LT4702B - Inhibitors of factor xa with a neutral p1 specificity group - Google Patents

Abstract

Below is the formula (1) of factor Xa inhibitor with neutral P1 specific group that is described in this invention:<IMAGE>and their pharmaceutically acceptable saline solutions where R and E could be groups similar to methoxy groups or halogens.

Description

The present invention is primarily directed to novel factor Xa inhibitors with neutral P1. a specific group, pharmaceutical compositions containing these compounds, and methods of using them as anticoagulant agents for the treatment and prophylaxis of thromboembolic disorders.

ORIGIN OF THE INVENTION

WO 96/28427 describes benzamidine anticoagulants of the formula:

R *

R ⁴ R ^s

R ⁷

wherein Z ₁ and Z ₂ are O, N (R), S or OCH ₂ and the central ring may be phenyl or various heterocycles. The compounds of the present invention are not substituted with Z ¹ or the same compounds as above.

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

R ¹⁵ R ¹⁴ \

R ¹ ^ v,

N'O

O

X 'Y wherein R ¹ may be a basic group, UV may be a six-membered aromatic ring, WX may be various linear or cyclic groups, and Y is an oxy group. Thus, all of these compounds have an acidic functional group (i.e., WXC (= 0) -Y). In contrast, the compounds of the present invention have no such acidic group.

EP 0.513.387 discloses active oxygen inhibitors which are oxazoles or thiazoles having the formula:

wherein X is O or S, R ^{2 is} preferably hydrogen, and R ¹ and R ² are substituted cyclic groups, at least one of which is phenyl. The compounds of the present invention have no association with these types of oxazoles or thiazoles.

WO 95/18111 is directed to fibrinogen receptor antagonists having basic and acidic ends of the formula:

R 10 wherein R ¹ represents a basic end, U is an alkylene or heteroatom bond, V may be a heterocycle, and the right side of the molecule represents an acidic end. The compounds of the present invention do not have the acidic end of the compounds of WO 95/18111.

U.S. Pat. 5,463,071 to Himmelsbach et al. depicts cell aggregation inhibitors which are 5-membered heterocycles of the formula:

: Χ3-Χ4 wherein the heterocycle may be aromatic and the A-B-C- and P-E-D- groups are attached to the ring system. A-B-C- can be a variety of substituents, including the base group attached to the aromatic ring. However, the F-E-D- group is an acidic functional group which is different from the present invention. In addition, the use of these compounds as factor Xa inhibitors is not discussed.

Baker et al. U.S. Patent No. 5,317,103 discusses 5-HT 1 agonists, which are heteroaromatic pentane compounds with an indole substituent of the formula:

wherein R ¹ may be pyrrolidine or piperidine and A may be a basic group Including amino and amidino. However, Baker et al. does not indicate that A may be a substituted ring system such as the heteroaromatic compounds of the present invention.

Baker et al. WO 94/02477 discloses 5-HT 1 agonists which are imidazoles, triazoles or tetrazoles of the formula:

wherein R ¹ represents a nitrogen-containing ring system or a cyclobutane substituted with nitrogen, and A may be a basic group including amino and amidino. But Baker et al. does not indicate that A may be a substituted ring system such as the heteroaromatic compounds of the present invention.

Tidwell et al., J. Med. Chem. 1978, 21 (7), 613-623 describes a series of diarylamidine derivatives including 3,5-bis (4-amidinophenyl) isoxol. This series of compounds was tested against thrombin, trypsin, and pancreatic calicrein. These types of compounds are not included in the present invention.

Activated factor Xa, which plays a predominant practical role in thrombin generation by limited, prothrombin proteolysis, occupies a central position by combining internal and external activation mechanisms into the final overall blood coagulation process. The generation of thrombin, the final serine protease in the fibrin clot pathway, from its precursor is enhanced by the formation of the prothrombinase complex (factor Xa, factor V, Ca ²⁺ and phospholipid). Because it is estimated 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 complex in amplification of blood coagulation.

Thromb. Res. 1979, 15, 617-629), to interrupt the blood coagulation system

Inhibition of factor Xa may be more effective than inactivation of thrombin

Thus, effective and specific factor Xa inhibitors are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. Therefore, it is desirable to discover novel inhibitors of factor Xa.

SUMMARY OF THE INVENTION

Thus, one object of the present invention is to provide novel factor Xa inhibitors with a neutral P1 specific group, or pharmaceutically acceptable salts thereof, or prodrug derivatives thereof.

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

It is another object of the present invention to provide the use of a therapeutically effective amount of at least one compound of the present invention, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, in the manufacture of a medicament for the treatment of thromboembolic disorder.

These and other objects, which will be apparent from the detailed description, have been achieved by the inventors, having discovered that the compounds of formula (I):

Wherein D, E, M and R are as described below, or pharmaceutically acceptable salts thereof, as effective inhibitors of factor Xa.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS [1] Thus, in a first embodiment, the present invention provides novel compounds of formula (I):

(I) in which:

D is a phenyl or pyridyl ring;

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

R is selected from H, F, Cl, Br, I, OR ³ , SR ³ , CO ² R ³ , NO 2 and CH ₂ OR ³ ; otherwise, E and R together form a methylenedioxy or ethylenedioxy group;

M is selected from the group:

s

nn oo

R ⁴ R ⁴

J is O or S;

J ^{a is} NH or NR ^1a ;

Z is selected from the bond, Ci. _4- alkylene, (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 C O (CH ₂ ) r, (CH ₂ ) r C (O) NR ³ (CH ₂ ) _r , (CH ₂ ) r NR ³ C (O) (CH 2) _r , (CH ₂ ) _r OC (O) O (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) f, (CH2) r S (O) p (CH 2) r, (CH2) rSO2NR ³ (CH 2) _r, (CH _{2) r} NR ³ SO 2 (CH 2) r and (CH 2) rNA ³ SO ² NR ³ (CH ₂ ) _r , with the proviso that Z does not form a bond to N, NO, NS, NCH ₂ N, NCH ₂ O or NCH ₂ S with ring M or group A;

R ^1a and R ^1b are absent or independently selected from - (CH 2) r R ¹ , -CH = CHR ¹ , NCH ² R ¹ ', OCH ² R ¹ ', SCH ² R ¹ ', NH (CH 2) 2 (CH 2) t R ¹ , O ( CH2) ₂ (CH _{2) t} R ^r S (CH _{2) 2} (CH _{2) t} R ^1;

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

alternatively, when Z is C (O) NH and R ^1a is attached to a carbon atom adjacent to Z, then R ^1a is C (O) which replaces Z amide hydrogen to form a cyclic imide;

R ¹ 'is selected from 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 . _6- carbocyclic moieties substituted with 0-2 R ⁴ and

5- to 10-membered heterocyclic systems containing from 1 to 4 heteroatoms selected from the group consisting of N, O and S, and substituted with 0-2 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 is in} each case selected from H, CF ₃ , Ci. _6- alkyl, benzyl, C ₃ . ₆ carbocyclic radicals substituted with 0-2 R ^4b substituents and 5-6 membered heterocyclic systems containing 1-4 heteroatoms selected from the group consisting of N, O and S and 0-2 substituents R ^4b ;

R ^{2a is in} each case selected from H, CF ₃ , C _1-6 alkyl, benzyl, phenethyl, C ₃ .

A 6-carbocyclic residue substituted with 0-2 R ^4b and 5-6 membered heterocyclic systems having 1-4 heteroatoms selected from the group consisting of N, O and S and substituted with 0-2 R ^4b ;

R ^{2b is in} each case selected from CF ₃ , C _1-4 alkoxy, O, R 6 alkyl, benzyl, C ₃ . _{A 6-} carbocyclic residue substituted with 0-2 R ^4b substituents and a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from the group consisting of N, O and S and 0-2 substituted R ^4b ;

R ^{2c is in} each case selected from CF ₃ , OH, Ci. ₄ -alkoxy, Ci- ₆ alkyl, benzyl, C _{3rd A 6-} carbocyclic residue substituted with 0-2 R ^4b , and

5-6 membered heterocyclic systems containing 1-4 heteroatoms selected from the group consisting of Ν ', O and S and substituted with 0-2 R ^4b ;

alternatively, R ² and R ^2a together with the atom to which they are attached form 5- or

A 6- membered saturated, partially saturated or unsaturated ring substituted with 0-2 R ^4b and having 0-1 additional heteroatoms selected from the group consisting of N, O and S;

R ^{3 is in} each case selected from H, Ci. _4- alkyl and phenyl;

R ^{3a is} at each occurrence selected from H, C 1-6 alkyl and phenyl;

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

R ^{3c is in} each case selected from Ci. _4- alkyl and phenyl;

A is selected from:

C ₃ .io carbocyclic residue substituted with 0-2 R ^4, and 5-10 membered heterocyclic system containing from 1-4 beteroatomus selected from the group consisting of N, O, and S substituted with 0-2 R ⁴ ;

B is selected from: H, Y and Χ-Υ;

X is selected from C 1-6 alkylene, -CR ² (CR ² R ^2b ) (CH 2) r, -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) p -, -S (O) pCR ² R ^2a -, -CR ² R ^2a S (O) p-, -S (O) 2NR ² -, -NR ² S (O) 2, -NR ² S (O) ² R ^2a 2CR - - 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:

(CH ₂ ) _r NR ² R ^2a , provided that Χ-Υ does not form a NN, ON, or SN bond, C ₃ -C 10 carbocyclic moieties substituted with 0-2 R ^4a and 5-10 membered heterocyclic systems having 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R ^4a ;

R ^{4 is} at each occurrence selected from H-, = O, (CH ₂ ) _r OR ² , F, Cl, Br, I, Ομ 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 , CH (= 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 ^ alkyl, NR ² SO 2 R ^5, S (O) PR ^5, (CF 2) _r CF _3, NCH ₂ R ^1, OCH2R ¹ SCH2R ^1, N (CH 2) ₂ (CH _{2) t} R ^1, O (CH2) 2 (CH2) tR ¹ 'and S (CH ₂ ) ₂ (CH ₂ ) _t R ^r ;

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

with the proviso that when B is H then R ⁴ is not tetrazole, C (O) -alkoxy and C (O) NR ² R ^2a ;

R ^{4a is} at each occurrence selected from 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) ² R ^2b, RNA, (CH2) _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 ¹ 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 Ci- ₄ alkyl, C (O) NHSO ₂ -C _{first 4} alkyl, NR ² SO 2 R ^5, S (O) PR ^5, and (CF _{2) r} CF ₃ ;

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

R ^{4b is} at each occurrence selected from 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, NR ³ C (= NR ³⁾ NR ³ R ^3a, SO 2 NR ³ R ^3a, NR ³ SO 2 NR ³ R ^3a, NR ³ SO 2 C1.4 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 is in} each case selected from CF ₃ , Ci. ₆ alkyl, phenyl substituted with 0-2 R ^6, and benzyl substituted with 0-2 ^R6;

R ^{6 is} at each occurrence selected from 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 C 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;

their stereoisomers or their pharmaceutically acceptable salts.

[2j] In a more preferred embodiment, the present invention provides novel compounds wherein;

M is selected from the group:

R ^1b

nn

Z is selected from (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) p (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 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-oxo 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, benzothiazole, indazole, benzisoxazole, benzisothiazole and isoindazole;

Y may also be selected from the following bicyclic heterocyclic ring systems:

K is selected from O, S, NH and N.

[3] In a more preferred embodiment of the present invention are provided novel compounds of formula la or Ib:

where:

D is a phenyl or pyridyl ring;

E is selected from F, Cl, Br and Ci- ₃ -alkoxy; R is selected from H, F, Cl, Br, OR ³ and CH ₂ OR ³ ;

M is selected from the group;

Z is selected from (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 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-oxo 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, 1,3,414 triazole, benzofuran, benzothiofuran, indole, benzimidazole, benzoxazole, benzothiazole, indazole, benzisoxazole , benzisothiazole and isoindazole.

[4] In a more preferred embodiment of the present invention are provided novel compounds wherein:

D is a phenyl ring;

E is selected from F, Cl, Br and OCH ₃ ;

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

M is selected from the group:

A is selected from:

C ₅ -6-carbocyclic radicals substituted with 0-2 R ⁴ and

5-6 membered heterocyclic systems containing 1-4 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 heterocyclic systems substituted with 0-2 R ^4a : phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, 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;

R ^{2 is in} each case selected from H, CF ₃ , Ci. ₆ alkyl, benzyl, C ₅ -6karbociklinės residue substituted with 0-2 R ^4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0- 2 substituents R ^4b ;

R ^{2a is} at each occurrence selected from H, CF ₃ , C _1-6 alkyl, benzyl, phenethyl, C ₅ s carbocyclic radicals substituted with 0-2 R ^4b , and 5-6 membered heterocyclic system having 1- 4 heteroatoms selected from the group consisting of N, O and S substituted with 0-2 R ^4b ;

R ^{2b is in} each case selected from CF ₃ , Ci. ₄ -alkoxy groups, Ci. _6- alkyl, benzyl, C ₅ -C 6 -carbocyclic moieties substituted with 0-2 R ^4b , and 5-6 membered heterocyclic systems containing 1-4 heteroatoms selected from the group consisting of N, O and S containing 0- 2 substituents R ^4b ;

R ^{2c is in} each case selected from CF ₃ , OH, Ci. _4- alkoxy, O, -6 alkyl, benzyl, C ₅ -C 6 -carbocyclic moieties substituted with 0-2 R ^4b , and 5-6 membered heterocyclic systems containing 1-4 heteroatoms selected from the group consisting of N, O and S substituted with 0-2 R ^4b ;

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

R ^{4 is} at each occurrence selected from H, = O, OR ² , CH ² OR ² , F, C 1, 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. 4 alkyl, S (O) 2 R ⁵ and CF 3 with the proviso that when B is H then R ⁴ is not tetrazole, C (O) -alkoxy and C (O) NR ² R ^2a ;

R ^4a in any case, is selected from H, = 0, (CH2) ROR ^2, F, Cl, Ci.4 alkyl, NR ² R ^2a, CH2NR ² R ^2a, NR ² R ^2b, R ^2b CH2NR ² ( 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 ; and

R ^{4b is} at each occurrence selected from 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 ^ Os-C ^ alkyl, NR ³ SO2CF _3, NR ³ SO ₂ -phenyl, S (O) ₂ CF _3, S (O) ₂ - Ci. _4- alkyl, S (O) _2- phenyl and CF ₃ .

[5] In a more preferred embodiment of the present invention are provided novel compounds selected from:

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

3-methyl-1- (2-methoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen4-yl) carboxamide;

3-methyl-1- (3-methoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen4-yl) carboxamide;

3-methyl-1- (4-methoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen4-yl) carboxamide;

3-methyl-1- (2-hydroxy) phenyl-1 H -pyrazol-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen4-yl) carboxamide;

3-methyl-1- (3-hydroxy) phenyl -1 H -pyrazol-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen4-yl) carboxamide;

3-methyl-1- (4-hydroxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen4-yl) carboxamide;

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

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

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

S-methyl-1- (4-methoxyphenyl-1H-pyrazole-5-methyl-4 '- (' 1,1 ') - biphen-4-yl) carboxamide;

3-methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-N-carboxyldimethylamino) phenyl) carboxamide;

3-methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-N-pyrrolidinocarbonyl) phenyl) carboxamide;

3-methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-a-methyl-N-pyrrolidino) phenyl) carboxamide;

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

3-trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-N-pyrrolidinocarbonyl) phenyl) carboxamide;

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

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

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazol-5- (N- (5-N-pyrrolidinocarbonyl) pyridin-2-yl) carboxamide; \

3-methyl-1- (4-methoxyphenyl) -1H-pyrazol-5- (N- (5- (2sulfonamido) phenyl) pyridin-2-yl) carboxamide;

3-methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (N-carboxyl-3-hydroxypyrrolidino) phenyl) carboxamide;

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 T] -biphen-4-yl) aminocarbonyl] thiazole;

2-chloro-4- (4-phenoxy) -5 - [(2'-aminosulfonyl- [1,1 T] -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 '] - biphen4-yl) aminocarbonyl] thiazole;

2- (1-pyrrolo) -4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [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) carboxamidomethyl-isoxazoline;

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

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) carboxamide;

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

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

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

1- (3,4-methylenedioxyanophenyl) -3-methyl-1 H -pyrazol-5 - [(2'-aminosulfonyl [1,1 '] - biphen-4-yl) carboxamide;

- (4-methoxyphenyl) -3-hidroksilmetilen 1 H _{c-pyrazole-5-} (4'pirolidinokarbonil) -anilido;

1- (4-methoxyphenyl) -3-formaldehyde-1H-pyrazole-5- (4'-pyrrolidinocarbonyl) anilide;

1- (4-methoxyphenyl) -5- (4'-pyrrolidinocarboryl) anilide-3-pyrazolecarboxylic acid;

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

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

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

- (3 ', 4'-dichlorophenyl) -3-methyl-1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1'] - biphen4-yl) carboxamide;

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

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

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

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

1- (4-methoxyphenyl) -3- (methylsulfonyl) -N- (5- (2'-methylsulfonylphenyl) pyrimidin-2-yl) pyrazole-5-carboxamide;

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

N- (4-benzoylpyrrolidino) -1- (4-methoxyphenyl) -3- (methylthio) -1H-pyrazole-5-carboxamide;

1- (4-methoxyphenyl) -N- (5- (2'-methylsulfonylphenyl) pyrimidin-2-yl) -3- (methylthio) -1H-pyrazole-5-carboxamide;

N- (4-benzoylpyrrolidino) -1- (4-methoxyphenyl) -3- (methylsulfonyl) -1H-pyrazole-5-carboxamide;

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

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

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

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

3-methyl-1- (4-methoxyphenyl) -1H-pyrazole-N- (4- (N-carboxyl-2-carbomethoxypyrrolidino) phenyl) carboxamide;

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

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

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

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

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

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) carboxamide;

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

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

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

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (N-pyrrolidino) formylN- (methanesulfamoyl) imino) phenyl) carboxamide;

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

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

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

3-trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazol-5- (N - ((1-pyridin-2-yl) methyl) piperidin-4-yl) carboxamide;

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

3-methyl- (4-methoxy) phenyl-1H-pyrazol-5- (N- {4- (5-methylimidazol-1-yl} phenyl) carboxamide;

3-methyl- (4-methoxy) phenyl-1 H -pyrazol-5- (N- {4- (4-methylimidazol-1-yl} phenyl) carboxamide;

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

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

- (4'-methoxyphenyl) -3-hydroxymethyl-1H-pyrazole-5- (N- (4'pyrrolidinocarbonyl) phenyl) carboxamide;

- (4'-methoxyphenyl) -3-formaldehyde-1H-pyrazole-5- (N- (4 '- (pyrrolidinocarbonyl) phenyl) carboxamide;

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

- (4'-methoxyphenyl) -3-methylcarboxylate-1H-pyrazole-5-N- (4'pyrrolidinocarbonyl) phenyl) carboxamide;

- (4'-methoxyphenyl) -3-cyanomethyl-1H-pyrazole-5-N- (4'pyrrolidinocarbonyl) phenyl) carboxamide;

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) carboxamide;

1- (4'-Methoxyphenyl) -3-aminomethyl-1 H -pyrazol-5-N- (2'-aminosulfonyl- [1,1 T] biphen-4-yl) carboxamide;

1- (4'-methoxyphenyl) -3- (N-methylsulfonylamino) methyl-1H-pyrazole-5-N- ^(2! Aminosulfonyl- [1,1 '] biphen-4-yl) carboxamide;

- (4'-methoxyphenyl) -3- (imidazol-1-yl) methyl-1 H -pyrazol-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide;

1- (4'-methoxyphenyl) -3-hydroxylmethyl-1 H -pyrazol-5-N- (2'-aminosulfonyl [1,1 '] - biphen-4-yl) carboxamide;

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

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

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

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

1- (4'-Methoxy-2'-hydroxycarbonyl-phenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'-tert-butylamino-sulfonyl- [1,1 '] -biphenyl) -carboxamide;

1- (4'-Methoxy-2'-hydroxycarbonyl-phenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1 ₍ 1 '] - biphen-4-yl) -carboxamide;

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

1- (4'-Methoxyphenyl) -3-methyl-1H-pyrazole-5-N- (4'-anthbutyl) phenyl) carboxamide;

1- (4'-methoxyphenyl) -3-methyl-1 H -pyrazol-5-N- (4 '- (3' -methyl-3 '-pyrazolin-5' on-2 '-yl) phenyl) carboxamide;

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

1- (4'-methoxyphenyl) -3-methyl-1H-pyrazole-5-N- (3 ', 4'-dibromophenyl) carboxamide;

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

1- (4'-methoxyphenyl) -3-methyl-1H-pyrazole-5-N- (4 '- (4' -methylpiperidino) phenyl) carboxamide;

1- (4'-methoxyphenyl) -3-methyl-1 H -pyrazol-5-N- (4 '- (2' -methylimidazol-1 'yl) phenyl) carboxamide;

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

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

3-Trifluoromethyl-1- (4-methoxyphenyl) -111-pyrazole-5- (N- (4-hydroxymethyl- (2- (1-benzylimidazol-2-yl) phenyl))) carboxamide;

1- (4-methoxyphenyl) -3-trifluoromethyl-1 H -pyrazol-5- (N- (4- (2-carboxyl (imidazol-2-yl) phenyl))) carboxamide;

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

1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5- (N- (4- (2-carboxy- (4,5-dihydro-thiazol-2-yl) -phenyl))) carboxamide;

1- (4-methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-N-4- (2- (4 ', 5'-dihydro-1'Himidazol-2'-yl) phenyl) carboxamide;

- (4-methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (4- (N-2'aminoethylenecarboxamide) phenyl) carboxamide;

- (4-methoxyphenyl) -3-trifluoromethyl-1H-pyrazol-5- [4- (1,4,5,6-tetrahydropyrimidin-2-yl) phenyl] carboxamide;

1- (4-Methoxyphenyl) -3-trifluoromethyl-1 H -pyrazol-5- [4- (N-methyl-4,5,6-trihydropyrimidin-2-yl) phenyl] carboxamide;

- (4-methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-N-1- (2-fluoro-imidazoline-phenyl) -carboxamide;

- (4-methoxyphenyl) -3-trifluoromethyl-1H-pyrazol-5-N-1- (2-fluoro-4-N-methylimidazolinophenyl) carboxamide;

- (4-methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- [4- (4,5-dihydro-1-N-methylimidazol-2-yl) phenyl] carboxamide;

1- (4-methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- [4-carbonylguanidine] phenylcarboxamide;

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

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

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

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

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

2- (3-methoxypropylamino) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl [1,1 '] - biphen-4-yl) carboxamide;

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

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

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

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

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

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

1 - [(4-methoxy) phenyl] -3- (carboxamide) -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxamide;

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

1 - [(4-methoxy) phenyl) -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxamide-3-hydroxy acid;

- [(4-methoxy) phenyl] -3- [phenylcarboxamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxamide;

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

- [(4-methoxy) phenyl] -3- [methylcarboxamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxamide;

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

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

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

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

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

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

1 - [(4-methoxy) phenyl] -3 - [(methoxycarbonyl) amino] '1 H -pyrazol-5 - [(2'aminosulfonyl- [1,1 T] -biphen-4-yl) carboxamide;

1 - [(4-methoxy) phenyl] -3-amino-1 H -pyrazol-5 - [(2'-aminosulfonyl- [1,1 T] -biphen4-yl) carboxamide;

1 - [(4-methoxy) phenyl] -3 - [(methoxycarbonyl) methylamino] -1H-pyrazol-5 - [(2'aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide;

1 - [(4-methoxy) phenyl] -3 - [(2-hydroxy) ethylamino] -1 H -pyrazol-5 - [(2'aminosulfonyl- [1,1]] - biphen-4-yl) carboxamide;

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

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

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

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

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

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

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

1 - [(4-methoxy) phenyl] -3-propyl-1 H -pyrazol-5 - [(2'-aminosulfonyl- [1,1 '] - biphen4-yl) carboxamide;

1 - [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4-azano-1 H -pyrazol-5 - [(2'-methylsulfonyl-3-fluoro [1,1 '] - biphen-4-yl) carboxamide;

1 - [(4-methoxy) phenyl] -3- (trifluoromethyl) -4- (amidino) -1H-pyrazole-5 - [(2'-methylsulfonyl-3-fluoro [1,1 T] -biphen-4-yl) ) carboxamide;

1 - [(4-methoxy) phenyl] -3- (trifluoromethyl) -4- (N-hydroxyamidino) -1H-pyrazole-5 [(2'-methylsulfonyl-3-fluoro [1,1 '] - biphenyl) 4-yl) carboxamide;

1 - [(4-methoxy) phenyl] -3- (trifluoromethyl) -4- (ethoxycarbonyl) -1H-pyrazole-5 - [(2'-methylsulfonyl-3-fluoro [1,1 '] - biphen-4-) il) carboxamide; and

1 - [(4-methoxy) phenyl] -3- (trifluoromethyl) -1H-pyrazole-5 - [(2'-methylsulfonyl-3-fluoro- [1,1 T] -biphen-4-yl) carboxamide-4-carboxylic acid.

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

(H) in which:

M is selected from the group:

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 1-3 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 ) pR ^2b, NR ² (CH 2) _r OR ^2, NR ² C (O) R ^2b, C (O) NR ² R ^2a, C (O) NR ² (CH 2) ² and SO 2 NR Ror ² R ^2b; R ^{2 is} at each occurrence selected from H, CF ₃ , C ₁ -C ₆ alkyl, benzyl, C ₃ . ₆ carbocyclic radicals substituted with 0-2 R ⁴ and 5-6 membered heterocyclic systems containing 1-4 heteroatoms selected from the group consisting of N, O and S substituted with 0-2 R ⁴ ;

R ^{2a is in} each case selected from H, CF ₃ , C 1-4 alkyl, benzo, C ₃ . ₆ carbocyclic radicals substituted with 0-2 R ⁴ and 5-6 membered heterocyclic systems containing 1-4 heteroatoms selected from the group consisting of N, Ojr S substituted with 0-2 R ⁴ ;

R ^{2b is in} each case selected from CF ₃ , Ci. ₄ -alkoxy groups, Ci. _6- alkyl, C ₃ . _6- carbocyclic residues substituted with 0-2 R ⁴ and 5-6 membered heterocyclic systems containing 1-4 heteroatoms selected from the group consisting of 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 5-6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R ⁴ having 0-1 additional heteroatoms selected a group consisting of N, O and S;

R ^{3 is in} each case selected from H, Ci. _4- alkyl and phenyl;

A is selected from phenyl, pyridyl and pyrimidyl and A is 0-2 substituents on R ⁴ ;

B is selected from: H and Y;

Y is selected from phenyl, pyridyl, tetrazolyl and morpholine, and Y is substituted with 0-2 R ^4a ;

R ^{4 is} at each occurrence selected from F, Cl, Br, I, C (O) NR ² R ^2a and (CF 2) r CF 3; and R ^{4a is} at each occurrence selected from 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) PR ⁵ and (CF 2) _r CF ₃ ;

R ^{5 is in} each case selected from CF ₃ , Ci. _6- alkyl, phenyl and benzyl;

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

their stereoisomers or their pharmaceutically acceptable salts.

