid. To a suspension of 1 - [(4-methoxy) phenyl] pyrazole (131 g, 0.65 mol) in 400 mL of water was added potassium permanganate (410 g, 2.6 mol). The mixture was glowed to 70 ° C and stirred for 1 hour. The reaction mixture was filtered and the filter cake was washed with hot water. The filtrate was acidified with HCl and then extracted twice with ethyl acetate. The combined organics were washed with brine, dried (MgSO ₄ ) and concentrated. The residue was triturated with chloroform to give 39.7 g (23%) of the title compound. LRMS (ES -): 260.9 (MH) ^- .

Dimethyl 1 - [(4-methoxy) phenyl] pyrazole-3,5-dicarboxylate. A solution of 1 - [(4-methoxy) efnyl] pyrazole-3,5-dicarboxylic acid (39.7 g, 0.15 mol) in 300 mL of anhydrous methanol was cooled to 0 ° C and then bubbled through the solution for 15 minutes anhydrous HCl. The vessel was tightly capped and the reaction mixture was stirred at ambient temperature for 24 hours. The volatiles were removed in vacuo. The residue was dissolved in ethyl acetate, filtered through a pad of silica gel and concentrated in vacuo to give 32.8 g (74%) of the title compound which was used without further purification. LRMS (NH ₄ -CI): 291.2 (M + H) ⁺ .

1 - [(4-Methoxy) phenyl] -5- (methoxycarbonyl) pyrazole-3-carboxylic acid. To a solution of dimethyl 1 - [(4-methoxy) phenyl] pyrazole-3,5-dicarboxylate (32.7 g, 110 mmol) in 50 mL dioxane and 100 mL water was added concentrated sulfuric acid (1.50 mL, 28.2 mmol). ). The resulting solution was stirred at 100 ° C for 18 hours and cooled to room temperature. The reaction mixture was basified with potassium carbonate and then extracted with ether to remove unreacted diester. The aqueous layer was acidified with HCl and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO ₄ ) and concentrated to give 19.2 g (63%) of the title compound along with 5.0 g

189 (15%) of unreacted starting material. The title compound was used without further purification. LRMS (ES -): 274.9 (M-H) -.

1 - [(4-Methoxy) phenyl] -3- (ethoxycarbonyl) -5- (methoxycarbonyl) pyrazole. A solution of 1 - [(4-methoxy) phenyl] -5- (methoxycarbonyl) pyrazole-3-carboxylic acid (7.50 g, 27.1 mmol) in 50 mL thionyl chloride was stirred at 80 ° C for 1 hour. The volatiles were removed and the residue azeotroped with 20 mL of toluene and dried in vacuo. The residue was dissolved in 100 mL of tetrahydrofuran, and then diisopropylethylamine (11.8 mL, 67.9 mmol) and absolute ethanol (3.2 mL, 54.3 mmol) were added. The reaction mixture was stirred at ambient temperature for 24 hours. The volatiles were removed and the residue was dissolved in ethyl acetate. This solution was filtered through a pad of silica gel and concentrated in vacuo to give 3.7 g (45%) of the title compound which was used without further purification. LPMS (DCI): 305.1 (M + H) &lt; + & gt ^; .

1 - [(4-Methoxy) phenyl] -3- (ethoxycarbonyl) pyrazole-5-carboxylic acid. To a solution of 1 - [(4-methoxy) phenyl] -3- (ethoxycarbonyl) -5- (methoxycarbonyl) pyrazole (4.0 g, 13.2 mmol) in 40 mL of tetrahydrofuran and 20 mL of water was added an aqueous solution of hydroxide monohydrate lithium (0.55 g, 13.2 mmol). The reaction mixture was stirred at ambient temperature for 1 hour.

Tetrahydrofuran was removed in vacuo and the aqueous layer was extracted with ether to remove unreacted diester. The aqueous layer was acidified with HCl and extracted with ethyl acetate. The organics were washed with brine, dried (MgSO ₄ ) and concentrated to give 3.2 g (84%) of the title compound which was used without further purification. LRMS (ES -): 289.0 (MH) ^- .

1 - [(4-Methoxy) phenyl] -3- (ethoxycarbonyl) -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide. A solution of 1 - [(4-methoxy) phenyl] -3- (ethoxycarbonyl) pyrazole-5-carboxylic acid (3.2 g, 11.1 mmol) in 20 mL of thionyl chloride was stirred at 80 ° C for 1 hour. Remove the volatiles and

190

the residue is azeotroped with 20 ml of toluene and dried under vacuum. The residue was dissolved in 50 mL of methylene chloride and then triethylamine (4.6 mL, 33.3 mmol) and 4- (N-pyrrolidinocarbonyl) aniline (3.2 mL, 54.3 mmol) were added. The reaction mixture was stirred at ambient temperature for 4 hours. The volatiles were removed and the residue was dissolved in ethyl acetate, washed sequentially with 10% aqueous HCl and brine, dried (MgSO ₄ ), filtered through a pad of silica gel and concentrated to give 2.5 g (50%) of the title compound. A small portion was further purified by preparative HPLC (C18 reverse phase column, eluting with a gradient of 0 O / CH 2 CN with 0.5% TFA) and lyophilized to afford the title compound as a white powder. LRMS (ES +): 463.1 (M + H) &lt; + & gt ^; .

Example 142

1 - [(4-Methoxy) phenyl] -3- (carboxyamide) -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide

1 - [(4-Methoxy) phenyl] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide-3-carboxylic acid. To a solution of 1 - [(4-methoxy) phenyl] -3- (ethoxycarbonyl) -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide (2.05 g, 4.43 mmol) in 10 Potassium hydroxide (0.32 g, 5.76 mmol) was added in THF (10 mL) and water (10 mL). The resulting solution was stirred at ambient temperature for 18 hours. THF was removed in vacuo and the aqueous layer was extracted with ether to remove unreacted ester. The aqueous layer was acidified with HCl and extracted with ethyl acetate. The organics were washed with brine, dried (MgS0 ₄₎ and concentrated to give 1.1 g (57%) of the title compound which was used without further purification. LRMS (ES -): 433.0 (MH) ^- .

1 - [(4-Methoxy) phenyl] -3- (carboxyamide) -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide. To a solution of 1 - [(4-methoxy) phenyl] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide-3-carboxylic acid (117 mg, 0.27 mmol) in 10 mL of 1: 1 THF Triethylamine (0.056 mL, 0.40 mL) was added

191

mmol) and isobutyl chloroformate (0.038 mL, 0.30 mmol). The mixture was stirred at ambient temperature for 30 minutes and methanolic ammonium solution (1.34 mL of a 2.0 M solution of ammonia in methanol, 2.7 mmol) was added. The reaction mixture was stirred for 1 hour and the volatiles were removed. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilized to give 50 mg (43%) of the title compound as a white powder. LRMS (ES +): 434.1 (M + H) &lt; + & gt ^; .

Example 143

1 - [(4-Methoxy) phenyl] -3 - [(2-hydroxyethyl) carboxyamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide

To a solution of 1 - [(4-methoxy) phenyl] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide-3-carboxylic acid (110 mg, 0.25 mmol) in 5 mL of acetonitrile was added triethylamine (0.053 mL, 0.38 mmol) and isobutyl chloroformate (0.036 mL, 0.28 mmol) were added. The mixture was stirred at ambient temperature for 30 minutes and ethanolamine (0.06 mL, 1.01 mmol) was added. The reaction mixture was stirred for 1 hour and the volatiles were removed. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilized to afford 80 mg (67%) of the title compound as a white powder. LRMS (ES +): 478.0 (M + H) &lt; + & gt ^; .

Example 144

1 - [(4-Methoxy) phenyl] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide-3-hydroxamic acid

To a solution of 1 - [(4-methoxy) phenyl] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide-3-carboxylic acid (100 mg, 0.23 mmol) in 5 mL of acetonitrile was added Add triethylamine (0.064 mL, 0.46 mmol) and isobutyl chloroformate (0.030 mL, 0.23 mmol). The mixture was stirred at ambient temperature for 30 minutes and added

192 hydroxylamine hydrochloride (16 mg, 0.023 mmol). The reaction mixture was stirred for 1 hour and the volatiles were removed. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilized to give 28 mg (27%) of the title compound as a white powder. LRMS (ES -): 562.1 (M-H + TFA).

Example 145

1 - [(4-Methoxy) phenyl] -3- [phenylcarboxyamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide

To a solution of 1 - [(4-methoxy) phenyl] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide-3-carboxylic acid (100 mg, 0.23 mmol) in 5 mL of acetonitrile was added Add triethylamine (0.064 mL, 0.46 mmol) and isobutyl chloroformate (0.030 mL, 0.23 mmol). The mixture was stirred at ambient temperature for 30 minutes and aniline (0.02 mL, 0.23 mmol) was added. The reaction mixture was stirred for 1 hour and the volatiles were removed. The residue was purified by preparative HPLC (reverse phase C18 column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilized to afford 22 mg (19%) of the title compound as a white powder. LRMS (ES):

510.2 (M + H) ^-.

Example 146

1 - [(4-Methoxy) phenyl] -3 - [(3-hydroxypropyl) carboxyamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide

To a solution of 1 - [(4-methoxy) phenyl] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide-3-carboxylic acid (100 mg, 0.23 mmol) in 5 mL acetonitrile triethylamine (0.064 mL, 0.46 mmol) and isobutyl chloroformate (0.030 mL, 0.23 mmol) were added. The mixture was stirred at ambient temperature for 30 minutes and 3-hydroxypropylamine (0.02 mL, 0.23 mmol) was added. The reaction mixture was stirred for 1 hour and the volatiles were removed. The residue is purified

- 193

preparative HPLC (C18 reverse phase column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilization gave 38 mg (30%) of the title compound as a white powder.

LRMS (ES +): 492.3 (M + H) &lt; ^- & gt ^; .

Example 147

1 - [(4-Methoxy) phenyl] -3- [methylcarboxyamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide

To a solution of 1 - [(4-methoxy) phenyl] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide-3-carboxylic acid (100 mg, 0.23 mmol) in 5 mL of acetonitrile was added triethylamine (0.096 mL, 0.69 mmol) and isobutyl chloroformate (0.033 mL, 0.25 mmol) were added. The mixture was stirred at ambient temperature for 30 minutes and methylamine hydrochloride (23 mg, 0.35 mmol) was added. The reaction mixture was stirred for 1 hour and the volatiles were removed. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilized to afford 15 mg (15%) of the title compound as a white powder.

LRMS (ES +): 448.2 (M + H) &lt; + & gt ^; .

Example 148

1 - [(4-Methoxy) phenyl] -3 - [(benzyl) carboxyamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide

To a solution of 1 - [(4-methoxy) phenyl] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide-3-carboxylic acid (100 mg, 0.23 mmol) in 5 mL of acetonitrile was added triethylamine (0.096 mL, 0.69 mmol) and isobutyl chloroformate (0.033 mL, 0.25 mmol) were added. The mixture was stirred at ambient temperature for 30 minutes and benzylamine hydrochloride (49 mg, 0.35 mmol) was added. The reaction mixture was stirred for 1 hour and the volatiles were removed. The residue was purified by preparative HPLC (reverse phase C18 column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and freeze-dried to give 19

194 mg (16%) of the title compound as a white powder.

LRMS (ES +): 524.2 (M + H) &lt; + & gt ^; .

Example 149

1 - [(4-Methoxy) phenyl] -3 - [(dimethyl) carboxyamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide

To a solution of 1 - [(4-methoxy) phenyl] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide-3-carboxylic acid (100 mg, 0.23 mmol) in 5 mL of acetonitrile was added triethylamine (0.096 mL, 0.69 mmol) and isobutyl chloroformate (0.033 mL, 0.25 mmol) were added. The mixture was stirred at ambient temperature for 30 minutes and aqueous dimethylamine (0.040 mL of a 40% aqueous solution, 0.80 mmol) was added. The reaction mixture was stirred for 1 hour and the volatiles were removed. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilized to give 20 mg (19%) of the title compound as a white powder. LRMS (ES +): 462.2 (M + H) &lt; + & gt ^; .

Example 150

1 - [(4-Methoxy) phenyl] -3 - [(phenylethyl) carboxyamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide

To a solution of 1 - [(4-methoxy) phenyl] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide-3-carboxylic acid (100 mg, 0.23 mmol) in 5 mL of acetonitrile was added triethylamine (0.096 mL, 0.69 mmol) and isobutyl chloroformate (0.033 mL, 0.25 mmol) were added. The mixture was stirred at ambient temperature for 30 minutes and phenethylamine (0.043 mL, 0.80 mmol) was added. The reaction mixture was stirred for 1 hour and the volatiles were removed. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilized to afford 15 mg (12%) of the title compound as a white powder. LRMS (ES +): 538.2 (M + H) &lt; + & gt ^; .

• ·

Example 151

1 - [(4-Methoxy) phenyl] -3 - [(2-hydroxyphenyl) carboxyamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide

To a solution of 1 - [(4-methoxy) phenyl] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide-3-carboxylic acid (100 mg, 0.23 mmol) in 5 mL of acetonitrile was added triethylamine (0.096 mL, 0.69 mmol) and isobutyl chloroformate (0.033 mL, 0.25 mmol) were added. The mixture was stirred at ambient temperature for 30 minutes and added

2-hydroxyaniline (75 mg, 0.69 mmol). The reaction mixture was stirred for 1 hour and the volatiles were removed. The residue was purified by preparative HPLC (reverse phase C18 column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilized to give 10 mg (8%) of the title compound as a white powder.

LRMS (ES +): 526.1 (M + H) &lt; + & gt ^; .

Example 152

1 - [(4-Methoxy) phenyl] -3 - [(3-hydroxyphenyl) carboxyamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide

To a solution of 1 - [(4-methoxy) phenyl] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide-3-carboxylic acid (100 mg, 0.23 mmol) in 5 mL of acetonitrile was added triethylamine (0.096 mL, 0.69 mmol) and isobutyl chloroformate (0.033 mL, 0.25 mmol) were added. The mixture was stirred at ambient temperature for 30 minutes and added

3-hydroxyaniline (75 mg, 0.69 mmol). The reaction mixture was stirred for 1 hour and the volatiles were removed. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilized to give 12 mg (10%) of the title compound as a white powder.

LRMS (ES +): 526.2 (M + H) &lt; + & gt ^; .

Example 153 • ·

- 196

1 - [(4-Methoxy) phenyl] -3 - [(4-hydroxyphenyl) carboxyamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide

To a solution of 1 - [(4-methoxy) phenyl] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide-3-carboxylic acid (100 mg, 0.23 mmol) in 5 mL of acetonitrile was added triethylamine (0.096 mL, 0.69 mmol) and isobutyl chloroformate (0.033 mL, 0.25 mmol) were added. The mixture was stirred at ambient temperature for 30 minutes and added

4-hydroxyaniline (75 mg, 0.69 mmol). The reaction mixture was stirred for 1 hour and the volatiles were removed. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilized to give 12 mg (10%) of the title compound as a white powder.

LRMS (ES +): 548.1 (M + Na) &lt; + & gt ^; .

Example 154

1 - [(4-Methoxy) phenyl] -3 - [(methoxycarbonyl) amino] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide

1 - [(4-Methoxy) phenyl] -3 - [(methoxycarbonyl) amino] -5- (methoxycarbonyl) pyrazole. To a solution of 1 - [(4-methoxy) phenyl] -5- (methoxycarbonyl) pyrazole-3-carboxylic acid (3.0 g, 10.9 mmol) in 50 mL acetone at 0 ° C was added triethylamine (1.66). mL, 11.9 mmol) and isobutyl chloroformate (1.14 mL, 11.9 mmol) was added. The resultant was stirred for 30 minutes and then aqueous sodium azide (2.82 g, 43.4 mmol) was added. The reaction mixture was stirred at 0 ° C for 1 hour. The reaction mixture was then diluted with ethyl acetate and washed with brine. The organics were dried (MgSO ₄ ) and concentrated in vacuo. The residue was dissolved in 50 ml of toluene and stirred at 100 ° C for 1 hour. The volatiles were removed in vacuo and the residue was dissolved in methanolic sodium methoxide (5 mL of a 25% solution of sodium methoxide in methanol, 21 mmol) and stirred at ambient temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and

- 197 brine, dried (MgSO ₄₎ and concentrated in vacuo. The residue was purified by flash chromatography (eluting with hexanes / ethyl acetate 1: 1) to give 1.1 g (33%) of the title compound as a solid. LRMS (DCI): 306.3 (M + H) &lt; + & gt ^; .

1 - [(4-Methoxy) phenyl] -3 - [(methoxycarbonyl) amino] -1H-pyrazole-5 - [(2'-tert-butylaminosulfonyl- [1,1 '] -biphen-4-yl) carboxyamide.

To a solution of (2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl) amine (0.90 g, 2.95 mmol) in 20 mL of methylene chloride was added dropwise trimethylaluminum (8 mL) at room temperature. 85 ml 2.0

M solution in toluene, 17.68 mmol). Stir the resulting solution until gas evolution (about 15 minutes). To this solution was added 1 - [(4-methoxy) phenyl] -3- (methoxycarbonylamino) -5- (methoxycarbonyl) pyrazole (0.90 g, 2.95 mmol) in 10 mL of methylene chloride. The resulting solution was stirred at 40 ° C for 16 hours and then cooled to ambient temperature and further cooled by addition of saturated aqueous NH ₄ Cl. After dilution with ethyl acetate, the organic layer was washed with 10% aqueous HCl, saturated NaHCO ₃ and brine, dried (MgSO ₄ ), filtered through a pad of silica gel, and concentrated in vacuo. The solid residue was recrystallized from hexanes / ethyl acetate to give 1.4 g (82%) of the title compound. LRMS (ES):

577.9 (M + H) &lt; + & gt ^; .

1 - [(4-Methoxy) phenyl] -3 - [(methoxycarbonyl) amino] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide. 1 - [(4-methoxy) phenyl] -3 - [(methoxycarbonyl) amino] -1H-pyrazole-5 - [(2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide solution (0.40 g, 0.69 mmol) in 5 mL of trifluoroacetic acid was stirred at reflux for 20 min and then cooled to ambient temperature and concentrated in vacuo. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilized to afford 200 mg (56%) of the title compound as a white powder. LRMS (ES):

521.8 (M + H) &lt; + & gt ^; .

<·

- 198 Example 155

1 - [(4-Methoxy) phenyl] -3-amino-1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide

To a solution of 1 - [(4-methoxy) phenyl] -3 - [(methoxycarbonyl) amino] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide ( 0.22 g (0.42 mmol) in 10 mL of 1: 1 water / methanol was added potassium hydroxide (2.0 g, 35 mmol). The resulting mixture was stirred at 70 ° C for 4 hours and then cooled to room temperature and acidified with aqueous HCl. The reaction mixture was diluted with ethyl acetate and the organics were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilized to afford 75 mg (38%) of the title compound as a white powder.

LRMS (ES +): 463.8 (M + H) &lt; + & gt ^; .

Example 156

1 - [(4-Methoxy) phenyl] -3 - [(methoxycarbonyl) methylamino] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide.

To a solution of 1 - [(4-methoxy) phenyl] -3-amino-1H-pyrazole-5 - [(2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide (1,0) g, 1.92 mmol) in 10 mL of DMF was added sodium bicarbonate (0.24 g, 2.88 mmol) and methyl bromoacetate (0.22 mL, 2.30 mmol). The resulting mixture was stirred at 85 ° C for 16 hours. The reaction is incomplete, so additional portions of sodium bicarbonate (0.48 g, 5.76 mmol) and methyl bromoacetate (0.22 mL,

2.30 mmol) and the reaction mixture was stirred at 95 ° C for an additional 6 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organics were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue was dissolved in 5 mL of trifluoroacetic acid and stirred at reflux for 20 minutes and then cooled to room temperature and concentrated in vacuo. The residue was purified by preparative HPLC (C18 column).

199 (reverse phase, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilization gave 450 mg (44%) of the title compound as a white powder. LRMS (ES +): 536.0 (M + H) &lt; + & gt ^; .

Example 157

1 - [(4-Methoxy) phenyl] -3 - [(hydroxy) ethylamino] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide.

1 - [(4-Methoxy) phenyl] -3- [N-glycyl] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] -biphen-4-yl) carboxyamide. To a solution of 1 - [(4-methoxy) phenyl] -3 - [(methoxycarbonyl) methylamino] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide ( 0.40 g (0.75 mmol) in 10 mL of 1: 1 methanol: water was added lithium hydroxide monohydrate (0.13 g, 2.98 mmol). The resulting mixture was stirred at ambient temperature for 16 hours. The reaction mixture was acidified with aqueous HCl and diluted with ethyl acetate.

The organics were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilized to afford 200 mg (51%) of the title compound as a white powder. LRMS (ES):

522.0 (M + H) &lt; + & gt ^; .

1 - [(4-Methoxy) phenyl] -3 - [(hydroxy) ethylamino] -1H-pyrazole-5 - [(2-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide. To a solution of 1 - [(4-methoxy) phenyl] -3- [N-glycyl] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide (0 Triethylamine (0.038 mL, 0.27 mmol) and ethyl chloroformate (0.026 mL, 0.27 mmol) were added at -20 ° C, 14 g, 0.27 mmol) in tetrahydrofuran. The mixture was stirred for 30 minutes and then sodium borohydride (20 mg, 0.54 mmol) was added in a minimal amount of water. The reaction mixture was stirred with slow warming to room temperature for 1 hour and then cooled with 10% aqueous HCl. After dilution with ethyl acetate, the organics were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue is cleaned •

Preparative HPLC (C18 reverse phase column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilization afforded 35 mg (26%) of the title compound as a white powder. LRMS (ES +): 507.9 (M + H) &lt; + & gt ^; .

Example 158

1 - [(4-Methoxy) phenyl] -3 - [(E-2- (methoxycarbonyl) ethenyl] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) ) carboxyamide.