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

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

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-4yl) aminocarbonyl] thiazole; and pharmaceutically acceptable salts thereof.

In a third embodiment, the present invention provides novel 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 the therapeutic use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of thromboembolic disorders.

DEFINITIONS

The compounds described herein may have asymmetric centers. The compounds of the present invention having an asymmetrically substituted atom may be isolated in optically active or racemic forms. One skilled in the art is familiar with the preparation of optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting compounds. The compounds described herein may contain many olefinic, C = N double bond isomers and the like; the present invention includes all such stable isomers. The eis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as individual isomeric forms. Unless a particular stereochemistry or isomeric form is specified, the invention is intended to include all chiral, diastereomeric, racemic and all geometric isomeric forms.

As used herein, the term "substituted" means that any one or more hydrogens attached to a specified atom is replaced by any one of a set of specified groups, provided that the normal valence of the specified atom is not exceeded, and that such substitution produces a stable compound. When the substituent is a keto group (i.e. = 0), then two hydrogens are substituted at the atom. Keto substituents are absent in aromatic residues.

The present invention is understood to include all isotopes of atoms in these compounds. Isotopes include atoms having the same atomic number but different mass numbers. As a common example (without limitation) hydrogen isotopes include tritium and deuterium. Carbon isotopes include C-13 and C-14.

When a variable (e.g., R ⁶ ) occurs more than once in any component or formula of a compound, its value in each case is independent of its value in any other case.

For example, if a group is shown to be substituted with 0-2 R ⁶ , then that group may have up to 2 R ⁶ groups and R ⁶ is independently selected from the group of R ⁶ values in each case. In addition, combinations of substituents and / or variables are allowed only to give stable compounds.

If a substituent bond is shown to cross a bond connecting two ring atoms, such a substituent may be attached to any atom of the ring. If a substituent does not specify an atom through which such a substituent is attached to the remainder of a given compound of the formula, then such substituent may be attached via any atom of this substituent. Combinations of substituents and / or variables are allowed only to give stable compounds.

The term "C 1-6 alkyl" as used herein is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, -butyl, i-butyl, sec-butyl, t-butyl, pentyl and hexyl; "alkenyl" is intended to include straight or branched chain hydrocarbon chains and one or more carbon-carbon unsaturated bonds which may be present at any stable position on the chain, such as ethenyl, propenyl and the like.

As used herein, the term "Hal or" halogen means fluorine, chlorine, bromine and iodine; while "counterion" means a small, negatively charged particle, such as chloride, bromide, hydroxide, acetate, sulfate, and the like.

As used herein, the terms "carbocycle or" carbocyclic residue "are intended to mean a stable 3-7 membered monocyclic or bicyclic, 7-13 membered bicyclic or tricyclic ring, which may be saturated, partially unsaturated or aromatic.

Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0] bicyclooctane, [4.3.0] bicyclononane, [4.4.0] bicyclodecane (decalin), [2.2. 2] bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl or tetrahydronaphthalene (tetralin).

As used herein, the terms "heterocycle" or "heterocyclic residue" are intended to mean a stable 5-7 membered monocyclic or bicyclic, 7-10 membered bicyclic heterocyclic ring, which is saturated, partially unsaturated, or unsaturated (aromatic), and carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and include any bicyclic group in which any of the above heterocyclic rings are fused to a benzene ring. If necessary, the nitrogen and sulfur atoms may be oxidized. The heterocyclic ring may be attached through its linking group to any heteroatom or carbon atom which gives a stable structure. The heterocyclic rings described herein may be substituted on a carbon or nitrogen atom if the resulting compound is stable. Unless specifically stated, heterocycle nitrogen may be quaternized. Preferably, when the total number of O and S atoms in the heterocycle exceeds 1, these heteroatoms would not be adjacent to one another. Preferably the total number of O and S atoms in the heterocycle is not more than 1. The term "aromatic heterocyclic system" as used herein is intended to mean a stable 5-7 membered monocyclic or bicyclic, 7-10 membered bicyclic heterocyclic aromatic ring consisting of carbon atoms and 1-4 heteroatoms independently selected from the group consisting of N, O, and S. Preferably, the total number of O and S atoms in the aromatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzothiazolyl, carbazolyl, benzothiazolinyl, benzisoxazolyl, benzisothiazolyl, benzimidazalinyl, benzimidazolinyl, benzimidazolinyl, / 7,6 / 7-1,5,2-dithiazinyl, dihydrofuro [2,3b] -tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1/7-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3/7 indolyl, isobenzofuran , - isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, , 3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl , phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazolyl, pyridothiazolyl, -pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4/7 -quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6/7 -1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl , 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiantrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, 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, 1/7-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolyl. Also included are fused rings and spiro compounds containing the above heterocycles.

As used herein, the phrase "pharmaceutically acceptable" means such compounds, materials, compositions and / or dosage forms which are medically suitable for use in contact with human or animal tissues without causing them any particular toxicity, irritation, allergic response or other problem or complication. benefit / risk ratio.

As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the compounds of this invention wherein the parent compound is modified to form its salts with acids or bases. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of basic residues, such as amines, with mineral or organic acids: salts of acidic residues, such as carboxylic acids, with alkali metals or organic bases; and etc. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound derived from non-toxic inorganic or organic acids. For example, such common non-toxic salts include salts with inorganic acids such as hydrochloride, hydrobromide, sulfate, sulfamate, phosphate, nitrate, etc .; and salts with organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamo, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanyl, 2-acetoxybenzoic, fumar, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxal, isethion and the like. salts of acids.

The pharmaceutically acceptable salts of the present invention may be synthesized from the parent compound containing the basic or acidic moiety by conventional chemical methods. Generally, such salts may be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of a particular base or acid in water or in an organic solvent or in a mixture thereof; non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are generally preferred. List of suitable salts are found in Remington's Pharmaceutical Sciences, 17 ^th ed., Mack Publishing Company, Easton, PA, 1985, p 1418, the disclosure which is incorporated by reference.

"Prodrugs" are intended to include any covalently bonded carrier which delivers the active parent drug of formula (I) in vivo when such a prodrug is administered to a mammal. Prodrugs of the compounds of formula (I) are prepared by modifying the functional groups present in the compound such that the modified derivatives are cleaved either by conventional manipulation or in vivo into the parent compound. Prodrugs include compounds of formula (I) wherein the hydroxyl, amino, or sulfhydryl group is attached to another group so that when the prodrug of a compound of formula (I) is obtained in a mammal, it is cleaved to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amino-functional groups of compounds of formula (I), and the like.

The terms "stable compound" and "stable structure" are considered to indicate that they are sufficiently resistant and retain release from the reaction mixture to an appropriate degree of purity and can be converted into an effective therapeutic agent?

SYNTHESIS

The compounds of the present invention may be prepared using the reactions and procedures described below. The reactions are carried out in a solvent suitable for the reagents and materials employed and suitable for the desired conversion. Experts in organic synthesis will appreciate that the functional groups present in the molecule must conform to the proposed transformations. Occasionally, it will be necessary to decide upon the order of the synthesis steps, or to choose one scheme rather than another in order to obtain the desired compound of the invention. It should also be recognized that another important point in planning the synthesis pathway in this field is the appropriate choice of protecting groups used to block reactive functional groups present in the compounds of the present invention. An authoritative source describing various alternatives to an experienced practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).

Preparation of compounds of formula I which contain a five membered heterocycle structural group

The general synthesis of the compounds of formula I is shown in Schemes 1a-b. The ring M can be attached via N- or C-atoms to the ring D in the following schemes. B 'and R ^f are blocked functional groups which can be converted to j R, B and R ^{1a respectively} . It should be understood that group E or precursor group E may be blocked or unblocked depending on the chemical transformation requirements used. These compounds can also be obtained by altering the sequence of the reactions described in Scheme 1. In the case of an N-linked M ring, ring D having the corresponding amino group is exposed to the chemistry of the Heterocyclic Compounds, Weissberger, A. and Taylor, EC Ed., John Wiley &amp; Sons, or under the conditions described below in the synthesis section. - atom attached M ring. Further modifications and deprotection yields an N-attached ring M substituted with R, ZAB and R ^1a .

a scheme

Heterocycle M is attached via nitrogen

To obtain the C-linked pentan ring m, the above aniline is diazotized with nitric acid and treated with NaBr to form the heterocyclic bromide. Treatment with n-BuLi followed by DMF gives the aldehyde which can be converted to the M ring as described in The Chemistry of Heterocyclic Compounds, by Weissberger, A. and Taylor, EC Ed., John Wiley & Sons or as described below in the synthesis. section. Other functional groups precursors such as acid, cyanide, methyl ketone, etc. may be used to form the M ring. Further modifications and deprotections may yield a five membered M ring substituted with R, ZAB and R ^1a . The corresponding C-linked six-membered M ring can be obtained by converting the bromide described above with n-butyllithium and triisopropylborate to a heterocyclic boronic acid. Suzuki copulation with the corresponding heterocyclic bromide followed by modifications and deprotections yields a six membered M ring with R, ZAB and R ^1a substituents.

Scheme 1b

Heterocycle M is connected

1. n-BuLi

2. DMF (CO ₂ H, CN, COCH 3)

V / ^ch °

D I

are made according to the methodologies shown in Scheme 2. The corresponding D-ring bromide can be converted to the beta-ketoester in several ways. One of the most suitable methods is transmetalation with an alkylate reagent followed by cleavage

DMF to afford the corresponding aldehyde. Addition of ethyldiazzoacetate in the presence of tin (II) chloride yields the beta-keto ester directly. Other methods are available to realize this transformation; one of them is the Reformatsky reaction of the aldehyde followed by oxidation to the beta-ketoester.

scheme

(Z = COCH ₂ ) (Z = CONH)

Another suitable method for converting the bromide to the beta-keto ester is palladium-catalyzed copulation with (ethoxyvinyl) tributyl tin followed by acid hydrolysis to give the corresponding acetyl derivative. There are many ways to convert this acetyl derivative into its beta-keto ester; one of the most suitable is the action of the acetyl derivative with a dialkyl carbonate in the presence of a base such as sodium hydride or lithium diisopropylamide. This beta-ketoester can be converted to the corresponding thiazole derivatives by bromination with NBS followed by cyclization with the corresponding thiourea or thioamide in a solvent such as ethanol or tetrahydrofuran. A one-step process for realizing this conversion involves the interaction of betaceto ester with hydroxytytosyloxyiodobenzene in acetonitrile to form an alpha-tosyl-beta-ketoester intermediate followed by addition of thiourea or thioamide to cyclize to the corresponding thiazole. Thereafter, the reaction of the ester group of these thiazoles with various reagents may yield compounds having the corresponding ZAB group. When Z = CONH, standard peptide coupling with the appropriate amine, such as the reaction of the ester with an amine-derived aluminum reagent, can be used. When Z = COCH ₂ , the corresponding zinc reagent can then be coupled with standard acid anhydride. Reactions can also be made with the R ^1a group on the thiazole ring and various other groups can be obtained. For example, when thiourea is used as a cyclization partner, 2-aminothiazole is obtained. This amino group can be readily diazotized and substituted with the corresponding copper halide to give the 2-halo-thiazoles. This halogen atom can then be readily substituted with various carbon, nitrogen, oxygen and sulfur containing nucleophiles to form a variety of R ^1a alkyl, aryl, heteroatom and heterocycle derivatives.

The tetrazoles of the present invention wherein Z is -CONH- may be prepared as shown in Scheme 3. The correspondingly substituted amine (ED-NH ₂ ) is acylated with ethyl oxalyl chloride. The resulting amide can be converted into tetrazole or by methods described by Duncia (J. Org. Chem. 1991, 2395-2400) or Thomas (Synthesis 1993, 767-768). The amide can first be converted to the iminoyl chloride and treated with NaN ₃ to form 5-carboethoxytetrazole (J. Org. Chem. 1993, 58, 32-35 and Bioorgan. &Amp; Med.

Chem. Lett. 1996, 6, 1015-1020). The 5-carboethoxytetrazole is then coupled with the corresponding amine (BANH ₂ ) according to Weinreb (Tetr. Lett. 1977,

48, 4171-4174). The final unblocking as described above yields the desired product.

The tetrazole compounds of the present invention wherein Z is -CO- may be prepared via iminoyl chloride (Chem. Ber. 1961, 94, 1116 and J. Org.

Chem. 1976, 41, 1073) using the correspondingly modified acyl chloride as starting material. The ketone moiety may be reduced to compounds wherein Z is alkyl.

scheme

be fabricated as shown in Scheme 4. The appropriately substituted thioisocyanate is treated with sodium azide to give 5-thiotetrazole (J. Org. Chem. 1967, 32, 3580-3592). This thio compound can be alkylated (J. Org. Chem. 1978, 43, 1197-1200), then oxidized to the sulfoxide or sulfone. This thio compound can also be converted to the sulfonyl chloride and treated with an amine to give the desired sulfonamide. The tetrazoles of the present invention wherein A is -O- can be prepared according to the same method described in Scheme 4 using the correspondingly modified isocyanate as starting material.

scheme

NCS Naisis to. _E CHCJj / HO

d-e

NHj-AB

N-N n y Νχ 'N

D.

s ^z o ₂

H

N - AB

The tetrazoles 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 shown in Scheme 4. The thio compound prepared according to Scheme 4 is alkylated with 2-chloroacetamide. The resulting compound is then refluxed 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

NN // \\ N _x

N I

D-E

O

NH,

NaOH / EtOH

N-N U \\

N

I

D-E 'NH,

The N-linked imidazole M ring can be synthesized according to the route shown in Scheme 6. Alkylation of ED-NH ₂ with 2-bromoethyl acetate followed by reaction with a Gold reagent in the presence of a base such as NaOMe or LDA gives the imidazole M-ring.

scheme

Br.

O OEt cr OEt

OEt

The general procedure for obtaining the C-linked imidazole M ring is described in Scheme 7. The aldehyde ED-CHO from Scheme 1 can be converted to the cyano compound by treatment with hydroxylamine followed by dehydration with POCl ₃ . The cyano compound can be obtained by the Pinner reaction which can be cyclized with an alpha-haloester, ketone or aldehyde to give the imidazole M-ring. The alkylation or acylation further modifies the imidazole ring M as described in Scheme 1.

scheme

As shown in Scheme 8, the pyrazole M-ring of compounds of general formula I such as those depicted in Scheme 1 may be obtained by condensation of the appropriately substituted hydrazine with various diketoesters. This type of condensation usually yields a mixture of pyrrole regioisomers which can be efficiently separated by chromatography on a silica gel column. Hydrolysis of the esters followed by copulation with the corresponding amine can give the desired intermediate amide. Subsequently, various benzo, heterocyclic and bicyclic compounds can be obtained by various substitutions at various N-positions of the pyrazole.

scheme ^R1a rr

CO.Et

NHNH, I ²

E-D

Applying the methodology described above to diketodar derivatives also results in a mixture of pyrazole regioisomers. They can also be subjected to various reactions to provide compounds of formula I as shown in Scheme 9.

scheme

OMe O

NHNH, I ²

E-D

R ^1a = amino, alkyl or aryl

Column chromatography, oxidation, esterification

As in Scheme 8

When ketoididates are used for condensation with hydrazines, the corresponding regioaducts of the pyrazole amino esters are obtained (Scheme 9). These intermediates can then be converted to the final compounds of Formula I by blocking a functional amino group with a suitable protecting group known to those skilled in the art or by preparing a derivative (e.g., sulfonamide as shown in Scheme 10) followed by preparing the compounds of this invention.

scheme

EtO ₂ C

H „N

N

D-E

N

D-E

CO ₂ Et Pyridine

EtO ₂ C

Me, SO, CI Ji \\ —-— N. 'N

D-E

MeCkSHN

NHSO ₂ Me or v

/ Γγ ^N x _M / ^ CO ₇ Et N ²

D-E as in Scheme 8

BAHNOC

MeO, SHN

H

N

D-E

... NHSO, Me N ² or

N D-E

CONHAB

The intermediate pyrazole ester can be further reacted to produce ketones according to Knochel et al. See the Croats methodology (Scheme 11). Alternatively, the ester may be reduced to either the alcohol or aldehyde in a manner known to those skilled in the art, followed by either reductive amination with the corresponding amine to alkylamine, or the alcohol group converted to a leaving group which in turn may be substituted with various nucleophiles. from which appropriate compounds of the present invention can be obtained.

scheme hydrogenation followed by chloro-anhydride, / OV-C00Et P ° ^t0 Br _E .x -

AB eE ⁿ

Zn, CuCN, THF [H]

ίΓ.V-ChįNHAB, CH, SAB or ChįSO ^ B

Thio compounds such as those described in Scheme 12 can be readily prepared by converting 5-hydroxypyrazole into its thiol by the action of Lawesson's reagent in boiling toluene.

scheme

R ^1a

l

D-E

S'-AB II

O

Compounds of the present invention wherein the pyrazole ring M is substituted with 1,2,3 triazole may be prepared as shown in Scheme 13.

N,

D-E

R

D-E

ED

N //

Scheme N _R 1a Ethyl Acetoacetate Heat

D-E

R ^1a = CH 3 KMnO 4 R ^1a = CH (OMe) 2 hydr.

followed by Ag ₂ O

N //

N _x

N

I

D-E

ED

CO ₂ Et

N— / \\

CO ₂ Et

COOH i ·

Ό · J

O

D-E

l.copulation, BANH ₂

2. HCl / MeOH

3. (NH ₄ ) ₂ CO ₃ MeOH

D-E

ED

N //

Νχ,

N i

D-E

1. copulation, BANH ₂

2. HCl / MeOH

3. (NH ₄ ) ₂ CO ₃ MeOH

COOH

Vnhab

N- /

N— / n \\ ^N \. ./CONHAB

N

I

D-E

N

I

D-E

CONHAB 'T r n

N I

D-E

N i

D-E

CONHAB

The compounds of the present invention wherein the ring M is 1,2,4-triazole can be readily obtained according to Huisgen et al. (Liebigs Ann. Chem. 1962, 653, 105) using the nitroprim (obtained by the action of triethylamine and chlorhydrazone) cycloprevention on the corresponding nitrile dipolar aryl as shown in Scheme 14.

scheme

l

D-E

HZCN

ZH

This methodology provides a wide variety of 1,2,4-triazoles with a variety of substituents at the 1,3 and 5 positions. Alternatively, 1,2,4-triazoles may be prepared according to Zechi et al. (Synthesis 1986, 9, 771) via Wittig azacondensation (Scheme 15).

Scheme (Ph) ₃ P;

E-D '

N

I.NH

CO ₂ Me

Here's the aril

Alternatively, 1,2,4-triazoles may also be prepared according to the procedure of Sauer et al (Tetr. Lett. 1968, 325) using the reaction of cyclic carbonate with the corresponding nitrile (Scheme 16).

scheme _R 1a _R ia

DE hv, EtOAc + R ^1b CN R ¹⁰ = ester, alkyl, aryl R ^1a = phenyl or ester

I

D-E

Esters of the compounds of the present invention can be converted into the intermediate amides using the method of Weinreb (Tetr. Lett. 1977, 48, 4171), i.e. ester condensation of the corresponding aluminum-amino complex (Scheme 17).

scheme

VN N ^N ^ N ^ CO2Et * ^Ν ^ ν / ΌΟΝΗΑΒ i I

D-E D-E

The isoxazoline M ring of the compounds of the general formula I, substituted at the 4 and 5 positions, can be prepared according to the procedure for 1,3-dipolar cycloprisjungin shown in Scheme 18. The corresponding benzhydroxyiminol chloride, heterocyclic oximinoyl chloride, or oxime in the 1,3-dipolar cycloprotein coupling reaction with an appropriately 1,2-disubstituted olefin as a dipolar aryl should yield a mixture of regioisomers. Separation of the regioisomers by column chromatography followed by the reaction sequence described above should yield the desired compound. Optically active isoxazolines may also be obtained by enzymatic resolution of the regioisomeric esters or by the use of an appropriate chiral auxiliary to dipolar aryl as described by Olsson et al. Ø. Org. Chem. 1988, 53, 2468).

scheme

bk

OH R 1a X = H, Cl

In the case of the compounds of the general formula I in which Z is an amide, a correspondingly substituted crotonic acid ester is used as a substrate in the cyclic coupling process described in Scheme 18. Crotonic acid esters can be obtained from commercial sources or from ethyl 4-bromocrotonate using the nucleophilic displacement reaction shown in Scheme 19.

scheme

Br ^C0 2 ^R MeOH, Cac .CO ₂ R or tetrazole, triazole, imidazole I, NaH / THF J '

-> R ^a

The substituted olefins as dipolar aryls can be obtained from ethyl propiolate using hump chemistry (Scheme 20) according to Deslongchamps et al. (Synlett 1994, 660).

scheme

R ^1a R

CO ₂ Et

R ₁ Me ₂ Cu, RX

CO ₂ Et

Compounds of the present invention wherein the ring M is 1,3,4-triazole can be readily obtained according to Moderhack et al. (J. Prakt. Chem. 1996, 338, 169) as shown in Scheme 21.

scheme

H ₂ N-NH 4 /

T

O

S ^ _N ^ CH (OEt) ₂

I

D-E | ABBr, NaH

NN {/ K \ _N ^ CH (OEt) ₂

D-E

BA.

Hydr.

NBS followed by alcohol

NN < ^v

Weinreb's method N N

N 'CO ₂ Et

D-E to [H]

D-E

O

N-N

N —AB

BA.

N-N 7th ^ CH (OEt) ₂ I D-E Hydr. oxidac. decarboxyl. _f as in Scheme 1 N-N y / W Y I D-E

D-E

AB X ⁼ absent ^or ba H, alkyl heteroatom

This reaction involves the condensation of a carbazide with an appropriately substituted commercial thioisocyanate to form a cyclic thiourea derivative as described previously. The alkylation or nucleophilic displacement reactions carried out with this intermediate thionium then give thioalkyl or aryl derivatives which can be hydrolyzed, oxidized and decarboxylated to form an intermediate 5-H-2-thio-triazole which can be easily converted the compounds of the present invention. Alternatively, the thiono-urea intermediate may be directly oxidized to the 2-H-triazole, which may then be converted to the ester, and then subjected to the numerous reactions described above to give the compounds of the present invention. Esters can also be converted into amines via Hofmann rearrangement, and various analogs similar to those shown above are obtained by this procedure. The intermediate cyclic thiono-urea can also be oxidized to the sulfonyl chloride as described in the previous examples. This in turn can give the sulfamides shown in Scheme 22.

scheme

H

N-N

S ^ _N ^ CH (OEt) ₂

I

D-E j as 21 in scheme N-N

O

N

I

D-E

I I

N-N

V

CL ,, AcOH

CO ₂ Et

N-N

O

N

I

DE 'N'' ^NH 2

'NHCOAB or NHSCAB

D-E

N-N <K nhch ^ b

Scheme D-E describes the general synthesis of pyrazoles, which are thio- and oxidized sulfur derivatives. The appropriately substituted amine is alkylated with ethyl bromoacetate and hydrolyzed to the glycine derivative. Sodium nitrite makes it easy to produce the N-nitroso compound (J. Chem. Soc. 1935, 899). Acetic anhydride is cyclized to the syndrome (J. Chem. Soc. 1935, 899), followed by introduction of the sulfide group using sulfoxide as solvent and acetyl chloride as activating reagent (Tetr. 1974, 30, 409). The photolytic cleavage of the synon in the presence of an acetylene compound yields 1,3,5-tri-substituted pyrazole as the major regioisomer (Chem. Ber. 1979, 112, 1206). These compounds can be processed by the methods described below to give the final compounds having sulfide, sulfoxide or sulfone functional groups.

scheme

the scheme shows one possible pathway for the synthesis of isoxazoles. The substituted benzaldehydes are treated with hydroxylamine, then chlorinated to give the hydroxyminoyl chloride according to the procedure described (J. Org. Chem. 1980, 45, 3916). Preparation of the nitrile oxide in situ with triethylamine and cyclization to the substituted alkyne yields a mixture of regiomeric isoxazoles as described by H. Kawakami (Chem. Lett. 1987, 1, 85). Disubstituted alkyne is prepared using an alkynyl anion nucleophilic attack on an electrophile as shown by Jungheim et al. (J. Org. Chem. 1987, 57, 4007).

Alternatively, hydroxyminoyl chloride with a group R ^1a can be prepared and reacted with an appropriately substituted alkyne to yield another set of regioisomeric isoxazoles which can be separated by chromatography.

E _x / CHO D

CHO _R 1a

1) ΝΗ, ΟΗ _

2) NCS Cat. HCl

1) NhOH

2) NCS Cat. HCl

where V = NCis, SO ₂ NR ₂ or CO ₂ Me, a synthetic precursor for -ZAB

Another procedure which yields only one regioisomer is described in Scheme 25. The methylated form of group V can be deprotonated and silylated. Chlorination with carbon tetrachloride or fluorination with difluorodibromomethane catalyzed by triethylborane as shown by Sugimotto (Chem. Lett. 1991, 1319) gives the geminal dihalo compound. Couplet-mediated conjugate coupling-cleavage as shown by Harding (J. Org. Chem. 1978, 43, 3874) yields the desired alkene.

Alternatively, it may be acylated with an acid chloro anhydride to give a ketone, as in Andrews (Tetr. Lett. 1991, 7731), followed by diazomethane to give the enol ether. As shown by Stevens (Tetr. Lett. 1984, 4587), each of these compounds can react with hydroxyminoyl chloride in the presence of triethylamine to give one regioisomer of isoxazole.

scheme

1) LDA ^X \ ^ ^Y

2) TBDMSCI U

3) CCI ₄ or CF ₂ Br ₂

BEU V

1) LDA MeO ^ / R ¹³

2) FUCOC1 j

3) CH ₂ N ₂ k _v (R% £ uLi

X = Cl or F

where Y = OMe, Cl or F

V = NCi, SO ₂ NR ₂ or CO ₂ Me, synthetic precursor for -ZAB

When the backbone substituent R ^1a is CH ₂ -Q, the synthesis is shown in Scheme 26. The initial ketone is treated with PhSSO ₂ Ph in the presence of an LDA to give a phenylthiolated compound which, in the presence of hydrazine, produces a pyrazole derivative. This pyrazole ester reacts with an amine or aniline (previously exposed to AIMe ₃ ) to give the amide. Oxidation of this sulfide to mCPBA yields the corresponding sulfone. Deprotonation of the sulfone with base, followed by electrophilic capture (QX) and exposure to Sml ₂ after deprotection affords the desired compound.

scheme

NH. I '

the scheme shows other methods for the synthesis of R ^1a = CH ₂ Q or C0Q. The blocking of the hydroxyl group of the hydroxyacetone with benzyl halide and the action on base and CO (CO ₂ Et) ₂ yields the tricarbonyl compound. Boiling with NH ₂ OMe HCl in pyridine and ethanol with the addition of 3A molecular mesh yields oxime. cyclisation of the acne with ED-NHNH ₂ yields a pyrazole which can be converted to the corresponding amide by reaction with an amine or aniline (previously activated in AIMe ₃ ). Debenzylation by catalytic hydrogenation yields alcohol. Using TsCl, the alcohol is converted to the tosylate and then replaced 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.

HO

NaOMe

O OEt

ED-NHNH, V HOAc

The scheme for the preparation of compounds of formula I having a six-membered heterocycle structure describes the synthesis of compounds wherein M is a benzene ring and V is a nitro group, a protected sulfonamide or ester group and a precursor of the Z group of compounds of formula I. Group V is introduced into the appropriately substituted phenol or by nitration as shown by Poirier et al. (Tetrahedron 1989, 45 (5), 1415), by sulfonylation as shown by Kuznetsov (Akad. Nauk SSSR Ser. Khim. 1990, 8, 1888) or by carboxylation according to Sartori et al. (Synthesis 1988, 10, 763). Bromination with triphenylphosphine and bromine (J. Am. Chem. Soc.T964, 86, 964) gives the desired bromide. Suzuki copulation with the corresponding boronic acid yields the desired substituted pyridine.

scheme

HO Br V

EDB (OH) _; (Ph ₃ P) ₄ Pd

Na ₂ CO ₃

Schemes 29-32 describe the synthesis of compounds wherein M is pyridine. Each scheme depicts a different arrangement of substituents on the pyridine ring. In Scheme 29, the appropriately blocked aldehyde is treated with an activated ester in a base-catalyzed condensation reaction to yield the desired aldehyde after deprotection. As shown by Dorow and Ische (Chem. Ber. 1956, 89, 876), ammonium chloride treatment yields pyridinol which is brominated in POBr ₃ (Tjeenk et al. Rec. Trav. Chim. 1948, 67, 380) to give the desired 2-. bromopyridine. Suzuki copulation with the corresponding boronic acid yields the desired substituted pyridine.

scheme

Treatment of the appropriately substituted 5-ethoxyoxazole with alkene as shown by Kondrat'eva et al. (Doc. Acad. Nauk SSSR 1965, 164, 816) gives a pyridine with a V substituent at the para-position. Bromination to the 3-position according to van der Does and Hertog (Rec. Trav. Khim. Pays-Bas 1965, 84, 951) followed by palladium-catalyzed copulation with boric acid gives the desired substituted pyridine.

scheme

Scheme 2 describes the synthesis of pyridine compounds of the third substitution type. The corresponding tricarbonyl compound, which may be prepared by the methods described in Scheme 29, is treated with ammonium chloride to give pyridinol, which is then brominated. Palladium catalyzed copulation yields the desired substituted pyridine.

scheme

Scheme I deploys a appropriately substituted dicarbonyl compound and is treated with ammonium chloride according to the reactions shown in Schemes 29 and 31. Bromination gives 3-bromopyridine which, after palladium-catalyzed copulation, gives the desired substituted pyridine.

scheme

V> R ^1b \\ // ^N

EDB (OH), ^R (Ph ₃ P) ₄ Pd Ά 7 /

Na ₂ CO ₃ / \

V

Schemes 33-35 describe the synthesis of compounds wherein M is pyridazine. Each scheme depicts a different arrangement of substituents on the pyridine ring. In Scheme 33, the activated ester is treated with substituted α-ketoaldehyde and hydrazine, respectively, according to Schmidt and Druey (Helv. Chim. Act 1954, 37, 134, and 1467). Pyridazinone is converted to the bromide using POBr ₃ , and palladium-catalyzed copulation yields the desired substituted pyridazine.

scheme

EtO ₂ C— \ V

R ^1b

EDB (OH ^ <Ph ₃ P) ₄ Pd

Well, C0 ₃

E-

D V

In Scheme ^1b , glyoxal can react with the activated ketone under basic conditions to give the desired ketoaldehyde after bromination / dehydrobromination. Alternatively, the blocked ketone may react with the activated aldehyde to be deprotected and oxidized after bromination / dehydrobromination to give the regioisomeric ketoaldehyde. Cyclization according to Sprio and Madonia (Ann. Chim. 1958, 48, 1316) with hydrazine followed by palladium-catalyzed copulation yields the desired substituted pyridazine.

scheme

In analogy to Scheme 34, in Scheme 35, the aldehyde may be treated with an activated ketone, brominated, dehydrobrominated and deprotected to give the desired diketone. Alternatively, the regioisomeric ketone may be subjected to the same reaction sequence to yield the isomeric ketoaldehyde. Reaction with hydrazine followed by palladium-catalyzed copulation yields the desired substituted pyridazine.

scheme

O

R ¹ M ^ -0

CHO

Schemes ΝΗ, ΝΗ ^ and 37 describe the synthesis of compounds wherein M is pyrimidine. Each scheme depicts a different arrangement of substituents on the pyrimidine ring. In Scheme 36, condensation with the appropriately substituted acid anhydride and the activated ester followed by reduction of the conjugate 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 gives the desired regioisomeric pyrimidine. Palladium catalyzed copulation yields the desired substituted pyrimidine.

scheme

EDB (OH) ^ (Ph ₃ P) ₄ Pd

Well, CO,

Ε _R 1b

R ^1b <= N λ

Using similar chemical transformations, Scheme 37 illustrates how an amidine can be condensed with a 1,3-dicarbonyl compound and then brominated at position 5 (J. Het. Chem. 1973, 10, 153) to give a specific regioisomeric bromopyridine. Palladium catalyzed copulation yields the desired substituted pyrimidine.

scheme .0

R ^1b -O 1) formamidine '-2) Br,

V _R ib or

OHC O

M ¹ ) Λ — NH, hn ^Z '/' Br /

/ Br V

E-D-B (OH).

(Ph ₃ P) ₄ Pd

Na ₂ CO ₃

N:

_E H ^E D v

2) Br ₂

Using the same ketoaldehyde from Scheme 37, cyclization with the appropriately substituted 1,2-diamine (Chimia 1967, 21, 510) followed by aromatization (Helv. Chim. Act 1967, 50, 1734) yields a mixture of pyrazine regioisomers as shown in Scheme 38. Bromination of the hydrobromide salt (U.S. Patent No. 2,403,740) provides the intermediate for the palladium-catalyzed copulation step which proceeds as shown above.

scheme _R 1b

OHC O

M v

h ₂ n nh ₂

2) CuO.Cr ₂ O ₃

3) HBr / Br ₂

EDB (OH) ^ / ^ ^R1b (Ph ₃ P) ₄ Pd ^N y \ /, ^N

Schemes for Na ₂ CO _{3 t} ^e ^ D and 40 describe the synthesis of compounds wherein M is 1,2,3-triazine. In Scheme 39, palladium-catalyzed vinyl bromide is coupled with a R ^1b substituent. Allyl bromination followed by substitution with azide provides a precursor to cyclization. The cyclization mediated by triphenylphosphine (J. Org. Chem. 1990, 55, 4724) yields 1-aminopyrazole which is then brominated with N-bromosuccinimide. The rearrangement mediated by lead acetate as shown by Neunhoeffer et al. (Ann. 1985, 1732) gives the desired regiometric 1,2,3-triazine. Palladium catalyzed copulation yields a substituted triazine.

scheme

Br

1) R ¹ ° CH ₂ Br _N Pd (0)

.N.

R ^{1 b Ph} 3 ^P - ^H 2 ^N N ^X ' ^{R1 b}

2) NBS V 3) NaN,

V _R 1b

EDB (OH) _; (Ph ₃ P) ₄ Pd

Well, CO ₃

N = N

V

1b λ // ^R v

in the scheme, the alkene is allylated by bromination and this bromide is replaced to give the azide regioisomer of scheme 39. Following the reaction sequence shown above, cyclization yields 1-aminopyrazole. Bromination followed by lead acetate-mediated rearrangement yields 1,2,3-triazine. Palladium-catalyzed copulation yields another desired triazine.

scheme

and Schemes 42 describe the synthesis of compounds wherein M is 1,2,4-triazine. In Scheme 41, using hydrazine, the nitrile is converted to amidrazone, which is then condensed with the α-ketoester to give the triazinone, as shown by Paudler and Lee (J. Org. Chem. 1971, 36, 3921). Bromination according to Rykovsky and van der Plas (J. Org. Chem. 1987, 52, 71) followed by palladium-catalyzed copulation yields the desired 1,2,4-triazine.

scheme

R ^1b CN

NHjNhis

Rib 1) EtO ₂ C \ .. V h ₂ n = N

NH.

2) POBr ₃ R ^1b

R ^1b

Br V

EDB (OH), (Ph ₃ P) ₄ Pd

Na.CO ₃ = N " ^N x, N _E M ^e dv, the above reaction scheme is modified by substitution of the blocked α-ketoester to give the opposite regioisomer. This allows the most nucleophilic nitrogen to attack the ester functional group in the opposite direction of regiochemical conversion. Deprotection and thermal cyclization yields the triazinone, which is brominated as shown above. Palladium-catalyzed copulation yields another desired 1,2,4-triazine.

N = Schematic

R1b

R ^1t

R ^1b CN

NhisNHis

H ₂ N

N

EtO ₂ C

2) Vand. HCl

NH

3) Δ

Br

V.

Scheme 2 describes the synthesis of compounds wherein M is 1,2,3,4-tetrazine. Addition of lithium to vinyl bromide, transmetallation with tin, palladium-catalyzed carbonylation, and hydrazone formation give the day a further Diels-Alder reaction according to Carboni and Lindsey (J. Am. Chem. Soc. 1959, 81, 4342). Reaction with dibenzyl azodicarboxylate followed by catalytic hydrogenation to debenzylate and decarboxylate after bromination should yield the desired

1,2,3,4-tetrazine. Palladium-catalyzed copulation gives the desired substitution pattern.

scheme

3) Pd (0), CO

4) BnNHNH,

1) nBuLi

N = N f \

N N

M

Br v

BnN \\ < 1) i N BnO ₂ C— * = K 2) H ₂ , Pd v 3) the NAF E-D-B (OH), N = N / \ N _v N H (Ph ₃ P) ₄ Pd 'Na ₂ CO ₃

CO ₇ Bn \ ² , NN

Ό

V

Preparation of compounds of formula I having a bicyclic structure and Schemes 45 illustrates the preparation of benzopyrrole and indole backbone intermediates suitable for the synthesis of compounds of formula I. The starting pyrazole N-oxide of Scheme 44 can be obtained according to Chem. Ber. (1926) 35-359. This pyrazole N-oxide can be reduced by any of a variety of methods, including triphenylphosphine in boiling toluene, followed by hydrolysis of the nitrile to the base with a carboxylic acid to give an intermediate benzopyrazole which can be copolished in a conventional manner to give a compound of formula I.

scheme

in the scheme, the starting indole can be obtained by Fisher indole synthesis (Org. Syn. Col. Vol. III 725) from phenylhydrazine and acetophenone, respectively. Work up using standard synthetic methods including the introduction of the 3-formyl group with POCl _{3 in} DMF, blocking the NH group of the indole with SEM (TMSCH2CH2OCH2Cl, NaH, DMF) and aldehyde oxidation to the carboxylic acid which is now ready for transformation into compounds of formula I.

scheme

Preparation of Group A-B of Formula I

Compounds of the present invention wherein B is a carbocyclic or heterocyclic moiety of Formula I or _K are copolymerized with A as shown generally and specifically in Schemes 46 and 47, respectively. One of them, either A or B, may be substituted with 0-2 R ⁴ . W represents a properly protected nitrogen such as NO ₂ or NHBOC; blocked sulfur such as S-tBu or SMOM; or methyl esters. The halogen-metal exchange in the bromo-B compound by the substitution of bromine with n-butyl lithium, cleavage with triisopropylborate and acid hydrolysis yields the required boronic acid BB (OH) ₂ . The WA-Br subunit may already be attached to the M ring before the Suzuki copulation reaction. Unblocking results in a complete subunit.

scheme

B-Br

1) n-BuLi

2) (iPrO) ₃ B

3) HCl

BB (OH) ₂

Pd (0)

W-A-B

Scheme Br describes a typical example of how a subunit A-B for attachment to an M ring can be made. 4-Bromanyline can be blocked by converting it to a Boc derivative and copolished with 2- (t-butylamino) sulfonylphenylboronic acid under Suzuki conditions. 2- (t-Butylamino) sulfonylphenylboronic acid is prepared according to the method described by River (Bioorg. Med. Chem. Lett. 1994, 189). Blocking with TFA can yield the aminobiphen-4-yl compound. This aminobiphen-4-yl can then be copolished with the framework ring structures as described below.

scheme

When B is described as Χ-Y, the following description applies. Groups A and B are either commercially available, known in the literature, or readily synthesized using standard techniques known to those skilled in the art of organic synthesis. The required reactive groups attached to analogs A and B are also either commercially available, known in the literature, or readily synthesized using standard techniques known to those skilled in the art of organic synthesis. The following tables show the chemical transformations required to connect A to B.

Table A: Preparation of the amide, ester, urea, sulfonamide and sulfamide linkages between A and B

if A has; ' this reactive Y substitution is: the following product Α-Χ-Υ is obtained: A-NHR ² as a substituent CIC (O) -Y A-NR ² -C (O) -Y secondary NH as part of a ring or chain CIC (O) -Y A-C (O) -Y A-OH as a substitute CIC (O) -Y A-O-C (O) -Y A-NHR ² as a substituent CIC (O) -CR ² R ^2a -Y A-NR ² -C (O) -CR ² R ^2a -Y secondary NH as part of a ring or chain CIC (O) -CR ² R ^2a -Y AC (O) -CR ² R ^2a -Y A-OH as a substitute CIC (O) -CR ² R ^2a -Y AOC (O) -CR ² R ^2a -Y A-NHR ² as a substituent CIC (O) -CNR ² -Y A-NR ² -C (O) CNR ² -Y secondary NH as part of a ring or chain CIC (O) -CNR ² -Y AC (O) -CNR ² -Y A-OH as a substitute CIC (O) -CNR ² -Y AOC (O) -CNR ² -Y A-NHR ² as a substituent CISO ₂ -Y a-nr ² -so ₂ -y secondary NH as part of a ring or chain CISO ₂ -Y a-so ₂ -y A-NHR ² as a substituent CISO ₂ -CR ² R ^2a -Y A-NR ² -SO ₂ -CR ² R ^2a -Y secondary NH as part of a ring or chain CISO ₂ -CR ² R ^2a -Y A-SO ₂ -CR ² R ^2a -Y A-NHR ² as a substituent CISO ₂ -NR ² -Y A-NR ² -SO ₂ -NR ² -Y secondary NH as part of a ring or chain ciso ₂ -nr ² -y a-so ₂ -nr ² -y A-C (O) Cl HO-Y as a replacement A-C (O) -O-Y A-C (O) Cl NHR ² -Y as a substitute AC (O) -NR ² -Y A-C (O) Cl secondary NH as part of the ring or chain A-C (O) -Y A-CR ² R ^2a C (O) CI HO-Y as a replacement A-CR ² R ^2a C (O) -OY A-CR ² R ^2a C (O) CI NHR ² -Y as a substitute A-CR ² R ^2a C (O) -NR ² -Y A-CR ² R ^2a C (O) CI secondary NH as part of the ring or chain A-CR ² R ^2a C (O) -Y v A-SO ₂ CI NHR ² -Y as a substitute a-so ₂ -nr ² -y A-SO 2 Cl secondary NH as ring A-SO2-Y

or part of a chain A-CR ² R ^2a SO ₂ CI NHR ² -Y as a substitute A-CR ² R ^2a SO ₂ -NR ² -Y A-CR ² R ^2a SO ₂ CI secondary NH as part of the ring or chain A-CR ² R ^2a SO ₂ -Y

The chemical transformations shown in Table A may be carried out in aprotic solvents such as chlorocarbons, pyridine, benzene or toluene from -20 ° C to the boiling point of the solvent, with or without the addition of a trialkylamine base,

Table B: Obtaining a ketone link between A and B

if A has: this reactive Y substitution is: the following product Α-Χ-Υ is obtained: A-C (O) Cl BrMg-Y A-C (O) -Y A-CR ² R ^2a C (O) CI BrMg-Y A-CR ² R ^2a C (O) -Y A-C (O) Cl BrMg-CR ² R ^2a -Y AC (O) -CR ² R ^2a -Y A-CR ² R ^2a C (O) Ci BrMg-CR ² R ^2a -Y A-CR ² R ^2a C (O) CR ² R ^2a -Y

The chemical transformations shown in Table B can be performed in various ways. The Grignard reagent required for Y is prepared from the halogen analog of Y in dry ether, dimethoxyethane or tetrahydrofuran from 0 ° C to the boiling point of the solvent. This Grignard reagent can be directly applied under very controlled conditions, i.e., at low temperatures (-20 ° C or below) and in large amounts of chloro-anhydride, or catalytic or stoichiometric amounts of the copper bromododimethylsulfide complex in dimethyl sulfide, or variants thereof. Other available techniques include the conversion of Grignard reagent to cadmium reagent and copulation according to the procedure of Carson and Prout (Org. Syn. Col. Vo! 3601, 1955), or copolymerization with Fe (acac) ₃ according to Fiandanese et al. (Tetr. Lett. 4805, 1984), or copolymerized by manganese (II) catalysis (Cahiez and Laboue, Tetr. Lett. 33 (31), 4437, 1992).

Table C: Preparation of etheric and thioetheric linkages between A and B

if A has: this reactive Y substitution is: the following product Α-Χ-Υ is obtained: A-OH Br-Y A-O-Y A-CR ² R ^2a -OH Br-Y A-CR ² R ^2a OY A-OH Br-CR 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 ^2a SY A-SH Br-CR ² R ^2a -Y A-SCR ² R ^2a -Y

The ether and thioether bond shown in Table C can be prepared by reacting both components in a polar aprotic solvent such as acetone, dimethylformamide or dimethylsulfoxide in a base such as potassium carbonate, sodium hydride or potassium t-butoxide, from room temperature to the boiling point of the solvent used.

Table D: Obtaining -SO- and -SO ₂ - Connections from Table C Thioethers

provided that the starting material is: it is oxidized with moist alumina / oxone to give: it is oxidized with michloroperbenzoic acid to give: A-S-Y A-S (O) -Y A-SOs-Y A-CR ² R ^2a SY A-CR ^ž R ^2a S (O) -Y A-CR ² R ^2a SO ₂ -Y A-SCR ² R ^2a -Y AS (O) CR ² R ^2a -Y A-SO ₂ CR ² R ^2a -Y

The thioethers of Table C are a convenient starting material for the preparation of the sulfoxide and sulfonic analogs of Table D. The combination of wet alumina and oxone can provide reliable reagents for thioether oxidation to sulfoxide, as demonstrated by Greenhalgh (Syn. Lett., 235,1992). The sultan can be prepared according to Satoh (Chem. Lett., 381, 1992) using m-chloroperbenzoic acid.

Other features of the present invention will become apparent from the following description of exemplary embodiments, which are given by way of illustration and are not intended to limit the scope thereof.

EXAMPLES

The following abbreviations are used in the examples: "° C - Celsius," d "- doublet," dd "- double doublet," eq. - equivalent or equivalents, "ESMS" means electron flux mass spectroscopy, "H" hydrogen or hydrogen, "val.", hour or hours, "g", gram or grams, "m", multiplet, "M", molarity, Mg / milligram or milligrams, MHz to megahertz, min to min or minutes, ml to 62 milliliters or milliliters, MS to mass spectroscopy, NMR to nuclear magnetic resonance spectroscopy, t-triplet , "TLC - thin layer chromatography," BOP "- benzotriazol-1-yloxitrile (dimethylamino) phosphonium hexafluorophosphate," DMAP "- dimethylaminopyridine," DME dimethoxyethane, "EDAC - 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride," "- lithium aluminum hydride," NBS "- N-bromosuccinimide," PyBrop-bromo-tris-pyrrolidinophosphonium hexafluorophosphate, "TBAF" tetrabutylammonium fluoride, "TBS-CI - t-butyldimethylsilyl chloride, and" TEA "triethylamine.

EXAMPLE

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

Ethyl 2-N- (methoxy) imino-4-oxopentanoate: A mixture of ethylpentanoate-2,4-dione (24.5 g, 154.9 mmol) and methoxyamine hydrochloride (13.58 g, 162.6 mmol) in ethanol (100 mL). ml) is kept on activated 3 A molecular grids (75 g) at room temperature for 18 hours. After filtration of the molecular sieves, dichloromethane (100 ml) was added and the reaction mixture was filtered. The resulting solution is evaporated and the residue is applied to a silica gel column. The title compound is isolated in homogeneous form by elution 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) in 2-methoxyethanol (5 mL) was heated at 105 ° C for 5 h. The reaction mixture was evaporated, dissolved in ethyl acetate and washed with 0.2 N HCl followed by water. The solution was dried (Na ₂ SO ₄ ), evaporated and the residue applied to a silica gel column. Elution with a gradient of 10: 1 to 5: 1 hexane: ethyl acetate gives 160 mg of ethyl 3-methyl-1-phenyl-1H-pyrazolecarboxylate; MSGMS (M + H) &lt; + &gt; m / z: 231.

3-Methyl-1-phenyl-1H-pyrazole-5- (N- (2'-Nt-butylaminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide: At 0 ° C 4- (2- A solution of Nt-butylaminosulfonyl) phenyl) aniline (0.22 g, 0.73 mmol) in dichloromethane (10 mL) was added to a solution of trimethyl aluminum (2.0 M in hexane, 5 eq., 1.75 mL). This mixture was stirred for 15 min, then a solution of 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 room temperature and stirred for 18 hours. The mixture is carefully quenched with water, diluted with ethyl acetate, separated, dried and evaporated. The residue is applied to a silica gel column and the desired compound is isolated by gradient elution using a 3: 1 to 1: 1 hexane: ethyl acetate mixture. 150 mg of 3-methyl-1-phenyl-1H-pyrazole-5- (N (2'-Nt-butylaminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide are obtained; DSGMS (M + H) ⁺ calcd m / z: 489.196038, found: 489.194346.

3- (Vfef / 7-7-Phen / 7-7 / 7-piperazin-5 - {N- (2'-amine) on / 7- / Y, 77-b / Y- 4- [7-Carboxamide: 150 mg of a solution of 3-methyl-1-phenyl-1H-pyrazole-5- (N- (2'-Nt-butylaminosulfonyl- [1,1]] -biphen-4-yl) -carboxamide in trifluoroacetic acid The reaction mixture was evaporated, the residue was dissolved in ethyl acetate and washed with 1N sodium hydroxide solution, the organic solution was dried and evaporated to give 140 mg of product, followed by 3-methyl-1-phenyl-1H-pyrazole-5 - (N- (2'-Aminosulfonyl- [1, T] -biphen-4-yl) carboxamide) is purified by HPLC using a gradient elution of water: acetonitrile with 0.05% trifluoroacetic acid over a reversed phase C18 (60 A) column. DSGMS (M + H) ⁺ calcd m / z: 433.1333438, found: 433.131005.

EXAMPLE

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

This compound was prepared following the same procedure described in Example 1 for replacing phenylhydrazine with 2-methoxyphenylhydrazine hydrochloride. 3-Methyl-1- (2-methoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1'J-biphen-4-yl) carboxamide; DSGMS (M + H) ⁺ ) is obtained. m / z calcd: 463.144002, found: 463.144162.

EXAMPLE

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

This compound was prepared according to the same procedure described in Example 1 by replacing phenylhydrazine with 3-methoxyphenylhydrazine hydrochloride. 3-Methyl-1- (3-methoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1'j-biphen-4-yl) carboxamide) was obtained; DSGMS (M + H) ⁺ calcd. m / z 463.144002, found 463.144301. "

EXAMPLE

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

This compound was prepared following the same procedure described in Example 1 for replacing phenylhydrazine with 4-methoxyphenylhydrazine hydrochloride. 3-Methyl-1- (4-methoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] -biphen-4-yl) carboxamide is obtained; DSGMS (M + H) ⁺ m / z calculated: 463.144002, found: 463.141980.

EXAMPLE

3-Methyl-1- (2-hydroxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen4-yl) carboxamide Example Product - 3-Methyl-1- ( 2-Methoxy) phenyl-1H-pyrazole-5- (N- (2'aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide (0.245 g, 0.53 mmol) in dichloromethane (20 mL) was cooled. to 0 ° C and add boron tribromide solution in dichloromethane (1.0 M, 6 equivalents, 3.2 mL) The reaction mixture was allowed to warm to room temperature and stirred for 18 h.

v

The reaction mixture was evaporated, the residue was poured onto a small layer of silica gel and eluted with ethyl acetate. This ethyl acetate solution is dried and evaporated. The material was purified by HPLC using a gradient elution of water: acetonitrile with 0.05% trifluoroacetic acid over a reversed phase C18 (60 A) column to afford the title compound; DSGMS (M + H) ⁺ calcd m / z 449.128352, found 449.129006.

EXAMPLE

3-Methyl-1- (3-hydroxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen4-yl) carboxamide Example Product - 3-Methyl-1- ( 3-Methoxy) phenyl-1H-pyrazole-5- (N- (2'aminosulfonyl- [1,1'] -biphen-4-yl) carboxamide was treated according to the procedure described in Example 5 to give the title compound; H) ⁺ calcd m / z 449.128352, found 449.127620.

EXAMPLE

3-Methyl-1- (4-hydroxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen4-yl) carboxamide Example Product - 3-Methyl-1- ( 4-Methoxy) phenyl-1H-pyrazole-5- (N- (2'aminosulfonyl- [1,1'] -biphen-4-yl) carboxamide was treated according to the procedure described in Example 5 to give the title compound; H) ⁺ calcd m / z 449.128352, found 449.127304.