1 - [(4-Methoxy) phenyl] -3- (hydroxymethyl) -1H-pyrazole-5- (methoxycarbonyl) pyrazole. To a solution of 1 - [(4-methoxy) phenyl] -1H-pyrazole-5- (methoxycarbonyl) pyrazole-3-carboxylic acid (2.4 g, 8.69 mmol) in 50 mL tetrahydrofuran at -20 ° C was added triethylamine (1.21 mL, 8.69 mmol) and ethyl chloroformate (0.83 mL, 8.69 mmol). The mixture was stirred for 30 minutes and then sodium borohydride (0.66 g, 17.4 mmol) in a minimal amount of water was added. The reaction mixture was stirred with slow warming to room temperature for 1 hour and then cooled with 10% aqueous HCl. After dilution with ethyl acetate, the organics were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by flash chromatography (eluting with a 3: 2 mixture of ethyl acetate and hexane) to give 1.4 g (61%) of the title compound. LRMS (DCI): 263.3 (M + H) &lt; + & gt ^; .

1 - [(4-Methoxy) phenyl] -3- (hydroxymethyl) -1H-pyrazole-5 - [(2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide. To a solution of (2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl) amine (1.44 g, 4.73 mmol) in 40 mL of methylene chloride was added dropwise trimethylaluminum (14 mL) at room temperature. 2 mL of a 2.0 M solution in toluene, 28.4 mmol). The resulting solution was stirred until gas evolution ceased (about 15 minutes). To this solution was added 1 - [(4-methoxy) phenyl] -3- (hydroxymethyl) -5- (methoxycarbonyl) pyrazole (1.24 g, 4.73 mmol) in 10 mL of methylene chloride. The resulting solution was stirred at 40 ° C. ° C for 16 hours and then cooled to ambient temperature and the addition of a saturated NH ₄ Cl aqueous solution. Dilute the mixture with ethyl acetate, wash the organic layer with 10% aqueous HCl, saturated aqueous NaHCO ₃ and brine, dry (MgSO ₄ ), filter through a pad of silica gel, and concentrate in vacuo. The solid residue was recrystallized from hexanes / ethyl acetate to give 1.7 g (68%) of the title compound. LRMS (ES +): 557.1 (M + Na) &lt; + & gt ^; .

1 - [(4-Methoxy) phenyl] -3- (carboxaldehyde) -1H-pyrazole-5 - [(2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide. To a solution of oxalyl chloride (0.33 mL, 3.81 mmol) in 20 mL of methylene chloride was added dimethyl sulfoxide (0.54 mL, 7.63 mmol) at -78 ° C. The mixture was stirred for 15 minutes and then 1 - [(4methoxy) phenyl] -3- (hydroxymethyl) -1H-pyrazole-5 - [(2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4) was added. -yl) carboxyamide (1.70 g, 3.18 mmol) in 10 mL of methylene chloride. The reaction mixture was stirred with slow warming to room temperature over 2 hours. Triethylamine (2.21 mL, 15.90 mmol) was added and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with 10% HCl, saturated NaHCO 3 and brine, dried (MgSO ₄ ), filtered through a pad of silica gel and concentrated in vacuo to give 1.3 g (76%) of the title compound. in the title as a substantially pure substance which is used without further purification. LRMS (ES +): 533.2 (M + H) &lt; + & gt ^; .

1 - [(4-Methoxy) phenyl] -3- [E-2- (methoxycarbonyl) ethenyl] -1H-pyrazole-5 - [(2'-tert-butylaminosulfonyl- [1,1 '] -biphene-4- yl) carboxyamide. To a solution of 1 - [(4-methoxy) phenyl] -3- (carboxyaldehyde) -1H-pyrazole-5 - [(2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide (1) (30 g, 2.44 mmol) in 30 mL of methylene chloride was added methyl (triphenylphosphoranylidene) acetate (0.98 g, 2.92 mmol). The mixture was stirred at ambient temperature for 18 hours. The volatiles were removed in vacuo and the residue was purified by flash chromatography (eluting with 1: 1 ethyl acetate: hexane) to give 1.2 g (83%) of the title compound. LRMS (ES +): 589.1 (M + H) &lt; + & gt ^; .

- 202 · - ·· · · · ·

1 - [(4-Methoxy) phenyl] -3- [E-2- (methoxycarbonyl) ethenyl] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide. Solution 1 - [(4-methoxy) phenyl] -3- [E-2- (methoxycarbonyl) ethenyl] -1H-pyrazole-5 - [(2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4) -yl) carboxyamide (1.2 g, 2.04 mmol) in 10 mL of trifluoroacetic acid was stirred at reflux for 20 min and then concentrated in vacuo. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilized to give 1 g (90%) of the title compound as a white powder. LRMS (ES +): 533.0 (M + H) &lt; + & gt ^; .

Example 159

1 - [(4-Methoxy) phenyl] -3- [2- (methoxycarbonyl) ethyl] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide

To a solution of 1 - [(4-methoxy) phenyl] -3- [E-2- (methoxycarbonyl) ethenyl] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4- yl) carboxyamide (35 mg, 0.065 mmol) in 20 mL of absolute ethanol was added 10% palladium on carbon catalyst (3.5 mg). The mixture was stirred under 1 atm. of hydrogen gas for 3 hours and then filtered through a pad of celite and concentrated in vacuo.

The residue was purified by preparative HPLC (C18 reverse phase column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilized to afford 15 mg (42%) of the title compound as a white powder. LRMS (ES &lt; + &gt;): 534.9 (M + H) &lt; + & gt ^; .

Example 160

1 - [(4-Methoxy) phenyl] -3- [E-2- (carboxy) ethenyl] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide

To a solution of 1 - [(4-methoxy) phenyl] -3- [E-2- (methoxycarbonyl) ethenyl]

-1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide (1.2 g, 2.25 mmol) in 20 mL of 1: 1 methanol / water at

205 ·· - ··· Lithium hydroxide monohydrate (0.19 g,

4.5 mmol). The mixture was stirred for 3 hours and then acidified with aqueous HCl and diluted with ethyl acetate. The organics were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilized to afford 1.0 g (83%) of the title compound as a white powder. LRMS (ES -): 516.8 (MH) ^- .

Example 161

1 - [(4-Methoxy) phenyl] -3- [2- (carboxy) ethyl] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide

To a solution of 1 - [(4-methoxy) phenyl] -3- [E-2- (carboxy) ethenyl] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] -biphene-4-) yl) carboxyamide (40 mg, 0.077 mmol) in 20 mL of absolute ethanol at room temperature was added 10% palladium on carbon catalyst (20 mg). The mixture was stirred under 1 atm. of hydrogen gas for 3 hours and then filtered through a pad of celite and concentrated in vacuo. The residue was purified by preparative HPLC (reverse phase C18 column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilized to give 10 mg (25%) of the title compound as a white powder. LRMS (ES +): 520.9 (M + H) &lt; + & gt ^; .

Example 162

1 - [(4-Methoxy) phenyl] -3- [E-2- (carboxyamide) ethenyl] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide

To a solution of 1 - [(4-methoxy) phenyl] -3- [E-2- (carboxy) ethenyl] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] -biphene-4-) yl) carboxyamide (140 mg, 0.27 mmol) in 10 mL acetonitrile was added triethylamine (0.11 mL, 0.81 mmol) and isobutyl chloroformate (0.039 mL, 0.30 mmol). The mixture was stirred at ambient temperature for 30 minutes and then stirred

A solution of methanolic ammonia (0.27 mL of a 2.0 M solution of ammonia in methanol, 0.54 mmol) was added. The reaction mixture was stirred for 16 hours and then the volatiles were removed. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilized to give 35 mg (25%) of the title compound as a white powder. LRMS (ES +): 517.9 (M + H) &lt; + & gt ^; .

Example 163

1 - [(4-Methoxy) phenyl] -3- [E-2- (hydroxymethyl) ethenyl] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide

To a solution of 1 - [(4-methoxy) phenyl] -3- [E-2- (carboxy) ethenyl] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4- yl) carboxyamide (1.0 g, 1.93 mmol) in 20 mL tetrahydrofuran at -20 ° C was added triethylamine (0.27 mL, 1.93 mmol) and isobutyl chloroformate (0.25 mL, 1.93 mmol) . The mixture was stirred at ambient temperature for 30 minutes and then sodium borohydride (0.22 g, 5.78 mmol) was added in a minimal amount of water. The reaction mixture was stirred with slow warming to room temperature for 1 hour and then cooled with 10% aqueous HCl. Dilute the mixture with ethyl acetate, wash the organics with brine, dry (MgSO ₄ ) and concentrate in vacuo. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilized to give 0.5 g (52%) of the title compound as a white powder. LRMS (ES +): 504.9 (M + H) &lt; + & gt ^; .

Example 164

1 - [(4-Methoxy) phenyl] -3- (3-hydroxypropyl) -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide and Example 165

1 - [(4-Methoxy) phenyl] -3-propyl-1H-pyrazole-5 - [(2'-aminosulfonyl205)

[1,1 '] - biphen-4-yl) carboxyamide

To a solution of 1 - [(4-methoxy) phenyl] -3- [E-2- (hydroxymethyl) ethenyl] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] -biphene-4- yl) carboxyamide (40 mg, 0.077 mmol) in 20 mL of methanol at room temperature was added 10% palladium on carbon catalyst (4 mg). The mixture was stirred under 1 atm. of hydrogen gas for 3 hours and then filtered through a pad of celite and concentrated in vacuo. The residue was purified by preparative HPLC (reverse phase C18 column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilized to give 15 mg (38%) of Example 164 as a white powder. LRMS (ES +): 506.9 (M + H) &lt; + & gt ^; . 8 mg (20%) of the compound of Example 165 was also obtained as a white powder. LRMS (ES +): 490.9 (M + H) &lt; + & gt ^; .

Example 166

1 - [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4-cyano-1H-pyrazole-5 - [(2'-methylsulfonyl-3-fluoro- [1,1 '] - biphen-4-yl) ) carboxyamide

1 - [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4-cyano-1H-pyrazole-5- (2-furyl) pyrazole. To a solution of 2-furoylacetonitrile (0.91 g, 6.73 mmol) in 20 mL of absolute ethanol was added sodium ethoxide (2.5 mL of a 21% w / w solution in ethanol, 6.73 mmol) followed by 2,2,2- trifluoroacetoyl bromide-N- (4-methoxyphenyl) hydrazone (2.0 g, 6.73 mmol). The mixture was stirred at ambient temperature for 4 hours. The volatiles were removed in vacuo and the residue was dissolved in ethyl acetate, washed with water and brine, dried (MgSO ₄ ) and concentrated. The residue was purified by recrystallization from hexane-ethyl acetate to give 1.1 g (49%) of the title compound.

1 - [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4-cyano-pyrazole-5-carboxylic acid. To a solution of 1 - [(4-methoxy) phenyl] -3- (trifluoromethyl) -4-cyano-5- (2-furyl) pyrazole (0.68 g, 2.04 mmol) in a mixture of carbon tetrachloride, acetonitrile and water 4: 4: 6

- 2o - ·; Add sodium periodate (1.96 g, 9.2 mmol) and ruthenium chloride monohydrate (42 mg, 0.20 mmol). The resulting biphasic mixture was stirred vigorously at ambient temperature for 24 hours. The reaction mixture was cooled with 10% HCl and diluted with ethyl acetate. The organics were washed with brine, dried (MgSO ₄ ), filtered through a pad of celite and concentrated. The residue was dissolved in 1: 1 hexanes / ethyl acetate and extracted with saturated aqueous Na ₂ CO ₃ (twice). The combined organic extracts were acidified and extracted with ethyl acetate. The ethyl acetate extracts were washed with brine, dried (MgSO ₄ ) and concentrated to give 0.42 g (67%) of the title compound as a solid. LRMS (ES -): 310.0 (MH) -.

1 - [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4-cyano-1H-pyrazole-5 - [(2'-methylsulfonyl-3-fluoro- [1,1 '] - biphen-4-yl) ) carboxyamide. To a solution of 1 - [(4-methoxy) phenyl] -3- (trifluoromethyl) -4-cyano-5-carboxylic acid (0.41 g, 1.32 mmol) in 20 mL of methylene chloride was added oxalyl chloride (0.17 mL). (1.98 mmol) and 2 drops of dimethylformamide. The reaction mixture was stirred at ambient temperature for 6 hours and then the volatiles were removed in vacuo. The residue was dissolved in 20 mL of methylene chloride and 4-dimethylaminopyridine (0.48 g, 3.96 mmol) was added. The reaction mixture was stirred for 10 minutes and (2'-methylsulfonyl-3-fluoro- [1,1 '] - biphen-4-yl) amine hydrochloride (0.47 g, 1.45 mmol) was added. The resulting mixture was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and the organics were washed with 10% aqueous HCl, saturated NaHCO ₃ and brine, dried (MgSO ₄ ), filtered through a pad of silica gel and concentrated to give 0.6 g (81% of the title compound as brownish). solid.

LRMS (ES +): 581.3 (M + Na) &lt; + & gt ^; .

Example 167

1 - [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4- (amidino) -1H-pyrazole-E - [(2'-methylsulfonyl-3-fluoro- [1,1 '] - biphen-4) -yl) carboxyamide

207 • · · · ·

and Example 168

1 - [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4- (N-hydroxyamidino) -1H-pyrazole-5 - [(2'-methylsulfonyl-3-fluoro- [1,1 '] - biphene -4-yl) carboxyamide

To a solution of 1 - [(4-methoxy) phenyl] -3- (trifluoromethyl) -4-cyano-1H-pyrazole-5 - [(2'-methylsulfonyl-3-fluoro - [1,1 '] - biphen-4- yl) carboxyamide (100 mg, 0.18 mmol) in 5 mL absolute ethanol was added hydroxylamine hydrochloride (38 mg, 0.54 mmol) and sodium carbonate (29 mg, 0.27 mmol). The mixture was stirred at 80 ° C for 16 hours. The reaction mixture was diluted with water and ethyl acetate. The organics were washed with brine, dried (MgSO ₄ ) and concentrated to a solid. The residue was dissolved in 10 mL of absolute ethanol and cyclohexene (1 mL) was added,

20% palladium hydroxide on carbon (50 mg) and acetic acid (0.02 mL, 0.36 mmol). The resulting mixture was stirred at 80 ° C for 6 hours. The reaction mixture was cooled and filtered through a pad of celite and concentrated in vacuo. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilized to give 20 mg (16%) of Example 167 as a white powder. LRMS (ES +): 576.2 (M + H) &lt; + & gt ^; . Also obtained was 15 mg (12%) of the compound of Example 168 as a white powder. LRMS (ES +): 592.2 (M + H) &lt; + & gt ^; .

Example 169

1 - [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4- (ethoxycarbonyl) -1H-pyrazole-5 - [(2'-methylsulfonyl-3-fluoro- [1,1 '] - biphen-4) -yl) carboxyamide

1 - [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4- (ethoxycarbonyl) -5- (2-furyl) pyrazole. To a solution of ethyl 3- (2-furyl) -3-ketopropionate (2.45 g, 13.4 mmol) in 20 mL of absolute ethanol was added sodium ethoxide (4.6 mL of a 21 wt% solution in ethanol, 12.2 mmol). ) followed by 2,2,2-trifluoroacetoyl bromide-N- (4-methoxy208 · phenyl) hydrazone (1.82 g, 6.1 mmol). The mixture was stirred at ambient temperature for 4 hours. The volatiles were removed in vacuo and the residue was dissolved in ethyl acetate, washed with water and brine, dried (MgSO ₄ ) and concentrated. The residue was purified by recrystallization from hexane-ethyl acetate to give 1.4 g (61%) of the title compound. LRMS (ES +): 381.2 (M + H) &lt; + & gt ^; .

1 - [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4- (ethoxycarbonyl) pyrazole-5-carboxylic acid. To a solution of 1 - [(4-methoxy) phenyl] 3- (trifluoromethyl) -4- (ethoxycarbonyl) -5- (2-furyl) pyrazole (1.0 g, 2.63 mmol) in a mixture of carbon tetrachloride, acetonitrile and water 4: 4: 6 was added sodium periodate (2.5 g, 11.8 mmol) and ruthenium chloride monohydrate (11 mg, 0.05 mmol). The resulting biphasic mixture was stirred vigorously at ambient temperature for 24 hours. The reaction mixture was cooled with 10% HCl and diluted with ethyl acetate. The organics were washed with brine, dried (MgSO ₄ ), filtered through a pad of Celite and concentrated. The residue was dissolved in a 1: 1 mixture of hexanes and ethyl acetate and extracted with saturated aqueous Na ₂ CO ₃ (twice). The combined organic extracts were acidified and extracted with ethyl acetate. The ethyl acetate extracts were washed with brine, dried (MgSO ₄ ) and concentrated to give 0.5 g (53%) of the title compound as a solid. LRMS (ES -): 357.0 (MH) ^- .

1 - [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4- (ethoxycarbonyl) -1H-pyrazole-5 - [(2'-methylsulfonyl-3-fluoro- [1,1 '] -bifen-4) -yl) carboxyamide. To a solution of 1 - [(4-methoxy) phenyl] -3- (trifluoromethyl) -4- (ethoxycarbonyl) pyrazole-5-carboxylic acid (0.5 g,

1.4 mmol) in 10 mL of methylene chloride was added oxalyl chloride (0.18 mL, 2.1 mmol) and 2 drops of dimethylformamide. The reaction mixture was stirred at ambient temperature for 6 hours and then the volatiles were removed in vacuo. The residue was dissolved in 20 mL of methylene chloride and 4-dimethylaminopyridine (0.51 g, 4.2 mmol) was added. The reaction mixture was stirred for 10 minutes and (2'-methylsulfonyl-3-fluoro- [1,1 '] - biphen-4-yl) amine hydrochloride (0.42 g, 1.4 mmol) was added. The resulting mixture was stirred at ambient temperature for 16 hours. The reaction mixture was quenched

209 ..

Dilute with ethyl acetate and wash the organics with 10% aqueous HCl, saturated NaHCO _3, and brine, dry (MgSO ₄ ), filter through a pad of silica gel, and concentrate to give 0.6 g (70% of Example 169) as a solid. was purified by preparative HPLC (C18 reverse phase column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilized to afford the title compound as a white powder. LRMS (ES +):

628.1 (M + Na) &lt; + & gt ^; .

Example 170

1 - [(4-Methoxy) phenyl] -3- (trifluoromethyl) -1H-pyrazole-5 - [(2 'methylsulfonyl-3-fluoro- [1,1'] - biphen-4-yl) carboxyamide-4- carboxylic acid. To a solution of 1 - [(4-methoxy) phenyl] -3- (trifluoromethyl) -4- (ethoxycarbonyl) -1H-pyrazole-5 - [(2'-methylsulfonyl-3-fluoro- [1,1 '] - biphene- 4-yl) carboxyamide (0.30 g, 0.49 mmol) in 10 mL of 1: 1 methanol / water was added potassium hydroxide (55 mg, 0.98 mmol). The reaction mixture was stirred at 60 ° C for 2 hours and then cooled to room temperature and acidified with 10% aqueous HCl. The mixture was diluted with ethyl acetate, washed with brine, dried (MgSO ₄ ) and concentrated. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with a gradient of H ₂ O / CH ₃ CN with 0.5% TFA) and lyophilized to give 150 mg (53%) of the title compound as a white powder. LRMS (ES -): 576.2 (MH).

• · · · ·

- 210

Table 1

Ex. RE M R ^la A-B 1 - Core-A ch ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 2 2-CH ₃ O Core-A ch ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 3 3-CH ₃ O Core-A ch ₃ 2'-H ₂ NSO ₂ -bifen-4-yl 4 _4-CH3 O Core-A ch ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 5 2-HO Core-A ch ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 6 3-HO Core-A ch ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 7 4-HO Core-A ch ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 8 _4-CH3 O Core-A ch ₃ 2'-H ₂ NSO ₂ -3-F-biphen-4-yl 9 _4-CH3 O Core-A ch ₃ 2'-H ₂ NSO ₂ -3-Br-biphen-4-yl 10 _4-CH3 O Core-A ch ₃ 2'-H ₂ NSO ₂ -3-I-biphen-4-yl 11 _4-CH3 O Core-A ch ₃ 21 ¹ -H ₂ NSO ₂ -3-methylbifen-4-yl 12 _4-CH3 O Core-A ch ₃ 4- (CH ₃ ) ₂ NC (O) C ₆ H ₄ 13 _4-CH3 O Core-A ch ₃ 4- (N-pyrrolidinocarbonyl) ^c 6 ^h 4 14 _4-CH3 O Core-A ch ₃ 4- (N-pyrrolidinomethyl) - ^C 6 ^H 4 15 Dec _4-CH3 O Core-A cf ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 16 _4-CH3 O Core-A cf ₃ 4- (N-pyrrolidinocarbonyl)

• ·

^C 6 ^H 4

17 _4-CH3 O Core-A cf ₃ 5- (2'-CH ₃ SO ₂ -C ₆ H ₄ ) pyrid-2-yl 18 _4-CH3 O Core-A cf ₃ 5- (N-pyrrolidinocarbonyl) pyrid-2-yl 19 Dec _4-CH3 O Core-A ch ₃ 5- (N-pyrrolidinocarbonyl) pyrid-2-yl 20 May _4-CH3 O Core-A ch ₃ 5- (2'-H ₂ NSO ₂ -C ₈ H ₄ ) pyrid-2-yl 21 _4-CH3 O Core-A ch ₃ 4- (3'-HO-N-pyrrolidinocarbonyl) C ₈ H ₄ 22nd _4-CH3 O Core-F nh ₂ 2'-H ₂ NSO ₂ -bifen-4-yl 23 _4-CH3 O Core-F Br 2'-H ₂ NSO ₂ -biphen-4-yl 24 _4-CH3 O Core-F Cl 2'-H ₂ NSO ₂ -bifen-4-yl 25 4-HO Core-F Cl 2'-H ₂ NSO ₂ -biphen-4-yl 26 _4-CH3 O Core-F ch ₃ o 2'-H ₂ NSO ₂ -bifen-4-yl 27 Mar: _4-CH3 O Core-F ch ₃ s 2'-H ₂ NSO ₂ -bifen-4-yl 28 _4-CH3 O Core-F CH ₃ S 2'-H ₂ NSO ₂ -biphen-4-yl 29 _4-CH3 O Core-F CH ₃ SO ₂ 2'-H ₂ NSO ₂ -biphen-4-yl 30 _4-CH3 O Core-F -CN 21 ¹ -H ₂ NSO ₂ -bifen-4-yl 31 _4-CH3 O Core-F (CH ₃ ) ₂ N 2'-H ₂ NSO ₂ -biphen-4-yl 32 _4-CH3 O Core-F pyrrol- 1-yl 2'-H ₂ NSO ₂ -bifen-4-yl 33 _4-CH3 O Core-E ^CH 2 ^CO 2 ^H 3 5- (2'-H ₂ NSO ₂ -C ₈ H ₄ ) pyrid-2-yl 34 _4-CH3 O Core-E ch ₂ every ₂ h 5- (2'-H ₂ NSO ₂ -C ₈ H ₄ ) pyrid-2-yl 35 _4-CH3 O Core-E (and) 5- (2'-H ₂ NSO ₂ -C ₈ H ₄ ) pyrid-2-yl 36 _4-CH3 O Core-E (b) 5- (2'-H ₂ NSO ₂ -C ₈ H ₄ ) pyrid-2-yl 37 _4-CH3 O Core-D - 2'-H ₂ NSO ₂ -biphen-4-yl 38 _4-CH3 O 3-C1 Core-A ch ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 39 4-CF ₃ O Core-A ch ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 40 3-Br Core-A ch ₃ 2'-H ₂ NSO ₂ -biphen-4-yl

• ·

212 ···· · · · ····· · · · ·

41 3-1 Core-A ch ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 42 3,4-OCH ₂ O Core-A ^CH 3 2'-H ₂ NSO ₂ -biphen-4-yl 43 _4-CH3 O Core-A ch ₂ oh 4- (N-pyrrolidinocarbonyl) C ₈ H ₄ 44 _4-CH3 O Core-A CHO 4- (N-pyrrolidinocarbonyl) C ₈ H ₄ 45 _4-CH3 O Core-A co ₂ h 4- (N-pyrrolidinocarbonyl) C ₈ H ₄ 46 _4-CH3 O Core-A co ₂ ch ₃ 4- (N-pyrrolidinocarbonyl) C ₈ H ₄ 47 4-C1 Core-A ch ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 48 4-C1 Core-A ch ₃ 5- (2'-H ₂ NSO ₂ -C ₈ H ₄ ) pyrid-2-yl 49 3,4- diCl Core-A ch ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 50 3-C1 Core-A ch ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 51 - Core-F nh ₂ 2'-H ₂ NSO ₂ -bifen-4-yl 52 - Core-F Cl 2'-H ₂ NSO ₂ -biphen-4-yl 53 3- Br 4- F Core-F nh ₂ 2'-H ₂ NSO ₂ -biphen-4-yl 54 4-F Core-F nh ₂ 2'-H ₂ NSO ₂ -biphen-4-yl 55 3-Br Core-F nh ₂ 2'-H ₂ NSO ₂ -biphen-4-yl 56 3-Br Core-F Cl 2'-H ₂ NSO ₂ -biphen-4-yl 57 _4-CH3 O Core-A ch ₃ s 2'-H ₂ NSO ₂ -biphen-4-yl 58 _4-CH3 O Core-A ch ₃ Sat ₂ 5- (2'-CH ₃ CO ₂ -C ₈ H ₄ ) pyrimid-2-yl 59 _4-CH3 O Core-A ch ₃ Sat ₂ 2'-H ₂ NSO ₂ -bifen-4-yl 60 _4-CH3 O Core-A ch ₃ s 4- (N-pyrrolidinocarbonyl) C ₈ H ₄ 61 _4-CH3 O Core-A ch ₃ s 2'-CH ₃ SO ₂ -biphen-4-yl 62 _4-CH3 O Core-A ch ₃ Sat ₂ 4- (N-pyrrolidinocarbonyl) C ₈ H ₄ 63 _4-CH3 O Core-A ch ₃ and ₂ 2'-H ₂ NSO ₂ -biphen-4-yl 64 _4-CH3 O Core-A CH ₃ OC 2'-H ₂ NSO ₂ -biphen-4-yl 65 _4-CH3 O Core-A ch ₃ so ₂ ch ₂ 2'-H ₂ NSO ₂ -biphen-4-yl

φ ·

- 213 -

_4-CH3 O Core-A cf ₃ 5- (2'-CH ₃ SO ₂ -C ₆ H ₄ ) pyrimid-2-yl _4-CH3 O Core-A ch ₃ 4- (2'-CH ₃ CO ₂ -pyrrolidinocarbonyl) C ₈ H _{4 4-CH3} O Core-A cf ₃ 4- (3'-H ₂ N-pyrrolidinocarbonyl) C ₈ H _{4 4-CH3} O Core-A ch ₃ 4- (3'-CH ₃ O-pyrrolidinocarbonyl) C ₈ H _{4 4-CH3} O Core-A cf ₃ 5- (2'-H ₂ NSO ₂ -C ₈ H ₄ ) pyrid-2-yl _4-CH3 O Core-A cf ₃ 4-amidinophenyl _4-CH3 O Core-A cf ₃ 4- (N-pyrrolidino-C (= NH)) - ^C 6 ^H 4 _4-CH3 O - cf ₃ 2'-H ₂ NSO ₂ -bifen-4-yl _4-CH3 O Core-B 3-CF _{3 R} 5 CO ₂ CH ₃ 2'-H ₂ NSO ₂ -bifen-4-yl _4-CH3 O Core-B 3-CF ₃ , 5- (CH ₂ ) ₂ OH 21 ¹ -H ₂ NSO ₂ -bifen-4-yl _4-CH3 O Core-A cf ₃ 4- (N-pyrrolidino-C (= NH)) - ^C 6 ^H 4 _4-CH3 O Core-A cf ₃ 4- (N-pyrrolidino-C (= NCO ₂ -butyl)) C ₈ H _{4 4-CH3} O Core-A cf ₃ 4- (N-pyrrolidino-C (= N) SO ₂ CH ₃ ) C ₈ H _{4 4-CH3} O Core-A ^CF 3 4-amidinophenylmethyl _4-CH3 O Core-A cf ₃ 4- (N-pyrrolidino-C (= NH ₂ )) ^C 6 ^H 4 ^-CH 2 - _4-CH3 O Core-A cf ₃ N-Benzyl-piperidin-4-yl _4-CH3 O Core-A cf ₃ N- (pyrid-2-ylmethyl) piperidin-4-yl _4-CH3 O Core-A cf ₃ 4- (2 -methylimidazolyl ¹⁾ - C ^H 4 _4-CH3 O Core-A ch ₃ 4- (5'-Methylimidazolyl) - ^C 6 ^H 4 _4-CH3 O Core-A ch ₃ 4- (4'-Methylimidazolyl) -

• ·

214

_4-CH3 O Core-A cf ₃ 4- (5'-CH ₃ C (O) -imidazolyl) - ^C 6 ^H 4 _4-CH3 O Core-A cf ₃ 4- (5'-carboxyimidazolyl) _4-CH3 O Core-A cf ₃ ^C 6 ^H 4 4- (5'-CH ₃ NHC (O) - _4-CH3 O Core-A cf ₃ imidazolyl) C ₄ H _g of 4- (5'-H ₂ NC (0) imidazolyl) - _4-CH3 O Core-A cf ₃ ^C 6 ^H 4 4- (5'-CH ₃ NHC (O) - _4-CH3 O Core-A ch ₂ oh imidazolyl) C H _{4 g of} 4- (N-pyrrolidinocarbonyl) - _4-CH3 O Core-A CHO ^C 6 ^H 4 4- (N-pyrrolidinocarbonyl) - _4-CH3 O Core-A CO ₂ H ^C 6 ^H 4 4- (N-pyrrolidino- _4-CH3 O Core-A co ₂ ch ₃ carbonyl) C ₄ H _{g of} 4- (N-pyrrolidino _4-CH3 O Core-A ch ₂ cn carbonyl) C ₄ H _{g of} 4- (N-pyrrolidino _4-CH3 O Core-A ch ₂ every ₂ h carbonyl) C ₄ H _{g of} 4- (N-pyrrolidino _4-CH3 O Core-A CH ₂ Br carbonyl) C H _{4 g} of 2'-H ₂ NSO ₂ biphen-4-yl _4-CH3 O Core-A ch ₂ nh ₂ 2'-H ₂ NSO ₂ -biphen-4-yl _4-CH3 O Core-A ch ₂ nh ₂ _ 2'-H ₂ NSO ₂ -biphen-4-yl _4-CH3 O Core-A Sat ₂ ch ₃ ch ₂ - 2'-H ₂ NSO ₂ -biphen-4-yl _4-CH3 O Core-A imidazole ch ₂ oh 2'-H ₂ NSO ₂ -biphen-4-yl _4-CH3 O Core-A ch ₂ - 2'-H ₂ NSO ₂ -biphen-4-yl _4-CH3 O Core-A OC (O) CF ₃ CF ₃ 2'-CH ₃ SO ₂ -biphen-4-yl 2-CO ₂ Me _4-CH3 O Core-A cf ₃ 2'-CH ₃ SO ₂ -biphen-4-yl 2-CO ₂ H _4-CH3 O Core-A cf ₃ 2'-H ₂ NSO ₂ -biphen-4-yl

• • r r · ·

- 215 «••• Φ ·· ··

2-CO ₂ CH _{3 4-CH3} O Core-A cf ₃ 2'-t-Bu-HNSO ₂ -bifen-4-yl 2-CO ₂ H 4 -CH ₃ O Core-A cf ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 2-CO ₂ H 4 -CH ₃ O Core-A cf ₃ 2'-H ₂ NSO ₂ -bifen-4-yl 2-CH ₂ OH 4-CH ₃ O Core-A ch ₃ 4-sec-Butyl-phenyl _4-CH3 O Core-A ch ₃ 4- (3'-Methyl-3'-pyrazoline- _4-CH3 O Core-A ch ₃ -5'-on-2'-yl) C ₈ H ₄ 4- (6'methylbenzothiazole- _4-CH3 O Core-A ch ₃ -2'-yl) C ₆ H ₄ 3,4-dibromophenyl _4-CH3 O Core-A ch ₃ 4-butylphenyl _4-CH3 O Core-A ch ₃ 4- (4-Methylpiperidinyl) - _4-CH3 O Core-A ch ₃ ^C 6 ^H 4 -4- (2 ¹ -methylimidazolyl) - _4-CH3 O Core-A cf ₃ ^C 6 ^H 4 4- (N-methylimidazol-2-yl) _4-CH3 O Core-A cf ₃ carbonyl) C ₈ H ₄ 4- (imidazol-2-yl-hydroxy- _4-CH3 O Core-A cf ₃ methyl) C ₈ H ₄ 4- (N-benzylimidazol-2-yl- _4-CH3 O Core-A cf ₃ hydroxymethyl) C ₈ H ₄ 4- (imidazol-2-yl- _4-CH3 O Core-A cf ₃ carbonyl) C ₉ H ₄ [(thiazol-2-yl) (4'-CH ₃ OC ₉ H _4-CH3 O Core-A cf ₃ NH) CH ₂ ] C ₈ H 4 - (2 ¹ thiazolin-2'yl- _4-CH3 O Core-A cf ₃ carbonyl) C ₈ H ₄ 4- (2'-imidazolin-2'yl) C ₉ H _{4 4-CH3} O Core-A cf ₃ 4- (H ₂ N (CH ₂ ) ₂ NHC (O)) C ₈ H _{4 4-CH3} O Core-A cf ₃ 4- (1 ', 4', 5 ', 6'-tetrahydro- _4-CH3 O Core-A cf ₃ pyrimid-2-yl) C ₈ H ₄ 4- (N-methyl-1 ', 4', 5 ', 6'-

tetrahydropyrimid-2-yl) C ₈ H ₄

- 216 * • 9 · «9 9 9 • 99 9 9 9 9 • 9 9 9 9 9

9 · 100 «100«

9 9 9 ········, 9 · 99

126 _4-CH3 O Core-A cf ₃ 4- (1 ', 4', 5 ', 6'-tetrahydropyrimid-2-yl) -2-F-C ₈ H ₄ 127 _4-CH3 O Core-A cf ₃ 4- (N-CH ₃ -4'-imidazolin-2'yl) -2-F-C ₈ H ₄ 128 _4-CH3 O Core-A cf ₃ 4- (N-CH ₃ -4'-Imidazolin-2'-yl) ^C 6 ^H 4 129 _4-CH3 O Core-A cf ₃ 4- (guanidino-carbonyl) C ₈ H ₄ 130 _4-CH3 O Core-A cf ₃ 4- (pyrimid-2-yl) phenyl 131 _4-CH3 O Core-F C (O) NH ₂ 2'-H ₂ NSO ₂ -biphen-4-yl 132 _4-CH3 O Core-F NH (CH _{2) 2} OCH ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 133 _4-CH3 O Core-F NH (CH ₂ ) ₃ - OH 2'-H ₂ NSO ₂ -biphen-4-yl 134 _4-CH3 O Core-F NH (CH ₂ ) ₂ - CN 2'-H ₂ NSO ₂ -biphen-4-yl 135 _4-CH3 O Core-F NH (CH ₂ ) ₃ - and ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 136 _4-CH3 O Core-F NH (CH ₂ ) ₂ every ₂ h 2'-H ₂ NSO ₂ -biphen-4-yl 137 _4-CH3 O Core-F NH-i-Pr 2'-H ₂ NSO ₂ -biphen-4-yl 138 _4-CH3 O Core-F NHCH (CH ₂ OH) ₂ 2'-H ₂ NSO ₂ -biphen-4-yl 139 _4-CH3 O Core-F nhch ₂ co ₂ ch- 2'-H ₂ NSO ₂ -biphen-4-yl 140 _4-CH3 O Core-F NHCH ₂ every ₂ h 2'-H ₂ NSO ₂ -biphen-4-yl 141 _4-CH3 O Core-A CO ₂ ^C 2 ^H 5 4- (N-pyrrolidinocarbonyl) C ₈ H ₄ 142 _4-CH3 O Core-A conh ₂ 4- (N-pyrrolidinocarbonyl) C ₈ H ₄ 143 _4-CH3 O Core-A C (O) NH (CH ₂ ) ₂ oh 4- (N-pyrrolidinocarbonyl) C ₈ H ₄ 144 _4-CH3 O Core-A CONHOH 4- (N-pyrrolidinocarbonyl) C ₈ H ₄ 145 _4-CH3 O Core-A CONHC _{5 g of} H 4- (N-pyrrolidinocarbonyl) C ₈ H ₄ 146 _4-CH3 O Core-A CONH- (ch ₂ ) ₃ oh 4- (N-pyrrolidinocarbonyl) C ₈ H ₄ 147 _4-CH3 O Core-A conhch ₃ 4- (N-pyrrolidino-

· · · * T t t t t t t t t t t t t t t t t t t t t t t t t t t t t · 9 · «9 * * * * *» »

- 217 - 148 _4-CH3 O Core-A CONH- carbonyl) C ₈ H ₄ 4- (N-pyrrolidino- 149 _4-CH3 O Core-A CH ₂ C 6 ^H 5 C0N _{(CH3) 2} carbonyl) C ₄ H _{g of} 4- (N-pyrrolidino 150 _4-CH3 O Core-A CONH- carbonyl) C ₄ H _{g of} 4- (N-pyrrolidino 151 _4-CH3 O Core-A (ch ₂ ) ₂ c ₆ h ₅ CONH-2- carbonyl) C ₄ H _{g of} 4- (N-pyrrolidino 152 _4-CH3 O Core-A OH-C ₆ H ₄ CONH-3- carbonyl) C ₄ H _{g of} 4- (N-pyrrolidino 153 _4-CH3 O Core-A oh-c ₆ hrs ₄ C0NH-4- carbonyl) C ₈ H ₄ 4- (N-pyrrolidino- 154 _4-CH3 O Core-A ohc ₆ h ₄ nhco ₂ ch ₃ carbonyl) (C ₈ H ₄ 2'-H ₂ NSO ₂ -bifen-4-yl) 155 _4-CH3 O Core-A nh ₂ 2'-H ₂ NSO ₂ -bifen-4-yl 156 _4-CH3 O Core-A nhch ₂ co ₂ ch- ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 157 _4-CH3 O Core-A NH (CH ₂ ) ₂ oh 2'-H ₂ NSO ₂ -biphen-4-yl 158 _4-CH3 O Core-A ch = chco ₁ ch · 3 2 ¹ -H ₂ NSO ₂ -bifen-4-yl 159 _4-CH3 O Core-A CH ₂ CH ₂ CO ₂ CH ₃ 2'-H ₂ NSO ₂ -bifen-4-yl 160 _4-CH3 O Core-A ch = chco ₂ hrs 2'-H ₂ NSO ₂ -biphen-4-yl 161 _4-CH3 O Core-A ch ₂ ch ₂ every ₂ h 2'-H ₂ NSO ₂ -biphen-4-yl 162 _4-CH3 O Core-A ch = chconh ₂ 2'-H ₂ NSO ₂ -biphen-4-yl 163 _4-CH3 O Core-A ch = chch ₂ oh 2'-H ₂ NSO ₂ -biphen-4-yl 164 _4-CH3 O Core-A (ch ₂ ) ₃ oh 2'-H ₂ NSO ₂ -biphen-4-yl 165 _4-CH3 O Core-A (CH ₂ ) ₂ CH ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 166 _4-CH3 O Core-C 3-CF ₃ 2'-CH ₃ SO ₂ -3-F-biphen-4-yl 167 _4-CH3 O Core-C 4-CN 3-CF ₃ 2'-CH ₃ SO ₂ -3-F-biphen-4-yl 168 _4-CH3 O Core-C 4-amidino 3-CF ₃ 2'-CH ₃ SO ₂ -3-F-biphen-4-yl

4-amidino-OH

169 _4-CH3 O Core-C 3-CF ₃ , 4-CO ₂ C ₂ H ₅ 2 ' -CH ₃ SO ₂ -3-F-biphen-4-yl 170 _4-CH3 O Core-C 3-CF ₃ , 4-CO ₂ H 2 ' -CH ₃ SO ₂ -3-F-biphen-4-yl

• · ·

218 (a) -CH ₂ C (O) NHCH ₂ CO ₂ CH ₃ (b) - (1,2,4-triazol-1-yl) CH ₂ (c)

• · ·

2J.9 ·

The following tables represent representative examples of the present invention. Each record in each table is meant to be paired with each formula at the beginning of the table. For example, Example 1 in Table 2 is intended to be paired with each of the formulas a -? - yg

Table 2

B, R ¹ = CH 3 R ¹ = b 2 b ₃ CF 3 R ¹ = SCH 3 R ^1a = b4 b SOCH3 ₅ R ^1a = R ^1a SO2CH3 b6 b7 = Cl R ¹ = Br R ¹ = BG CO2CH3 b9 R ^1a = CH2OCH3

C, R ¹ = CH 3 C 2 R ¹ = CF 3, C ₃ R ^1a = SCH3 c4 R ^1a = SOCH3 5 R ^1a = SO2CH3 c6, R ¹ = C 7 R ^1a = Br c8, R ^1a = CO2CH ₃ -C R ¹ = CH ₂ OCH ₃ a-ι R ^1a = CH 3 a 2 R ^1a = CF 3 and ₃ R ^1a = SCH 3 a 4 R ^1a = SOCH 3 and ₅ R ^1a = SO 2 CH 3 a 5 R ^1a = CI a 7 R ^1a = Br a 3 t + ' ^a = CO ₂ CH ₃ and ₉ R ^1a = CH ₂ OCH ₃

D, R ¹ = CH3 d2, R ¹ = CF 3 d ₃ R ^1a = SCH3 d4 R ^1a = SOCH3 _d5 R ^1a = SO2CH3 d6 R ¹ = Cl d7 R ^1a = Br d8 R ^1a = CO2CH3 dg R ^1a = CH 2 C≡CH ₃ e R ^1a = CH 3 e2 R ¹ = CF 3 e ₃ R ¹ = SCH 3 e4 R ^1a = SOCK3 e ₅ R ^1a = SO2CH3 e6 R ¹ = Cl E7 R ^1a = Br e8 R ^1a = CO2CH3 e ₉ R ¹ = CH 2 C≡CH ₃ h R ^1a = CH3 f 2 R ^1a = CF 3 f ₃ R ^1a = SCH 3 f 4 R ^1a = SOCH 3 f ₅ R ^1a = SO 2 CH 3 fg R ^1a = CI f 7 R ^1a = Br fg R ^1a = CO 2 CH ₃ f R ^1a = CH ₂ OCH ₃ Phenyl phenyl phenyl phenyl phenyl phenyl phenyl

2-pyridyl

2-pyridyl

2-pyridyl

2-pyridyl

2-pyridyl

2-pyridyl

2- pyridyl

3-pyridyl 3-pyridyl 3-pyridyl 3-pyridyl 3-pyridyl 3-pyridyl 3-pyridyl 2-pyrimidyl 2-pyrimidyl 2-pyrimidyl 2-pyrimidyl 2-pyrimidyl 2-pyrimidyl 2-pyrimidyl 5-pyrimidyl 5-pyrimidyl 5- pyrimidyl 5-pyrimidyl 5-pyrimidyl 5-pyrimidyl

2- (aminosulfonyl) phenyl 2- (methylaminosulfonyl) phenyl

1-pyrrolidinocarbonyl

2- (methylsulfonyl) phenyl 4-morpholino

2- (1'-CF _3- tetrazol-2-yl) phenyl 4-morpholinocarbonyl 2- (aminosulfonyl) phenyl 2- (methylaminosulfonyl) phenyl

1-pyrrolidinocarbonyl

2- (methylsulfonyl) phenyl 4-morpholino

2- (1 ¹ -CF-tetrazol-2-yl) phenyl 4-morpholinocarbonyl 2- (aminosulfonyl) phenyl 2- (methylaminosulfonyl) phenyl