EXAMPLE

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

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazolecarboxylic acid: Ethyl 3-methyl-1- (4-methoxyphenyl) -1H-pyrazolecarboxylate (0.01797 mol, 5.197 g) and potassium hydroxide (3.362 g, 3.0) eq.) in ethanol (70 mL) was stirred at room temperature for 5 h. The solvent is evaporated off under vacuum and the residue is dissolved in water. This solution is extracted with methylene chloride (3 x) to remove unreacted starting material. The aqueous solution is acidified (pH 3) by dropwise addition. HCl at 0 ° C and a white acid precipitate is obtained. The solid acid is filtered off and vacuum dried for several hours to dry. This procedure yields 4.23 g of pure product (91

%); melt temp. 161.8 ° C.

2-Fluoro-4- (2-aminosulfonylphenyl) aniline: 2-Fluoro-4-bromoaniline (0.01 mol, 2.51 g), boric acid (2.57 g, 1.0 equiv.), Sodium carbonate ( A mixture of 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 room temperature for 30 min. by bubbling nitrogen through the mixture to remove oxygen. The reaction mixture was then refluxed 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, the residue dissolved in water and then extracted with ethyl acetate (3x); Ethyl Acetate s extracts were washed with brine, dried (MgSO ₄₎ and evaporated. The residue was purified by flash column chromatography on silica gel (150 g) eluting with 2.5: 1 hexane: ethyl acetate to give 1.976 g of pure product (61%).

3-Methyl-1- (4-methoxy) phenyl-1H-pyrazole-5- (N- (3-fluoro- (2'-aminosulfonyl- [1,1 '] · biphen-4-yl) carboxamide): J 3 Thionyl chloride (0.3 mL, 4.0 eq.) was added to a solution of -methyl-1- (4-methoxyphenyl) -1H-pyrazolecarboxylic acid (0.001 mol, 0.232 g) in dry acetonitrile (10 mL). At room temperature for 1 hour, then allow to cool to room temperature and stir for 1 hour The solvent and excess thionyl chloride are removed in vacuo and the residue is vacuum dried for several hours to further dry.

To this dried residue was added 2-fluoro-4 - ((2-N-t-butylsulfonamide) phenyl) aniline (0.322 g, 1.0 eq.) And triethylamine (0.14 mL, 1.0 eq., 2.0 eq.). In the case of HCl salt) mixture 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 flash column chromatography on silica gel (50 g) eluting with 3: 1 hexane: ethyl acetate to give 0.301 g of pure product with t-butylsulfonamide (56%).

This product was treated with trifluoroacetic acid at 55 ° C for 2 hours to deprotonate the sulfonamide; Purification by reverse phase HPLC afforded 0.287 g of pure product: desired product DSGMS (M + H) ⁺ calcd m / z: 481.134581, found: 481.133650.

EXAMPLE

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

2-Bromo-4- (2-aminosulfonylphenyl) aniline: This compound is prepared according to the procedure for the preparation of 2-fluoro-4- (2-aminosulfonylphenyl) aniline described in Example 8 using 2,4-dibromaniline as starting material instead of 2-fluoro-4-bromoaniline. .

3-Methyl-1- (4-methoxy) phenyl-1H-pyrazole-5- (N- (3-bromo-4- (2'-aminosultone [1,1 '] - biphen-4-yl) carboxamide): This The compound is prepared according to the procedures described in Example 8 by copying 2-bromo-4 - ((2-Nt-butylsulfonamido) phenyl) aniline instead of 2-fluoro-4 - ((2-Nt-butylsulfonamido) phenyl) aniline. , yields pure desired product: DSGMS (MtH) ⁺ calcd m / z: 541.054513, found: 541.055340.

EXAMPLE

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

2-Iodo-4- (2-aminosulfonylphenyl) aniline: This compound is prepared according to the method of 2-fluoro-4- (2-aminosulfonylphenyl) aniline described in Example 8 using 2-iodo-4 as starting material instead of 2-fluoro-4-bromaniline. -bromanyline.

3- (Wef) 7-7- (4-mefox (Xen) 7-7H-prazazo-5- {N- (3- {od- (2'-amo-nos) -7-f7, 77biphen-4-yl) carboxamide: This compound is prepared according to the procedures described in Example 8 by copying 2-iodo-4 - ((2-Nt-butylsulfonamide) instead of 2-fluoro-4 - ((2-Nt-butylsulfonamide) phenyl) -aniline. ) Phenyl) aniline Purification by reverse phase HPLC affords the pure desired product;

DSGMS (M + H) ⁺ calcd m / z; 589,040654, found: 589,039223.

EXAMPLE

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

2-Methyl-4- (2-aminosulfonylphenyl) aniline: This compound is prepared according to the method for preparing 2-fluoro-4- (2-aminosulfonylphenyl) aniline described in Example 8 using 2-methyl-4-bromoaniline instead of 2-fluoro-4-bromoaniline as starting material. .

3-Methyl-1- (4-methoxy) phenyl-1H-pyrazole-5- (N- (3-methyl- (2'-aminosulfonyl- [1,1'l] biphen-4-yl) carboxamide): This compound is prepared according to the procedures described in Example 8 by copying 2-methyl-4 - ((2-Nt-butylsulfonamide) phenyl) aniline instead of 2-fluoro-4 - ((2-Nt-butylsulfonamide) phenyl) aniline. DSGMS (M + H) ⁺ calcd m / z 477.159652, found 477.159337.

EXAMPLE

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-N-carboxydimethylamino) phenyl) carboxamide

4- (N-Carboxydimethylamino) aniline: To a solution of p-nitrobenzoyl chloride (1.5 g, 8.1 mmol) in dichloromethane (50 mL) at 0 ° C was added twice dimethylamine (about 0.73 g). The reaction mixture is then evaporated to dryness and the residue is dissolved in ethyl acetate. The solution was washed with 1N hydrochloric acid and brine, then dried and evaporated to give 4- (N-carboxyldimethylamino) nitrobenzene.

This material was reduced under a hydrogen gas atmosphere (345 kPa) in methanol (100 mL) in the presence of 10% palladium on carbon as a catalyst (100 mg). After about 2 hours. reduction occurs; the reaction mixture is purged with gaseous nitrogen and the catalyst is filtered through a pad of celite. Evaporation of the solvent affords the desired compound.

3- Methyl-1- (4-methoxy) phenyl-1H-pyrazole-5- (N- (4-N-carboxydimethylamino) phenyl) carboxamide: This compound was prepared according to the procedures described in Example 8 instead of 2-fluoro-4- ((2-Nt-Butylsulfonamido) phenyl) -aniline by copying 4- (N-carboxyldimethylamino) aniline followed by the final step of trifluoroacetic acid deprotection. Purification by reverse-phase HPLC gives the pure desired product; DSGMS (M + H) ⁺ calcd m / z: 379.177016, found; 379.176235.

EXAMPLE

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

4- (N-Pyrrolidinocarbonyl) aniline: To a solution of p-nitrobenzoyl chloride (1.5 g, 8.1 mmol) in dichloromethane (50 mL) at 0 ° C was added twice pyrrolidine (1.15 g, 16.2 mmol) ). The reaction mixture is then evaporated to dryness and the residue is dissolved in EtOAc. The solution was washed with 1N hydrochloric acid and brine, then dried and evaporated to give 4- (N-pyrrolidinocarbonyl) nitrobenzene.

This material was reduced under a hydrogen gas atmosphere (345 kPa) in methanol (100 mL) in the presence of 10% palladium on carbon as a catalyst (100 mg). After about 2 hours. reduction occurs; the reaction mixture is purged with gaseous nitrogen and the catalyst is filtered through a pad of celite. Evaporation of the solvent affords the desired compound.

3-Methyl-1- (4-methoxy) phenyl-1H-pyrazole-5- (N- (4-N-pyrrolidinocarbonyl) · phenyl) carboxamide: This compound was prepared according to the procedures described in Example 8 instead of 2-fluoro-4- ((2-Nt-Butylsulfonamido) phenyl) -aniline by copying 4- (N-pyrrolidinocarbonyl) aniline and then passing the final step of trifluoroacetic acid deprotection. Purification by reverse-phase HPLC gives the pure desired product; DSGMS (M + H) ⁺ calcd m / z; 404.184841, found: 404.182119.

EXAMPLE

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-a-methyl-Npyrrolidino) phenyl) carboxamide

4- (α-Pyrrolidino) methylaniline: To a solution of 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 refluxed for 2 hours, then stirred at room temperature for 18 hours. Water is added to the reaction mixture, followed by separation of the layers. The chloroform layer is dried and evaporated to give 1.55 g of the N-alkylation product; MSGMS (M + H) &lt; ⁺ &gt; m / z: 207.2.

The nitro group reduction of the above material was accomplished by stirring this material with tin (II) chloride dihydrate (8.5 g, 37.6 mmol) in ethanol (50 mL) at room temperature for 18 hours. The reaction mixture was diluted with 1N sodium hydroxide solution and extracted with ethyl acetate (3x). The extracts were washed with brine, dried and evaporated to give 1.23 g of 4- (α-N-pyrrolidine) methylaniline; MSGMS (M + H) &lt; ⁺ &gt; m / z: 177.2.

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-a-methyl-N-pyrrolidino) phenyl) carboxamide: 3-Methyl-1- (4-methoxyphenyl) ) A mixture of -1 H -pyrazolecarboxylic acid (100 mg, 0.43 mmol), 4- (aN-pyrrolidino) methylaniline (76 mg, 0.43 mmol) in dimethylformamide (3 mL) was cooled to 0 ° C. N-methylmorpholine is added. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was diluted with 1N sodium hydroxide then extracted with ethyl acetate. The extracts are washed with saturated NaCl solution, dried and evaporated. This material was purified by HPLC using a gradient elution of water: acetonitrile with 0.05% trifluoroacetic acid over a reverse phase C18 (60 A) column to afford the title compound (70 mg); MSGMS (M + H) &lt; ⁺ &gt; m / z: 391.2.

EXAMPLE

3-ΤπίΙυοπηθΐϊΙ-1- (4-πιβΙοΚ3ίίθηΗ) -1Η-ρΪΓ3ΖθΙ-5- (Ν- (2'-3ΠΉηθ8υΙίοηϊΙ- [1> 1 '] · biphen-4-yl) carboxamide

3-Trifluoromethyl-5-methyl-1- (4-methoxyphenyl) -1H-pyrazole: 1,1,1-Trifluoro-2,4-pentanedione (0.02 mol, 2.4 mL) and 4-methoxyphenylhydrazine hydrochloride (4, A mixture of 54 g (1.3 eq) in 2-methoxyethanol (100 mL) and acetic acid (30 mL) was refluxed for 6 h. The reaction mixture was evaporated and purified by flash column chromatography on silica gel (400 g) eluting with 4: 1 hexane: ethyl acetate to give 4.5 g of pure product (88%).

3-Trifluoromethyl-5-hydroxymethyl-1- (4-methoxyphenyl) -1H-pyrazole: 3-trifluoromethyl-5-methyl-1- (4-methoxyphenyl) -1H-pyrazole (0.017756 mol, 4, A mixture of 5 g), Nbromo-succinimide (3.439 g, 1.1 eq.) And AIBN (0.1 g) in carbon tetrachloride (100 ml) was refluxed for 18 hours. The reaction mixture was filtered through celite to remove solid impurities and washed with carbon tetrachloride (100 mL). Evaporation of the filtrate and purification by flash column chromatography on silica gel (400 g) eluting with 4: 1 hexane: ethyl acetate afforded 3.826 g of pure product (65%).

This material was treated with calcium carbonate (2.637 g, 1.5 equiv.) In dioxane (80 mL) and water (20 mL) at 55-60 ° C for 18 h. The reaction mixture was evaporated and purified by flash column chromatography on silica gel (400 g) eluting with 4: 1 hexane: ethyl acetate to give 1.198 g of pure product (39%). Recrystallization from benzene: hexane gives an analytically pure sample; melt temp. 79.0 ° C; CHNF: theoretically:% C 52.95,% H 4.07,% N 10.29, 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: into a solution of 3-trifluoromethyl-5-hydroxymethyl-1- (4-methoxyphenyl) -1H-pyrazole (4.4007 mmol, 1.198 g) acetonitrile (20 mL) and water (20 mL) at 0 ° C were added sodium periodate (1.977 g, 2.1 eq.) and several crystals of ruthenium (III) chloride. The reaction mixture is stirred at room temperature for 18 hours. To remove the solid impurities, the reaction mixture is filtered through celite and the precipitate is washed on the filter with 1: 1 acetonitrile: water. The filtrate was evaporated in vacuo and the residue dissolved in water. The aqueous solution was acidified (pH 3) by dropwise addition of HCl at 0 ° C, followed by extraction with ethyl acetate (3x); The ethyl acetate extracts were washed with brine, dried (MgSO ₄ ) and evaporated to give 1.13 g of pure product (90%).

3-Tr / 7 / urmorph-7-i- (4-mephox / phen //) - 7H-piperazo--5- (N- (2'-f-buf / 7am / nosu / phon / 7 [ 1,1 '] - Biphen-4-yl) carboxamide: J 300 mg of 3-trifluoromethyl-1- (4-methoxyphenyl) 1H-pyrazole-5-carboxylic acid (1.05 mmol) in dichloromethane (10 mL) at 0 ° C a solution of oxalyl chloride in dichloromethane (2M, 1.5 eq., 1.58 mmol, 0.8 mL) was added followed by a drop of dimethylformamide, After 4 h, the solvent was evaporated and the chloro anhydride was used in the next reaction.

The above material was dissolved in dichloromethane (20 mL) and then over a period of 15-20 min. 4- (2-N-t-butylaminosulfonyl) phenyl) aniline (1.2 eq, 1.25 mmol, 0.365 g), pyridine (10 eq, 12.5 mmol, 0.99 g) were added at 0 ° C. 1.0 mL) and a solution of N, N-dimethylaminopyridine (1.2 equiv., 1.25 mmol, 0.155 g) in dichloromethane (20 mL). The reaction mixture is kept at 0 [deg.] C. until thin-layer chromatography shows that all the starting chlorohydride has reacted. The reaction mixture is evaporated and then the residue is suspended in 1N hydrochloric acid solution. This suspension is extracted with ethyl acetate; the extracts are washed with 1N hydrochloric acid solution (2x), dried and evaporated. 660 mg v of the desired product are obtained; MSGMS (M + Na) &lt; ⁺ &gt; m / z: 594.5.

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] biphen-4-yl) carboxamide: 3-Trifluoromethyl-1- (4 -methoxyphenyl) -1H-pyrazole-5- (N (2'-t-butylaminosulfonyl- [1,1 '] -biphen-4-yl) carboxamide (0.66 g) was dissolved in trifluoroacetic acid (20 mL) and boiled Reflux for 30 min The reaction mixture is evaporated, then dissolved in ethyl acetate and washed with 1N sodium hydroxide solution (2x) and brine, then dried and evaporated to 0.48 g of crude product. Chromatography on a 200 g silica gel column eluting with 2: 1 hexane: ethyl acetate followed by recrystallization of the homogeneous chromatographic product from chloroform gave 0.262 g of the title compound, mp 237.3 ° C; CHNF:% 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, 29th

EXAMPLE

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-Nyropyrrolidinocarbonyl) phenyl) carboxamide

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-N-pyrrolidinocarbonyl) phenyl) carboxamide: 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5-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 room temperature for 24 hours.

The volatiles are evaporated under reduced pressure and the residue is vacuum dried. 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 min. The resulting chloro anhydride was dissolved in anhydrous CH ₂ Cl ₂ (5 mL) and added dropwise to the reaction mixture. The reaction mixture was warmed to room temperature and stirred overnight. The mixture is concentrated in vacuo. Purification by silica gel chromatography eluting with ethyl acetate: hexanes v (1: 1) gave 325 mg (95% purity by HPLC). MSGMS (M + H) <^+>

459 C ₂₃ H ₂₁ N ₄ O3F3. DSGMS: Calcd. For C ₂₃ H ₂₁ N ₄ O ₃ F ₃ (M + H) ⁺

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 (d, 2H, J = 6.59 Hz), 8.42 (s, 1H).

EXAMPLE

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

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazol-5- (N- (5- (2-methanesulfonyl) phenyl) pyridin-2-yl) carboxamide: This material is prepared according to the methods described in Example 15 except that in the copulation step 4- (2N-t-butylaminosulfonyl) phenylaniline is replaced by 2-amino-5- (2-N-tbutylaminosulfonyl) phenyl) pyridine. Purification by HPLC using a gradient elution of water: acetonitrile with 0.05% trifluoroacetic acid over a reverse phase C18 (60 A) column afforded a pure sample of the title compound: MSGMS (M + H) ⁺ m / z: 517, (M ⁺ + Na) ⁺ m / z: 539.

EXAMPLE

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazol-5- (N- (5-N-pyrrolidinocarbonyl) pyridin-2-yl) carboxamide

2-Amino-5- (N-pyrrolidinocarbonyl) pyridine: A mixture of 2-aminonicotinic acid (2.26 g, 16.4 mmol) and pyrrolidine (1.16 g, 16.4 mmol) in dimethylformamide (20 mL) was cooled to 0 ° C. To this mixture was added M-methylmorpholine (3.31 g, 32.7 mmol) and HBTU (6.2 g, 16.4 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The mixture was diluted with 1N sodium hydroxide and extracted with ethyl acetate. The product was purified by flash chromatography using 10% methanol in chloroform as eluent; 1.65 g of product are isolated; MSGMS (M + H) @ ⁺ m / z: 192.

3- Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazol-5- (N- (5-N-pyrrolidinocarbonyl) pyridin-2'-yl) carboxamide: This material is prepared according to the methods described in Example 15 except that the 4- (2N-tbutylaminosulfonyl) phenylaniline is replaced by 2-amino-5- (N-pyrrolidinocarbonyl) pyridine Purified by HPLC using a gradient elution of water: acetonitrile with 0.05% trifluoroacetic acid in a reversed phase C18 (60 A) column to give pure sample of the title compound, MSGMS (M + H) ⁺ m / z: 517, (M + Na) ⁺ m / z: 460.2.

EXAMPLE

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

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazol-5- (N- (5-N-pyrrolidinocarbonyl) pyridin-2-yl) carboxamide: To 3-Methyl-1- (4-methoxyphenyl) -1H- To a solution of pyrazole carboxylic acid (1.02 g, 4.4 mmol) in dichloromethane (20 mL) at 0 ° C was added 4.4 mL of a 2M oxalyl chloride solution in dichloromethane followed by a drop of dimethylformamide. After 2 or. the solvent is evaporated to give 1.12 g of the chloro-anhydride. This material is used in the next step without further purification.

To the 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 the previously prepared chloro anhydride (0.5 g, 2.0 mmol) in dichloromethane (10 mL). The reaction mixture was allowed to warm to room temperature and evaporated. The product is isolated by flash chromatography eluting with 10% chloroform in methanol. Purification by HPLC using a gradient elution of water: acetonitrile with 0.05% trifluoroacetic acid over a reversed phase C18 (60 A) column gives a pure sample of the title compound; DSGMS (M + H) ⁺ calcd m / z: 405.189090, found: 405.180328.

EXAMPLE

3- Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (5- (2-sulfonamido) phenyl) pyridine <

V2-yl) carboxamide

This compound is prepared according to the methods described in Example 19 except that 2-amino-5- (2-Nt-butylsulfonamide) phenylpyridine is used in place of 2-amino-5- (N-pyrrolidinocarbonyl) pyridine in the coupling step. The resulting product was stirred in trifluoroacetic acid (20 ml) for 18 hours, after which the solvent was evaporated under reduced pressure. Purification of the crude product by HPLC using a gradient elution of water: acetonitrile with 0.05% trifluoroacetic acid over a reverse phase C18 (60 A) column afforded a pure sample of the title compound: DSGMS (M + H) ⁺ calcd m / z: 464.139251, found: 464.138485.

EXAMPLE

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

4- (N-Carboxyl-3-t-butyldimethylsilyloxypyrrolidine) aniline: 3-Hydroxypyrrolidine hydrochloride (1.63 g, 14.9 mmol) and triethylamine (1.51 g, 14.9 mmol) in dichloromethane (50 mL) at 0 ° C at room temperature was added a solution of pnitrobenzoyl 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. The solution is washed with 1N hydrochloric acid and brine, then dried and evaporated to give 2.22 g of product; MSGMS (M + H) @ ⁺ m / z: 237.

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

v

The above material (2.07 g) was reduced under a hydrogen gas atmosphere (345 kPa) in methanol (100 mL) in the presence of 10% palladium on carbon as catalyst (200 mg). After about 2 hours. the reaction ends;

the reaction mixture is purged with nitrogen and the catalyst is filtered through a pad of celite. Evaporation of the solvent afforded 1.75 g of 4- (N-carboxyl-3-t-butyldimethylsilyloxypyrrolidine) aniline; MSGMS (M + H) &lt; + &gt; m / z: 321.

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5-N- (4- (N-carboxyl-3-hydroxy-pyrrolidino) phenyl) carboxamide: This compound was prepared according to the procedure described in Example 19 except , that 4- (N-carboxyl-3-t-butyldimethylsilyloxypyrrolidine) aniline is used in place of amino-2- (N-pyrrolidinocarbonyl) pyridine instead of 2 amino acids. The blocking t-butyldimethylsilyl group is cleaved by treatment with 2 equivalents of tetrabutylammonium fluoride in tetrahydrofuran. The solvent was evaporated and the residue was dissolved in ethyl acetate and washed with water. After drying and evaporation of the solvent, the crude product is purified by HPLC using a gradient elution of water: acetonitrile with 0.05% trifluoroacetic acid over a reverse phase C18 (60 A) column to give a pure sample of the title compound; DSGMS (M + H) ⁺ calcd m / z: 420.179756, found: 420.175589.

EXAMPLE

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

1 '(4-Methoxyphenyl) -r- (4-bromophenyl) aminocarbonylacetone: 4-Methoxyacetophenone (3.00 g, 19.97 mmol) was dissolved in 60 mL THF, followed by addition of LDA (2.0 M THF, 10.0) ml, 20 mmol) and stirred at room temperature for 1 h. 4-Bromophenyl isocyanate (3.95 g, 19.97 mmol) is added and the reaction mixture is stirred at room temperature overnight. The solution is acidified with 10% HCl and diluted with 300 mL of EtOAc. The solution was washed with a saturated NaCl solution (300 mL), dried over MgSO ₄ , filtered through a pad of silica gel and the volatiles evaporated in vacuo. The product is isolated by recrystallization from hot diethyl ether (3.08 g, 44%).

2-Amino-4- (4-methoxyphenyl) -5- (4-bromophenyl) thiazole: 1- (4-Methoxyphenyl) -1 '- (4-bromophenyl) aminocarbonylacetone (3.08 g, 8.84 mmol) and hydroxy ( tosyloxy) iodobenzene (3.46 g, 8.84 mmol) was stirred in 100 mL of acetonitrile, refluxed for 45 min, then thiourea (0.673 g, 8.84 mmol) was added and refluxed for 4 h. The volatiles were evaporated in vacuo and the residue triturated with hot MeOH (1.68 g, 47%). MS (NH4-DCI) 404.0 (M + H) ⁺ .

2-Amino-4- (4-methoxyphenyl) -5 - [(2'-tert-butylaminosulfonyl- [1,1'J-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) ) phenylboronic acid (1.50 g, 5.82 mmol) was stirred in a solution of 1: 1: 4 benzene: acetonitrile: water and degassed with N _{2 for} 15 min. After degassing, N _{2 is} added with tetrakistriphenylphosphine palladium (O) and the reaction mixture is refluxed overnight. The solution was diluted with EtOAc, transferred to a separatory funnel and washed with 150 mL portions of saturated NaCl solution. The organic solution was dried over MgSO ₄ , filtered through a pad of silica gel, and the volatiles evaporated in vacuo. The residue was dissolved in a minimal amount of hot CHCL, triturated with Et ₂ O and isolated by vacuum filtration (1.59 g, 71.3%). MS (NH 3 -DCl) 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'-tert-Butylaminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole (1.59 g, 2.96 mmol) was dissolved in 20 mL of TFA and refluxed for 1 h. . The volatiles are evaporated in vacuo and the title compound is purified by preparative HPLC. MS (NH3-DCI) 481.1 (M + H) ⁺ .

EXAMPLE

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

Methyl 3- (methoxyphenyl) -3-oxopropionate: Dissolve bis- (trimethylsilyl) amine (158.2 mL, 0.750 mol) in 150 mL THF and cool to -78 ° C in a dry ice / acetone bath. This system is injected with a syringe into N-butyllithium (2.5 M in hexane, 300 mL, 0.750 mol) and stirred at this temperature for 20 min. 4-Methoxyacetophenone (51.20 g, 0.340 mol) was added via a solid addition funnel and stirred at -78 ° C for 3 h. Dimethyl carbonate (87.0 mL, 1.02 mol) was added via cannula and the system was allowed to warm to room temperature overnight. The solution is acidified with 10% HCl, diluted with 1 L EtOAc and washed three times with 400 mL of 10% HCl. The organic solution was dried over MgSO ₄ , filtered through a pad of silica gel, and the volatiles evaporated in vacuo. The title compound is obtained as a viscous brown oil (65.09 g, 91.7%). MS (NH ₃ -Cl) 347.9 (M + H) ⁺ .

2-Amino-4- (4-methoxyphenyl) -5- (carbomethoxy) thiazole: Methyl 3- (methoxyphenyl) -3-oxopropionate (33.34 g, 95.75 mmol) and hydroxy (tosyloxy) iodobenzene (37, 55 g, 95.75 mmol) is stirred in 350 mL of acetonitrile, refluxed for 45 min, then thiourea (7.29 g, 95.75 mmol) is added and the mixture is refluxed for 2 h. The volatiles were evaporated in vacuo and the residue was dissolved in 50/50 EtOAc / hexane and passed through a pad of silica gel. After washing the impurities, the product is obtained by eluting with 100% EtOAc and evaporating the volatiles in vacuo. The title compound is obtained as a tan solid (38.52 g, 75%). MS (NH3-DCI) 254.2 (M + H) ⁺ .

2-Bromo-4- (4-methoxyphenyl) -5- (4-bromophenyl) thiazole: Copper bromide (11.42 g, 51.17 mmol) and tert-butyl nitrite (6.93 mL, 58.16 mmol) are mixed. 75 ml of acetonitrile are refluxed until gas evolution ceases. To this solution, 2-amino-4- (4-methoxyphenyl) -5- (4-bromophenyl) thiazole (12.3 g, 46.55 mmol) was added to acetonitrile and refluxed until gas evolution ceased. The solution was diluted with 300 mL EtOAc and washed again with 250 mL saturated Na ₂ CO 3 solution. The organic solution was dried

MgSO ₄ , filtered through a pad of silica gel and the volatiles evaporated in vacuo. The residue was purified by preparative HPLC to give the title compound as a brown oil, 8.95 g (57%), MS (NH ₃ DCI) 328.0 (M + H) ⁺ .