1-pyrrolidinocarbonyl

2- (methylsulfonyl) phenyl 4-morpholino

2- (1'-CF _3- tetrazol-2-yl) phenyl 4-morpholinocarbonyl 2- (aminosulfonyl) phenyl 2- (methylaminosulfonyl) phenyl

1-pyrrolidinocarbonyl

2- (methylsulfonyl) phenyl 4-morpholino

- (1'-CF-1-tetrazol-2-yl) phenyl 4-morpholinocarbonyl 2- (aminosulfonyl) phenyl 2- (methylaminosulfonyl) phenyl

1-pyrrolidinocarbonyl

2- (methylsulfonyl) phenyl 4-morpholino

2- (1'-CF 3 -tetrazol-2-yl) phenyl

2 * 21 · 5-pyrimidyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-F-phenyl 2- F-phenyl 2-F-phenyl 2-F-phenyl 2-F-phenyl 2-F-phenyl 2-F-phenyl 2,5-diF-phenyl 2,5-diF-phenyl 2,5-diF-phenyl 2 5-diF-phenyl 2,5-diF-phenyl 2,5-diF-phenyl 2,5-diF-phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl

4-morpholinocarbonyl

2- (aminosulfonyl) phenyl

2- (methylaminosulfonyl) phenyl

1-pyrrolidinocarbonyl

2- (methylsulfonyl) phenyl

4-morpholino

2- (1'-CF _3- tetrazol-2-yl) phenyl

4-morpholinocarbonyl

2- (aminosulfonyl) phenyl

2- (methylaminosulfonyl) phenyl

1-pyrrolidinocarbonyl

2- (methylsulfonyl) phenyl

4-morpholino

2- (1'-CF _3- tetrazol-2-yl) phenyl

4-morpholinocarbonyl

2- (aminosulfonyl) phenyl

2- (methylaminosulfonyl) phenyl

1-pyrrolidinocarbonyl

2- (methylsulfonyl) phenyl

4-morpholino

2- (1'-CF _3- tetrazol-2-yl) phenyl

4-morpholinocarbonyl

2- (N-pyrrolidin-methyl) phenyl

2- (N-piperidinylmethyl) phenyl

2- (N-morpholinomethyl) phenyl

2- (N, N'-methylmorpholinium-methyl) phenyl

2- (N-pyridinium-methyl) phenyl

2- (N-4- (N, N'-dimethylamino) pyridinium methyl) phenyl

2- (N-azatanyl-methyl) phenyl

2- (N-azetidinylmethyl) phenyl

2- (N-piperazinylmethyl) phenyl

2- (N, N'-BOC-piperazinylmethyl) phenyl

2- (N-imidazolylmethyl) phenyl

2- (N-methoxy-N-methylamino-methyl) phenyl

- 222

phenyl 2- (N-pyridonylmethyl) phenyl phenyl 2- (N- (Ν ', N'-dimethylhydrazinylmethyl) phenyl) phenyl 2- (amidinyl) phenyl phenyl 2- (N-guanidyl) phenyl phenyl 2- (imidazolyl) phenyl phenyl 2- (imidazolidinyl) phenyl phenyl 2- (2-imidazolidinylsulfonyl) phenyl phenyl 2- (2-pyrrolidinyl) phenyl phenyl 2- (2-piperidinyl) phenyl phenyl 2- (amidinylmethyl) phenyl phenyl 2- (2-imidazolidinylmethyl) phenyl phenyl 2- (N- (2-aminoimidazolyl) methyl) phenyl phenyl 2-dimethylaminoimidazolyl-1-yl phenyl 2- (3-aminophenyl) phenyl 2- (3-pyrrolidinylcarbonyl) phenyl 2-glycinoyl phenyl 2- (imidazol-1-ylacetyl) 2-pyridyl 2- (N-pyrrolidin-methyl) phenyl 2-pyridyl 2- (N-piperidinylmethyl) phenyl 2-pyridyl 2- (N-morpholinomethyl) phenyl 2-pyridyl 2- (N, N'-methylmorpholinium-methyl) - phenyl 2-pyridyl 2- (N-pyridinium-methyl) phenyl 2-pyridyl 2- (N-4- (N, N'-dimethylamino) pyridinium methyl) phenyl 2-pyridyl 2- (N-azatanyl-methyl) phenyl 2-pyridyl 2- (N-azetidinylmethyl) phenyl 2-pyridyl 2- (N-piperazinylmethyl) phenyl 2-pyridyl 2- (N, N'-BOC-piperazinylmethyl) phenyl 2-pyridyl 2- (N-imidazolylmethyl) phenyl 2-pyridyl 2- (N-methoxy-N-methylamino-methyl) phenyl 2-pyridyl 2- (N-pyridonylmethyl) phenyl 2-pyridyl 2- (N- (Ν ', N'-dimethylhydrazinylmethyl) phenyl) 2-pyridyl 2- (amidinyl) phenyl

· · · · · · · · · · · Λ · · · · · · · · · · · · · · · · ·

223 223 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl

2- pyridyl

3-Pyridyl 3-pyridyl 3-pyridyl 3-pyridyl

3-pyridyl 3-pyridyl

3-Pyridyl 3-Pyridyl 3-Pyridyl 3-Pyridyl 3-Pyridyl 3-Pyridyl 3-Pyridyl 3-Pyridyl

3-pyridyl 3-pyridyl 3-pyridyl 3-pyridyl 3-pyridyl

2- (N-guanidyl) phenyl

2- (imidazolyl) phenyl

2- (imidazolidinyl) phenyl

2- (2-imidazolidinylsulfonyl) phenyl 2- (2-pyrrolidinyl) phenyl 2- (2-piperidinyl) phenyl 2- (amidinylmethyl) phenyl 2- (2-imidazolidinylmethyl) phenyl 2- (N- ( 2-Aminoimidazolyl) methyl) phenyl 2-dimethylaminoimidazolyl-1-yl 2- (3-aminophenyl)

2- (3-pyrrolidinylcarbonyl)

2-glycinoyl

2- (imidazol-1-ylacetyl)

2- (N-pyrrolidin-methyl) phenyl

2- (N-piperidinylmethyl) phenyl

2- (N-morpholinomethyl) phenyl

2- (N, N'-methylmorpholinium-methyl) phenyl

2- (N-pyridinium-methyl) phenyl

2- (N-4- (N, N'-dimethylamino) pyridinium methyl) phenyl

2- (N-azatanyl-methyl) phenyl

2- (N-azetidinylmethyl) phenyl

2- (N-piperazinylmethyl) phenyl

2- (Ν, Ν'-BOC-piperazinyl-methyl) phenyl 2- (N-imidazolyl-methyl) phenyl 2- (N-methoxy-N-methylamino-methyl) phenyl 2- (N-pyridonylmethyl) phenyl 2 - (Ν- (Ν ', N'-dimethylhydrazinylmethyl) phenyl

2- (amidinyl) phenyl

2- (N-guanidyl) phenyl

2- (imidazolyl) phenyl

2- (imidazolidinyl) phenyl

2- (2-imidazolidinylsulfonyl) phenyl

- 224 n · · · · · · · · · · · · · · · · · · · · · ·

3-Pyridyl 3-Pyridyl 3-Pyridyl 3-Pyridyl 3-Pyridyl 3-Pyridyl 3-Pyridyl 3-Pyridyl 3-Pyridyl 2-Pyrimidyl 2-Pyrimidyl 2-Pyrimidyl 2-Pyrimidyl

2-pyrimidyl 2-pyrimidyl

2-pyrimidyl-2-pyrimidyl-2-pyrimidyl-2-pyrimidyl-2-pyrimidyl-2-pyrimidyl-2-pyrimidyl-2-pyrimidyl

2-pyrimidyl-2-pyrimidyl-2-pyrimidyl-2-pyrimidyl-2-pyrimidyl-2-pyrimidyl-2-pyrimidyl-2-pyrimidyl-2-pyrimidyl

2- (2-pyrrolidinyl) phenyl

2- (2-piperidinyl) phenyl

2- (amidinylmethyl) phenyl

2- (2-imidazolidinylmethyl) phenyl 2- (N- (2-aminoimidazolyl) methyl) phenyl 2-dimethylaminoimidazolyl-1-yl 2- (3-aminophenyl)

2- (3-pyrrolidinylcarbonyl)

2-glycinoyl

2- (imidazol-1-ylacetyl)

2- (N-pyrrolidin-methyl) phenyl

2- (N-piperidinylmethyl) phenyl

2- (N-morpholinomethyl) phenyl

2- (N, N'-methylmorpholinium-methyl) phenyl

2- (N-pyridinium-methyl) phenyl

2- (N-4- (N, N'-dimethylamino) pyridinium methyl) phenyl

2- (N-azatanyl-methyl) phenyl

2- (N-azetidinylmethyl) phenyl

2- (N-piperazinylmethyl) phenyl

2- (Ν, Ν'-BOC-piperazinyl-methyl) phenyl 2- (N-imidazolyl-methyl) phenyl 2- (N-methoxy-N-methylamino-methyl) phenyl 2- (N-pyridonylmethyl) phenyl 2 - (Ν- (Ν ', Ν'-dimethylhydrazinylmethyl) phenyl

2- (amidinyl) phenyl

2- (N-guanidyl) phenyl

2- (imidazolyl) phenyl

2- (imidazolidinyl) phenyl

2- (2-imidazolidinylsulfonyl) phenyl 2- (2-pyrrolidinyl) phenyl 2- (2-piperidinyl) phenyl 2- (amidinylmethyl) phenyl 2- (2-imidazolidinylmethyl) phenyl

2-Pyrimidyl 2-Pyrimidyl 2-Pyrimidyl 2-Pyrimidyl 2-Pyrimidyl 2-Pyrimidyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl

2-Cl-phenyl 2-Cl-phenyl

2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl

2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl

2- (N- (2-Aminoimidazolyl) methyl) phenyl 2-dimethylaminoimidazolyl-1-yl 2- (3-aminophenyl)

2- (3-pyrrolidinylcarbonyl)

2-glycinoyl

2- (imidazol-1-ylacetyl)

2- (N-pyrrolidin-methyl) phenyl

2- (N-piperidinylmethyl) phenyl

2- (N-morpholinomethyl) phenyl

2- (N, N'-methylmorpholinium-methyl) phenyl

2- (N-pyridinium-methyl) phenyl

2- (N-4- (N, N'-dimethylamino) pyridinium methyl) phenyl

2- (N-azatanyl-methyl) phenyl

2- (N-azetidinylmethyl) phenyl

2- (N-piperazinylmethyl) phenyl

2- (Ν, Ν ¹ -BOC-piperazinyl-methyl) phenyl 2- (N-imidazolyl-methyl) phenyl 2- (N-methoxy-N-methylamino-methyl) phenyl 2- (N-pyridonylmethyl) phenyl 2 - (Ν- (Ν ', N'-dimethylhydrazinylmethyl) phenyl

2- (amidinyl) phenyl

2- (N-guanidyl) phenyl

2- (imidazolyl) phenyl

2- (imidazolidinyl) phenyl

2- (2-imidazolidinylsulfonyl) phenyl 2- (2-pyrrolidinyl) phenyl 2- (2-piperidinyl) phenyl 2- (amidinylmethyl) phenyl 2- (2-imidazolidinylmethyl) phenyl 2- (N- ( 2-Aminoimidazolyl) methyl) phenyl 2-dimethylaminoimidazolyl-1-yl 2- (3-aminophenyl)

2- (3-pyrrolidinylcarbonyl) •

2-Cl-phenyl 2-glycinoyl 2-Cl-phenyl 2- (imidazol-1-ylacetyl) 2-F-phenyl 2- (N-pyrrolidin-methyl) phenyl 2-F-phenyl 2- (N-piperidinylmethyl) phenyl 2-F-phenyl 2- (N-morpholinomethyl) phenyl 2-F-phenyl 2- (N, N'-methylmorpholinium-methyl) phenyl 2-F-phenyl 2- (N-pyridinium-methyl) phenyl 2-F-phenyl 2- (N-4- (N, N'-dimethylamino) pyridinium methyl) phenyl 2-F-phenyl 2- (N-azatanyl-methyl) phenyl 2-F-phenyl 2- (N-azetidinylmethyl) phenyl 2-F-phenyl 2- (N-piperazinylmethyl) phenyl 2-F-phenyl 2- (N, N'-BOC-piperazinylmethyl) phenyl 2-F-phenyl 2- (N-imidazolylmethyl) phenyl 2-F-phenyl 2- (N-methoxy-N-methylamino-methyl) phenyl 2-F-phenyl 2- (N-pyridonylmethyl) phenyl 2-F-phenyl 2- (Ν- (Ν ', Ν'-dimethylhydrazinylmethyl) phenyl 2-F-phenyl 2- (amidinyl) phenyl 2-F-phenyl 2- (N-guanidyl) phenyl 2-F-phenyl 2- (imidazolyl) phenyl 2-F-phenyl 2- (imidazolidinyl) phenyl 2-F-phenyl 2- (2-imidazolidinylsulfonyl) phenyl 2-F-phenyl 2- (2-pyrrolidinyl) phenyl 2-F-phenyl 2- (2-piperidinyl) phenyl 2-F-phenyl 2- (amidinylmethyl) phenyl 2-F-phenyl 2- (2-imidazolidinylmethyl) phenyl 2-F-phenyl 2- (N- (2-aminoimidazolyl) methyl) phenyl 2-F-phenyl 2-dimethylaminoimidazolyl-1-yl 2-F-phenyl 2- (3-aminophenyl) 2-F-phenyl 2- (3-pyrrolidinylcarbonyl) 2-F-phenyl 2-glycinoyl 2-F-phenyl 2- (imidazol-1-ylacetyl) 2,5-diF-phenyl 2- (N-pyrrolidin-methyl) phenyl 2,5-diF-phenyl 2- (N-piperidinylmethyl) phenyl

· · · · · · · · · · · · · · · · · · · ·

2,5-diF-phenyl 2- (N-morpholinomethyl) phenyl 2,5-diF-phenyl 2- (Ν, Ν ^1- methylmorpholinium methyl) phenyl 2,5-diF-phenyl 2- (N-pyridinium-methyl) phenyl 2,5-diF-phenyl 2- (N-4- (Ν, Ν'-dimethylamino) - pyridinium-methyl) phenyl 2,5-diF-phenyl 2- (N-azatanyl-methyl) phenyl 2,5-diF-phenyl 2- (N-azetidinylmethyl) phenyl 2,5-diF-phenyl 2- (N-piperazinylmethyl) phenyl 2,5-diF-phenyl 2- (Ν, Ν ¹ -BOC-piperazinyl-methyl) phenyl 2,5-diF-phenyl 2- (N-imidazolylmethyl) phenyl 2,5-diF-phenyl 2- (N-methoxy-N-methylamino-methyl) phenyl 2,5-diF-phenyl 2- (N-pyridonylmethyl) phenyl 2,5-diF-phenyl 2- (Ν- (Ν ', Ν'-dimethylhydrazinylmethyl) phenyl 2,5-diF-phenyl 2- (amidinyl) phenyl 2,5-diF-phenyl 2- (N-guanidyl) phenyl 2,5-diF-phenyl 2- (imidazolyl) phenyl 2,5-diF-phenyl 2- (imidazolidinyl) phenyl 2,5-diF-phenyl 2- (2-imidazolidinylsulfonyl) phenyl 2,5-diF-phenyl 2- (2-pyrrolidinyl) phenyl 2,5-diF-phenyl 2- (2-piperidinyl) phenyl 2,5-diF-phenyl 2- (amidinylmethyl) phenyl 2,5-diF-phenyl 2- (2-imidazolidinylmethyl) phenyl 2,5-diF-phenyl 2- (N- (2-aminoimidazolyl) methyl) phenyl 2,5-diF-phenyl 2-dimethylaminoimidazolyl-1-yl 2,5-diF-phenyl 2- (3-aminophenyl) 2,5-diF-phenyl 2- (3-pyrrolidinylcarbonyl) 2,5-diF-phenyl 2-glycinoyl 2,5-diF-phenyl 2- (imidazol-1-ylacetyl)

• ·

AND (B) phenyl 2- (aminosulfonyl) phenyl phenyl 2- (methylaminosulfonyl) phenyl phenyl 1-pyrrolidinocarbonyl phenyl 2- (methylsulfonyl) phenyl phenyl 4-morpholino phenyl 2- (1'-CF _3- tetrazol-2-yl) phenyl phenyl 4-morpholinocarbonyl 2-pyridyl 2- (aminosulfonyl) phenyl 2-pyridyl 2- (methylaminosulfonyl) phenyl 2-pyridyl 1-pyrrolidinocarbonyl 2-pyridyl 2- (methylsulfonyl) phenyl

• ·

- 229 -

2-pyridyl 4-morpholino 2-pyridyl 2- (1'-CF _3- tetrazol-2-yl) phenyl 2-pyridyl 4-morpholinocarbonyl 3-pyridyl 2- (aminosulfonyl) phenyl 3-pyridyl 2- (methylaminosulfonyl) phenyl 3-pyridyl 1-pyrrolidinocarbonyl 3-pyridyl 2- (methylsulfonyl) phenyl 3-pyridyl 4-morpholino 3-pyridyl 2- (1 ¹ _{-CF3-tetrazol-2-yl)} phenyl 3-pyridyl 4-morpholinocarbonyl 2-pyrimidyl 2- (aminosulfonyl) phenyl 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 2-pyrimidyl 1-pyrrolidinocarbonyl 2-pyrimidyl 2- (methylsulfonyl) phenyl 2-pyrimidyl 4-morpholino 2-pyrimidyl 2- (1'-CF ₃ -tetrazol-2-yl) phenyl 2-pyrimidyl 4-morpholinocarbonyl 5-pyrimidyl 2- (aminosulfonyl) phenyl 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 5-pyrimidyl 1-pyrrolidinocarbonyl 5-pyrimidyl 2- (methylsulfonyl) phenyl 5-pyrimidyl 4-morpholino 5-pyrimidyl 2- (1'-CF ₃ -tetrazol-2-yl) phenyl 5-pyrimidyl 4-morpholinocarbonyl 2-Cl-phenyl 2- (aminosulfonyl) phenyl 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 2-Cl-phenyl 1-pyrrolidinocarbonyl 2-Cl-phenyl 2- (methylsulfonyl) phenyl 2-Cl-phenyl 4-morpholino 2-Cl-phenyl 2- (1 ¹ _{-CF3-tetrazol-2-yl)} phenyl 2-Cl-phenyl 4-morpholinocarbonyl 2-F-phenyl 2- (aminosulfonyl) phenyl 2-F-phenyl 2- (methylaminosulfonyl) phenyl 2-F-phenyl 1-pyrrolidinocarbonyl 2-F-phenyl 2- (methylsulfonyl) phenyl 2-F-phenyl 4-morpholino

230

2-F-phenyl 2- (1'-CF-1-tetrazol-2-yl) phenyl 2-F-phenyl 4-morpholinocarbonyl 2,5-diF-phenyl 2- (aminosulfonyl) phenyl 2,5-diF-phenyl 2- (methylaminosulfonyl) phenyl 2,5-diF-phenyl 1-pyrrolidinocarbonyl 2,5-diF-phenyl 2- (methylsulfonyl) phenyl 2,5-diF-phenyl 4-morpholino 2,5-diF-phenyl 2- (1'-CF-1-tetrazol-2-yl) phenyl 2,5-diF-phenyl 4-morpholinocarbonyl phenyl 2- (N-pyrrolidin-methyl) phenyl phenyl 2- (N-piperidinylmethyl) phenyl phenyl 2- (N-morpholinomethyl) phenyl phenyl 2- (N, N'-methylmorpholinium-methyl) - phenyl phenyl 2- (N-pyridinium-methyl) phenyl phenyl 2- (N-4- (N, N'-dimethylamino) pyridinium methyl) phenyl phenyl 2- (N-azatanyl-methyl) phenyl phenyl 2- (N-azetidinylmethyl) phenyl phenyl 2- (N-piperazinylmethyl) phenyl phenyl 2- (N, Ν'-BOC-piperazinylmethyl) phenyl phenyl 2- (N-imidazolylmethyl) phenyl phenyl 2- (N-methoxy-N-methylamino-methyl) phenyl phenyl 2- (N-pyridonylmethyl) phenyl phenyl 2- (N- (Ν ', Ν'-dimethylhydrazinylmethyl) phenyl) phenyl 2- (amidinyl) phenyl phenyl 2- (N-guanidyl) phenyl phenyl 2- (imidazolyl) phenyl phenyl 2- (imidazolidinyl) phenyl phenyl 2- (2-imidazolidinylsulfonyl) phenyl phenyl 2- (2-pyrrolidinyl) phenyl phenyl 2- (2-piperidinyl) phenyl phenyl 2- (amidinylmethyl) phenyl phenyl 2- (2-imidazolidinylmethyl) phenyl phenyl 2- (N- (2-aminoimidazolyl) methyl) phenyl

- 2 *> 1 * phenyl phenyl phenyl phenyl phenyl

2-pyridyl

2-pyridyl

2-pyridyl

2-pyridyl

2-pyridyl

2-pyridyl

2-Pyridyl 2-Pyridyl 2-Pyridyl 2-Pyridyl 2-Pyridyl 2-Pyridyl 2-Pyridyl 2-Pyridyl

2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl 2-pyridyl

2-dimethylaminoimidazolyl-1-yl

2- (3-aminophenyl)

2- (3-pyrrolidinylcarbonyl)

2-glycinoyl

2- (imidazol-1-ylacetyl)

2- (N-pyrrolidin-methyl) phenyl

2- (N-piperidinylmethyl) phenyl

2- (N-morpholinomethyl) phenyl

2- (Ν, Ν'-methylmorpholinium-methyl) phenyl

2- (N-pyridinium-methyl) phenyl

2- (N-4- (Ν, Ν'-dimethylamino) pyridinium methyl) phenyl

2- (N-azatanyl-methyl) phenyl

2- (N-azetidinylmethyl) phenyl

2- (N-piperazinylmethyl) phenyl

2- (N, N'-BOC-piperazinyl-methyl) phenyl 2- (N-imidazolyl-methyl) phenyl 2- (N-methoxy-N-methylamino-methyl) phenyl 2- (N-pyridonylmethyl) phenyl 2 - (Ν- (Ν ', Ν'-dimethylhydrazinylmethyl) phenyl

2- (amidinyl) phenyl

2- (N-guanidyl) phenyl

2- (imidazolyl) phenyl

2- (imidazolidinyl) phenyl

2- (2-imidazolidinylsulfonyl) phenyl

2- (2-pyrrolidinyl) phenyl

2- (2-piperidinyl) phenyl

2- (amidinylmethyl) phenyl

2- (2-imidazolidinylmethyl) phenyl

2- (N- (2-aminoimidazolyl) methyl) phenyl

2-dimethylaminoimidazolyl-1-yl

2- (3-aminophenyl)

2- (3-pyrrolidinylcarbonyl)

2-glycinoyl

22 * 2 - *

2- pyridyl

3-Pyridyl 3-pyridyl 3-pyridyl 3-pyridyl

3-pyridyl 3-pyridyl

3-Pyridyl 3-Pyridyl 3-Pyridyl 3-Pyridyl 3-Pyridyl 3-Pyridyl 3-Pyridyl 3-Pyridyl

3-pyridyl 3-pyridyl 3-pyridyl 3-pyridyl 3-pyridyl 3-pyridyl 3-pyridyl 3-pyridyl 3-pyridyl 3-pyridyl 3-pyridyl 3-pyridyl 3-pyridyl 3-pyridyl 3-pyridyl 2-pyrimidyl 2- pyrimidyl 2-pyrimidyl

2- (imidazol-1-ylacetyl)

2- (N-pyrrolidin-methyl) phenyl

2- (N-piperidinylmethyl) phenyl

2- (N-morpholinomethyl) phenyl

2- (N, N'-methylmorpholinium-methyl) phenyl

2- (N-pyridinium-methyl) phenyl

2- (N-4- (N, N'-dimethylamino) pyridinium methyl) phenyl

2- (N-azatanyl-methyl) phenyl

2- (N-azetidinylmethyl) phenyl

2- (N-piperazinylmethyl) phenyl

2- (N, N'-BOC-piperazinyl-methyl) phenyl 2- (N-imidazolyl-methyl) phenyl 2- (N-methoxy-N-methylamino-methyl) phenyl 2- (N-pyridonylmethyl) phenyl 2 - (Ν- (Ν ', Ν'-dimethylhydrazinylmethyl) phenyl

2- (amidinyl) phenyl

2- (N-guanidyl) phenyl

2- (imidazolyl) phenyl

2- (imidazolidinyl) phenyl

2- (2-imidazolidinylsulfonyl) phenyl 2- (2-pyrrolidinyl) phenyl 2- (2-piperidinyl) phenyl 2- (amidinylmethyl) phenyl 2- (2-imidazolidinylmethyl) phenyl 2- (N- ( 2-Aminoimidazolyl) methyl) phenyl 2-dimethylaminoimidazolyl-1-yl 2- (3-aminophenyl)

2- (3-pyrrolidinylcarbonyl)

2-glycinoyl

2- (imidazol-1-ylacetyl)

2- (N-pyrrolidin-methyl) phenyl

2- (N-piperidinylmethyl) phenyl

2- (N-morpholinomethyl) phenyl

- 23.T

2-pyrimidyl

2-pyrimidyl

2-pyrimidyl

2-pyrimidyl-2-pyrimidyl-2-pyrimidyl-2-pyrimidyl-2-pyrimidyl-2-pyrimidyl-2-pyrimidyl-2-pyrimidyl

2-pyrimidyl

2-pyrimidyl

2-pyrimidyl

2-pyrimidyl

2-pyrimidyl

2-pyrimidyl

2-pyrimidyl

2-pyrimidyl

2-pyrimidyl

2-pyrimidyl

2-pyrimidyl

2-pyrimidyl

2-pyrimidyl

2-pyrimidyl

2-pyrimidyl

2-Cl-phenyl

2-Cl-phenyl

2-Cl-phenyl

2-Cl-phenyl

2-Cl-phenyl 2-Cl-phenyl

2- (N, N'-methylmorpholinium-methyl) phenyl

2- (N-pyridinium-methyl) phenyl

2- (N-4- (N, N'-dimethylamino) pyridinium methyl) phenyl

2- (N-azatanyl-methyl) phenyl

2- (N-azetidinylmethyl) phenyl

2- (N-piperazinylmethyl) phenyl

2- (Ν, Ν'-BOC-piperazinyl-methyl) phenyl 2- (N-imidazolyl-methyl) phenyl 2- (N-methoxy-N-methylamino-methyl) phenyl 2- (N-pyridonylmethyl) phenyl 2 - (Ν- (Ν ', N'-dimethylhydrazinylmethyl) phenyl

2- (amidinyl) phenyl

2- (N-guanidyl) phenyl

2- (imidazolyl) phenyl

2- (imidazolidinyl) phenyl

2- (2-imidazolidinylsulfonyl) phenyl 2- (2-pyrrolidinyl) phenyl 2- (2-piperidinyl) phenyl 2- (amidinylmethyl) phenyl 2- (2-imidazolidinylmethyl) phenyl 2- (N- ( 2-Aminoimidazolyl) methyl) phenyl 2-dimethylaminoimidazolyl-1-yl 2- (3-aminophenyl)

2- (3-pyrrolidinylcarbonyl)

2-glycinoyl

2- (imidazol-1-ylacetyl)

2- (N-pyrrolidin-methyl) phenyl

2- (N-piperidinylmethyl) phenyl

2- (N-morpholinomethyl) phenyl

2- (N, N'-methylmorpholinium-methyl) phenyl

2- (N-pyridinium-methyl) phenyl

2- (N-4- (N, N'-dimethylamino) - 234)

2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl

2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-F-phenyl 2-F-phenyl 2-F-phenyl 2-F-phenyl

2-F-phenyl

2-F-phenyl

2-F-phenyl

2-F-phenyl

(2-F-phenyl pyridinium-methyl) phenyl

2- (N-azatanyl-methyl) phenyl

2- (N-azetidinylmethyl) phenyl

2- (N-piperazinylmethyl) phenyl

2- (Ν, Ν ¹ -BOC-piperazinyl-methyl) phenyl 2- (N-imidazolyl-methyl) phenyl 2- (N-methoxy-N-methylamino-methyl) phenyl 2- (N-pyridonylmethyl) phenyl 2 - (Ν- (Ν ', Ν'-dimethylhydrazinylmethyl) phenyl

2- (amidinyl) phenyl

2- (N-guanidyl) phenyl

2- (imidazolyl) phenyl

2- (imidazolidinyl) phenyl

2- (2-imidazolidinylsulfonyl) phenyl 2- (2-pyrrolidinyl) phenyl 2- (2-piperidinyl) phenyl 2- (amidinylmethyl) phenyl 2- (2-imidazolidinylmethyl) phenyl 2- (N- ( 2-Aminoimidazolyl) methyl) phenyl 2-dimethylaminoimidazolyl-1-yl 2- (3-aminophenyl)

2- (3-pyrrolidinylcarbonyl)

2-glycinoyl

2- (imidazol-1-ylacetyl)

2- (N-pyrrolidin-methyl) phenyl

2- (N-piperidinylmethyl) phenyl

2- (N-morpholinomethyl) phenyl

2- (Ν, Ν'-methylmorpholinium-methyl) phenyl

2- (N-pyridinium-methyl) phenyl

2- (N-4- (Ν, Ν'-dimethylamino) pyridinium methyl) phenyl

2- (N-azatanyl-methyl) phenyl

2- (N-azetidinylmethyl) phenyl

2- (N-piperazinylmethyl) phenyl

4 * 4 4 4 4 4 4 4

4 4 4 4

44 44 4444

- 235 -

2-F-phenyl 2- (Ν, Ν ¹ -BOC-piperazinyl-methyl) phenyl 2-F-phenyl 2- (N-imidazolylmethyl) phenyl 2-F-phenyl 2- (N-methoxy-N-methylamino-methyl) phenyl 2-F-phenyl 2- (N-pyridonylmethyl) phenyl 2-F-phenyl 2- (Ν- (Ν ', Ν'-dimethylhydrazinyl-) methyl) phenyl 2-F-phenyl 2- (amidinyl) phenyl 2-F-phenyl 2- (N-guanidyl) phenyl 2-F-phenyl 2- (imidazolyl) phenyl 2-F-phenyl 2- (imidazolidinyl) phenyl 2-F-phenyl 2- (2-imidazolidinylsulfonyl) phenyl 2-F-phenyl 2- (2-pyrrolidinyl) phenyl 2-F-phenyl 2- (2-piperidinyl) phenyl 2-F-phenyl 2- (amidinylmethyl) phenyl 2-F-phenyl 2- (2-imidazolidinylmethyl) phenyl 2-F-phenyl 2- (N- (2-aminoimidazolyl) methyl) phenyl 2-F-phenyl 2-dimethylaminoimidazolyl-1-yl 2-F-phenyl 2- (3-aminophenyl) 2-F-phenyl 2- (3-pyrrolidinylcarbonyl) 2-F-phenyl 2-glycinoyl 2-F-phenyl 2- (imidazol-1-ylacetyl) 2,5-diF-phenyl 2- (N-pyrrolidin-methyl) phenyl 2,5-diF-phenyl 2- (N-piperidinylmethyl) phenyl 2,5-diF-phenyl 2- (N-morpholinomethyl) phenyl 2,5-diF-phenyl 2- (Ν, Ν'-methylmorpholinium-methyl) phenyl 2,5-diF-phenyl 2- (N-pyridinium-methyl) phenyl 2,5-diF-phenyl 2- (N-4- (Ν, Ν'-dimethylamino) - pyridinium-methyl) phenyl 2,5-diF-phenyl 2- (N-azatanyl-methyl) phenyl 2,5-diF-phenyl 2- (N-azetidinylmethyl) phenyl 2,5-diF-phenyl 2- (N-piperazinylmethyl) phenyl 2,5-diF-phenyl 2- (Ν, Ν'-BOC-piperazinylmethyl) phenyl 2,5-diF-phenyl 2- (N-imidazolylmethyl) phenyl 2,5-diF-phenyl 2- (N-methoxy-N-methylamino-methyl) phenyl 2,5-diF-phenyl 2- (N-pyridonylmethyl) phenyl

• · • ·

- 23 * 6.

2,5-diF-phenyl 2- (Ν- (Ν ', Ν'-dimethylhydrazinylmethyl) phenyl 2,5-diF-phenyl 2- (amidinyl) phenyl 2,5-diF-phenyl 2- (N-guanidyl) phenyl 2,5-diF-phenyl 2- (imidazolyl) phenyl 2,5-diF-phenyl 2- (imidazolidinyl) phenyl 2,5-diF-phenyl 2- (2-imidazolidinylsulfonyl) phenyl 2,5-diF-phenyl 2- (2-pyrrolidinyl) phenyl 2,5-diF-phenyl 2- (2-piperidinyl) phenyl 2,5-diF-phenyl 2- (amidinylmethyl) phenyl 2,5-diF-phenyl 2- (2-imidazolidinylmethyl) phenyl 2,5-diF-phenyl 2- (N- (2-aminoimidazolyl) methyl) phenyl 2,5-diF-phenyl 2-dimethylaminoimidazolyl-1-yl 2,5-diF-phenyl 2- (3-aminophenyl) 2,5-diF-phenyl 2- (3-pyrrolidinylcarbonyl) 2,5-diF-phenyl 2-glycinoyl 2,5-diF-phenyl 2- (imidazol-1-ylacetyl)

• · • ·

Table 4

R ^1a = CH3 a2 R ^1a = CF3 and ₃ R ^1a = SCH3 a4 R ^1a = SOCH3 and ₅ R ^1a = SC> 2CH3 a6 R ^1a = CI a7 R ^1a = Br and R 6 CCfcCH 5 a9 R ^1a = CH 2 OCH 3 b, R ^1a = CH3 b2 R ^1a = CF3 b ₃ R ^1a = SCH3 b4 R ^1a = SOCH3 b ₅ R ^1a = SO2CH3 b6 R ^1a = CI b7 R ^1a = Br b8 R ^1a = CO 3> CH 3 b ₉ R ^1a = CH ₂ OCH ₃ d R ^1a = CH 3 R ^1a = c 2 c ₃ CF 3 R ^{1 a} = R ¹ SCH3 c4 = SOCH3 C ₅ R ^1a = R ^1a S02CH3 c6 c7 = Cl R ¹ = Br R ^la Cg = Cg CO2CH3 ^la R = CH 2 C≡CH ₃

d ₄ R ¹ = CH3 d2, R ¹ = CF 3 d ₃ R ^1a = SCH3 d4 R ^1a = SOCH3 _d5 R ^1a = SO2CH3 d6 R ¹ = C d ₇ R ^1a = Br d8 R ^1a = C02CH3 d ₉ R ¹ = CH 2 C≡CH ₃ e, R ¹ = CH 3 e2 R ¹ = CF 3 e ₃ R ¹ = SCH 3 e4 R ^1a = SOCH3 e ₅ R ^1a = SO2CH3 e6 R ¹ = Cl E7 R ^1a = Br e8 R ^1a = CO2CH3 e ₉ R ¹ = CH 2 C≡CH ₃ F, R ¹ = CH 3 f2 R ¹ = CF 3 F ₃ R ^1a = SCH3 F4 R ^1a = SOCH3 f ₅ R ^1a = SO2CH3 (6 R ¹ = Cl f7, R ^1a = Br F8 R ^1a = CO2CH3 F ₉ R ^1a = CH ₂ OCH ₃

Ex # AND (B) 1 phenyl 2 - ((Me) ₂ N-methyl) phenyl 2 phenyl 2 - ((Me) NH-methyl) phenyl 3 phenyl 2- (H ₂ N-methyl) phenyl 4 phenyl 2-HOCH ₂ -phenyl 5 2-F-phenyl 2 - ((Me) ₂ N-methyl) phenyl

238

2-F-phenyl 2 - ((Me) NH-methyl) phenyl 2-F-phenyl 2- (H ₂ N-methyl) phenyl 2-F-phenyl 2-HOCH ₂ -phenyl phenyl 2-Methylimidazol-1-yl phenyl 2-ethylimidazol-1-yl phenyl 2 - ((Me) ₂ N -methyl) imidazol-1-yl phenyl 2-CH ₃ SO ₂ -imidazol-1-yl phenyl 2-CH ₃ OCH ₂ -imidazol-1-yl 2-F-phenyl 2-Methylimidazol-1-yl 2-F-phenyl 2-ethylimidazol-1-yl 2-F-phenyl 2 - ((Me) ₂ N -methyl) imidazol-1-yl 2-F-phenyl 2-CH ₃ SO ₂ -imidazol-1-yl 2-F-phenyl 2-CH ₃ OCH ₂ -imidazol-1-yl 2-Cl-phenyl 2-Methylimidazol-1-yl 2-Cl-phenyl 2-ethylimidazol-1-yl 2-Cl-phenyl 2 - ((Me) ₂ N -methyl) imidazol-1-yl 2-Cl-phenyl 2-CH ₃ SO ₂ -imidazol-1-yl 2-Cl-phenyl 2-CH ₃ OCH ₂ -imidazol-1-yl 2- (Me) ₂ N-phenyl 2-Methylimidazol-1-yl 2- (Me) ₂ N-phenyl 2-ethylimidazol-1-yl 2- (Me) ₂ N-phenyl 2 - ((Me) ₂ N -methyl) imidazol-1-yl 2- (Me) ₂ N-phenyl 2-CH ₃ SO ₉ -imidazol-1-yl 2- (Me) ₂ N-phenyl 2-CH ₃ OCH ₂ -imidazol-1-yl phenyl N-methylimidazol-5-yl phenyl 4-Methylimidazol-5-yl phenyl 5-CF ₃ -pyrazol-1-yl 2-F-phenyl N-methylimidazol-5-yl 2-F-phenyl 4-Methylimidazol-5-yl 2-F-phenyl 5-CF ₃ -pyrazol-1-yl phenyl guanidino phenyl 2-Thiazolin-2-ylamine phenyl N-methyl-2-imidazolin-2-yl phenyl N-methyl-1,4,5,6-tetrahydropyrimide- -2-yl phenyl N-methylimidazol-2-ylthiol phenyl tert-butoxycarbonylamine

• · · ·· ·· ·· ·· • · · · · · ···· • · · · · · · · · ··· ··· • · · · · · · _Λ _ ·· ·· · ······ ·· ·· - 239 - phenyl phenyl (N-pyrrolidino) formylimino (N-pyrrolidino) formyl-N- 2-F-phenyl 2-F-phenyl 2-F-phenyl 2-F-phenyl (methanesulfamoyl) imino guanidino 2-Thiazolin-2-ylamine N-methyl-2-imidazolin-2-yl N-methyl-1,4,5,6-tetrahydropyrimide 2-F-phenyl 2-F-phenyl 2-F-phenyl 2-F-phenyl -2-yl N-methylimidazol-2-ylthio tert-butoxycarbonylamine (N-pyrrolidino) formylimino (N-pyrrolidino) formyl-N- 2-CH ₃ O-phenyl 2-CH ₃ O-phenyl -methanesulfamoyl) imino (N-pyrrolidino) formylimino (N-pyrrolidino) formyl-N (methanesulfamoyl) imino

Table 5

% K ₃

Ex # AND (B) 1 phenyl 2 - ((Me) ₂ N-methyl) phenyl 2 phenyl 2 - ((Me) NH-methyl) phenyl 3 phenyl 2- (H ₂ N-methyl) phenyl 4 phenyl 2-HOCH ₂ -phenyl 5 2-F-phenyl 2 - ((Me) ₂ N-methyl) phenyl 6 2-F-phenyl 2 - ((Me) NH-methyl) phenyl 7 2-F-phenyl 2- (H ₂ N-methyl) phenyl 8 2-F-phenyl 2-HOCH ₂ -phenyl 9 phenyl 2-Methylimidazol-1-yl 10 phenyl 2-ethylimidazol-1-yl

241

phenyl 2 - ((Me) ₂ N -methyl) imidazol-1-yl phenyl 2-CH ₃ SO ₂ -imidazol-1-yl phenyl 2-CH ₃ OCH ₂ -imidazol-1-yl 2-F-phenyl 2-Methylimidazol-1-yl 2-F-phenyl 2-ethylimidazol-1-yl 2-F-phenyl 2 - ((Me) ₂ N -methyl) imidazol-1-yl 2-F-phenyl 2-CH ₃ SO ₂ -imidazol-1-yl 2-F-phenyl 2-CH ₃ OCH ₂ -imidazol-1-yl 2-Cl-phenyl 2-Methylimidazol-1-yl 2-Cl-phenyl 2-ethylimidazol-1-yl 2-Cl-phenyl 2 - ((Me) ₂ N -methyl) imidazol-1-yl 2-Cl-phenyl 2-CH ₃ SO ₂ -imidazol-1-yl 2-Cl-phenyl 2-CH ₃ OCH ₂ -imidazol-1-yl 2- (Me) ₂ N-phenyl 2-methylimidazol-1-yl 2- (Me) ₂ N-phenyl 2-ethylimidazol-1-yl 2- (Me) ₂ N-phenyl 2 - ((Me) ₂ N -methyl) imidazol-1-yl 2- (Me) ₂ N-phenyl 2-CH ₃ SO ₂ -imidazol-1-yl 2- (Me) ₂ N-phenyl 2-CH ₃ OCH ₂ -imidazol-1-yl phenyl N-methylimidazol-5-yl phenyl 4-Methylimidazol-5-yl phenyl 5-CF ₃ -pyrazol-1-yl 2-F-phenyl N-methylimidazol-5-yl 2-F-phenyl 4-Methylimidazol-5-yl 2-F-phenyl 5-CF ₃ -pyrazol-1-yl phenyl guanidino phenyl 2-Thiazolin-2-ylamine phenyl N-methyl-2-imidazolin-2-yl phenyl N-methyl-1,4,5,6-tetrahydropyrimid-2-yl phenyl N-methylimidazol-2-ylthiol phenyl tert-butoxycarbonylamine phenyl (N-pyrrolidino) formylimino phenyl (N-pyrrolidino) formyl-N-methanesulfamoyl) imino 2-F-phenyl guanidino 2-F-phenyl 2-Thiazolin-2-ylamine

- 242

45 2-F-phenyl N-methyl-2-imidazolin-2-yl 46 2-F-phenyl N-methyl-1,4,5,6-tetrahydropyrimide -2-yl 47 2-F-phenyl N-methylimidazol-2-ylthio 48 2-F-phenyl tert-butoxycarbonylamine 49 2-F-phenyl (N-pyrrolidino) formylimino 50 2-F-phenyl (N-pyrrolidino) formyl-N-methanesulfamoyl) imino 51 2-CH ₃ O-phenyl (N-pyrrolidino) formylimino 52 2-CH ₃ O-phenyl (N-pyrrolidino) formyl-N-

(methanesulfamoyl) imino

243

Table 6

c, R ⁴ = OCH ₃ c ₂ R ⁴ = CO ₂ CH ₃ c ₃ r ⁴ = ch2och ₃ c ⁴ R ⁴ = CH 3 c ₅ R ⁴ = CF 3 c ₆ R ⁴ = CI c7 R ⁴ = F

OCH ₃

D _OCH3, ^R4 = OCH3, ^R4 = d2 CO2CH ₃ d ₃ = R ⁴ d4 CH2OCH3 R ⁴ = CH 3 R ⁴ d ₅ d 6 = CF 3, R ⁴ = Cl d7 ^R4 = F i