2-Bromo-4- (4-methoxyphenyl) -5 - [(2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole: To (2'-tert-Butylaminosulfonyl- [ A solution of 1,1 '] -biphen-4-yl) amino (2.57 g, 8.47 mmol) in 50 mL of methylene chloride was added dropwise at 25 ° C with trimethylaluminium (12.7 mL of a 2.0 M solution in toluene). The resulting solution was stirred until no further gas evolved (-15 min), and 2-bromo-4- (4-methoxyphenyl) -5- (4-bromophenyl) thiazole (2.94 g, 9 g) was added to the solution. 31 mmol) and stirred under reflux for 2 hours. The solution was partitioned between saturated NH ₄ Cl, diluted with 200 mL of EtOAc, and washed twice with 200 mL of saturated NaCl solution. The organic solution was dried over MgSO _4, filtered through silica gel and evaporated cover film agglomerated material is dried in vacuo to afford the title compound as a golden kieta.medžiaga (5.0 g, 98%) MS (NHa-DCI) 600.3 (M + H ) ⁺ .

2-Bromo-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) · aminocarbonylthiazole: 2-Bromo-4- (4-methoxyphenyl) -5 - [(2'-tert-Butylaminosulfonyl- [1,1 '] - biphen-4-yl) -aminocarbonyl] -thiazole. Deprotection (1.00 g, 1.66 mmol) using trifluoroacetic acid, as in the final step of Example 1, affords the title compound. It was isolated by preparative HPLC as a white solid, MS (ESI) 543.8 (M + H) ⁺ .

EXAMPLE

2-Chloro-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 T] -biphen-4-yl) aminocarbonyl] thiazole

Using similar to Example 2, the methods with the exception that 2-amino-4- (4-methoxyphenyl) -5- (4-bromophenyl) thiazole diazotizing and halogenating reaction using _two instead CUCI CUBRI ₂ gives 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, is isolated as a white solid by preparative HPLC;

MS (NH 3 -DCl) 500.3 (M + H) ⁺ .

EXAMPLE

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'J-biphen-4-yl) aminocarbonyl] thiazole (0.40 g, 0.8 mmol) was dissolved in 5 mL of CH ₂ Cl ₂ , cooled to 0 ° C, then BCI ₃ (1.0 M solution in CH ₂ Cl ₂ , 4.8 mL, 4.8 mmol) was added and stirred for 72 h. at room temperature. The solution was diluted with 10% HCl and the volatiles evaporated in vacuo. The title compound was purified by preparative HPLC MS (NH3-DCI) 485.9 (M + H) ⁺ .

EXAMPLE

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- [(2'-Aminosulfonyl- [1,1 '] biphen-4-yl) aminocarbonyl] thiazole (0.120 g, 0.240 mmol) and sodium methoxide (0.10 g, 2.0 mmol) were dissolved in 20 mL of methanol and boiled with Refrigerator; the reaction is controlled by TLC. Preparative HPLC isolated the title compound, MS (ESI) 518.0 (M + Na) ⁺ .

EXAMPLE

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 '] - benzen-4-yl) · aminocarbonylthiazole: 2-Chloro-4- (4-methoxyphenyl) -5 - [(1''-Aminosulfonyl- [1,1] biphen-4-yl) aminocarbonyl] thiazole (0.700 g, 1.4 mmol) and sodium thiomethoxide (0.490 g, 7.0 mmol) were refluxed in 50 mL of THF. , and the reaction is controlled by TLC (-4 h). The volatiles are removed in vacuo and the title compound is purified by preparative HPLC; MS (ESI) 534.0 (M + H) &lt; + &gt;.

AND EXAMPLES 29

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

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

2-Methylsulfone-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4yl) aminocarbonyl] thiazole, MS (ES0'543.9 (M + H) ⁺ ).

EXAMPLE

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

2-Cyano-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1'J-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) are mixed in 35 mL of DMF, stirred at room temperature over overnight, then warm to 70 ° C for several hours. The solution was diluted with 300 mL EtOAc, washed with three portions of 200 mL of saturated brine, dried over MgSO _4, filtered through a silica lamellae and the volatiles were removed in vacuo. Preparative HPLC gives the title compound as a white solid. MS (ESI) 490.9 (M + H) &lt; + &gt;.

EXAMPLE

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

2-N, N-Dimethylamino-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4yl) 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, 0 mmol) 50 mL of THF was stirred at room temperature overnight. The volatiles were evaporated in vacuo and the title compound was purified by preparative HPLC: MS (ESI) 509.0 (M + H) ⁺ .

EXAMPLE

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

2- (1-Pyrrole) -4- (4-methoxyphenyl) -5 - [(2'-ammosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonylthiazole: 2-Amino-4- (4-methoxyphenyl) ) -5 - [(2'-Aminosulfonyl [1,1 '] - biphen-4-yl) aminocarbonylthiazole (0.050 g, 0.104 mmol) and 2,5-dimethoxytetrahydrofuran (0.015 mL, 0.114 mmol) were refluxed with 20 mL of acetic acid. 1 or. The volatiles are removed in vacuo and the title compound is purified by preparative HPLC; MS (ESI) 531.0 (M + H) &lt; + &gt;.

EXAMPLE

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

Oxime of 4-methoxybenzaldehyde: Dissolve 4-methoxybenzaldehyde (10.0 g, 73.4 mmol) in 200 mL of ethanol. A solution of hydroxyamine hydrochloride (6.38 g, 91.8 mmol) in 50 mL H ₂ O was 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. 12 or. The ethanol was evaporated 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 light yellow oil. 1 H NMR showed 80% purity (92% yield). This material is used in the next step without further purification (CDCl ₃ ): δ 2.15 (s, 1H), 3.83 (s, 3H), 6.92 (d, 2H), 7.50 (d, 2H), 8.10 (s, 1H).

3- (4-Methoxyphenyl) -5-carbomethoxymethyl-isoxazolin-5-ylcarboxylic acid: 4-Methoxybenzaldehyde oxime (5.00 g, 33.1 mmol) and itaconic acid monomethyl ester (5.72 g, 39.7 mmol) were added together with 200 mL of THF. To this mixture was added hypochlorite (84 mL of 0.67 M aqueous solution) at room temperature. The reaction mixture was then stirred at room temperature under N _{2 for} 12 h. The THF was evaporated 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 on silica gel eluting with 10-30% MeOH in CH ₂ Cl ₂ 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, 2H), 3.80 (s, 3H), 7.00 (d, 2H), 7.61 (d, 2H).

3- (4-Methoxyphenyl) -5-N- [5- (2'-t-butylaminosulfonylphenyl'-1'yl) pyridin-2-yl] aminocarbonyl-5-carbomethoxymethyl-isoxazoline: 3- (4-Methoxyphenyl) -5-carbomethoxymethyl -isoxazolin-5-ylcarboxylic acid (1.89 g, 6.44 mmol) was refluxed with 100 mL of acetonitrile and 4.70 mL (64.4 mmol) of thionyl chloride under N _{2 for} 1 h. The solvent is evaporated off under vacuum. The remaining thionyl chloride is removed by addition of toluene and then evaporated to dryness. The resulting solid was dissolved in 100 mL CH 2 Cl 2, treated with 2 amino-5 - [(2'-t-butylaminosulfonyl) phenyl] pyridine (1.57 g, 5.15 mmol) followed by N, N-dimethylpyridine (0.94 g). , 7.73 mmol). The reaction mixture was stirred at room temperature; the reaction is completed in less than 30 minutes. The mixture was diluted with CH 2 Cl 2 and the solution was washed with water and saturated NaCl solution. It is dried over MgSO ₄ and concentrated. The crude product 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- [5- (2'-aminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl-5-carbomethoxymethyl-isoxazoline: 3- (4-Methoxyphenyl) -5-N [5- (2'-t-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. in the atmosphere for 22 hours. TFA is evaporated in vacuo and the crude product is chromatographed (silica gel, eluting with ethyl acetate and 5% methanol in CH ₂ Cl ₂ ); 1.10 g of the desired product are obtained (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- [5- (2'-aminosulfonylphenyl-1-yl) pyridin-2-yl] -aminocarbonyl-5-carbomethoxymethyl-isoxazoline (0.95 g, 1.78 mmol) dissolved in 20 ml of THF. Aqueous LiOH (2.3 mL of 1M solution) was added. The mixture was stirred at room temperature under N _{2 for} 1.5 h. The THF was evaporated in vacuo, the residue diluted with water and extracted with EtOAc. The aqueous mixture was then acidified with HCl and extracted with EtOAc. The EtOAc solution was washed with brine, dried over MgSO ₄ and concentrated to give a pale yellow foam (0.85 g, 94%). MS (ES ⁺ ) 511.0 (M + H); 533.0 (M + Na).

EXAMPLE

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

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

EXAMPLE

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

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 K ₂ CO ₃ (11.23 g, 31.3 mmol) are added to 100 mL of DMF. Methyl 2- (bromomethyl) acrylate (13.0 g, 72.6 mmol) was added. The mixture was stirred at room temperature under N _{2 for} 4 h. The mixture was poured into water and extracted with EtOAc. The combined organic solutions were 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) were added to 100 mL of CH ₂ Cl _2. . Hypochlorite (23 mL of 0.67 M aqueous solution) is added dropwise at room temperature. The reaction mixture was then stirred at room temperature under N _{2 for} 12 h. The mixture was diluted with CH ₂ Cl ₂ and washed with water and saturated NaCl solution. It was dried over MgSO ₄ , concentrated, and chromatographed on silica gel, eluting with 30-100% EtOAc in CH ₂ Cl ₂ , to give 1.81 g of the desired product (66%).

The above ester (1.81 g) was dissolved in 25 mL of THF and aqueous LiOH (7.2 mL of 1M solution) was added. The mixture was stirred at room temperature under N _{2 for} 0.5 h. The THF was evaporated in vacuo. The aqueous mixture was diluted with water and extracted with EtOAc. The resulting aqueous solution was acidified and then extracted with EtOAc. The white precipitate formed is filtered off and dried (1.30 g). 1 H NMR (DMSO-d 6): δ 3.75 (kv, 2H), 3.78 (s, 3H), 4.74 (kv, 2H), 6.98 (d, 2H), δ

7.53 (d, 2H), 7.92 (s, 1H), 8.51 (s, 1H), 13.75 (s, 1H).

3- (4-Methoxyphenyl) -5-N- [5- (2'-t-butylaminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl-5- (T, 2,4-triazol-1-yl) methyl-isoxazoline: 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 of acetonitrile and 0.75 mL (10.3 mmol) of thionyl chloride under N _{2 for} 1 h. The solvent is evaporated off under vacuum. The remaining thionyl chloride is removed by adding toluene and then evaporated to dryness. The resulting solid was dissolved in 20 mL of CH ₂ Cl ₂ and 2 amino-5 - [(2'-t-butylaminosulfonyl) phenyl] pyridine (0.25 g, 0.82 mmol) was added followed by NN-dimethylpyridine (0.15 g). , 1.24 mmol). The reaction mixture was stirred at room temperature; reaction ended in less than 30 min. The mixture was diluted with CH ₂ Cl ₂ and the solution was washed with water and saturated NaCl solution.

It was dried over MgSO _4, and concentrated ^again. The crude product is chromatographed on silica gel eluting with methylene chloride / ethyl acetate (30-100%) to give 0.31 g of the desired product (51%). MS (ES ⁺ ) 590.2 (M + H); 612.1 (M + Na).

3- (4-Methoxyphenyl) -5-N- [5- (2'-aminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl-5- (1,2,4-triazol-1-yl) methH- isoxazoline: 3- (4-Methoxyphenyl) -5-N- [5 (2'-t-butylaminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl-5- (1,2,4-triazole-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 h. TFA is evaporated in vacuo and the crude product is chromatographed on silica gel eluting with ethyl acetate; 0.19 g of the desired product is obtained (87%). MS (ES ⁺ ) 534.0 (M + H); 556.0 (M + Na).

EXAMPLE

1- (4-Methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 T] -biphen-4-yl) aminocarbonyl] tetrazole

1- (4-Methoxyphenyl) -5-carboethoxy-tetrazole: Dissolve 4-methoxyaniline (20.0 g, 0.16 mol) and triethylamine (26.3 mL, 0.19 mol) in CH ₂ Cl ₂ (200 mL). . Ethyl oxalyl chloride (18.1 mL, 0.16 mol) was added dropwise. The mixture was stirred at room temperature under N _{2 for} 15 min. It is diluted with CH ₂ Cl ₂ and washed with water and saturated NaCl solution. The CH ₂ Cl ₂ solution was dried over MgSO ₄ and concentrated to a yellow-brown solid (34.7 g, 96%). MS (DCI-NH 3) 244, (M + H), 241 (M + NH ₄ ).

The above amide (34.0 g, 0.15 mol) was refluxed for 20 hours. with a solution of triphenylphosphine (56.6 g, 0.22 mol) in 500 mL CCI ₄ . (The solution is stirred at 0 ° C for 15 min before the amide is added).

The reaction mixture was cooled and hexane was added. The precipitate is filtered off. The filtrate is concentrated to a solid. This material was dissolved in 400 mL 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 h. The solvent v is evaporated. The solid was dissolved in EtOAc and washed with water and saturated NaCl solution. The solution was dried over MgSO ₄ , concentrated, and chromatographed on silica gel (eluting with CH ₂ Cl ₂ ) to give 27.7 g (58%) of the desired product. MS (DCI-NH ₃ ) 249 (M + H), 266 (M + NH ₄ ) ⁺ .

1- (4-Methoxy-phenyl) -5 - [(2'-t-butylaminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -tetrazole: 2'-t-Butylaminosulfonyl-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 min, then 1- (4-methoxyphenyl) -5-carboethoxytetrazole (1.50 g, 6.04 mmol) was added. The reaction mixture was stirred at room temperature under N _{2 for} 18 h. The mixture was carefully quenched with 0.1 N aqueous HCl. It is diluted with CH ₂ Cl ₂ and washed with water and saturated NaCl solution. The organic solution was then 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;.

- (4-Methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] tetrazole: 1- (4-Methoxyphenyl) -5 - [(2'-t- butylaminosulfonyl- [1,1'J-biphen-4-yl) aminocarbonyl] -tetrazole (1.20 g, 2.37 mmol) was dissolved in 10 mL TFA. The mixture was refluxed under N _{2 for} 1 h. TFA was evaporated in vacuo. Purification of the crude material by reverse phase HPLC gave 0.12 g of the desired product (11%). MS (ESI) 451.0 (M + H) &lt; + &gt;.

EXAMPLE

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

This compound is prepared according to the procedure described in Example 1 using 4-methoxy-3-chlorophenylhydrazine-HCl in place of phenylhydrazine. 3-Methyl-1- (4-methoxy-3-chloro) phenyl) -1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1'J-biphen4-yl) carboxamide) is obtained; + H) ⁺ calcd m / z: 497.1050, found: 497.1045.

EXAMPLE

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

This compound is prepared according to the procedure described in Example 1 using 4-trifluoromethoxyphenylhydrazine-HCl in place of phenylhydrazine. Obtained 3-methyl-1- (4-trifluoromethoxy) phenyl) -1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] -biphen-4yl) carboxamide; DSGMS (M + H) ⁺ calcd. m / z 517.1177, found 517.1176.

EXAMPLE

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

This compound is prepared according to the procedure described in Example 1 using 3-bromophenylhydrazine-HCl in place of phenylhydrazine. 1- (3-Bromophenyl) 3-methyl-1 H -pyrazol-5 - [(2'-aminosulfonyl- [1,1 T] -biphen-4-yl) carboxamide is obtained;

DSGMS (M + H) ⁺ calcd m / z: 511.043949, found: 511.043295.

EXAMPLE

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

This compound is prepared according to the procedure described in Example 1 using 3-iodophenylhydrazine HCl in place of phenylhydrazine. 1- (3-iodophenyl) -3-methyl-1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1'J-biphen-4yl) carboxamide is obtained; DSGMS (M + H) ⁺ calcd m / z: 559.030090, found: 559.027878.

EXAMPLE

1- (3,4-Methylenedioxanophenyl) -3-methyl-1 H -pyrazol-5 - [(2'-aminosulfonyl- [1,1 '] biphen-4-yl) carboxamide

This compound is prepared according to the procedure described in Example 1 using 3,4-methylenedioxanophenylhydrazine-HCl in place of phenylhydrazine. 1- (3,4-methylenedioxanophenyl) -3-methyl-1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] -biphen-4-ylcarboxamide) was obtained; DSGMS (M + H) ⁺ calcd m / z : 477.123267, Found: 477.124553,

EXAMPLE

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

1- (4-Methoxyphenyl) -3-hydroxylmethylene-1H-pyrazole-5-ethylcarboxylate: a solution of 1- (4-methoxyphenyl) -3-methyl-1H-pyrazole-5-ethylcarboxylate (1.58 g, 7.1 mmol) CCl ₄ (250 mL) was added NBS (1.5 g, 8.5 mmol) and benzoyl peroxide (73 mg, 4 mmol), the mixture was degassed, then saturated with nitrogen. After refluxing under nitrogen for 18 hours, cool to room temperature, dilute with CH ₂ Cl ₂ (100 mL), wash with 10% NaOH (20 mL x 3), water (20 mL x 3), and brine (10 mL). ml x 2), and dried over MgSO ₄ . Filtration and concentration gave crude bromide (2.4 g). To a solution of this 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 h. The mixture is filtered to remove excess Cu ₂ O and the filtrate is extracted with ethyl ether. The ether layer was washed with saturated NaCl solution (10 mL x 5) and dried over MgSO ₄ . Filtration and concentration followed by flash chromatography eluting with EtOAc-CH ₂ Cl ₂ (1: 1) afforded 1- (4-methoxyphenyl) -3-hydroxylmethylene-1H-pyrazol-5-ethylcarboxylate (1.5 g, 81%). %). MSGMS (M + H) &lt; + &gt; m / z: 277.

1- (4-Methoxyphenyl) -3-hydroxylmethylene-1H-pyrazole-5- (4'-pyrrolidinocarbonyl) anilide: A solution of 4- (4'-pyrrolidinoncarbonyl) aniline (390 mg, 2.05 mmol) in CH ₂ Cl ₂

V, (20 mL) at 0 ° C was added AIMe ₃ (2M in hexanes, 3 mmol). After stirring at room temperature for 15 min, a solution of 1- (492 methoxyphenyl) -3-hydroxylmethylene-1H-pyrazole-5-ethylcarboxylate (560 mg, 2.05 mmol) in CH ₂ Cl ₂ (5 mL) was added and the mixture was stirred overnight. The mixture was quenched with water (5 mL) and filtered through a pad of celite to remove Al (OH) ₃ . The filtrate was washed with water and brine, dried over MgSO, and _fourth Filtration, concentration, and purification by flash chromatography eluting with EtOAc-CH ₂ Cl ₂ afforded 1- (4-methoxyphenyl) -3-hydroxylmethylene-1H-pyrazole-5- (4'-pyrrolidinocarbonyl) anilide (570 mg, 67% yield). ESMS (M + Na) ⁺ m / z: 443. DSGMS (M + H) ⁺ calcd m / z: 420.1798, found 420.1771.

EXAMPLE

1- (4-Methoxyphenyl) -3-formaldehyde-1H-pyrazole-5- (4'-pyrrolidinocarbonyl) 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 mL). eq.) and the resulting mixture was refluxed for 12 hours. The mixture was filtered to remove excess MnO ₂ and concentrated the filtrate to give 1- (4-methoxyphenyl) -3-formaldehyde-1H-pyrazole-5- (4'-pyrrolidinocarbonyl) anilide as a solid in almost quantitative yield. MSGMS (M + H) &lt; + &gt; m / z: 419.

EXAMPLE

1- (4-Methoxyphenyl) -5- (4'-pyrrolidinocarbonyl) anilide-3-pyrazolecarboxylic acid To a solution of AgNO ₃ (34 mg, 0.2 mmol) in H ₂ O (0.5 mL) was added NaOH (16 mg, , 4 mmol), then a solution of 1- (4-methoxyphenyl) -3-formaldehyde-1H-pyrazole-5- (4'-pyrrolidinocarbonyl) anilide (42 mg, 0.1 mmol) in MeOH (0.5 mmol) was added at 0 ° C. ml). After stirring the resulting mixture at room temperature for 30 minutes, the mixture is carefully acidified. HCl (35 μΙ) to pH 22 and concentration gave a residue which was purified by flash chromatography to give 1- (4-methoxyphenyl) -5- (4'93 pyrrolidinocarbonyl) anilide-3-pyrazole carboxylic acid (25 mg, 58 %). ESMS (M + Na) ⁺ m / z; 456.9.

EXAMPLE

1- (4-Methoxyphenyl) -3-methylcarboxylate-1H-pyrazole-5- (4'-pyrrolidinocarbonyl) anilide to 1- (4-methoxyphenyl) -3-formaldehyde-1H-pyrazole-5- (4'-pyrrolidinocarbonyl) ) of 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 eluting with EtOAc to give 1- (4-methoxyphenyl) -3-methylcarboxylate-1H-pyrazole-5- (4'-pyrrolidinocarbonyl) anilide (38 mg, 85% yield). ESMS (M + Na) ⁺ m / z: 471.

EXAMPLE

1- ^(4! -Chlorfenil) -3-methyl-1 H-pyrazole-5 - [(2'-aminosulfonyl- [1, T] biphen-4-yl) carboxamide

This compound is prepared according to the procedure described in Example 1 using 4-chlorophenylhydrazine HCl in place of phenylhydrazine. 1- (4'-Chlorophenyl) -3-methyl-1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1''-biphen-4yl) carboxamide is obtained; DSGMS (M + H) ⁺ calcd m / z: 467.094465, found: 467.093532.

EXAMPLE 1 - ('- Chlorophenyl-5-methyl-1H-pyrazole-5-N' - 'aminosulfonyl-1-pyridyl-1'-phenyl] -4-yl) carboxamide

This compound is prepared according to the procedure described in Example 8 using 4-chlorophenylhydrazine-HCl in place of phenylhydrazine and using 2-amino-5- (2-N-t-butylaminosulfonylphenyl) pyridine in the coupling step.

The desired product is obtained: DSGMS (M + H) ⁺ calcd: 468.089714, found: 468.088873.

EXAMPLE

1- (3 ', 4'-Dichlorophenyl) -3-methyl-1H-pyrazole-5 - [(2'-aminosulionyl- [1,1'] - biphen-4-ylcarboxamide)

This compound is prepared according to the procedure described in Example 1 using 3,4-dichlorophenylhydrazine HCl in place of phenylhydrazine. The desired product is obtained; DSGMS (M + H) ⁺ calcd: 501.055493, found: 501.053920.

EXAMPLE

1- (3'-Chlorophenyl) -3-methyl-1H-pyrazol-5 - [(2'-aminosulfonyl- [1,1 '] - BIF ^en -4-yl) carboxamide

This compound is prepared according to the procedure described in Example 1 using 3-chlorophenylhydrazine-HCl in place of phenylhydrazine. The desired product is obtained; DSGMS (M + H) ⁺ calcd: 467.0944465, found: 467.091517.

EXAMPLE

2-Amino-4-phenyl-5 - [(2'-aminosulfonyl- [1.T] b ^_ <I ^en-4-yl) aminocarbonyl) thiazole

2-Amino-4-phenyl-5-carboethoxythiazole: To a solution of ethyl 3-phenyl-3-oxopropionate (5.0 g, 26.0 mmol) in 100 mL acetonitrile was added hydroxy (tosyloxy) iodobenzene (11.2 g, 28, 6 mmol). The resulting suspension was stirred at 65 ° C for 1 h; during this time, the reaction mixture becomes a homogeneous solution. Thiourea (2.2 g, 28.6 mmol) was added and stirring was continued at 65 ° C for 2 h. The mixture is cooled and concentrated, the residue is dissolved in ethyl acetate, washed with a saturated aqueous solution of Na ₂ CO ₃ and a saturated NaCl solution, dried (MgSO ₄ ) and concentrated. The residue is triturated with ethyl ether to give 4.9 g (70%) of the title compound as a yellow solid. ¹ H NMR (CDCl ₃ ) δ 7.65 (m, 2H), 7.39 (m, 3H), 5.98 (m.p., 2H), 4.18 (s, 2H), 1.22 ( t, 3H).

2-Amino-4-phenyl-5 - [(2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl) thiazole:? (2'-tert-butylaminosulfonyl- [1,1' ] -Biphen-4-yl) amino (0.68 g, 2.22 mmol) was added dropwise to 15 mL of methylene chloride at 25 ° C in trimethylaluminium (3.3 mL of a 2.0 M solution in toluene, 6.68 mmol). The resulting solution was stirred until no more gas evolution was observed (~ 15 min). 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 h, then cooled to 25 ° C and quenched with saturated aqueous NH ₄ Cl. After dilution with ethyl acetate, the organic layer is washed with 10% aq. HCl, saturated water NaHCO ₃ and brine, dried (MgSO ₄ ) and concentrated in vacuo. Purification of the residue by flash chromatography (eluting with 1: 1 hexanes / ethyl acetate) afforded 0.3 g (54%) of the title compound as a solid. MS (ESI) 507.1 (M + H) &lt; + &gt;.

2-Amino-4-phenyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl) · thiazole: 2-Amino-4-phenyl-5 - [(2'-tertiary) A solution of -butylaminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonylthiazole (80 mg, 0.16 mmol) in 3 mL of trifluoroacetic acid was stirred and refluxed for 20 min, then cooled to room temperature and concentrated in vacuo. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with H ₂ O / CH ₃ CN with a gradient of 0.5% TFA) to give, after lyophilization, 50 mg (71%) of the title compound as a white powder. MS (ESI) 451.0 (M + H) &lt; + &gt;.

i

EXAMPLE

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) aminocarbonylthiazole: solution of copper (II) chloride (54 mg, 0.4 mmol) 5 ml of acetonitrile was added tert-butyl nitrite (42 mg, 0.4 mmol). 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, 0.4) was added. mmol). Stirring at 80 ° C is continued for 1 hour; during this time the gas ceases to separate. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 10% aq. HCl, saturated water NaHCO ₃ , saturated with NaCl solution, was dried (MgSO ₄ ) and concentrated to give 0.2 g (95%) of the title compound which was used crude. 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'-tertiary) A solution of -butylaminosulfonyl- [1,1 '] -biphen-4-yl) aminocarbonylthiazole (100 mg, 0.19 mmol) in 5 mL of trifluoroacetic acid was stirred and refluxed for 20 min, then cooled to room temperature and concentrated in vacuo. . The residue was purified by preparative HPLC (C18 reverse phase column, eluting with H ₂ O / CH ₃ CN with a gradient of 0.5% TFA) to give, after lyophilization, 50 mg (56%) of the title compound as a white powder. MS (ESI) 469.9 / 471.9 (M + H) &lt; + &gt;.