E, R ⁴ = OCH 3 e2 ^R4 = CO2CH _{3 3} e R ⁴ = CH2OCH3 e4 ^R4 = CH3 R ⁴ e ₅ e 6 = CF 3, ^R4 = CI C7 ^R4 = F

H R ⁴ = OCH 3 R ⁴ f 2 = f ₃ CO2CH ₃ ^R4 = CH2OCH3 f4 ^R4 = CH3 F ₅ CF 3 r ⁴ = r ⁴ = f6 or f7 ^R4 = F

gi R ⁴ = OCH ₃ hi R ⁴ = OCH ₃ HR ⁴ = OCH ₃ hr ⁴ = och ₃ g ₂ R ⁴ = CO ₂ CH ₃ h ₂ R ⁴ = CO ₂ CH ₃ i ₂ R ⁴ = CO ₂ CH ₃ j ₂ R ⁴ = CO ₂ CH ₃ g ₃ R ⁴ = CH ₂ OCH ₃ h ₃ R ⁴ = CH ₂ OCH 3 ₁₃ R ⁴ = CH ₂ OCH ₃ j ₃ r ⁴ = ch ₂ and ₃ g ₄ R ⁴ = CH ₃ h ₄ R ⁴ = CH ₃ i ₄ r ⁴ = ch ₃ ^{4 4} r ⁴ = ch ₃ g ₅ R ⁴ = CF ₃ h ₅ R ⁴ = CF _{3 5 5} R ⁴ = cf ₃ js R ⁴ = CF ₃ g ₆ R ⁴ = Cl h ₆ r ⁴ = ci i ₆ r ⁴ = ci j ₆ R ⁴ = ci g ₇ R ⁴ = F h ₇ R ⁴ = F i ₇ r ⁴ = f J 7 R ⁴ = f

• ·

244 · ->

phenyl phenyl phenyl phenyl phenyl phenyl phenyl

2-pyridyl

2-pyridyl

2-pyridyl

2-pyridyl

2-pyridyl

2-pyridyl

2- pyridyl

3-Pyridyl 3-pyridyl 3-pyridyl 3-pyridyl 3-pyridyl 3-pyridyl 3-pyridyl

2-pyrimidyl-2-pyrimidyl-2-pyrimidyl-2-pyrimidyl-2-pyrimidyl-2-pyrimidyl-5-pyrimidyl-5-pyrimidyl-5-pyrimidyl-5-pyrimidyl-5-pyrimidyl-5-pyrimidyl

2- (aminosulfonyl) phenyl 2- (methylaminosulfonyl) phenyl

1-pyrrolidinocarbonyl

2- (methylsulfonyl) phenyl 4-morpholino

2- (1'-CF _3- tetrazol-2-yl) phenyl 4-morpholinocarbonyl 2- (aminosulfonyl) phenyl 2- (methylaminosulfonyl) phenyl

1-pyrrolidinocarbonyl

2- (methylsulfonyl) phenyl 4-morpholino

2- (1'-CF ₃ -tetrazol-2-yl) phenyl 4-morpholinocarbonyl 2- (aminosulfonyl) phenyl 2- (methylaminosulfonyl) phenyl

1-pyrrolidinocarbonyl

2- (methylsulfonyl) phenyl 4-morpholino

2- (1'-CF _3- tetrazol-2-yl) phenyl 4-morpholinocarbonyl 2- (aminosulfonyl) phenyl 2- (methylaminosulfonyl) phenyl

1-pyrrolidinocarbonyl

2- (methylsulfonyl) phenyl 4-morpholino

2- (1'-CF _3- tetrazol-2-yl) phenyl 4-morpholinocarbonyl 2- (aminosulfonyl) phenyl 2- (methylaminosulfonyl) phenyl

1-pyrrolidinocarbonyl

2- (methylsulfonyl) phenyl 4-morpholino

2- (1 ¹ _{-CF3-tetrazol-2-yl)} -phenyl • • · ·

- 245

5-pyrimidyl 4-morpholinocarbonyl 2-Cl-phenyl 2- (aminosulfonyl) phenyl 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 2-Cl-phenyl 1-pyrrolidinocarbonyl 2-Cl-phenyl 2- (methylsulfonyl) phenyl 2-Cl-phenyl 4-morpholino 2-Cl-phenyl 2- (1'-CF 3 -tetrazol-2-yl) phenyl 2-Cl-phenyl 4-morpholinocarbonyl 2-F-phenyl 2- (aminosulfonyl) phenyl 2-F-phenyl 2- (methylaminosulfonyl) phenyl 2-F-phenyl 1-pyrrolidinocarbonyl 2-F-phenyl 2- (methylsulfonyl) phenyl 2-F-phenyl 4-morpholino 2-F-phenyl 2- (1'-CF ₃ -tetrazol-2-yl) phenyl 2-F-phenyl 4-morpholinocarbonyl 2,5-diF-phenyl 2- (aminosulfonyl) phenyl 2,5-diF-phenyl 2- (methylaminosulfonyl) phenyl 2,5-diF-phenyl 1-pyrrolidinocarbonyl 2,5-diF-phenyl 2- (methylsulfonyl) phenyl 2,5-diF-phenyl 4-morpholino 2,5-diF-phenyl 2- (1'-CF _3- tetrazol-2-yl) phenyl 2,5-diF-phenyl 4-morpholinocarbonyl

- 246 fl fll fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl

Table 7

OCH ₃

C! R ⁴ = OCH ₃ c ⁴ R ⁴ = CO ₂ CH ₃ c ₃ R ⁴ = CH 2 OCH ₃ c ⁴ R ⁴ = CH 3 c ₅ R ⁴ = CF 3 c ₆ R ⁴ = CI c7 R ⁴ = F

d! R ⁴ = OCH 3 d2 ^R4 = CO2CH _{3 3} and R ⁴ d4 = CH2OCH3 R ⁴ = CH 3 R ⁴ d ₅ d 6 = CF 3, R ⁴ = Cl d7 ^R4 = F

och ₃ β! R ⁴ = OCH 3 e2 ^R4 = CO2CH _{3 3} e R ⁴ = CH2OCH3 e4 ^R4 = CH3 R ⁴ e ₅ e 6 = CF 3, ^R4 = CI C7 ^R4 = F

f, r ⁴ = och3 f2 R ⁴ = CO2CH ₃ f ₃ r ⁴ = ch2och3 f4 R ⁴ = CH 3 f ₅ R ⁴ = cf3 f6 r ⁴ = ci f7 r ⁴ = f

gi R ⁴ = OCH ₃ g ₂ R ⁴ = CO ² CH ₃ g ₃ R ⁴ = ch2och ₃ g ⁴ R ⁴ = CH 3 95 R ⁴ = CF ₃ g ₆ R ⁴ = CI 97 R ⁴ = F

Ιη ^R4 = OCH3, ^R4 = H 2 CO2CH ₃ H ₃ R ⁴ = CH2OCH3 h4 ^R4 = CH3 H ₅ R ⁴ = CF 3 h6 ^R4 = CI h7 ^R4 = F H R ⁴ = OCH ₃

1 ₂ R ⁴ = CO ₂ CH ₃

1 ₃ r ⁴ = ch ₂ and ₃

1 ₄ r ⁴ = ch ₃

1 ₅ r ⁴ = cf ₃

1 ₆ r ⁴ = ci

1 ₇ R ⁴ = F br ⁴ = och3 j2 R ⁴ = CO2CH ₃ j ₃ r ⁴ = ch2och3 i4 r ⁴ = ch3 js R ⁴ = CF3 is R ⁴ = CI j7 R ⁴ = F • ·

- 247 fl · · fl fl fl fl a a a a a a a fl a fl fl

AND (B) phenyl 2 - ((Me) ₂ N-methyl) phenyl phenyl 2 - ((Me) NH-methyl) phenyl phenyl 2- (H ₂ N-methyl) phenyl phenyl 2-HOCH ₂ -phenyl 2-F-phenyl 2 - ((Me) ₂ N-methyl) phenyl 2-F-phenyl 2 - ((Me) NH-methyl) phenyl 2-F-phenyl 2- (H ₂ N-methyl) phenyl 2-F-phenyl 2-HOCH ₂ -phenyl phenyl 2-Methylimidazol-1-yl phenyl 2-ethylimidazol-1-yl phenyl 2 - ((Me) ₂ N -methyl) imidazol-1-yl phenyl 2-CH ₃ SO ₂ -imidazol-1-yl phenyl 2-CH ₃ OCH ₂ -imidazol-1-yl 2-F-phenyl 2-Methylimidazol-1-yl 2-F-phenyl 2-ethylimidazol-1-yl 2-F-phenyl 2 - ((Me) ₂ N -methyl) imidazol-1-yl 2-F-phenyl 2-CH ₃ SO ₂ -imidazol-1-yl 2-F-phenyl 2-CH ₃ OCH ₂ -imidazol-1-yl 2-Cl-phenyl 2-Methylimidazol-1-yl 2-Cl-phenyl 2-ethylimidazol-1-yl 2-Cl-phenyl 2 - ((Me) ₂ N -methyl) imidazol-1-yl 2-Cl-phenyl 2-CH ₃ SO ₂ -imidazol-1-yl 2-Cl-phenyl 2-CH ₃ OCH ₂ -imidazol-1-yl 2- (Me) ₂ N-phenyl 2-Methylimidazol-1-yl 2- (Me) ₂ N-phenyl 2-ethylimidazol-1-yl 2- (Me) ₂ N-phenyl 2 - ((Me) ₂ N -methyl) imidazol-1-yl 2- (Me) ₂ N-phenyl 2-CH ₃ SO ₂ -imidazol-1-yl 2- (Me) ₂ N-phenyl 2-CH ₃ OCH ₂ -imidazol-1-yl phenyl N-methylimidazol-5-yl phenyl 4-Methylimidazol-5-yl phenyl 5-CF ₃ -pyrazol-1-yl 2-F-phenyl N-methylimidazol-5-yl 2-F-phenyl 4-Methylimidazol-5-yl 2-F-phenyl 5-CF ₃ -pyrazol-1-yl

• ·

- 248 *

phenyl guanidino phenyl 2-Thiazolin-2-ylamine phenyl N-methyl-2-imidazolin-2-yl phenyl N-methyl-1,4,5,6-tetrahydropyrimide -2-yl phenyl N-methylimidazol-2-ylthiol phenyl tert-butoxycarbonylamine phenyl (N-pyrrolidino) formylimino phenyl (N-pyrrolidino) formyl-N-methanesulfamoyl) imino 2-F-phenyl guanidino 2-F-phenyl 2-Thiazolin-2-ylamine 2-F-phenyl N-methyl-2-imidazolin-2-yl 2-F-phenyl N-methyl-1,4,5,6-tetrahydropyrimid-2-yl 2-F-phenyl N-methylimidazol-2-ylthio 2-F-phenyl tert-butoxycarbonylamine 2-F-phenyl (N-pyrrolidino) formylimino 2-F-phenyl (N-pyrrolidino) formyl-N-methanesulfamoyl) imino 2-CH ₃ O-phenyl (N-pyrrolidino) formylimino 2-CH 2 O-phenyl (N-pyrrolidino) formyl-N (methanesulfamoyl) imino

24a ··

The compounds of the present invention are useful as anticoagulants for treating or preventing thromboembolic diseases in mammals. The term thromboembolic disease as used herein refers to arterial or venous cardiovascular or cerebrovascular thromboembolic diseases such as unstable angina, first or recurrent myocardial infarction, sudden death from ischemia, transient ischemic attack, stroke, atherosclerosis, thrombus, venous thrombus venous thrombophlebitis, arterial embolism, coronary and cerebral artery thrombus, cerebral embolism, renal embolism and pulmonary embolism. The anticoagulant effect of the compounds of the present invention is believed to be due to inhibition of factor Xa or thrombin.

The activity of the compounds of the invention as factor Xa inhibitors is determined using purified factor Xa and a synthetic substrate. The rate of hydrolysis of factor Xa of the chromogenic substrate S2222 (Kabi Pharmacia, Franklin, OH) is measured both in the absence and presence of the compounds of the invention. Substrate hydrolysis results in pNA release, which is monitored spectrophotometrically by measuring the increase in absorbance at 405 nM. A decrease in the rate of change in absorbance at 405 nm in the presence of an inhibitor indicates inhibition of the enzyme. The results of this assay are expressed as inhibition constant

Factor Xa determinations were performed in 0.10 M sodium phosphate buffer, pH 7.5, containing 0.20 M NaCl and 0.5% PEG 8000. The Michaelis constant, for substrate hydrolysis, was determined at 25 ° C using the Lineweaver method and Burka. Values are determined by allowing 0.2-0.5 nM human Factor Xa (Enzyme Research Laboratories, South Bend, IN) to react with the substrate (0.20 mM-Ι mM) in the presence of inhibitor. The reaction is stirred for 30 minutes and the rate (rate of change of absorbance versus time) is measured over 25 to 30 minutes. The following equation is used to calculate the values:

• ·

25Ď (in _o -v _s ) / in _s = Ι / (Κ _± (1 + S / Kn,)) where:

νθ is the rate of regulation in the absence of inhibitor;

v _s is the rate in the presence of an inhibitor

I is the concentration of inhibitor is the dissociation constant of the enzyme: inhibitor complex

S is the substrate concentration is the Michaelis constant.

Using the above methodology, a number of compounds of the invention were determined to exhibit 15 µΜ, confirming the utility of the compounds of the invention as Xa inhibitors.

The antithrombotic effect of the compounds of the invention is demonstrated in a thrombotic module using arterio-venous (AV) diversion in rabbits. In this model, rabbits weighing 2-3 kg are anesthetized with a mixture of xylazine (10 mg / kg i.m.) and ketamine (50 mg / kg i.m.). An AV divert device filled with saline is inserted between the femoral arterial and femoral venous cannula. The AV diversion device consists of a 6-cm tygon tube containing a piece of silk. Blood flows from the femoral artery through the diversion of the AV into the femoral vein. exposure to blood flowing into the silk induces the formation of a significant thrombus. After forty minutes, the diversion is detached and the silk covered with a precipitate is weighed. Test reagents or vehicles (i.v., i.p., s.c. or orally) are administered prior to opening diversion of AV. Percent inhibition of thrombus formation was determined for each group. ID50 values (dose that causes 50% inhibition of thrombus) are determined by linear regression.

The compounds of formula I may also be useful as serine protease inhibitors, in particular thrombin,

Plasma kallikrein and plasmin. Because of their inhibitory action, these compounds are intended for use in the prevention or treatment of physiological reactions, blood coagulation and inflammation catalyzed by the above class of enzymes. Specifically, the compounds are useful as medicaments for treating diseases caused by increased thrombin activity, such as myocardial infarction and as agents used as anticoagulants in blood and plasma processing for diagnostic and other commercial purposes.

Certain compounds of the invention directly act as action inhibitors of the serine protease thrombin by their ability to inhibit the cleavage of small substrate molecules by thrombin in a purified system. In vitro inhibition constants are determined by the method described by Kettner et al. in J. Biol. Chem. 265, 18289-18297 (1990), incorporated herein by reference. In these assays, thrombin-mediated hydrolysis of the chromogenic substrate S2238 (Helena Laboratories,

Beaumount, TX) follows spectrophotometrically. Addition of inhibitor to the test mixture results in a decrease in absorbance and indicates inhibition of thrombin. Human thrombin (Enzyme Research Laboratories, Inc., South Bend, IN) at 0.2 nM in 0.10 M sodium phosphate buffer pH 7.5, 0.20 NaCl and 0.5% PEG 6000 is incubated with various substrate concentrations in the range 0.20-0.02 mM. After 25-30 minutes of incubation, thrombin activity is assayed by observing the rate of increase in absorbance at 405 nm resulting from substrate hydrolysis. Inhibition constants are derived from reciprocal response rate plots as a function of substrate concentration using the standard Lineweaver and Burk method. Using the methodology described above, some compounds of the invention were evaluated and found to be less than 15 µπι, confirming the ability of the compounds of the invention to be potent inhibitors of Xa.

The compounds of the present invention may be:

252. administered alone or in combination with one or more other therapeutic agents. These agents include other anticoagulants or coagulation inhibiting agents, antiplatelet agents or platelet inhibitors, thrombin inhibitors or thrombolytic or fibrinolytic agents.

The compounds are administered to a mammal in a therapeutically effective amount. A therapeutically effective amount is an amount of a compound of formula (I) which, when administered alone or in combination with an additional therapeutic agent, is capable of preventing a thromboembolic condition or the development of a disease.

By combination or combination therapy is meant that a compound of formula I and one or more additional therapeutic agents are administered concurrently to the mammal being treated. For combination administration, each component may be administered at the same time, or the individual components may be administered one after another in any order and at different times.

Thus, both components can be administered separately, but at a sufficiently short time interval to achieve the desired therapeutic effect. Other anticoagulant agents (or coagulation inhibitors) that may be used in combination with the compounds of the invention include warfarin and heparin as well as other factor Xa inhibitors as described in the prior art publications.

As used herein, antiplatelet agents (or platelet inhibitors) are agents that inhibit platelet function by inhibiting platelet aggregation, adhesion, or granular secretion. These agents include various non-steroidal anti-inflammatory agents (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone and piroxicam, their pharmaceutically acceptable salts and prodrugs. Among NSAIDS, aspirin (acetylsalicylic acid) is preferred.

253 * - ·· or piroxicam. Other suitable antiplatelet agents include ticlopidine, pharmaceutically acceptable salts and prodrugs thereof. Ticlopidine is also preferred as it is known to be gentle on the gastrointestinal tract in use. Other suitable platelet inhibitors include ILb / IIIa antagonists, thromboxane A2 receptor antagonists and thromboxane A2 synthase inhibitors, as well as pharmaceutically acceptable salts and prodrugs thereof.

The term thrombin inhibitors (antithrombin agents) as used herein refers to thrombin serine protease inhibitors. Inhibition of thrombin interrupts various thrombin-mediated processes, such as thrombin-mediated platelet activation (such as platelet aggregation and / or granular secretion of plasminogen activator inhibitor-1 and / or serotonin) or fibrin formation. A variety of thrombin inhibitors are known to those skilled in the art and can be used in combination with the compounds of the invention. Such inhibitors include, but are not limited to, boroarginine derivatives, boropeptides, heparins, hirudin, and argatroban, and pharmaceutically acceptable salts and prodrugs thereof. Boroarginine derivatives and boropeptides include N-acetyl and peptide boronic acid derivatives, such as C-terminal α-aminoboronic acid derivatives derived from lysine, ornithine, arginines, homoarginine, and their corresponding isothiourinium analogs. As used herein, hirudin refers to suitable hirudin derivatives or analogs, referred to herein as hirulogs, such as disulatohirudin. Boropeptide thrombin inhibitors include the compounds described in Kettner et al., US Patent No. 5,187,157 and European Patent Application Publication No. 293,881 A2. Other suitable boroarginine derivatives and boropeptide thrombin inhibitors are described in PCT 92/07869 and European Patent Application Publication No. 471 651 A2.

• ·

254 ’

The term thrombolytic (or fibrinolytic) agents (or thrombolytics or fibrinolytics) as used herein refers to agents that break down blood clots (thrombs). Such agents are tissue plasminogen activator, antistreplase, urokinase or streptokinase, and pharmaceutically acceptable salts and prodrugs thereof. The term antistreplase as used herein refers to a plasminogen-streptokinase activator complex, as described, for example, in European Patent Application No. 028 489. Urokinase as used herein refers to a double or single urokinase chain. A single urokinase chain is also referred to herein as prourokinase.

Administration of the compounds of Formula I of the invention in combination with such additional therapeutic agents may be more advantageous than administration of the compounds themselves, and thus a dose reduction of each drug may be achieved. Lower doses minimize the possible side effects, thereby achieving an increased safety margin.

The compounds of the invention are also useful as reference compounds, for example, as a quality standard or control in assays involving factor Xa inhibition. These compounds may be included in commercial kits, for example, for use in pharmaceutical studies, including factor Xa. For example, a compound of the invention can be used as a reference in an assay to compare its known potency against a compound of unknown potency. This will ensure that the investigator will perform the assay properly and provide a basis for comparison, especially if the test compound is a derivative of a reference compound. In developing new assays or protocols, the compounds of the invention will be used to test their efficacy.

The compounds of the invention may also be used in diagnostic assays involving factor Xa. For example,

The presence of factor Xa in an unknown sample can be determined by adding chromogenic substrate S2222 to a number of solutions containing the test sample and optionally one of the compounds of the invention. If pNA production is observed in a solution containing the test sample but not in the compound of the invention, factor Xa is present.

The compounds of the invention may be administered in such oral dosage forms as tablets and capsules (including sustained or delayed release forms), pills, powders, granules, elixirs, elixirs, suspensions, syrups, and emulsions. Similarly, they can also be administered by intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular routes, each using dosage forms well known to those skilled in the pharmaceutical art. They can be administered alone, but are usually administered with pharmaceutical carriers selected with respect to the route of administration and standard pharmaceutical practice.

The dosage regimen of the compounds of the invention will, of course, vary depending on such known factors as the pharmacodynamic properties of the particular agent employed, the mode and route of administration, the species, age, sex, medical condition, weight of the patient, type and extent of symptoms, , frequency of treatment, route of administration, renal and hepatic function of the patient, and desired effect. An effective amount of a medicament for preventing a disease, countering a disease or arresting a disease or condition can be readily determined and prescribed by a physician or veterinarian with ordinary skill in the art.

When used for the above indications, the compounds of the invention will generally have an oral dose in the range of about 0.001 to about 1000 mg / kg body weight, preferably 0.01 to 100 mg / kg body weight, most preferably

- 25čf ’

1.0 to 20 mg / kg body weight. For intravenous administration, the most preferred dosage is in the range of about 1 to about 10 mg / kg / minute at a constant infusion rate. The compounds of the invention may be administered as a single dose per day, but the total daily dose may also be divided into 2, 3 or 4 sub-doses.

The compounds of the invention may also be administered intranasally using topical compositions containing suitable intranasal vehicles. Transdermal routes may also be used, using transdermal patches. If transdermal drug delivery systems are used, the dosage regimen is, of course, continuous and not intermittent.

The compounds of the invention are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (all referred to as pharmaceutical carriers), suitably selected with respect to the intended form of administration, ie. oral tablets, capsules, elixirs, syrups and the like in accordance with conventional pharmaceutical practice.

For example, when the active ingredient is to be administered orally in the form of a tablet or capsule, it is combined with oral non-toxic inert suitable carrier materials such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. carrier materials suitable for liquid oral compositions include oral non-toxic pharmaceutically acceptable inert carrier materials such as ethanol, glycerol, water, and the like. In addition, if desired or necessary, suitable binders, lubricants, disintegrants and coloring agents may be added. Suitable binders include starch, gelatin, natural sugars such as glucose or S-lactose, starch sweeteners, natural and synthetic resins such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. · «·» »» »

Dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Non-limiting examples of disintegrants include disintegrants, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.

The compounds of the invention may also be administered in the form of liposomal delivery systems including small monolayer vesicles, large monolayer vesicles and multilayer vesicles. Liposomes can be formed from various phospholipids such as cholesterol, stearylamine and phosphatidylcholines.

The compounds of the invention may also be combined with soluble polymers as drug carriers to target the desired site of action. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol or polyethylene oxide-polylysine substituted with palmitic acid residues. Furthermore, it is also possible to combine the compounds of the invention with a class of biodegradable polymers that is useful for achieving controlled drug release. Non-limiting examples of suitable biodegradable polymers include polylactic acid, polyglycolic acid, lactic-glycolic acid copolymers, poly-epsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates and cross-linked or amphipatic block copolymers.

Dosage forms (pharmaceutical compositions) suitable for administration to patients may contain from about 1 mg to about 100 mg of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient will be present in an amount of from about 0.5 to about 95% by weight based on the total weight of the composition.

• ·

The gelatin capsules may contain the active ingredient and powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar diluents may also be used in the manufacture of compressed tablets. Both tablets and capsules can be manufactured as sustained release forms suitable for continuous release of the drug over a period of hours. Compressed tablets may be coated with sugar coatings or suitable films to mask unpleasant taste and to protect the tablets from the external atmosphere or enteric coatings in order to achieve selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration may contain coloring and flavoring agents to increase patient acceptance.

Suitable carriers for parenteral solutions include water, suitable oils, sodium chloride solution, dextrose (glucose) solution and similar sugar solutions, as well as glycols such as propylene glycol or polyethylene glycols. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizers and, if necessary, buffers. Suitable stabilizers include antioxidants such as sodium bisulfite, sodium sulfite and ascorbic acid, which can be used singly or in mixtures. Also used are citric acid and its salts and sodium ethylenediaminetetraacetic acid (EDTA). In addition, parenteral solutions may contain preservatives such as benzalkonium chloride, methyl or propylparaben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing, which is a standard guide in the art. Useful pharmaceutical dosage forms of the compounds of this invention are illustrated below.

• ·

Capsule

Large-scale capsules are prepared by filling a standard two-piece hard gelatin cassette each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

Soft gelatin capsules

A mixture of the active ingredient and an edible oil, such as soybean oil, cottonseed oil or olive oil, is injected into the gelatin by means of a positive displacement pump to give soft gelatin capsules each containing 100 mg of the active ingredient. The casies formed are rinsed and dried.

Tablets

Tablets are prepared in a conventional manner, each containing 100 mg of active ingredient, 0.2 mg of colloidal silica, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose. Tablets may be provided with suitable coatings to increase patient acceptance and delay absorption.

Injectable product

A parenteral formulation suitable for injection is prepared by mixing 1.5% by weight of the active ingredient in 10% (v / v) propylene glycol in water. The resulting solution is isotonic with sodium chloride and sterilized.

Suspension

An aqueous suspension for oral administration is prepared which contains 5 mg of the finely divided active ingredient in 5 ml, 200 mg.

260 sodium carboxymethylcellulose, 5 mg sodium benzoate, 1.0 g sorbitol according to the US Pharmacopoeia and 0.025 ml vanillin.

When the compounds of the invention are combined with anticoagulants, for example, a daily dose of about 0.1 to 100 mg of a compound of formula I and about 1 to 7.5 mg of anticoagulant per kilogram of patient weight may be mentioned as a general guide. In tablets, the compounds of the invention are generally present in an amount of about 5 to 10 mg per dosage unit, and the anticoagulant is present in an amount of about 1 to 5 mg per dosage unit.

When the compounds of the present invention are administered in combination with an antiplatelet agent, a typical daily dosage is about 0.01 to 25 mg of a compound of Formula I and about 50 to 150 mg antiplatelet agent, preferably about 0.1 to about 25 mg. 1 mg of a compound of formula I and about 1 to 3 mg of an antiplatelet agent per kilogram of patient weight.

When the compounds of the invention are administered in combination with a thrombolytic agent, a typical daily dosage is about 0.1 to 1 mg of a compound of formula I. The dose of thrombolytic agent typically when administered alone, when administered in combination with a compound of Formula I can be reduced by about 70 to 80%.

When two or more second therapeutic agents are co-administered with a compound of Formula I, the amount of each component may generally be reduced relative to the usual dose of the agent administered alone in a typical daily dose and typical dosage form. This reduction is possible due to the additive or synergistic effect of the therapeutic agents administered in combination.

In particular, when both therapeutic agents are administered in the form of a single dosage unit, there is a possibility of chemical interaction between the mixed active ingredients. When a compound of formula I is combined with a second therapeutic agent in a single dosage unit, the dosage unit is made such that physical contact between the two active ingredients is minimized (i.e. reduced), even though both active ingredients are contained in a single dosage unit. . For example, one of the active ingredients may be coated with an enteric coating. When one of the active ingredients is provided with an enteric coating, it is not only possible to minimize contact between the active ingredients contained in the combination, but also to control the release rate of one of these ingredients in the gastrointestinal tract so that one of these ingredients is not released in the stomach. in the intestines. One of the active ingredients may also be coated with a sustained release agent. In such a case, not only is the sustained release of the active ingredient in the gastrointestinal tract achieved, but also of minimizing physical contact between the active ingredients constituting the combination. The sustained release component may additionally be provided with an enteric coating to ensure that it is not released in the intestines. Yet another approach involves providing a combination product composition in which one component is coated with a sustained and / or enteric release polymer and the other component is also coated with a polymer such as hydroxypropylmethylcellulose (HPMC) of low viscosity type or other suitable materials known in the art. to further separate the active ingredients from one another. The polymer coating thus forms an additional barrier to prevent interaction with the second component.

These and other ways of minimizing contact between the components of the combination products of the present invention when administered in a single dosage form or in separate forms but at the same time and in the same manner are obvious.

262 · .-.

a person skilled in the art armed with the knowledge given in the description.

However, there are many modifications and variations of the present invention in light of the above techniques. It will be appreciated that other conditions not mentioned in this specification may be used as long as they are within the scope of the invention.

Claims (10)