EXAMPLE

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 in a 60% suspension in mineral oil, washed with hexane, 27.6 mmol) was added 50 ml of tetrahydrofuran. 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 h, 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 flash chromatography (eluting with 3: 1 hexane / ethyl acetate) 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: According to the procedure in Example 51, methyl 3- [3- (bromo) -4- (fluoro) -phenyl] - 3-Oxopropionate (1.0 g, 3.66 mmol) was converted to 0.6 g (50%) of the title compound. ¹ H NMR (CDCl 3) δ 7.97 (m, 1H), 7.90 (m.s, 2H), 7.68 (m, 2H), 3.61 (s, 3H).

2-Amino-4- [3- (bromo) -4- (fluoro) phenyl] -5 - ^[(2! -Aminosulfoni! - [1,1 '] - biphen-4-yl) aminocarbonyl) thiazole: By The procedure described in Example 51 is converted to 2-amino-4- [3- (bromo) -4- (fluoro) -phenyl] -5-carbomethoxythiazole (0.25 g, 0.75 mmol) to give the title compound which is white after purification by HPLC. powder. 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;.

EXAMPLE

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

According to the procedures described in Example 51, 4'-fluoroacetophenone is converted to the desired 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

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

According to the procedures described in Example 51, 3'-bromoacetophenone is converted to the desired 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), 7.60-7.45 (m, 6H), 7 30-7.22 (m, 4H), 7.18 (m.p., 2H), 5.4 (m.s, 2H). MS (ESI) 528.8 / 530.8 (M + H) ⁺ .

EXAMPLE

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

According to the procedures described in Example 52, the nitrogen of 2-amino-4- [3-bromophenyl] -5 - [(2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl) -aminocarbonyl) is converted to the desired compound - 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;.

EXAMPLE

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

Ethyl N- (4-methoxyphenyl) glycine: To a solution of 15.00 g (122 mmol) of p-anisidine in 100 mL of DMF N _{2 was} added 23.5 g (141 mmol) of ethyl bromoacetate and 14.95 g (141 mmol) of anhydrous of sodium carbonate. The mixture is heated at 70 ° C for 16 hours, then cooled to room temperature. water (500 mL) was added and the mixture was stirred vigorously until a precipitate formed. The solid is filtered off, washed with 100 ml of water and dried in vacuo to give 19.59 g (88%) of the desired product 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 (kv, J = 7.0, 2H) ), 4.10 (s, 1H), 3.86 (s, 2H), 3.75 (s, 3H), 1.28 (t, J = 7.0, 1H).

N- (4-Methoxyphenyl) glycine: To a solution of 19.59 g (108 mmol) of ethyl N- (4-methoxyphenyl) glycine in 100 mL of THF under N ₂ is added 5.44 g (130 mmol) of lithium hydroxide monohydrate in 25 mL of water. . After 15 or. the mixture is evaporated in vacuo to a volume of% initial volume, then acidified to pH 3 with concentrated hydrochloric acid to give a precipitate. The solid is filtered off, washed with 100 mL of water and then dried under vacuum to give 9.92 g (51%) of the title compound as a off-white solid. Ή NMR (CDCl ₃ ): δ 6.68 (d, J = 8.8, 2H), 6.49 (d, J = 8.8, 2H), 3.73 (s, 2H), 3.64 (s, 3H), 2.49 (s, 2H).

N- (4-Methoxyphenyl) -N-nitrosoglycine: To a suspension of N- (4-methoxyphenyl) glycine (9.92 g, 54.7 mmol) in 50 mL of water under N _{2 was} added sodium nitrite (3.97 g, 57). 5 mmol) in 10 mL of water. The mixture is stirred at room temperature until it becomes clear (about 6 hours). The solution is acidified to pH 3 with concentrated hydrochloric acid and a precipitate is formed. The solid is filtered off, washed with 50 ml of water, and then dried under vacuum to give 11.50 g (100%) of the title compound as a white solid. ¹ H NMR (CDCl ₃ ): δ 7.17 (d, J = 8.8, 2H), 6.70 (d, J = 8.8, 2H), 4.30 (s, 2H), 3, 56 (s, 3H); 2.29 (s, 2H).

N- (4-Methoxy-phenyl) -4-oxy-1,2,3-oxadiazole: N- (4-methoxyphenyl) -N-nitrosoglycine (11.50 g, 54.7 mmol) was dissolved in 100 mL of acetic anhydride and heated At 70 ° C for 14 hours. The reaction mixture was cooled and then poured into 300 ml of ice water. Stir for 30 minutes to decompose excess acetic anhydride; the reaction mixture was filtered to give 10.50 g (100%) of a clear, thick oil. ¹ H NMR (CDCl ₃ ): δ 7.65 (d, J = 9.2, 2H), 7.08 (d, J = 9.2, 2H), 6.63 (s, 1H), 3, 91 (s, 3H). MS (NH ₃ -Cl) m / z 193.3 (M + H) ⁺ .

1- (3-Cyanophenyl) -4-oxy-5-methylthio-1,2,3-oxadiazole: N- (4-Methoxyphenyl) -4-oxy-1,2,3-oxadiazole (2.03 g, 10.6 g) mmol) dissolved in 26 mL dry DMSO

100 and cooled to 0 ° C. Very slowly, _{under an} atmosphere of N _2, acetyl chloride (1.66 g, 21.1 mmol) is injected below the surface of the liquid. The reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with 100 mL Et ₂ O and washed twice with 25 mL saturated aqueous NaHCO ₃ , then three times with 25 mL water to remove DMSO. The organic extract is dried over MgSO ₄ and concentrated in vacuo to give 1.83 g of a red solid which is 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 propionate (6.45 g, 76.8 mmol) were dissolved in 10 mL of CH ₂ Cl ₂ and the quartz reaction vessel purged with N _2. The reaction mixture was irradiated in a Rayonet RPR-100 photochemical reactor for 14 h. The crude product is concentrated in vacuo, then chromatographed on silica gel eluting with 20% EtOAc / hexanes 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 (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'-butylaminosulfonyl- [1,1 '] -biphen-4-yl) -1- (4-methoxyphenyl) -3-methylthio · pyrazole-5-carboxamide: 2'-t-butylaminosulfonyl- To 4-amino- [1,1'J-biphen-4-yl (215 mg, 0.71 mmol) in CH ₂ Cl ₂ (5 mL) was added trimethylaluminum (1.4 mL, 2.0 M in heptane, 2.8 mmol). After stirring at room temperature under N _{2 for} 75 minutes, a solution of methyl 1- (4-methoxyphenyl) -3-methylthio-pyrazole-5-carboxylate (197 mg, 0.71 mmol) in CH ₂ Cl ₂ (2 mL) was added and the resulting solution stirred for 70 h. The reaction mixture was quenched by the dropwise addition of 1M HCl, diluted with H ₂ O and extracted with CH ₂ Cl ₂ . The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product is 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

101 (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- (2'-Aminosulfonyl- [1,1 '] -biphen-4-yl) -1- (4-methoxyphenyl) -3-methylthio-pyrazole-5-carboxamide: N- (2'-t-Butylaminosulfonyl- [1 , 1 '] - Biphen-4-yl) -1- (4-methoxyphenyl) 3-methylthio-pyrazole-5-carboxamide (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); a yellow solid was obtained (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

1- (4-Methoxyphenyl) -3- (methylsulfonyl) -N- (5- (2'-methylsulfonylphenyl) pyrimidin-2-yl) pyrazole-5-carboxamide

2- M Ethylthiophenylboronic acid: 2-Bromothioanisole (29.0 g, 143 mmol) was dissolved in dry THF (400 mL) and cooled to -75 ° C. Within 50 minutes n-BuLi (62.0 mL, 2.5 M in hexane, 155 mmol) was added. After stirring for 25 minutes, triisopropylborate (46 mL, 199 mmol) was added over 35 minutes. The cooling bath is removed and the reaction mixture is stirred at room temperature for 16 hours. The resulting solution was cooled in an ice bath and 6M HCl (100 mL) was added. This mixture is stirred at room temperature for 5 hours and concentrated to about half its initial volume. The concentrated solution is partitioned between Et ₂ O and water. The organic layer was extracted with 2 M NaOH, which was then acidified with 6M HCl and extracted several times back Et ₂ O. The Et ₂ O extracts were dried over Na ₂ SO _4, filtered and evaporated to give a brown 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).

102

2- [Bis (tert-Butoxycarbonyl) amino] -5-bromopyrimidine: To 2-amino-5-bromopyrimidine (10.0 g, 57 mmol) in dry THF (500 mL) at 0 ° C was added 2 times sodium hydride (5, 06 g, 60%, 127 mmol). After stirring for 30 min, di-t-butyl dicarbonate (27.6 g, 126 mmol) was added. The resulting mixture was refluxed for 17 hours, carefully quenched with water and concentrated. The concentrated mixture was diluted with EtOAc and extracted with water. The combined aqueous layers were extracted with ethyl acetate. All organic layers were combined, dried over Na ₂ SO _4l filtered and evaporated. The crude product is chromatographed on silica gel (10-15% EtOAc / hexanes) to give the desired product (15.48 g, 72%). Δ NMR (CDCl ₃ ): δ 8.78 (s, 2H), 1.47 (s, 18H).

2- [Bis (tert-Butoxycarbonyl) amino] -5- (2'-methylthiophenyl) pinimidine: 2- [Bis (tert-Butoxycarbonyl) amino] -5-bromopyrimidine (2.00 g, 5.3 mmol) is dissolved in benzene (130 mL). 2-Methylthiophenylboronic acid (2.24 g,

13.3 mmol), vand. 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 is first purged of air, purged with argon, then refluxed for 17 hours. The cooled mixture was diluted with EtOAc and water. The layers were separated, 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 re-chromatographed on silica gel (30-50%).

EtOAc / hexanes) to give the desired product (2.13 g, 96%). ¹ H 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'-methylsulfonylphenyl) pinimidine: 2 [Bis (tert-butoxycarbonyl) amino] -5- (2'-methylthiophenyl) pyrimidine (2.13 g, 5, 1 mmol) was dissolved in MeOH (20 mL) and cooled to 0 ° C. In a separate beaker, prepare a solution of oxone (5.49 g), diluting to 27 ml with water.

Part of this solution (17 mL, 5.6 mmol) was separated and saturated Na3PO ₄ solution (4.7 ml) adjusted to pH 4.2. The mixture was poured into the reaction and stirred for 23 hours.

103 at room temperature. The resulting mixture was diluted with water and extracted with CHCl ₃ . The organic extracts are mixed, washed with water and. brine, dried over Na2S _4, filtered and evaporated. The crude product was chromatographed on silica gel (50-100% EtOAc / hexanes) to give the broth (1.28 g, 56%). ¹ H NMR (CDCl 3): δ 8.81 (s, 2H), 8.28 (dd, 1H, J = 7.6, J 1 = 1.4), 7.72 (m, 2H), 7 39 (dd, 1H, J = 7.3, J '= 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) is suspended in HCl / dioxane ( 10 mL, 4.0 M) and stirred for 20 h. 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 + a few drops of MeOD): 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), 2.9476 (s, 3H).

Methyl 1- (4-methoxyphenyl) -3-methylsulfonylpyrazole-5-carboxylate: Methyl 1- (4-methoxyphenyl) -3-methylthio-pyrazole-5-carboxylate (434 mg, 1.6 mmol) in CH ₂ Cl ₂ (40 ml) m-CPBA (1.18 g, 57-86%, 3.9 mmol) was added and stirred at room temperature for 24 h. Additional m-CPBA (600 mg, 57-86%, 1.9 mmol) was added and stirred for 2.5 days. The reaction mixture was extracted with saturated Na ₂ SO ₄ 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 / hexanes) to give the desired product (416 mg, 86%). Ή NMR (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-Methoxy-phenyl) -3-methylsulfonyl-pyrazole-5-carboxylic acid: A suspension of methyl 1- (4-methoxy-phenyl) -3-methyl-sulfonyl-pyrazole-5-carboxylate (272 mg, 0.88 mmol) in MeOH (10 mL) was added. hydroxide solution (1.3 mL, 1.0 M, 1.3 mmol) and stirred at room temperature for 17 h. The resulting mixture was concentrated and partitioned between EtOAc and H ₂ O. Organic extract

104 was poured out and the aqueous extract was acidified with 1M HCl and extracted twice with EtOAc. The organic extracts of this extraction were combined, dried over Na ₂ SO ₄ , filtered and evaporated to give the product (266 mg).

¹ H NMR (CDCl ₃ + several drops of 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-carboxamide: 1- (4-Methoxyphenyl) -3-methylsulfonylpyrazole- A solution of 5-carboxylic acid (262 mg, 0.88 mmol) in dry CH ₂ Cl ₂ (5 mL) was added at room temperature to oxalyl chloride (120 μΙ, 1.4 mmol) and dry DMF (2 drops) and stirred under N _{2 for} 2 h. The resulting solution was evaporated and the residue briefly maintained in a deep vacuum, then redissolved in CH ₂ Cl ₂ (2 mL). 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 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 h, diluted with CH ₂ Cl ₂ , extracted with H ₂ O, dried over Na ₂ SO ₄ , filtered and evaporated. The crude product is chromatographed on silica gel (75100% EtOAc / hexanes) to give the crude white solid which is dissolved in toluene and filtered to give the pure product (191 mg, 41%). Ή 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

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

N- (2'-t-Butylaminosulfonyl- [1,1 '] - biphen-4-yl) -1- (4-methoxyphenyl) -3 (methylsulfonyl) -1H-pyrazole-5-carboxamide: 2'-t -Butylaminosulfonyl-4-amino- [1,1 '] - biphen-4-yl (142 mg, 0.47 mmol) in CH ₂ Cl ₂ (5 mL) was added trimethylaluminum (930 μΙ, 2.0 M in heptane, 1.86 mmol ). After mixing the room

A solution of methyl 1- (4-methoxyphenyl) -3-methylsulfonyl-pyrazole-5-carboxylate (145 mg, 0.47 mmol) in CH ₂ Cl ₂ (2 mL) was added at 105 ° C under N _{2 for} 60 min, and the resulting solution was stirred for 51 min. or. The reaction mixture was quenched by careful dropwise addition of 0.1 M HCl, diluted with H ₂ O and extracted twice with 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 (pi, 1H), 8.16 (dd, 1H, J = 7.6, J '= 1.1), 7.57 (m, 3H), 7 46 (m, 5H), 7.39 (s, 1H), 7.27 (d, 1H, J = 7.3), 6.99 (d, 2H, J = 8.8), 3.86 ( s, 3H), 3.31 (s, 3H), 1.03 (s, 9H).

N- (2'-Aminosulfonyl- [1,1 '] - biphen-4-yl) -1- (4-methoxyphenyl) -3- (methylsulfonyl) · 1H-pyrazole-5-carboxamide: N- (2'-t -Butylaminosulfonyl- [1,1 '] -biphen-4-yl) -1- (4-methoxyphenyl) -3- (methylsulfonyl) pyrazole-5-carboxamide (274 mg, 0.47 mmol) was stirred in TFA (5 mL) 74 or . The solvent is evaporated. The crude product was recrystallized from CHCl ₃ to give a white solid (236 mg, 95%). ¹ H NMR (CDCl 3 + a few drops of 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

N- (4-Benzoylpyrrolidino) -1- (4-methoxyphenyl) -3- (methylthio) -1H-pyrazole-5-carboxamide

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

106

%). 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-Benzoylpyrrolidino) -1- (4-methoxyphenyl) -3- (methylthio) -1H-pyrazole-5-carboxamide: 1- (4-Methoxyphenyl) -3-methylthio-1H-pyrazole-5-carboxylic acid ( Oxalyl chloride (140 μΙ, 1.6 mmol) and dry DMF (2 drops) were added (275 mg, 1.0 mmol) in dry CH 2 Cl 2 (8 mL) and stirred under N _{2 for} 100 min. The resulting solution was evaporated and the residue was briefly maintained under a deep vacuum, then redissolved in CH ₂ Cl ₂ (8 mL). (4-Aminobenzoyl) pyrrolidine (198 mg, 1.0 mmol) was added followed by 4-dimethylaminopyridine (190 mg, 1.6 mmol). The resulting solution was stirred at room temperature for 17 h, 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 saturated NaCl solution. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product is chromatographed on silica gel (75-100% EtOAc / hexanes) to give the desired product (464 mg, 100%). ¹ H NMR (CDCl 3): δ 7.91 (pi,

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

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

1- (4-M Ethoxyphenyl) -N- (5- (2'-methylsulfonylphenyl) pyrimidin-2-yl) -3- (methylthio) -1H-pyrazole-5-carboxamide: To 2-Amino-5- (2 ') -methylsulfonylphenyl) pyrimidine hydrochloride (208 mg, 0.73 mmol) in CH ₂ Cl ₂ (5 mL) was added trimethylaluminum (1.5 mL, 2.0 M in heptane, 3.0 mmol). After stirring at room temperature under N _{2 for} 75 min, 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) was added, and the resulting solution was stirred for 70 h. The reaction mixture was quenched by careful dropwise addition of 1M HCl,

107 was diluted with 1M HCl and extracted with CH2Cl2. The organic layer was dried over Na ₂ SO 4, filtered and evaporated. The crude product is chromatographed on silica gel (50-100% EtOAc / hexanes) to give the desired product (101 mg, 28%). This material was mixed with 19 mg of material from another reaction and purified by preparative HPLC over a C-18 reverse phase column (30-100% MeCN / H ₂ O / 0.05% TFA); a white powder (111 mg) is obtained. ¹ H NMR (CDCl 3): δ 8.67 (s, 2H), 8.24 (d, 1H, J = 7.3), 7.71 (m, 2H), 7.44 (d, 2H, J = 9.1), 7.33 (d, 1H, J = 8.4), 6.96 (d, 2H, J = 9.2),

6.86 (s, 1H), 3.84 (s, 3H), 2.79 (s, 3H), 2.59 (s, 3H).

EXAMPLE

N- (4-Benzoylpyrrolidino) -1- (4-methoxyphenyl) -3- (methylsulfonyl) -1H-pyrazole-5-carboxamide

N- (4-Benzoylpyrrolidino) -1- (4-methoxyphenyl) -3- (methylsulfonyl) -1H-pyrazole-5 5-carboxamide: N- (4-Benzoylpyrrolidinone) -1- (4-methoxyphenyl) - 3- (Methylthio) -1H-pyrazole-5-carboxamide (200 mg, 0.46 mmol) was dissolved in MeOH (6 mL). 1 ... A solution of oxone (561 mg, 0.91 mmol) in water (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 over a C-18 reverse phase column (10-70% MeCN / H2O / 0.05% TFA) to give a white powder (200 mg,

%). 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

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

108

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-1H-pyrazole-5-carboxylate (2.00 g, 7.83 mmol) was dissolved in 30 mL of CCl 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, then cooled to room temperature. The succinimide is filtered off and the solvent is evaporated. The reaction mixture was chromatographed on silica gel (20% EtOAc / hexanes) to give 0.94 g (36%) of monobromide. ¹ H NMR (CDCl 3): δ 7.34 (d, J = 8.8, 2H), 7.06 (s, 1H), 6.96 (d, J = 8.8, 2H), 4.53 (s,

2H), 4.24 (kv, J = 7.0, 2H), 3.85 (s, 3H), 1.27 (t, J = 7.0, 3H). Dibromide (0.34 g, 10%) is 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 (s, 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 M NaOMe in methanol and refluxed for 14 hours. The reaction mixture is cooled and evaporated to 1/10 of its original volume. The reaction mixture was dissolved in 20 mL of water and extracted with EtOAc. The aqueous mixture was acidified with 1N HCl and extracted with EtOAc to give 0.236 g (61%) of the desired product. A mixture of ethyl and methyl esters (~ 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, 2H), 3.85 (s, 3H), 3.44 (s, 3H).

N- (2'-t-ButhaminosulfoneH- [1,1'J-biphen-4-yl) -1- (4-methoxyphenyl) -3 (methoxymethyl) -1H-pyrazole-5-carboxamide: To 1- (4) -methoxyphenyl) -3 (methoxymethyl) -1H-pyrazole-5-carboxylic acid (236 mg, 0.90 mmol) in dry CH ₂ Cl ₂ (5 mL) at room temperature was added oxalyl chloride (460 mg, 3.6 mmol) and dry DMF (2 drops), and stirred under N _{2 for} 2 h. The resulting solution was evaporated and the residue briefly maintained in a deep vacuum, then redissolved in CH ₂ Cl ₂ (2 mL). Add this solution to a solution of 2'-butylaminosulfonyl-4-amino- [1,1 '] - biphen-4-yl (288 mg, 0.945 mmol) in 5 mL over several minutes.

109

CH ₂ Cl ₂ . The resulting solution was stirred at room temperature under N _{2 for} 23 h, 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) m / z 571.0 (M + Na) ⁺ .

N- (2'-Aminosulfonyl- [1,1 '] - biphen-4-yl) -1- (4-methoxyphenyl) -3- (methoxymethyl) 1H-pyrazole-5-carboxamide: N- (2'-t -Butylaminosulfonyl- [1,1 '] - biphen-4-yl) -1- (4-methoxyphenyl) -3- (methoxymethyl) -1H-pyrazole-5-carboxamide (110 mg, 0.20 mmol) was dissolved in 5 mL of TFA and Stir at room temperature for 16 hours. The solvent was evaporated and the product was purified by preparative HPLC over 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 (m.s, 1H), 7.53 (m, 4H), 7.43 (m, 4H), 7.32 (d, J = 7.3, 1H), 7.01 (s, 1H), 6.96 (d, J = 9.2, 2H), 4.59 (s, 2H) , 4.26 (m.p., 2H), 3.86 (s, 3H), 3.49 (s, 3H), DSGMS m / z 493.1546 (M + H) ⁺ .

EXAMPLE

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

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) dissolved in 2 mL of THF, lithium hydroxide (34 mg, 0.816 mmol) was also dissolved in 0.5 mL of water and poured into methanolic solution. After stirring at room temperature for 16 h, the solvent was evaporated, the residue was dissolved in 10 mL of water, acidified with 1N HCl, and extracted with EtOAc and evaporated to give 66 mg (33%) of the desired product. ¹ H NMR (CDCl ₃ ): δ 10.06 (s, 1H), 7.56 (s, 1H), 7.40 (d, J = 9.1, 2H), 7.01 (d, J = 9.1, 2H), 4.54 (s, 2H), 3.88 (s, 3H).

110

N- (2'-t-Butylaminosulfonyl- [1,1 '] - biphen-4-yl) -3-formyl-1- (4-methoxyphenyl) -1H-pyrazole-5-carboxamide: to 3-formyl-1- ( 4-Methoxyphenyl) -1H-pyrazole-5-carboxylic acid (66 mg, 0.25 mmol) in dry CH ₂ Cl ₂ (2 mL) at room temperature was added oxalyl chloride (20 μ25, 0.25 mmol) and dry DMF (2 drops) and stirring under N _{2 for} 2 h. The resulting solution was evaporated and the residue briefly maintained in a deep vacuum, then redissolved in CH ₂ Cl ₂ (2 mL). This solution was poured into a solution of 2'-t-butylaminosulfonyl-4-amino [1,1'J-biphen-4-yl (51 mg, 0.17 mmol) in 2 mL CH ₂ Cl ₂ over several minutes. The resulting solution was stirred at room temperature under N _{2 for} 23 h, 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 (ss, 1H), 7.56 (m, 3H ), 7.49 (m, 4H), 7.40 (m, 1H), 7.25 (m, 2H), 7.04 (d, J = 8.8, 2H), 3.89 (s, 3H), 3.61 (ss, 1H), 1.02 (s, 9H).

N- (2'-t-Butylaminosulfonyl- [1,1 '] - biphen-4-yl) -3-carbomethoxy-1- (4'-methoxyphenyl) -1H-pyrazole-5-carboxamide: N- (2'- t-Butylaminosulfonyl- [1,1 '] biphen-4-yl) -3-formyl-1- (4-methoxyphenyl) -1H-pyrazole-5-carboxamide (16.2 mg, 0.03 mmol), KCN ( 6.9 mg, 0.11 mmol), manganese dioxide (activated) (100 mg) and acetic acid (1.7 μΙ, 0.03 mmol) were dissolved / suspended in 1 ml methanol and stirred at room temperature for 24 hours. The reaction mixture was filtered through celite and evaporation gave 14 mg (82%) of the desired product. ¹ H NMR (CDCl 3): δ 8.16 (d, J = 8.1, 1H), 7.67 (m.s, 1H), 7.53 (m, 3H), 7.48 (m, 4H) ), 7.27 (m, 2H), 7.02 (d, J = 8.8, 2H), 3.99 (s, 3H), 3.87 (s, 3H), 1.02 (s, 9H).

N- (2'-aminosulfonyl- ^[1,1] -biphen-4-yl) -3-carbomethoxy-'l- (4-methoxyphenyl) -1H-pyrazol-5-carboxamide: N- (2'-t-butylaminosulfonyl - [1,1 '] -Biphen-4-yl) -3-carbomethoxy-1- (4-methoxyphenyl) -1H-pyrazole-5-carboxamide (14 mg, 0.02 mmol) was dissolved in 2 mL of TFA and stirred at room temperature for 16 h. or. The solvent was evaporated and the product was purified by preparative HPLC over C-18

111 reverse phase column (10-90% MeCN / H ₂ 0 / 0.05% TFA) to give a white powder (9 mg, 81%). Ή NMR (CDCl _3): δ 8.16 (d, J = 8.1, 1H), 7.67 (br s,

1H), 7.50 (m, 11H), 7.31 (d, J = 7.0, 1H), 7.00 (d, J = 8.8, 2H), 4.59 (s, 2H) ),

4.20 (m.p., 2H), 3.99 (s, 3H), 3.87 (s, 3H), DSGMS m / z 507.1260 (M + H) ⁺ .

EXAMPLE

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

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 THF with potassium thiomethoxide (0.248 g, 2.88 mmol) and reflux for 14 hours. The reaction mixture is cooled and evaporated to 1/10 of its original volume. This reaction mixture was dissolved in 20 mL of water, extracted with EtOAc and oxidized in air for 24 h. 0.358 g of crude mixture is obtained. The product was purified by preparative HPLC over a C-18 reverse phase column (10-90% MeCN / H ₂ O / 0.05% TFA) to give the desired product as a white powder (47 mg, 11%). ¹ H NMR (CDCl 3): δ 7.32 (d, J = 8.8, 1H), 7.18 (s, 1H), 6.97 (d, J = 8.8, 2H), 4.37 (s, 2H), 4.25 (s, J = 7.1, 2H), 3.86 (s, 3H), 1.28 (t, J = 7.1, 3H).

N- ^{(2-t-butylaminosulfonyl-} _[1! 1 '] - biphen-4-yl) -1- (4-methoxyphenyl) -3 (metilsulfonilmetil) -1H-pyrazole-5-carboxamide To 2'-t trimethylaluminum (0.41 mL, 2.0 M in heptane, 0) was added butylaminosulfonyl-4-amino- [1,1 '] -biphen-4-yl (50.6 mg, 0.166 mmol) in CH ₂ Cl ₂ (5 mL). 83 mmol). After stirring at room temperature under N _{2 for} 75 min, a solution of ethyl 1- (4-methoxyphenyl) -3- (methylsulfonylmethyl) -1H-pyrazole-5-carboxylate (47 mg, 0.139 mmol) in CH ₂ Cl ₂ (2 mL) was added, and the resulting solution was stirred for 70 h. The reaction mixture was quenched by the dropwise addition of 1M HCl, diluted with H ₂ O and extracted with CH ₂ Cl ₂ . The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product is purified by preparative HPLC over a C-18 reverse phase column (10-90% MeCN / H ₂ O / 0.05% TFA) to give

112 desired product (80 mg, 100%), 1 H NMR (CDCl 3): δ 8.16 (d, J = 8.1, 1H),

7.76 (ss, 1H), 7.49 (m, 8H), 7.27 (m, 1H), 7.08 (m, 1H). 7.01 (d, J = 8.8, 2H),

4.41 (s, 2H), 3.87 (s, 3H), 2.96 (s, 3H), 1.02 (s, 9H).

N- (2'-Aminosulfonyl- [1,1 '] -biphen-4-yl) -1- (4-methoxyphenyl) -3- (methylsulfonylmethyl) -1H-pyrazole-5-carboxamide: N- (2'- t-Butylaminosulfonyl- [1,1 '] - biphen-4yl) -1- (4-methoxyphenyl) -3- (methylsulfonylmethyl) -1H-pyrazole-5-carboxamide (80 mg, 0.15 mmol) Dissolve in 2 ml TFA and stir at room temperature for 16 hours. The solvent was evaporated and the product was purified by preparative HPLC over a C-18 reverse phase column (10-90% MeCN / H ₂ O / 0.05% TFA) to give a white powder (47 mg, 58%). Δ NMR (CDCl3): δ 8.16 (d, J = 8.1, 1H), 8.06 (ppm, 1H), 7.60 (m, 4H), 7.44 (m, 4H) , 7.33 (m, 1H), 7.09 (s, 1H), 7.01 (d, J = 9.1, 2H), 4.43 (s, 2H), 4.38 (m.p. .s, 2H), 3.87 (s, 3H), 2.97 (s, 3H). DSGMS m / z 541.1137 (M + H) ⁺ .

EXAMPLE

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

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazol-5- (N- (5- (2-methanesulfonyl) phenyl) pyrimidin-2-yl) carboxamide; This material is prepared according to the procedures described in Example 15 except that the 4- (2N-t-butylaminosulfonyl) phenyl) aniline is substituted for 2-amino-5- (2-methanesulfonyl) phenyl) -pyrimidine in the coupling step. Purification by HPLC using a gradient elution of water: acetonitrile with 0.05% trifluoroacetic acid in a reverse phase C18 column (60 A) afforded a pure sample of the title compound: DSGMS (M + H) ⁺ calcd m / z: 518.110986. , found: 518.108715.

EXAMPLE

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

113

N- (4-Nitrobenzoyl) -2-carbomethoxypyrrolidine: 2-carbomethoxypyrrolidine (dl-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 was added dropwise to 4-nitrobenzoyl chloride (2.36 g, 12.7 mmol) in CH ₂ Cl ₂ (25 mL). The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was evaporated and applied to a flash silica gel column eluting with a gradient of 2: 1 hexane: EtOAc to 1: 2 hexane: EtOAc. 1.3 g of the title compound are isolated; MSGMS (M + H) &lt; + &gt; m / z = 279.

N- (4-Aminobenzoyl) -2-carbomethoxypyrrolidine: Shake N- (4-Nitrobenzoyl) -2-carbomethoxypyrrolidine (0.54 g, 1.94 mmol) in MeOH (50 mL) with 10% Pd-C (0.10 g). of gaseous H ₂ (345 kPa) for 4 hours. The reaction mixture was filtered through a pad of Celite® and evaporated to give 0.41 g of this aniline; MSGMS (M + H) &lt; + &gt; m / z = 249.

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (N-carboxyl-2-carbomethoxypyrrolidino) phenyl) carboxamide: This compound is prepared according to the procedures described in Example 19 except that the N- (4-aminobenzoyl) 2-carbomethoxypyrrolidine is used in place of 2-amino-5- (N-pyrrolidinocarbonyl) pyridine The solvent is evaporated, the residue is dissolved in ethyl acetate and washed with water, and the crude product is purified by HPLC using water gradient elution: acetonitrile with 0.05% trifluoroacetic acid in a reversed phase C18 column (60 A) to give a pure sample of the title compound, mp 46 ° C, DSGMS (M + H) ⁺ calcd m / z: 462.190320, found: 462.188795.

EXAMPLE

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

114

3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (N-carboxyl-3-azidopyrrolidinino) phenyl) carboxamide: J 3-Methyl-1- (4-methoxyphenyl) - 1H-pyrazole-5-Ν (4- (N-carboxyl-3-hydroxypyrrolidino) phenyl) carboxamide (prepared in Example 21, 0.14 g, 0.33 mmol) with Et ₃ N (0.05 g, 0, Methanesulfonyl chloride (0.057 g, 0.05 mmol) in CH ₂ Cl ₂ (5 mmol) was added and after 18 h, the reaction was complete: evaporated, dissolved in EtOAc, washed with 1N HCl, dried and evaporated to give 0.21 g of methanesulfonate; -SO ₂ CH ₃ ) ⁺ m / z = 403.

This previously prepared methanesulfonate (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 h. Saturated NaCl solution 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 azide; MSGMS (MN ₂ ) ⁺ m / z = 418.

3- Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (N-carboxyl-3-aminopyrrolidino) phenyl) carboxamide: This previously prepared azide (0.10 g, 0.22 mmol) MeOH (20 mL) was stirred with 10% Pd-C in gaseous H ₂ atmosphere (101.3 kPa) After 2 hours the reaction mixture was purged with N ₂ , filtered through a pad of Celite® and evaporated. gradient elution of water: acetonitrile with 0.05% trifluoroacetic acid over a reverse phase C18 column (60 A) to give a pure sample of the title compound, mp 133.4 ° C, DSGMS (M + H) ⁺ calcd. / z: 420.203565, found: 420.203373.

69'S EXAMPLE

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

4- (N-Carboxyl-3-methoxypyrrolidine) aniline: To a solution of 3-hydroxypyrrolidine hydrochloride (1.63 g, 14.9 mmol) and triethylamine (1.51 g, 14, mmol) in dichloromethane (50 mL) at 0 ° C of p-nitrobenzoyl chloride at room temperature

A solution of 115 (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. The solution was washed with 1N hydrochloric acid and saturated NaCl solution, then dried and evaporated to give 2.22 g of product; MSGMS (M + H) @ ⁺ m / z:

237.

A suspension of NaH (0.16 g, 60% in mineral oil, 6.89 mmol) in THF (30 mL) was added dropwise to a solution of the previously prepared hydroxy compound (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 room 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 the methyl ester (0.47 g); MSGMS (M + H) &lt; + &gt; m / z: 251.

A solution of this methyl ester (0.42 g, 1.68 mmol) in MeOH (50 mL) with 10% Pd-C (0.05 g) was stirred under gaseous H ₂ (101.3 kPa) for 3 h. The reaction mixture was purged with N ₂ , filtered through a pad of Celite®, and evaporated to give 0.28 g of the desired aniline; MSGMS (M + H) &lt; + &gt; m / z: 221.

3-Meph-7-7- (4-mephoxy-phenyl) -7H-piperazin-5 - {[N - (4 - ((N-) - arbor 7-3-mepho) / '· Pyrrolidino) phenyl) carboxamide: This compound is prepared according to the procedures described in Example 19 except that the

2-Amino-5- (N-pyrrolidinocarbonyl) pyridine is used in 4- (N-carboxyl-3-methoxypyrrolidine) aniline. The solvent was evaporated and the residue was dissolved in ethyl acetate and washed with water. After drying and evaporation of the solvent, the crude product is purified by HPLC using a gradient elution of water: acetonitrile with 0.05% trifluoroacetic acid over a reverse phase C18 column (60 A) to give a pure sample of the title compound; melt temp. 40.2 ° C, DSGMS (M + H) ⁺ calcd m / z: 434.195406, found: 434.194469.

EXAMPLE%

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazol-5- (N- (5- (2aminosulfonyl) phenyl) pyridin-2-yl) carboxamide

116

3- Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazol-5- (N- (5- (2-aminosulfonyl) phenyl) pindin-2-yl) carboxamide: This material is prepared according to the procedures described in Example 15 except that copulation stage instead

4- (2-Nt-Butylaminosulfonyl) phenylaniline is 2-amino-5- (2-N-tbutylaminosulfonyl) phenyl) pyridine. The t-butylsulfonamide group is cleaved by refluxing TFA for 1 h. Purification of the final product by HPLC using a gradient elution of water: acetonitrile with 0.05% trifluoroacetic acid over a reverse phase C18 column (60 A) afforded a pure sample of the title compound: DSGMS (M + H) ⁺ calcd m / z: 518 , 110986, found: 518.112930.

EXAMPLE

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4amidino) phenyl) carboxamide · TFA

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-cyano) phenyl) carboxamide: 3-trifluoromethyl-5-methyl-1- (4-methoxyphenyl) -1H- pyrazole (Example 15, 0.6 g, 2.1 mmol) in CH ₂ Cl ₂ (20 mL) at 0 ° C was added oxalyl chloride CH ₂ Cl ₂ (2M solution, 1.6 mL, 3.15 mmol) followed by several drops DMF. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was evaporated and vacuum evacuated for several hours to remove traces of HCl. This chloroanhydride was mixed with paminobenzonitrile (0.3 g, 2.52 mmol) and DMAP (0.77 g, 6.3 mmol) in CH ₂ Cl ₂ (40 mL) and stirred at room temperature for 18 h. The reaction mixture was evaporated and then partitioned between 1N HCl and EtOAc. The EtOAc layer was dried and evaporated to give 0.79 g of crude product. Further purification was done by MPLC over a 200 g silica gel column, eluting with 3: 1 hexane: EtOAc and collecting 25 mL fractions. 0.25 g of the desired nitrile is obtained from fractions 30-65: m.p. temp. 188.2 ° C; DSGMS (M + H) ⁺ calcd m / z: 386.099081, found: 386.098101. ^%

117

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (O-methyl) formimino) phenyl) carboxamide · ΗΟΙ: Through 3-trifluoromethyl-1- (4-methoxyphenyl) - A solution of 1H-pyrazole-5 (N- (4-cyano) phenyl) -carboxamide (225 mg, 0.58 mmol) in dry MeOAc (25 mL) and dry MeOH (5 mL) was allowed to dry at 0 ° C until dry gas HCl was added. until the solution is saturated. After 18 hours. At 10 ° C, the stoppered flask is opened and the solvent is distilled off under vacuum. The residue is evaporated again by the addition of dry Et2O, followed by vacuum for several hours to remove traces of HCl.

3-Tr / Y / Fluor / Neph (7-i-f4-mephox / phen / 7) -1H-pyrazo / -5-fN-f4-a / n / d / no) Phen / 7) Carboxamide · TFA: This previously prepared imidate (0.58 mmol) was dissolved in dry MeOH (10 mL) and (NH ₄ ) 2 CO ₃ (0.32 g, 3.33 mmol) was added. The mixture is stirred at room 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 over a reverse phase C18 column (60 A) gives a pure sample of the title compound; melt temp. 232.5 ° C; DSGMS (M + H) ⁺ calcd for m / z: 404.133435, found: 404.132331. *

EXAMPLE

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (N-pyrrolidino) formylimino) phenyl) carboxamide · TFA

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (N-pyrrolidino) formylimino) phenyl) carboxamide * TFA; The previously prepared 3-trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (0-methyl) formimino) -phenyl) carboxamide HCl (Example 71, 0.58 mmol) was dissolved in dry MeOH (10 mL). ml) and pyrrolidine (0.12 g, 1.74 mmol) was added. The mixture was stirred at room 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 over a reverse phase C18 column (60 A) gives a pure sample of the title compound; melt

118 temp. 89.5 ° C; DSGMS (M + H) ⁺ calcd m / z: 458.180385, found:

458.183032.

EXAMPLE

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: 1,1,1-Trifluoroacetaldehyde ethyl semi-acetal (4.2 g, 34.17 mmol) and 4-methoxyphenylhydrazine-HCl (4.97 g, 28.48 g). The mixture is heated to reflux in EtOH (100 mL) and cooled to room temperature after all components have dissolved. The reaction mixture is evaporated to dryness to give 5.34 g of a black oil which is used in the crude stage; MSGMS (M + H) &lt; ⁺ &gt; m / z = 219.2.

1,1,1-Trifluoroacetoyl bromide-N- (4-methoxyphenyl) hydrazone: To this black oil (0.87 g, 4 mmol) in DMF (25 mL) at 0 ° C was added Nbromosuccinimide (0.72 g, 4 mmol) in portions. ). The reaction is complete within 2 hours. (TLC, 3: 1 Hexane: EtOAc). The reaction mixture was diluted with saturated NaCl solution and extracted with EtOAc. The extracts are washed with brine (5x), dried (MgSO ₄ ) and evaporated to give 0.69 g of product which is a black oil. This material is used crude.

4- (2-Nt-Butylaminosulfonyl) phenyl) bromomaleimide: bromo-maleic anhydride (0.29) was added to 4- (2-Nt-butylaminosulfonyl) phenyl) aniline (0.5 g, 1.65 mmol) in THF (10 mL). g, 1.65 mmol). After 1 or. the solution was cooled to 0 ° C, 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 room temperature and stirred for 18 hours. The reaction mixture was evaporated, dissolved in EtOAc, washed with 1N HCl, dried and evaporated. The product was purified by MPLC using a 200 g silica gel column chromatography eluting with 3: 1

119 hexane: EtOAc; 25 ml fractions are collected. The desired product (0.39 g) is isolated from fractions 35-65; DSGMS (M + H) ⁺ calcd m / z: 462.024890, found: 462.025783.

3-Trifluoromethyl-5- (N- (2'-Nt-butylaminosulfonyl- [1,1 '] - biphen-4-yl)) - 1- (4-methoxyphenyl) pyrrolo [3,4-d] pyrazole-4,6 - (1H, 5H) 'dione: 1,1,1-Trifluoroacetoyl bromide-N- (4-methoxyphenyl) hydrazone (0.68 g, 2.29 mmol) and 4- (2-N-t-butylaminosulfonyl) phenyl) bromomaleimide (0.2 g, 0.4 mmol) in Et ₃ N (0.35 g, 3.45 mmol) in toluene was refluxed for 3 hours. The reaction mixture was diluted with EtOAc, washed with 1N HCl, dried (MgSO ₄ ) and evaporated to give 0.35 g of crude product. This product was isolated by MPLC eluting the crude material from a flash column of silica gel (200 g) in 3: 1 hexane: EtOAc to collect 25 mL fractions. The pure material (0.15 g) was isolated from fractions 33-58; melt temp.

196.1 ° C; DSGMS (M + H) ⁺ calcd m / z: 653.165176, found: 653.166000.

3-Trifluoromethyl-5- (N- (2'-aminosulfonyl-1,1'J-biphen-4-yl)) - 1- (4-methoxyphenH) · pyrrolo [3,4-d] pyrazole-4,6 - (1H, 5H) -dione: The product obtained above (0.15 g, 0.25 mmol) was refluxed with TFA for 1 h. After cooling and evaporating the reaction mixture, 0.14 g of crude material is obtained. The product was isolated by MPLC eluting the crude material from a flash column of silica gel (200 g) in 2: 1 hexane: EtOAc to collect 25 mL fractions. Fractions 55-90 are mixed and triturated with a small amount of Et ₂ O. 0.06 g of pure material is obtained; melt temp. 210.7 ° C; DSGMS (M + H) ⁺ calcd m / z 543.095002, found 543.097942.

EXAMPLE

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

AND EXAMPLE 75

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

120

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5-carbomethoxy- (N '(2'-tert-butylaminosulfonyl- [1,1'] - biphen-4-yl)) carboxamide and 3-trifluoromethyl Preparation of -1- (4-methoxyphenyl) -1H-pyrazole-5-hydroxymethyl- (N- (2'-Nt-butylaminosulfonyl [1,1 '] - biphen-4-yl)) carboxamide: J NaBH ₄ (0.096 g, A solution of 2.48 mmol) in MeOH (20 mL) was added dropwise at 0 ° C to 3-trifluoromethyl-5 (N- (2'-Nt-butylaminosulfonyl- [1,1 '] -biphen-4-yl)) - 1 - ( A solution of 4-m ethoxyphenyl) pyrrolo [3,4-d] pyrazole-4,6- (1H, 5H) -dione (0.37 g, 0.62 mmol) in AcCN (30 mL). The reaction is completed in less than 1 hour. (TLC, 3: 1 Hexane: EtOAc). The mixture was evaporated, dissolved in EtOAc and washed with 1N HCl. The organic layer was dried and evaporated to give the title compound (0.37 g). This mixture was partitioned by MPLC using a 400 g silica gel column column and eluting with 2: 1 hexane: EtOAc to collect 25 mL of eluate.

Fractions 50-66 isolate 3-trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5-carbomethoxy- (N- (2'-tN-butylaminosulfonyl- [1,1 '] - biphen-4-yl)) carboxamide (0.15 g); DSGMS (M + Na) ⁺ calcd m / z: 653.165761, found: 653.164400.

From 69-100 fractions, 3-trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5-hydroxymethyl- (N- (2'-tN-butylaminosulfonyl- [1,1'J-biphen-4-yl)) carboxamide is isolated. (0.12 g): DSGMS (M + Na) ⁺ calcd m / z: 625.170847, found: 625.169900.

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5-carbomethoxy- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl)) carboxamide: Product from Fractions 50-66 (0.15 g) was refluxed with TFA for 1 h. The reaction mixture was cooled and evaporated to give 0.14 g of crude material. Purification of the final product by HPLC using a gradient elution of water: acetonitrile with 0.05% trifluoroacetic acid over a reverse phase C18 column (60 A) gives a pure sample of Example 74: m.p. temp. 233.3 ° C; DSGMS (M + H) ⁺ calcd m / z: 575.121216, found: 575.120500.

121

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5-hydroxymethyl- (N- (2'aminosulfonyl- [1,1 '] - biphen-4-yl)) carboxamide: Product from 69-100 fractions ( 0.12 g) is refluxed with TFA for 1 h. The reaction mixture 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 over a reverse phase C18 column (60 A) yields a pure sample of Example 75; melt temp. 115.4 ° C; DSGMS (M + H) ⁺ calcd m / z; 547.126302, Found: 547.124400.

EXAMPLE

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (2-fluoro (4- (Npyrrolidino) formylimino) phenyl) carboxamide · TFA

3-Fluoro-4-nitrobenzamide: 3-Fluoro-4-nitrobenzoic acid (5.0 g, 27 mmol) and SOCl 2 (6.42 g, 54 mmol) were refluxed in several drops of DMF in benzene (100 mL) for 3 hours. . The reaction mixture was evaporated to dryness, then evaporated several times with Et ₂ O; yield 5.56 g.

The above chloro anhydride is dissolved in EtOAc (50 mL) and added dropwise to 0 mL of EtOAc (50 mL) and almost. NH ₄ OH (100 mL) in a biphasic mixture. After 30 minutes Separate the layers, saturate the aqueous layer with NaCl, and extract with EtOAc. The combined organic extracts were dried and evaporated to give 4.85 g of benzamide; MSGMS / ES '(MH +) m / z = 182.9.

3-Fluoro-4-aminobenzonitrile: To a solution of 3-fluoro-4-nitrobenzamide (4.85 g, 25.4 mmol) and Et ₃ N (5.34 g, 52.8 mmol) at 0 ° C in EtOAc (150 mL) ml) dropwise a solution of 1,1,1-trichloroacetyl chloride (5.28 g, 29.04 mmol) in CH ₂ Cl ₂ (50 mL). The reaction is complete within 2 hours. (TLC, 1: 1 Hexane: EtOAc) followed by% washing with 1N HCl, drying (MgSO ₄ ) and evaporation to give 4.1 g of the corresponding nitrile.

122

This 4-nitrobenzonitrile derivative (4.1 g, 24.7 mmol) in EtOH / water (80 mL / 40 mL) was refluxed with iron powder (8.3 g, 148 mmol) and NH ₄ Cl (0.83). g, 15.3 mmol) 2 or. The reaction mixture was filtered and evaporated to dryness. The residue was dissolved in EtOAc, washed with saturated NaCl solution and dried (MgSO ₄ ) to give 2.68 g of product. MSGMS (M + H) &lt; ⁺ &gt; m / z = 137.0. This product was purified again by MPLC over a 360 g flash silica gel column eluting with 3: 1 hexane: EtOAc; 25 ml fractions are collected. Fractions 128-195 yield 1.32 g of pure product.

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (2-fluoro-4-cyano) phenyl) · carboxamide: to 3-trifluoromethyl-5-methyl-1- (4-methoxyphenyl) ) -1H-pyrazole (Example 15, 1.13 g, 3.95 mmol) in CH ₂ Cl ₂ (100 mL) at 0 ° C was added oxalyl chloride CH ₂ Cl ₂ (2M solution, 2.96 mL, 5.93) mmol) followed by a few drops of DMF. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was evaporated and vacuum dried for several hours to remove traces of HCl.

This chloro-anhydride was mixed with 3-fluoro-4-aminobenzonitrile (0.59 g, 4.35 mmol) and DMAP (1.45 g, 11.85 mmol) in CH ₂ Cl ₂ (100 mL) and stirred at room temperature for 18 h. The reaction mixture was evaporated and then partitioned between 1N HCl and EtOAc. The EtOAc layer was dried and evaporated to give 0.79 g of crude product. Further purification by MPLC over a 360 g silica gel column eluting with 4: 1 hexane: EtOAc, collecting 25 mL fractions. Fractions 91-133 afforded 0.83 g of the desired nitrile; melt temp. 160.6 ° C, MSGMS (M + H) ⁺ m / z = 405.0.

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (2-fluoro (4- (0-methyl) formimino) phenyl) carboxamide · HCl: Through 3-trifluoromethyl-1- (4-Methoxyphenyl) 1H-pyrazole-5- (N- (4-cyano) phenyl) carboxamide (0.83 g, 2.05 mmol) in% MeOH (50 mL) and MeOH (10 mL) at 0 ° A stream of dry gaseous HCl is allowed at C until the solution is saturated.

At 123 ° C, the stoppered flask is opened and the solvent is distilled off under vacuum. The residue is then evaporated several times with dry

Et ₂ O, and vacuum for several hours to remove traces of HCl.

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (2-fluoro-4- (Npyrrolidino) formylimino) phenyl) carboxamide * TFA: Previously prepared 3trifluoromethyl-1- (4- methoxyphenyl) -1H-pyrazole-5- (N- (2-fluoro (4- (O-methyl) formimino) phenyl) carboxamide HCl (2.05 mmol) was dissolved in dry MeOH (15 mL) and pyrrolidine (0.44 g, 6.15 mmol) This mixture was stirred at room temperature for 18 h then evaporated to dryness, and the final product was purified by HPLC using a gradient elution of water: acetonitrile with 0.05% trifluoroacetic acid over a C18 reverse phase column (60 A) gives a pure sample of the title compound: mp 61.8 ° C, DSGMS (M + H) ⁺ calcd m / z: 476.170963, found: 476.170693.

EXAMPLE

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (N-pyrrolidino) formylN - ((2-propyl) methylcarbamoyl) imino) phenyl) carboxamide

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (N-pyrrolidino) formyl-N ((2-propyl) methylcarbamoyl) imino) phenyl) carboxamide: to 3- trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (N-pyrrolidino) formylimino) phenyl) carboxamide • TFA (Example 72, 0.311 g) was added 1N NaOH (25 mL) and the resulting suspension 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 free base. This free base was dissolved in CH ₂ Cl ₂ (20 mL), cooled to 0 ° C, then Et ₂ N (0.08 g, 0.78 mmol) was added. To this cooled solution is added 4.4 ml (0.44 mmol) of a 0.1 N isobutyl chloroformate solution (from 0.01 mol [1.3 ml] pure isobutyl chloroformate in 100 ml CH ₂ Cl ₂ ) and stir at 0 ° C for 2 hours. . The reaction mixture was evaporated and partitioned between EtOAc and 1N HCl. The EtOAc layer was dried and evaporated to give 0.10 g of crude material. This stuff

The 124 was purified again by MPLC using a 200 g silica gel column chromatography eluting with 2: 1 hexane: EtOAc. Collect 25 ml fractions and isolate 0.056 g of pure product from fractions 40-80; melt temp. 90.1 ° C,

DSGMS (M + H) ⁺ calcd m / z: 558.2345, found: 558.2334.

EXAMPLE

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (N-pyrrolidino) formyl-N- (methanesulfamoyl) imino) phenyl) carboxamide

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (N-pyrrolidinino) formyl-N (methanesulfamoyl) imino) phenyl) carboxamide: J 3-Trifluoromethyl-1- (4-methoxyphenyl) ) -1H-pyrazole-5- (N- (4- (N-pyrrolidino) formylimino) phenyl) carboxamide TFA (Example 72, 0.332 g) was added 1N 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 free base. This free base was dissolved in CH ₂ Cl ₂ (25 mL), cooled to 0 ° C, then DMAP (0.095 g, 0.78 mmol) was added. To this cooled solution was added 4.2 mL (0.42 mmol) of a 0.1 N methanesulfonyl chloride solution (0.01 mol [0.78 mL] of pure methanesulfonyl chloride in 100 mL of CH ₂ Cl ₂ ) and stir at 0 ° C for 2 h. . The reaction mixture was evaporated and partitioned between EtOAc and 1N HCl. The EtOAc layer was dried and evaporated to give 0.11 g of crude material. This material was purified by MPLC using a 200 g silica gel column chromatography eluting with 2: 1 hexane: EtOAc. Collect 25 ml fractions and isolate 0.050 g of pure product from fractions 81-130; melt temp. 117.2 ° C, DSGMS (M + Na) ⁺ found m / z: 558.1381.