PATENT CLAIMS Compounds of formula I or a stereoisomeric or pharmaceutically acceptable salt thereof, wherein; ring D is phenyl or pyridyl; E is selected from the group consisting of F, Cl, Br, I, OH, C ₃ _ ₄ alkoxy, SH, 0 _1-3 alkyl-S, S (O) R ^3b, S (O) 2 R ^3a, S ( O) 2NR ² R ^2a , and OCF ₃ ; R is selected from the group consisting of H, F, Cl, Br, I, OR ^3, SR ^3, CO 2 R ^3, N02, and _{CH2 OR3;} alternatively, E and R joined to form methylenedioxy or ethylenedioxy; M is selected from: • · • 0 264 • · Z is selected from the group consisting of a bond, C 1-4 alkylene, - 266 9 · · to · (CH ₂ ) _r O (CH ₂ ) _r , (CH ₂ ) _r NR ³ (CH ₂ ) _r , (CH ₂ ) _r C (O) (CH ₂ ) _r , (CH ₂ ) _r C (O) O (CH ₂ ) _r , (CH ₂ ) _r OC (O) (CH ₂ ) _r , (CH ₂ ) _r C (O) NR ³ (CH 2) r, (CH 2) r NR ³ (CO) (CH 2) _r , (CH ₂ ) _r OC (O) 0 (CH ₂ ) _r , (CH ₂ ) _r OC (O) NR ³ (CH ₂ ) _r , (CH ₂ ) _r NR ³ C (O) O (CH 2) r, (CH 2) r NR ³ C (O) NR ³ (CH 2) _r , (CH ₂ ) _r S (O) _p (CH ₂ ) _r , (CH ₂ ) _r SO ₂ NR ³ (CH ₂ ) _{r, (CH2) r} ^NR3 SO2 (CH2) r, and (CH 2) r NR ³ SO 2 NR ³ (CH _{2) r,} provided that Z does not form a ring M or group a is a group of the NN, N-0, NS, NCH ₂ N, NCH ₂ O or NCH ₂ S; R ^1a and R ^1b are independently absent or selected from the group consisting of - (CH ₂ ) _r -R ¹ -CH = CH-R ¹ 'NC ¹ R ¹ ', OCT ¹ R ¹ , SC ¹ R ¹ , NH (CH 2) 2 (CH 2) t R ¹ ', O (CH 2) ₂ (CH ₂ ), -R ¹ ', and SiCH ₂ CH ₂ R ¹ '; alternatively R ^1a and R ^1b , when attached to adjacent carbon atoms, together with the carbon atoms to which they are attached a 5-8 membered saturated, partially saturated or saturated ring substituted with 0-2 R ⁴ and containing 0-2 heteroatoms selected from N, O and S; alternatively, when Z is C (O) NH and R ^1a is bonded to a carbon atom of the ring adjacent to Z, then R ^1a is a C (O) group that replaces the amide hydrogen of Z to form a cyclic imide; R ¹ 'is selected from the group consisting of H, C ₃ _ ₄ alkyl, F, Cl, Br, I, -CN, -CHO, (CF ₂ ) _r CF ₃ (CH ₂ ) _r OR ² , NR ² R ^2a , C (O) R ^{2 c} , OC (O) R ² , (CF ² ) r CO ² R ^2c , S (O) p R ^2b , NR ² (CH ₂ ) _r OR ² , CH (= NR ^2c) NR ² R ^2a, NR ² C (O) R ^2b, NR ² C (0) NHR ^2b, NR ² C (O) ₂ R ^2a, OC (O) NR ^2a R ^2b , C (O) NR ² R ^2a , C (O) NR ² (CH 2) r OR ² , SO ² NR ² R ^2a , NR ² SO ² R ^2b , C _3-6 carbocyclic radical substituted with 0-2 R ⁴ and a 5 to 10 membered heterocyclic system containing 1 to 4 heteroatoms selected from the group consisting of N, O and S substituted with 0 to 2 R ⁴ ; ♦ ft ftft · * * * ft ft 267 ftft ftft ftc ftc fc 9 ft 9 ft ft R ¹ is selected from H, CH (CH ² OR ² ) 2, C (O) R ^2c , C (O) NR ² R ^2a , S (O) R ^2b , S (O) 2 R 2 ^t> , and SO ² NR ² R ^2a ; R at each occurrence is selected from the group consisting of H, _CF3, C ^ _G alkyl, benzyl, C ₃ _G carbocyclic residue substituted with 0-2 R ^4b, and 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N , O and S substituted with 0-2 R ^4b ; R ^2a, at each occurrence is selected from the group consisting of H, CF _3, C ₄ _G alkyl, benzyl, phenethyl, C ₃ _G carbocyclic residue substituted with 0-2 R ^4b, and 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O and S substituted with 0-2 R ^4b ; R ^a, at each occurrence is selected from the group consisting of CF3, _Cl _ ₄ alkoxy, C ₄ _G alkyl, benzyl, C ₃ _G carbocyclic residue substituted with 0-2 R ^4b, and 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O and S substituted with 0-2 R ^4b ; R ^2c, at each occurrence is selected from the group consisting of CF _3, OH, C _1-4 alkoxy, C ^ g alkyl, benzyl, C ₃ _G carbocyclic residue substituted with 0-2 R ^4b, and 5-6 membered heterocyclic system containing 1 to 4 heteroatoms selected from N, O and S substituted with 0 to 2 R ^4b ; alternatively, R ² and R ^2a , together with the atom to which they are attached, form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R ^4b and containing 0 to 1 additional heteroatoms selected from the group consisting of N, O and WITH; R ³ , at each occurrence, is selected from the group consisting of H, C _1-4 alkyl and phenyl; • · • · - 268 R ^3a , at each occurrence, is selected from H, C _1-4 alkyl and phenyl; R ^3b, at each occurrence is selected from the group consisting of H, C ₄ _ ₄ alkyl and phenyl; R ^3c, at each occurrence is selected from the group consisting of H, C ₄ _ ₄ alkyl and phenyl; A is selected from the group consisting of: ^C 3-10 ^carboxylic t> ocyklický residue substituted with 0-2 ^R4, and 5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S substituted with 0-2 R ^4; B is selected from: Η, Y and X-Y; X is selected from the group consisting of C ₁ _ ₄ alkylene, -CR ² (CR ² R ^2b ) (CH 2) t -, -C (O) -, - (C = NR ¹ ) -, -CR ² (NR ¹ R ² ) -, -CR ² (OR ² ) -, -CR ² (SR ² ) -, -C (O) CR ² R ^2a -, -CR ² R ^2a C (O), -S (O) -S (O) pCR ² R ^2a -, -CR ² R ^2a (SO) -S (O) 2 NR ² -, -NR ² S (O) ₂ -, -NR ² S (O) ² CR ² R ^2a -, -CR ² R ^2a S (O) 2 NR ² -, -NR ² S (O) ₂ NR ² -, -C (O) NR ² -, -NR ² C (O) -, -C (O) NR ² CR ² R ^2a -, -NR ² C (O) CR ² R ^2a -, -CR ² R ^2a C (0) NR ² -, -CR ² R ^2a NR ² C (O) -, -NR ² C (O) O-, -OC (O) NR ² -, -NR ² C (O) NR ² -, -NR ² -, -NR ² CR ² R ^2a -, -CR ² R ^2a NR ² -, O, -CR ² R ^2a O and -OCR ² R ^2a -; Y is selected from a file that includes: (CH ₂ ) _r NR ² R ^2a , provided that XY does not form a bond NN, O-N or SN ^C 3-10 ^carboxylic tiocyklický residue substituted with 0-2 R ^4a, and 5-10 membered heterocyclic system containing 1-4 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R ^4a; at each occurrence it is selected from a file that includes • · · · · · · - 269 Η = 0, (CH _{2) r} OR ^2, F, Cl, Br, I, C ₁ _ ₄ alkyl, CN, N0 _2, (CH _{2) r} NR ² R ^2a, (CH _{2) r} C ( 0) R ^2c, NR ² C (0) R ^2b, C (O) NR ² R ^2a, NR ² C (O) NR ² R ^2a , CH (= NR ² ) NR ² R ^2a , CH (= NS (0) 2 R ⁵ ) NR ² R ^2a , NHC (= NR ² ) NR ² R ^2a , C ( 0) NHC (= NR ²⁾ NR ² R ^2a, SO 2 NR ² R ^2a, NR ² SO 2 NR ² R ^2a, NR ² SO 2 -C ₁ _ ₄ alkyl, NR ² S02R ^5, S (0) p R ^5, (CF ₂ ) _r CF _3, NCH ₂ R ¹ ^, OC ^ R ^1, SC ^ R ^1, N (CH _{2) 2} (CH _{2) t} R ¹ ', O (CH2) 2 (CH2) t R ^1', and S (CH2) ₂ (¾) j R ¹ '; alternatively one R ⁴ is a 5-6 membered aromatic heterocycle containing 1 to 4 heteroatoms selected from the group consisting of N, O and S; R ^4a , at each occurrence, is selected from the group consisting of H, = O, (CH 2) _r OR ² , (CH 2) _r -F, (CH ₂ ) _r -Br, (CH ₂ ) _r -Cl, I, C _1-4 alkyl, -CN, NO ₂ , (CH ₂ ) _r NR ² R ^2a , (CH ₂ ) _r NR ² R ^2b , (CH ₂ ) _r C (O) R ^2c , NR ² C (O) R ^2b , C (O) NR ² R ^2a , C (O) NH (CH ₂ ) ₂ NR ² R ^2a , NR ² C (O) NR ² R ^2a , CH (= NR ² ) NR ² R ^2a , NHC (= NR ²⁾ NR ² R ^2a, S0 ₂ NR ² R ^2a, NR ² SO 2 NR ² R ^2a, NR ² SO 2 -C ₁ _ ₄ alkyl, C (O) NHSO ₂ -C ₁ _ ₄ alkyl, NR ² SO 2 R ^5, S (O) p R ^5, and (CF _{2) r} CF _3; alternatively one R ⁴ is a 5-6 membered aromatic heterocycle containing 1 to 4 heteroatoms selected from the group consisting of N, O and S and substituted with 0 to 1 R ⁵ ; / 1 V * \ R at each occurrence is selected from the group consisting of H, = 0, (CH _{2) r} OR ^3, F, Cl, Br, I, C ₁ _ ₄ alkyl, -CN, NO _2, (CH _{2) r} NR ³ R ^3a , (CH 2) _r C (O) R ³ , (CH 2) _r C (O) OR ^3c , NR ³ C (O) R ^3a , C (O) NR ³ R ^3a , NR ³ C (0) ) NR ³ R ^3a, CH (= NR ³⁾ NR ³ R ^3a, NHC (= NR ³⁾ NR ³ R ^3a, SO 2 NR ³ R ^3a, NR ³ SO 2 NR ³ R ^3a, NR ³ SO 2 -C 1-4 alkyl, NR ³ SO2CF ₃ , NR ³ SO ₂ -phenyl, S (O) _p CF _3, S (O) _p -C ₁ _ ₄ alkyl, S (O) _p -phenyl, and (CF _{2) r} CF _3; R ⁵ at each occurrence is selected from the group consisting of CF _3, C ₄ _G alkyl, phenyl substituted with 0-2 R ^, and benzyl substituted with 0-2 R f. • · - 270 R ⁶ , at each occurrence, is selected from the group consisting of H, OH, (CH 2) r OR ² , F, Cl, Br, I, C _1-4 alkyl, CN, NO ₂ , (CH ₂ ) _r NR ² R ^2a , (CH 2) r C (O) R ^2b , NR ² C (O) R ^2b , NR ² C (O) NR ² R ^2a , CH (= NH) NH 2, NHC (= NH) NH ₂ , SO ₂ NR ² R ^2a, NR ² SO 2 NR ² R ^2a, NR ² SO 2 Cl and ₁ _ ₄ alkyl; n is selected from 0, 1, 2 and 3; m is selected from 0, 1 and 2; p is selected from 0, 1 and 2; r is selected from 0, 1, 2 and 3; s is selected from 0, 1 and 2; and t is selected from 0 and 1; A compound according to claim 1, selected from the group: where M is f m 271 Z is selected from the group consisting of (CH ₂ ) _r C (O) (CH ₂ ) _r , (CH ₂ ) _r C (O) O (CH ₂ ) _r , (CH ₂ ) _r C (O) NR ³ (CH ₂ ) _r , (CH ₂ ) _r S (O) (CH ₂ ) _r , _and (CH ₂ ) _r SO ₂ NR ³ (CH ₂ ) _r ; and Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R ^4a ; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl; 272 furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazole, thiadiazole, triazole, 1,2.3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, benzofuran, benzothiofuran, indole, benzimidazole, benzoxazole, benzthiazole, indazole, benzisoxazole, benzisothiazole, and isoindazole; Y may be selected from the following bicyclic heteroaryl ring systems: K is selected from 0, S, NH and N. The compound of claim 2, wherein the compound has the general formula Ia or 1b: ring D is phenyl or pyridyl; where: • · · 273 from the group consisting of F, Cl, Br and C _1-3 E is selected from alkoxy; R is selected from ₂ or ³ M is selected from the group consisting of H, F, Cl, Br, OR, and from the group: bb hh jj 274 Z is selected from the group consisting of (CH ₂ ) _r C (O) (CH ₂ ) _r and (CH ₂ ) _r C (O) NR ³ (CH ₂ ) _r ; and Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R ^4a ; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazole, thiadiazole, triazole, 1,2.3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, benzofuran, benzothiofuran, indole, benzimidazole, benzoxazole, benzthiazole, indazole, benzisoxazole, benzisothiazole, and isoindazole; The compound of claim 3, wherein: ring D is phenyl; E is selected from the group consisting of F, Cl, Br and OCH ₃ ; R is selected from H, F, Cl and Br M is selected from: • · - 275 - And it is selected from the file: Cg_g carbocyclic residue substituted with 0-2 ^R4, and 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S substituted with 0-2 R ^4; Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R ^4a ; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, benzimidazolyl, oxadiazole, thiadiazole, triazole, 1,2,3-oxadiazole, 1,2,3-oxadiazole, 1,2,3-oxadiazole 2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole and 1,3,4-triazole, R at each occurrence is selected from the group consisting of H, CF _3, C ^ g alkyl, benzyl, C ₅ _G carbocyclic residue substituted with 0-2 R ^4b, and 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O and S 276 substituted with 0-2 R ^4b ; R ^2a, at each occurrence is selected from the group consisting of H, CF _3, C ₁ _ ₆ alkyl, benzyl, phenethyl, C ₅ _G carbocyclic residue substituted with 0-2 R ^4b, and 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O and S substituted with 0-2 R 2; R ^2b, at each occurrence is selected from the group consisting of CF _3, C -] __ ₄ alkoxy, C ^ g alkyl, benzyl, C ₅ _G carbocyclic residue substituted with 0-2 R ^4b, and 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O and S substituted with 0-2 R ^4b ; R ^2c , at each occurrence, is selected from the group consisting of CF _3, OH, C _1-4 alkoxy, C ₄ _G alkyl, benzyl, C ₅ _G carbocyclic residue substituted with 0-2 R ^4b, and 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S substituted with 0 up to 2 R ^4b ; alternatively, R ² and R ^2a , together with the atom to which they are attached, form a ring selected from imidazolyl, morpholino, piperazinyl, pyridyl and pyrrolidinyl, substituted with 0-2 R ^4b ; R ⁴ , at each occurrence, is selected from the group consisting of H, = O, OR ² , CH ² OR ² , F, Cl, C 1-4 alkyl, NR ² R ^2a , CH ₂ NR ² R ^2a , C (O) R ^2c , CH ₂ C (O) R ^2c , C (O) NR ² R ^2a , CH (= NR ² ) NR ² R ^2a , CH (= NS (O) 2 R ⁵ ) NR ² R ^2a , SO ² NR ² R ^2a , NR ² SO ² -C 1-4 alkyl, S (O) 2 R ⁵ and CF 3, provided that if B is H then R ⁴ is other than tetrazole, C (O) -alkoxy and C (O) NR ² R ^2a ; R 1, at each occurrence, is selected from the group consisting of H, = O, (CH ₂ ) _r OR ² , F, Cl, C 1-4 alkyl, NR ² R ^2a , CH ² NR ² R ^2a , 277 NR ² R ^2b, CH 2 NR ² R ^2b, (CH 2) _r C (O) R ^2c, NR ² C (O) R ^2b, C (O) NR ² R ^2a , C (O) NH (CH ₂ ) ₂ NR ² R ^2a , NR ² C (O) NR ² R ^2a , SO ₂ NR ² R ^2a , S (O) 2 R ⁵ and CF 3; R ^4b , at each occurrence, is selected from the group consisting of H, = O, (CH 2) r OR ³ , F, Cl, C _1-4 alkyl, NR ³ R ^3a , CH 2 NR ³ R ^3a , C (O) R ³ , CH ² C (O) R ³ , C (O) OR ^3c , C (O) NR ³ R ^3a , CH (= NR ³⁾ NR ³ R ^3a, SO 2 NR ³ R ^3a, NR ³ S02-C ₁ _ ₄ alkyl, -NR ³ NR ³ SO2CF3 SO2-phenyl, S (O) ₂ CF _3, S (O) ₂ -C ₁ _ ₄ alkyl, S (0) ₂ -phenyl, and CF _3; The compound of claim 1, wherein the compound is selected from the group consisting of: 3-Methyl-1-phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl)) carboxyamide; 3-Methyl-1- (2-methoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide); 3-Methyl-1- (3-methoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide); 3-Methyl-1- (4-methoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide); 3-Methyl-1- (2-hydroxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide); 3-Methyl-1- (3-hydroxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide); 3-Methyl-1- (4-hydroxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; 3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (3-fluoro- (2,2'278) · 0 · 0 · 0 0 · · · 0 0 0 0 0 · 0 · 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 · 0 · · 0 · 0 00 · 0 0 00 · 0 00 ·· -aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; 3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (3-bromo-4- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide); 3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (3-iodo- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide); 3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (3-methyl- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl)) carboxyamide; 3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (4- (4-N-carboxyldimethylamine) phenyl) carboxyamide; 3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (4- (4-N-pyrrolidinocarbonyl) phenyl) carboxyamide; 3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-α-methyl-N-pyrrolidino) phenyl) carboxyamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (2'-aminosulfonyl [1,1 '] - biphen-4-yl) carboxyamide); 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (Ν- (4-N-pyrrolidinocarbonyl) phenyl) carboxyamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (5- (2-methanesulfonyl) phenyl) pyridin-2-ylcarboxyamide); 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (5-N-pyrrolidinocarbonyl) pyridin-2-ylcarboxyamide); 3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (5-N-pyrrolidinocarbonyl) pyridin-2-ylcarboxyamide); 3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (5- (2-sulfone)) (279) 4 (4 (4) (amido) phenyl) pyridin-2-ylcarboxyamide; 3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5-N- (4- (N-carboxyl-3-hydroxypyrrolidino) phenyl) carboxyamide; 2-Amino-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] biphen-4-yl) aminocarbonyl] thiazole; 2-Bromo-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] biphen-4-yl) aminocarbonyl] thiazole; 2-Chloro-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] biphen-4-yl) aminocarbonyl] thiazole; 2-Chloro-4- (4-phenoxy) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole; 2-Methoxy-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole; 2-Thiomethyl-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole; 2-Methylsulfoxide-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole; 2-Methylsulfone-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole; 2-Cyano-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole; 2-N, N-Dimethylamino-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole; 2- (1-Pyrrole) -4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl280) and α · * · »·» »♦ · · · · · Β φ φ φ φ φ φ φ β β β β β β β β β β β φ φ φ φ [1,1 '] biphen-4-yl) aminocarbonyl] thiazole; 3- (4-Methoxyphenyl) -5- [5- (2'-aminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl-5-carbomethoxymethyl-isoxazoline; 3- (4-Methoxyphenyl) -5- [5- (2'-aminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl-5-carboxymethyl-isoxazoline; 3- (4-Methoxyphenyl) -5- [5- (2'-aminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl-5- (N-carbomethoxymethyl) carboxyamido methyl isoxazoline; 3- (4-Methoxyphenyl) -5- [5- (2'-aminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl-5- (1,2,4-triazol-1-yl) methyl isoxazoline; 1- (4-Methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] tetrazole; 3-Methyl-1- (4-methoxy-3-chloro) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide); 3-Methyl-1- (4-trifluoromethoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide); 1- (3-Bromophenyl) -3-methyl-1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; 1- (3-iodophenyl) -3-methyl-lH-pyrazole-5- [(2 ¹ -aminosulfony 1- [1,1 '] - biphen-4-yl) carboxyamide; 1- (3,4-Methylenedioxanphenyl) -3-methyl-1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; 1- (4-Methoxyphenyl) -3-hydroxylmethylene-1H-pyrazole-5- (4'-pyrrolidinecarbonyl) anilide; 281 1- (4-Methoxyphenyl) -3-formaldehyde-1H-pyrazole-5- (4'-pyrrolidinecarbonyl) anilide; 1- (4-Methoxyphenyl) -5- (4'-pyrrolidinecarbonyl) anilide-3-pyrazolecarboxylic acid; 1- (4-Methoxyphenyl) -3-methylcarboxylate-lH-pyrazole-5- ⁽¹ 4 -pyrrolidinkarbonyl) anilide; 1- (4'-Chlorophenyl) -3-methyl-1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; 1- (4'-Chlorophenyl) -3-methyl-1H-pyrazole-5 - [(2'-aminosulfonyl- [1-pyridyl-1'-phenyl] -4-yl) carboxyamide; 1- (3 ', 4 ^{1-dichlorophenyl)} -3-methyl-lH-pyrazole-5 - [(2'-aminosulfonyl - [1,1'] - biphen-4-yl) carboxyamide; 1- (3'-Chlorophenyl) -3-methyl-1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; 2-Amino-4-phenyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole; 2-Chloro-4-phenyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole; 2-Amino-4- [3- (bromo) -4- (fluoro) -phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole; 2-Amino-4- [4-fluorophenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole; 2-Amino-4- [3-bromophenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole; - 282 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Flfl · 2-Chloro-4- [3-bromophenyl] -5 - [(2'-aminosulfonyl- [1,1 '] -biphen-4-yl) aminocarbonyl] thiazole; N- (2'-Aminosulfonyl- [1,1 '] - biphen-4-yl) -1- (4-methoxyphenyl) -3- (methylthio) pyrazole-5-carboxyamide; 1- (4-Methoxyphenyl) -3- (methylsulfonyl) -N- (5- (2'-methylsulfonylphenyl) pyrimid-2-yl) pyrazole-5-carboxyamide; N- (2'-Aminosulfonyl- [1,1 '] -biphen-4-yl) -1- (4-methoxyphenyl) -3- (methylsulfonyl) -1H-pyrazole-5-carboxyamide; N- (4-Benzoylpyrrolidno) -1- (4-methoxyphenyl) -3- (methylthio) 1H-pyrazole-5-carboxyamide; 1- (4-Methoxyphenyl) -N- (5- (2'-methylsulfonylphenyl) pyrimid-2-yl) -3- (methylthio) -1H-pyrazole-5-carboxyamide; N- (4-Benzoylpyrrolodino) -1- (4-methoxyphenyl) -3- (methylsulfonyl) -1H-pyrazole-5-carboxyamide; N- (2'-Aminosulfonyl- [1,1 '] - biphen-4-yl) -1- (4-methoxyphenyl) -3- (methoxymethyl) -1H-pyrazole-5-carboxyamide; N- (2'-Aminosulfonyl- [1,1 '] - biphen-4-yl) -1- (4-methoxyphenyl) -3-carbomethoxy-1H-pyrazole-5-carboxyamide; N- (2'-Aminosulfonyl- [1,1 '] -biphen-4-yl) -1- (4-methoxyphenyl) -3- (methylsulfonylmethyl) -1H-pyrazole-5-carboxyamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (5- (2-methanesulfonyl) phenyl) pyrimidin-2-yl) carboxyamide; 3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5-N- (4- (N-carboxyl-2 carbomethoxypyrrolidino) phenyl) carboxyamide; • • • - 283 3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5-N- (4- (N-carboxyl-3-aminopyrrolidino) phenyl) carboxyamide; 3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5-N- (4- (N-carboxyl-3methoxypyrrolidino) phenyl) carboxyamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (5- (2-aminosulfonyl) phenyl) pyridin-2-yl) carboxyamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-amidino) phenyl) carboxyamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (N-pyrrolidino) formylimino) phenyl) carboxyamide; 3-Trifluoromethyl-5- (N- (2 ¹ aminosulfonyl- [1,1 '] - biphen-4-yl)) -1- (4-methoxyphenyl) pyrrolo [3,4-d] pyrazole-4,6 - (1H, 5H) dione; 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5-carbomethoxy- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl)) carboxyamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5-hydroxymethyl- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl)) carboxyamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N-2-fluoro (4- (N-pyrrolidino) formylimino) phenyl) carboxyamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (N-pyrrolidino) formyl-N - ((2-propyl) methylcarbamoyl) imino) phenyl) carboxyamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (N) -) - 284 • · · · -pyrrolidino) formyl-N- (methylsulfamoyl) imino) phenyl) carboxyamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N - ((4-amidino) phenyl) methyl) carboxyamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N - ((4- (N-pyrrolidino) formylimino) phenyl) methyl) carboxyamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N - ((1-benzyl) piperidin-4-yl) carboxyamide); 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazol-5- (N - ((1 (pyridin-2-yl) methyl) piperidin-4-yl) carboxyamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (2-methylimidazo-1-yl)) phenyl) carboxyamide; 3-Methyl- (4-methoxy) phenyl-1H-pyrazole-5- (N- {4- (5-methylimidazol-1-yl} phenyl) carboxyamide; 3-Methyl- (4-methoxy) phenyl-1H-pyrazole-5- (N- (4- (4-methylimidazol-1-yl) phenyl) carboxyamide); 3-Trifluoromethyl- (4-methoxy) phenyl-1H-pyrazole-5- (N- {4- (5-carbomethoxyimidazol-1-yl} phenyl) carboxyamide; 3-Trifluoromethyl- (4-methoxy) phenyl-1H-pyrazole-5- (N- {4- (5-carboxyimidazol-1-yl} phenyl) carboxyamide; 1- (4'-methoxyphenyl) -3-hydroxymethyl-lH-pyrazole-5-N- (4 ¹ - (pyrrolidinocarbonyl) phenyl) carboxyamide; 1- (4'-Methoxyphenyl) -3-formaldehyde-1H-pyrazole-5-N- (4'- (pyrrolidinocarbonyl) phenyl) carboxyamide; • · · · · · · · · · · · · - 285 1- (4'-Methoxyphenyl) -5-N- (4 '- (pyrrolidinocarbonyl) anilide) -1H-pyrazol-3-ylcarboxylic acid; 1- (4'-Methoxyphenyl) -3-methylcarboxylate-β-pyrazole-5-N- (4'-pyrrolidinocarbonyl) phenyl) carboxyamide; 1- (4 ¹ methoxyphenyl) -3-cyanomethyl-lH-pyrazole-5-N- (4 ¹ -pyrrolidinokarbonyl) phenyl) carboxyamide; 2- (1 '- (4' '- Methoxyphenyl) -5' - (4 '' - pyrrolidinyl-one) anilide-1H-pyrazol-3'-yl) acetic acid; 1- (4'-Methoxyphenyl) -3-bromomethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; 1- (4'-Methoxyphenyl) -3-aminomethyl-β-pyrazole-5-N- (2H-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; 1- (4'-Methoxyphenyl) -3- (N-methylsulfonylamino) methyl-1 H -pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; 1- (4'-Methoxyphenyl) -3- (imidazol-1-yl) methyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; 1- (4'-Methoxyphenyl) -3-hydroxylmethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; 1- (4'-Methoxyphenyl) -3-trifluoroacetylhydroxylmethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; 1- (4'-Methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'-methylsulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; 1- (4'-Methoxy-2'-hydroxycarbonylphenyl) -3-trifluoromethyl-1 H- 286 • · ········ -pyrazole-5-N- (2'-methylsulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; 1- (4'-Methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; 1- (4'-Methoxy-2'-hydroxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'-tert-butylaminosulfonyl- [1,1 '] biphen-4-yl) carboxyamide; 1- (4'-Methoxy-2'-hydroxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] biphen-4-yl) carboxyamide; 1- (4'-Methoxy-2'-hydroxylmethyl-phenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] -biphen-4-yl) carboxyamide; 1- (4'-Methoxyphenyl) -3-methyl-1H-pyrazole-5-N- (4 '- (3' '- methyl -3' '- pyrazolin-5' '- on-2' '- yl) phenyl) carboxyamide; 1- (4'-Methoxyphenyl) -3-methyl-1H-pyrazole-5-N- (4 '- (6' '- methyl benzothiazol-2' '- yl) phenyl) carboxyamide; 1- (4'-Methoxyphenyl) -3-methyl-1H-pyrazole-5-N- (4 '- (4' '- methylpiperidino) phenyl) carboxyamide; 1- (4'-Methoxyphenyl) -3-methyl-1H-pyrazole-5-N- (4 '- (2' '- methylimidazol-1' '- yl) phenyl) carboxyamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-carboxy (N-methylimidazo-2-yl) phenyl) carboxyamide); 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-hydroxymethyl (2- (imidazol-2-yl) phenyl))) carboxyamide; 287 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-hydroxymethyl (2- (1-benzylimidazol-2-yl) phenyl))) carboxyamide; 1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5- (N- (4- (2-carboxy (imidazol-2-yl) phenyl))) carboxyamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (N- (4-methoxyphenyl) amino- (2-thiazolyl) methyl) phenyl))) carboxyamide; 1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5- (N- (4- (2-carboxy (4,5-dihydrothiazol-2-yl) phenyl))) carboxyamide; 1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-N-4- (2- (4 ', 5'-dihydro-1'H-imidazol-2' yl) phenyl) carboxyamide; 1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5- [4- (1,4,5,6-tetrahydropyrimid-2-yl) phenyl] carboxyamide; 1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5- [4- (N-methyl-4,5,6-trihydropyrimid-2-yl) phenyl] carboxyamide; 1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-N-1- (2-fluoro-4-imidazolophenyl) carboxyamide; 1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-N-1- (2-fluoro-4-N-methylimidazolylphenyl) carboxyamide; 1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- [4- (4,5-dihydro-1-N-methylimidazo-2-yl) phenyl] carboxyamide; 1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- [4- (pyrimidin-2-yl) phenyl] carboxyamide; 288 2- (Carboxyamide) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole; 2- (2-Methoxyethylamino) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole; 2- (3-Hydroxypropylamino) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole; 2- (2-Cyanoethylamino) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole; 2- (3-Methoxypropylamino) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole; 2- (N-b-Alanyl) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole; 2- (Isopropylamino) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole; 2- (1,3-Dihydroxy-2-propylamino) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole ; 2 - [(Methoxycarbonyl) methylamino] -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] -biphen-4-yl) carboxyamide] thiazole; 2- (N-Glycyl-4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] biphen-4-yl) carboxyamide] thiazole; 1 - [(4-Methoxy) phenyl] -3- (ethoxycarbonyl) -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1 - [(4-Methoxy) phenyl] -3- (carboxyamide) -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; • · - 289 1 - [(4-Methoxy) phenyl] -3 - [(2-hydroxyethyl) carboxyamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1 - [(4-Methoxy) phenyl] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide-3-hydroxamic acid; 1 - [(4-Methoxy) phenyl] -3- [phenylcarboxyamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1 - [(4-Methoxy) phenyl] -3 - [(3-hydroxypropyl) carboxyamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1 - [(4-Methoxy) phenyl] -3- [3-methylcarboxyamide] -1H-pyrazole-5 - [(4 - (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1 - [(4-Methoxy) phenyl] -3 - [(benzyl) carboxyamide] -1H-pyrazole-5 - [(4 - (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1 - [(4-Methoxy) phenyl] -3 - [(dimethyl) carboxyamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1 - [(4-Methoxy) phenyl] -3 - [(phenylethyl) carboxyamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1 - [(4-Methoxy) phenyl] -3 - [(2-hydroxyphenyl) carboxyamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1 - [(4-Methoxy) phenyl] -3 - [(3-hydroxyphenyl) carboxyamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1 - [(4-Methoxy) phenyl] -3 - [(4-hydroxyphenyl) carboxyamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1 - [(4-Methoxy) phenyl] -3 - [(methoxycarbonyl) amino] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; • · - 290 - ·· ·· 1 - [(4-Methoxy) phenyl] -3-amino-1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; 1 - [(4-Methoxy) phenyl] -3 - [(methoxycarbonyl) methylamino] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; 1 - [(4-Methoxy) phenyl] -3 - [(2-hydroxy) ethylamino] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; 1 - [(4-Methoxy) phenyl] -3- [E-2- (methoxycarbonyl) ethenyl] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; 1 - [(4-Methoxy) phenyl] -3- [2- (methoxycarbonyl) ethyl] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; 1 - [(4-Methoxy) phenyl] -3- [E-2- (carboxy) ethenyl] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; 1 - [(4-Methoxy) phenyl] -3- [2- (carboxy) ethyl] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; 1 - [(4-Methoxy) phenyl] -3- [E-2- (carboxyamide) ethenyl] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; 1 - [(4-Methoxy) phenyl] -3- [E-2- (hydroxymethyl) ethenyl] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; 1 - [(4-Methoxy) phenyl] -3- (hydroxypropyl-1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; 1 - [(4-Methoxy) phenyl] -3-propyl-1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; • · - 291 1 - [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4-cyano-1H-pyrazole-5 - [(2'-methylsulfonyl-3-fluoro- [1,1 '] -biphen-4-yl) carboxyamide; 1 - [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4- (amidino) -1H-pyrazole-5 - [(2'-methylsulfonyl-3-fluoro- [1,1 '] - biphen-4) -yl) carboxyamide; 1 - [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4- (N-hydroxyamidino) -1H-pyrazole-5 - [(2'-methylsulfonyl-3-fluoro- [1,1 '] - biphene) -4-yl) carboxyamide; 1 - [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4- (ethoxycarbonyl) -1H-pyrazole-5 - [(2'-methylsulfonyl-3-fluoro- [1,1 '] - biphen-4) -yl) carboxyamide; and 1 - [(4-Methoxy) phenyl] -3- (trifluoromethyl) -1H-pyrazole-5 - [(2'-methylsulfonyl-3-fluoro- [1,1 '] -biphen-4-yl) carboxyamide-4 -carboxylic acid; and pharmaceutically acceptable salts thereof 6. Compound of formula II: Or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein M is selected from: • · · 292 Z is selected from C (O) CH ₂ and C (O) NR ³ ; R ^1a is - (CH ₂ ) _r -R ^{1 '} ; R ¹ 'is selected from H, C 1-4 alkyl, F, Cl, Br, CH (CH ² OR ² ) 2, (CF ₂ ) _r CF ₃ , (CH ₂ ) ₂ OR ² , NR ² R ^2a , S (O) p R ^2b , NR ² (CH 2) _r OR ² , NR ² C (O) R ^2b , C (O) NR ² R ^a , C (O) NR ² (CH 2) r OR ² , and SO ² NR ² R ^2a ; R at each occurrence is selected from the group consisting of H, CF _3, C ₄ _G alkyl, benzyl, C ₃ _G carbocyclic residue substituted with 0-2 ^R4, and 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N , O and S substituted with 0-2 R ⁴ ; R ^2a, at each occurrence is selected from the group consisting of H, CF _3, C ₄ _G alkyl, benzyl, phenethyl, C ₃ _G carbocyclic residue substituted with 0-2 ^R4, and 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O and S substituted with 0-2 R ⁴ ; R ^2b, at each occurrence is selected from the group consisting of CF _3, Cl-4 alkoxy, C ₄ _G alkyl, benzyl, C ₃ _G carbocyclic residue substituted with 0-2 ^R4, and 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O and S substituted with 0-2 R ⁴ ; alternatively, R ² and R ^2a , together with the atom to which they are attached, form a 5- or 6-membered saturated, partially saturated or unsaturated ring substituted with 0-2 R ⁴ containing 0 to 1 additional heteroatoms selected from the group consisting of N, O, and S; R ^3, at each occurrence, is selected from the group consisting of H, C ₄ _ ₄ alkyl, and phenyl; - 293 - A is selected from the group consisting of phenyl, pyridyl, pyrimidyl, and A is substituted with 0-2 R ⁴ ; B is selected from H and Y; Y is selected from phenyl, pyridyl, tetrazolyl, and morpholino, and Y is substituted with 0-2 R ^4a ; R ⁴ , at each occurrence, is selected from the group consisting of F, Cl, Br, I, C (O) NR ² R ^2a , and (CF ₂ ) _r CF ₃ ; R ^4a , at each occurrence, is selected from the group consisting of F, Cl, Br, I, C 1-4 alkyl, C (O) NR ² R ^2a , SO ² NR ² R ^2a 'NR ² SO ² -C 1-4 alkyl, S ( O) p R ^5, and (CF 2) _r CF _3; R ^5, at each occurrence, is selected from the group consisting of CF _3, C ₁ _ ₆ alkyl, phenyl and benzyl; p is 0,1 and 2; and r is 0, 1, 2a3. The compound of claim 6, wherein the compound is selected from the group consisting of: 3-Methyl-1-phenyl-1H-pyrazole-5- (N- (2-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide); 2-Amino-4-phenyl-5 - ^[(1 2 aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole; and 2-Chloro-4-phenyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole; and a pharmaceutically acceptable salt thereof. • · · · * · · · * * * -? Q A · · · · · · · · · · · · A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for use in medicine. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of thromboembolic diseases.