EXAMPLE

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N - ((4amidino) phenyl) methyl) carboxamide · TFA α-Amino-4-cyanotoluene: 4-Cyanobenzyl bromide (3 g, 15.3 mmol) and NaN ₃ (1.99 g, 30.6 mmol) in DMF (20 mL) was stirred at room temperature

125 or. The reaction mixture was diluted with saturated NaCl solution and extracted with EtOAc. The organic extracts were washed with brine (5x), dried (MgSO ₄ ) and evaporated to give 1.87 g of benzyl azide.

This benzylic azide (1.87 g, 11.84 mmol) and SnCl3-hbO (7.25 g, 32.2 mmol) in MeOH (50 mL) were stirred at room temperature for 18 h. The solution was evaporated to dryness, then the residue was dissolved in 1N NaOH and extracted with EtOAc. The EtOAc layer was washed with saturated NaCl solution, dried and evaporated to give 0.83 g of α-amino-4-cyanotoluene.

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N - ((4-cyano) phenyl) methyl) · carboxamide: J 3-Trifluoromethyl-5-methyl-1- (4-methoxyphenyl) -1H-pyrazole (Example 15, 0.4 g, 1.4 mmol) and N-methylmorpholine (0.156 g, 1.54 mmol) in CH ₂ Cl ₂ (30 mL) at 0 ° C were added isobutyl chloroformate (0.21) g, 1.54 mmol). The reaction mixture was stirred for 30 min. At 0 ° C and 0.203 g of α-amino-4-cyanotoluene (1.54 mmol) in CH ₂ Cl ₂ (8 mL) was added. After 18 or. the reaction mixture was washed with 1N HCl and 1N NaOH, then dried and evaporated to give 0.54 g of crude material. Further purification was carried out by MPL.C using a 200 g silica gel column chromatography eluting with 2: 1 hexane: EtOAc and collecting 25 mL fractions. Fractions 61-120 yield 0.32 g of the desired nitrile: m.p. temp. 197.5 ° C, MSGMS (M + H) ⁺ m / z = 401.0.

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (2-fluoro-4- (0-methyl) formimino) phenyl) methyl) carboxamide »HCl: Through 3-trifluoromethyl-1 - (4-Methoxyphenyl) -1H-pyrazole-5- (N - ((4-cyano) phenyl) methyl) carboxamide (0.32 g, 0.8 mmol) in dry MeOAc (25 mL) and dry MeOH (5 mL) A stream of dry gaseous HCl is allowed at 0 ° C until the solution is saturated. After 18 hours. At 10 ° C, the stoppered flask is opened and the solvent is distilled off under vacuum. The residue is then evaporated several times with dry Et ₂ O and vacuum evacuated for several hours to remove traces of HCl.

126

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N - ((4-amidino) phenyl) methyl) carboxamideTFA: This prepared imidate (0.4 mmol) 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 room 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 over a reverse phase C18 column (60 A) gives a pure sample of the title compound: m.p. temp. 131.4 ° C; DSGMS (M + H) ⁺ found m / z: 418.1478.

EXAMPLE

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N - ((4- (N-pyrrolidino) formylimino) phenyl) methyl) carboxamide · TFA

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N - ((4- (N-pyrrolidino) formylimino) phenyl) methyl) carboxamide-TFA: Previously prepared 3-trifluoromethyl-1- (4-methoxyphenyl) ) -1H-Pyrazole-5- (N - ((4- (O-methyl) formimino) phenyl) methyl) carboxamide. HCl (Example 79, 0.4 mmol) was dissolved in dry MeOH (15 mL) and pyrrolidine (0) was added. , 09 g, 1.2 mmol). The mixture was stirred at room 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 over a reverse phase C18 column (60 A) afforded a pure sample of the title compound: MSGMS (M + H) ⁺ m / z: 472, 3.

EXAMPLE

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N - ((1-benzyl) piperidin-4-yl) carboxamide · TFA

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazol-5- (N - ((1-benzyl) piperidin-4-yl) carboxamide-TFA:? 3-trifluoromethyl-5-methyl-1- (4) -methoxyphenyl) -1H-pyrazole (Example 15, 2.86 g, 10 mmol) and N-methylmorpholine (1.01 g, 10 mmol) in THF (50 mL) at 0 ° C were added isobutyl chloroformate (1.36 g, 10 mmol).

127

The reaction mixture was stirred for 30 min. At 0 ° C and 1.90 g of 1-benzyl-4-aminopiperidine (10 mmol) was added. After 18 or. the reaction mixture was evaporated to dryness, dissolved in 1N NaOH and extracted with EtOAc. The EtOAc layer is washed with saturated NaCl solution, dried and evaporated to give 4.36 g of crude material. Recrystallization from n-butyl chloride gives 1.16 g of product; melt temp. 120.8 ° C.

To obtain the TFA salt, dissolve 0.10 g of the sample in Et ₂ O and add TFA. Trituration with Et ₂ O and n-butyl chloride yields 0.015 g of pure product; melt temp. 175.6 ° C; DSGMS (M + H) ⁺ calcd m / z: 459.200, found: 459.199.

EXAMPLE

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazol-5- (N - ((1- (pyridin-2-yl) methyl) piperidin-4-yl) carboxamide TFA

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (piperidin-4-yl) carboxamide-HCl: 3-trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole -5- (N - ((Benzyl) piperidin-4-yl) carboxamide (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, then evaporated to dryness, dissolved in MeOH (50 mL) and refluxed for 1 hour to give 0.8 g of product, MSGMS (M + H). ⁺ m / z: 369.2.

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N - ((1- (pyridin-2-yl) methyl) · piperidin-4-yl) carboxamide-TFA: 3-trifluoromethyl -1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (piperidin-4-yl) carboxamide HCl (0.21 g) and K ₂ CO ₃ (0.3 g) in AcOH (20 mL) were added 2- picolyl chloride (0.16 g) The reaction mixture was stirred at room temperature for 18 hours, diluted with water and extracted with EtOAc (3x), the extracts dried (MgSO ₄ ) and evaporated to give 0.29 g of crude product. gradient elution of water: acetonitrile with 0.05%

128 Trifluoroacetic acid mixture, via a reverse phase C18 column (60 A), gives a pure sample of the title compound; MSGMS (M + H) &lt; ⁺ &gt; m / z: 460.3.

EXAMPLE

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazol-5- (N- (4- (2-methylimidazo-1-yl) phenyl) carboxamide TFA

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazol-5- (N- (4- (2-methylimidazo-1-yl) phenyl) carboxamide-TFA: 3-Trifluoromethyl-5-methyl-1- ( 4-methoxyphenyl) -1H-pyrazole (Example 15, 0.20 g, 0.7 mmol), BOP (0.44 g, 1 mmol), Et ₃ N (0.1 g, mmol) and 1- (4-aminophenyl) ) A mixture of -2-methylimidazole (0.17 g, 1 mmol) in DMF (20 mL) was heated at 50-55 ° C for 1 h, then cooled to room temperature and stirred for 18 h. The reaction mixture was diluted with water and extracted with EtOAc. The EtOAc extracts were washed with water (5x), dried (MgSO ₄ ), and evaporated to give a pure desired product after purification by HPLC using a gradient elution of water-acetonitrile with 0.05% trifluoroacetic acid in a reverse phase C18 column (60 A). compound sample: mp 103.7 ° C; DSGMS (M + H) ⁺ m / z: 442.188.

EXAMPLE

3-Methyl- (4-methoxy) phenyl-1H-pyrazol-5- (N- {4- (5-methylimidazol-1-yl} phenyl) carboxamide

AND EXAMPLE 85

3-Methyl- (4-methoxy) phenyl-1H-pyrazol-5- (N- {4- (4-methylimidazol-1-yl} phenyl) carboxamide

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). After refluxing for 18 hours, the reaction mixture is cooled and concentrated under reduced pressure.

The residue is treated with water, the mixture is extracted with ethyl acetate and

129 dried over magnesium sulfate. The organic layer is concentrated and the residue is purified by flash chromatography (methanol / methylene chloride, 0.5: 9.5); 1.8 g (62%) of p-nitro-4 (5) -methyl-imidazol-1-yl is obtained which is 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 379 kPa for 20 h at room temperature followed by celite filtration gave 1.4 g (93%) of p-amino-4 (5) -methyl-imidazol-1-yl.

3-Methyl- (4-methoxy) phenyl-1H-pyrazole-5- (N- {4- (5-methylimidazol-1-yl} phenyl) carboxamide and 3-methyl- (4-methoxy) phenyl-1H-pyrazole Preparation of a mixture of -5- (N- {4- (4-methyl-imidazol-T-yl} phenyl) carboxamide: 3-Methyl-1- (4-methoxyphenyl) -1H-pyrazolecarboxylic acid (200 mg, 0.8 mmol) in acetonitrile ( The resulting mixture was refluxed for 2 h, cooled, concentrated, dissolved in methylene chloride (5 mL) and treated with DMAP (0.22 mg, 1.8 mmol) and N- (4-aminophenyl). ) -5-Methylimidazole (131 mg, 0.7 mmol) The reaction mixture was stirred at room temperature for 18 h, treated with water, extracted with ethyl acetate and dried over magnesium sulfate, the organic layer was concentrated and the residue was purified by silica gel flash chromatography (methanol / methylene chloride). 0.5: 9.5): 3-methyl (4-methoxy) phenyl-1H-pyrazol-5- (N- {4- (5-methylimidazol-1-yl} phenyl) carboxamide and 3-methyl- ( 4-methoxy) phenyl-1H-pyrazole-5- (N- {4- ( 4-methylimidazol-1-yl} phenyl) carboxamide. 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. speed example: 3-methyl- (4-methoxy) phenyl-1H-pyrazole-5- (N- {4- (5-methyl-imidazole · 1-yl} phenyl) carboxamide: ¹ H NMR (CDCl): 2 , 19 (s, 3H), 2.38 (s, 3H), 3.85 (s, 3H), 6.76 (s, 1H), 6.97 (m, 2H), 7.14 (m, 1H), 7.25 (m, 2H), 7.39 (m, 2H), 7.50 (s, 1H), 7.71 (m, 2H), 8.05 (s, 1Η) Λ

Example 130: 3-methyl- (4-methoxy) phenyl-1H-pyrazole-5- (N- {4- (4 ~ methyl-imidazol1-yl} phenyl) carboxamide: ¹ H NMR (CDCl): 2.31 ( s, 3H), 2.36 (s, 3H), 3.83 (s,

3H), 6.71 (s, 1H), 6.94 (m, 2H), 7.26 (m, 2H), 7.39 (m, 2H), 7.58 (m, 2H), 7, 92 (s, 1H); 8.23 (s, 1H).

EXAMPLE

3-Trifluoromethyl- (4-methoxy) phenyl-1H-pyrazol-5- (N- {4- (5-carbomethoxyimidazol-1-yl} phenyl) carboxamide

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-butylglyoxylate (8 g, 53.8 mmol). After stirring at room temperature for 18 hours, the reaction mixture is concentrated under reduced pressure. The residue is taken up in water, the mixture is extracted with ethyl acetate and dried over magnesium sulfate. Concentration of the organic layer yields, almost quantitatively, the desired compound which is used crude.

4-Amino- (5- (carbomethoxy) imidazol-1-yl) benzene: To a solution of butylglyoxyl (4nitroaniline) imine (1.6 g, 6.9 mmol) in methyl alcohol (10 mL) was added potassium carbonate (1, 9 g, 13.9 mmol) and tosylmethyl isocyanate (2.3 g, 11.8 mmol). The solution is stirred for 1 hour. at room temperature, then the solvent was evaporated in vacuo. The residue is treated with a saturated sodium chloride solution and the mixture is extracted with methylene chloride. The organic extract is concentrated and triturated with methyl alcohol. The precipitate was filtered off and dried to give 4-nitro- (5- (carbomethoxy) imidazol-1-yl) benzene intermediate (1.5 g, 94%). MS (ES) m / z (relative intensity) 249 (M ⁺ , 100).

The reduction to 4-amino- (5- (carbomethoxy) imidazol-1-yl) benzene is carried out according to the procedures described in Examples 84 and 85; MS (ES) m / z (rel intensity) 219 (M ⁺ , 100).

3-Trifluoromethyl- (4-methoxy) -enyl-1H-pyrazol-5- (N- {4- (5-carbomethoxyimidazol-1-yl} phenyl) carboxamide: 4-Amino- (5- (carbomethoxy) imidazol-1131-yl) ) A solution of benzene (152 mg, 0.7 mmol) is 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. chromatography (methanol / methylene chloride, 1: 9) affords 3-trifluoromethyl- (4-methoxy) -phenyl-1H-pyrazol-5- (N- {4- (5-carborethoxy-imidazol-1-yl) -phenyl) -carboxamide ( 70 mg, 20%), MS (ES) m / z (rel intensity) 486 (M ⁺ , 100).

EXAMPLE

3-Trifluoromethyl- (4-methoxy) phenyl-1H-pyrazole-5- (N- {4 '(5-carboximidazole) ·

1-yl} phenyl) carboxamide

3-Tn7 (fluorophenyl) - (4-mephoxyl) phen (7-7H-piperazinyl) -5- (N - {4- (5-carboxyl-7,7-dazolyl) phenyl) carboxamide: 3 -Trifluoromethyl- (4-methoxy) phenyl-1H-pyrazol-5- (N- {4- (5-carbomethoxy-imidazol-1-yl} phenyl) carboxamide (147 mg, 0.3 mmol) is suspended in 4: 1 TFA and water, and treated with LiOH (37 mg, 0.9 mmol) in 0.5 mL of water, The reaction mixture was stirred for 1 h at room temperature, neutralized with 1N HCl, extracted with ethyl acetate, dried over MgSO ₄ and concentrated to give the final product by reverse phase HPLC. by means of a gradient starting with a Vydec® C-18 column eluting with a mixture of solvents A (water: TFA, 99.5: 0.5) and B (acetonitrile: water: TFA, 90: 9.5: 0.5). from 100% A and changing to 100% B over 60 min; MS (ES) m / z (rel intensity) 471.9 (M ⁺ , 100).

EXAMPLES 88-90

Crude acid - 3-trifluoromethyl- (4-methoxy) phenyl-1H-pyrazol-5- (N- {4- (5-carboxyimidazol-1-yl} phenyl) carboxamide - is dissolved in acetonitrile, treated with excess thionyl chloride and Refluxing for 2 hours The solvent was evaporated under reduced pressure, and the following amines were coupled according to the procedures described in Examples 84 and 85 to give compounds 88-90.

132 phase HPLC over a Vydec® C-18 column, eluting with a mixture of solvents A (water: TFA, 99.5: 0.5) and B (acetonitrile: water: TFA, 90: 9.5: 0.5) using a gradient starting from 100% A and changing to 100% B in 60 min; Examples 88-90 are obtained in the form of TFA salts.

Example: 3-Trifluoromethyl- (4-methoxy) phenyl-1H-pyrazol-5- (N- {4- (5-N-methylurea-imidazol-1-yl} phenyl) carboxamide: Prepared using excess N-methylamino-HCl ¹ H NMR (CDCl 3): 2.89 (d, J = 4.7 Hz, 3H), 6.13 (m, 1H), 6.89 (d, J = 9.1 Hz, 3H), δ , 15 (d, J = 8.8 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H), 7.48 (m, 3H), 7.59 (s, 1H), δ , 79 (s, 1H).

Example 3: 3-Trifluoromethyl- (4-methoxy) phenyl-1H-pyrazol-5- (N- {4- (5-urea-imidazol-1-yl} phenyl) carboxamide: Prepared by saturating the solution of chloro anhydride in CH ₂ Cl _{2 at} 0 ° C gaseous NH ₃ ; MS (ES) m / z (rel intensity) 468.9 (M ⁺ , 100).

Example 3-Trifluoromethyl- (4-methoxy) phenyl-1H-pyrazole-5- (N- {4- (5-methylsulfonylurea-1-imidazol} phenyl) carboxamide: Prepared as the amino component using methanesulfonamide; MS (ES) m / z ( relative intensity) 546.9 (M ⁺ , 100).

EXAMPLE.

1- (4'-Methoxyphenyl) -3-hydroxylmethyl-1H-pyrazole-5- (N- (4'pyrrolidinocarbonyl) phenyl) carboxamide

T (4'-Methoxyphenyl) -3-hydroxylmethyl-1H-pyrazole-5-ethylcarboxylate: To 1- (4-Methoxyphenyl) -3-methyl-1H-pyrazole-5-ethylcarboxylate (1.58 g, 7.1 mmol) a solution of CCI ₄ (250 mL) was added NBS (1.5 g, 8.5 mmol) and benzoyl peroxide (73 mg, 4 mmol). The mixture is degassed and saturated with nitrogen, refluxed under nitrogen for 18 hours, 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

133 dried over MgSO ₄ . Filtration and concentration provided crude 1- (4'methoxyphenyl) -3-bromomethyl-1H-pyrazole-5-ethylcarboxylate (2.4 g). To a solution of this crude material 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 h. The mixture is filtered to remove excess Cu ₂ O and the filtrate is extracted with ethyl ether. The ether layer was washed with saturated NaCl solution (10 mL x 5) and dried over MgSO ₄ . Filtration and concentration followed by purification by silica gel column chromatography eluting with EtOAc / CH ₂ Cl ₂ (1: 1) gave the title compound (1.5 g, 81% yield). ESMS (M + H) ⁺ m / z: 277.

1- (4'-Methoxyphenyl) -3-hydroxylmethyl-1H-pyrazole-5- (N- (4'-pyrrolidinocarbonyl) phenyl) carboxamide: J 4- (Pyrrolidinyl) aniline (390 mg, 2.05 mmol) in CH ₂ Cl ₂ (20 mL) at 0 ° C was added to AIMe ₃ (2M in hexane, 3 mmol). The mixture is stirred at room temperature for 15 min. and adding a solution of 1 (4'-methoxyphenyl) -3-hydroxylmethylene-1H-pyrazole-5-ethylcarboxylate (560 mg, 2.05 mmol) in CH ₂ Cl ₂ (5 mL). The resulting mixture was stirred overnight, quenched with water (5 mL) and filtered through a pad of celite to remove Al (OH) ₃ . The filtrate was washed with water, brine and dried over MgSO ₄ . Filtration, concentration, and purification by silica gel column chromatography eluting with a solvent gradient (CH ₂ Cl ₂ to EtOAc) gave the title compound (570 mg, 67% yield). ESMS (M + Na) ⁺ m / z: 443. DSGMS (M + H) ⁺ calcd m / z: 420.1798, found; 420.1771.

EXAMPLE

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

J A solution of 1- (4-methoxyphenyl) -3-hydroxy-methyl-1H-pyrazole-5- (N - (4'-pyrrolidinecarbonyl) phenyl) carboxamide (140 mg, 0.33 mmol) in THF (20 mL). MnO ₂ (435 mg, 4.95 mmol) was added and the resulting mixture was refluxed for 12 hours. The mixture is filtered to remove excess MnO ₂ , and

Concentration of the filtrate 134 afforded Example 92 (138 mg, 100%) as a white solid. ESMS (M + H) ⁺ m / z; 419.

EXAMPLE

1- (4'-Methoxyphenyl) -5-N- (4'-pyrrolidinocarbonyl) anilide) -1H-pyrazol-3-ylcarboxylic acid

1- ^(4! -Metoksifenil) -5-N- (4'-pyrrolidinocarbonyl) aniHd) -1H-pyrazol-3-yl carboxylic acid · J AgNO ₃ (34 mg, 0.2 mmol) in H ₂ O (0 NaOH (16 mg, 0.4 mmol) was added and 1- (4'-methoxyphenyl) 3-formaldehyde-1H-pyrazole-5- (N- (4'-pyrrolidinocarbonyl) phenyl) was added at 0 ° C. carboxamide (Example 92, 42 mg, 0.1 mmol) in MeOH (0.5 mL). After stirring at room temperature for 30 minutes, the mixture is carefully acidified almost. HCl (35 mL) to pH -2 and concentrated to a residue which was purified by silica gel column chromatography eluting with a solvent gradient (CH ₂ Cl ₂ to EtOAc) to give the title compound (25 mg, 58% yield). ESMS (M + Na) ⁺ m / z: 456.9.

EXAMPLE

1- (4'-Methoxyphenyl) -3-methylcarboxylate-1H-pyrazole-5-N- (4'pyrrolidinocarbonyl) phenyl) carboxamide

1- (4'-Methoxyphenyl) -3-methylcarboxylate-1H-pyrazole-5-N- (4'-pyrrolidino-carbonyl) phenyl) carboxamide: 1- (4'-Methoxyphenyl) -3-formaldehyde-1H- To a solution of pyrazole 5- (N - ((4'-pyrrolidinocarbonyl) phenyl) carboxamide (Example 92, 42 mg, 0.1 mmol) in MeOH (1 mL) was added KCN (7.8 mg, 0.12 mmol), HOAc (7 mL). , 2 mg, 0.12 mmol) and MnO ₂ (120 mg, 0.83 mmol) and the resulting mixture was stirred at room temperature for 12 h, 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 chromatography on a silica gel column eluting with EtOAc to give the title compound (38 mg, 85% yield). ESMS (M + Na) ⁺ m / z: 471.

135

EXAMPLE

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

1- (4'-Methoxyphenyl) -3-cyanomethyl-1H-pyrazole-5-N- (4'-pyrrolidinocarbonyl) phenyl) carboxamide: to 1- (4'-methoxyphenyl) -3-hydroxymethyl-1H-pyrazole- To a solution of 5 - ((4'-pyrrolidinocarbonyl) phenyl) carboxamide (120 mg, 0.29 mmol) in CH ₂ Cl ₂ (15 mL) was added MsCl (48 mg, 0.43 mmol) and Et ₃ N (11 mg, 0, 43 mmol). After stirring at room temperature for 2 hours, the resulting mixture is concentrated. The residue solution in DMF (3 mL) was treated with NaCN (43 mg, 0.87 mmol) and stirred for 16 h. EtOAc (50 mL) and water (5 mL) were added to the reaction mixture, and the EtOAc layer was washed with saturated NaCl solution (10 mL x 5), dried over MgSO ₄ , concentrated and purified by TLC silica gel plates, eluting with EtOAc to afford the title compound (57 mg, 46%). ESMS (M + Na) ⁺ m / z: 430.

EXAMPLE

2- (1 '- (4 "-Methoxyphenyl) -5' - (4" -pyrrolidinocarbonyl) anilide-1H-pyrazol-3'yl) acetic acid

2- (1 '- (4' -Methoxyphenyl) -5 '- (4' -pyrrolidinocarbonyl) anilide-TH-pyrazol-3'-yl) acetic acid: J 1- (4'-methoxyphenyl) -3-cyanomethyl- 1H-Pyrazole-5-N- (4'-pyrrolidinocarbonyl) phenyl) carboxamide (27 mg, 0.063 mmol) was added with 6N HCl (1 mL) and the resulting mixture was stirred at 75 ° C for 16 h. The mixture was extracted with EtOAc, the organic layer was dried over MgSO ₄ , concentrated and purified by TLC silica gel plates eluting with 20% MeOH in EtOAc to give the title compound (2 mg, 7%). MS (ES-) (MH ⁺ ) m / z: 447.

EXAMPLE

136

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

1- (4'-Methoxyphenyl) -3-hydroxylmethyl-1H-pyrazole-5-N- (2'-tert-butylarninosulfonyl- [1,1 '] - biphen-4-yl) carboxamide: J 4- (2') -Tert-butylaminosulfonylphenyl) aniline (1.33 g, 4.3 mmol) in CH 2 Cl 2 (40 mL) at 0 ° C was added to AIMe ₃ (2M in hexane, 6.5 mmol). After stirring at room temperature for 30 min, a solution of 1- (4'-methoxyphenyl) -3-hydroxylmethyl-1H-pyrazole-5-ethylcarboxylate (1.09 g, 3.95 mmol) in CH ₂ Cl ₂ (5 mL) was added. the mixture is refluxed for 6 hours. and quenched with water (5 mL).

The mixture was filtered through a pad of celite, the filtrate washed with water and saturated NaCl solution, and dried over MgSO ₄ . Filtration, concentration and purification by silica gel column chromatography eluting with a gradient of solvents (CH ₂ Cl ₂ to EtOAc and up to 10% MeOH / EtOAc) gave the title compound (1.8 g, 85%). ESMS (M + H) ⁺ m / z: 535.

1- (4'-Methoxyphenyl) -3-bromomethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] biphen-4-yl) carboxamide: 1- (4'-methoxyphenyl) -3-hydroxylmethyl-1H-pyrazole-5N- (2'-tert-butylamino-sulfonyl- [1,1 '] - biphen-4-yl) carboxamide (880 mg, 2.49 mmol) in CH ₂ Cl ₂ (100 mL) was added PBr ₃ (675 mg, 2.49 mmol). The resulting mixture was stirred at room temperature for 2 hours, then concentrated.

The residue was treated with TFA (10 mL), refluxed for 2 hours, then concentrated. The residue was dissolved in EtOAc (50 mL) and water (5 mL).

The EtOAc layer was washed with saturated NaCl solution (10 mL), dried over MgSO ₄ , concentrated and purified by silica gel column chromatography eluting with a solvent gradient (hexane to EtOAc) to give the title compound (800 mg, 90%). ESMS (M + H) ⁺ m / z: 541/543.

EXAMPLE

1 * (4'-Μ6ΐοΚ8ίΥ6ηίΙ) -3-3ΠΉηοηΊβΙίΙ-1Η-ρίΓ3ΖθΙ-5-Ν · (2′-3ΐηίηο5ΐιΙίοηίΙ · [1, Γ] * ^v bifen-4-yl) carboxamide

137

1- (4'-Methoxyphenyl) -3-aminomethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] · biphen-4-yl) carboxamide: J 1- (4'-methoxyphenyl) ) -3-Bromomethyl-1 H -pyrazol-5-Ν (2'-aminosulfonyl- [1,1 T] -biphen-4-yl) carboxamide (140 mg, 0.259 mmol) in a solvent mixture (EtOH / CH ₃ CN / H ₂ O = 10: 5: 1, 20 mL) NaN ₃ (50.5 mg, 0.776 mmol) was added. After refluxing for 16 hours, the resulting solution was cooled to room temperature, treated _{with a} solution of SnCl _{2 -} 2H ₂ O (350 mg, 1.55 mmol) in MeOH (4 mL) and stirred at room temperature for 2 hours. The mixture was neutralized with 1N NaOH to pH 8-9 and extracted with EtOAc. The EtOAc layer was concentrated and purified by chromatography on silica gel TLC plates eluting with 20% MeOH in CH ₂ Cl ₂ to give the title compound (126 mg, -100%). ESMS (M + H) ⁺ m / z: 478.1.

EXAMPLE

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

1- (4'-Methoxyphenyl) -3- (N-methylsulfonylamino) methyl-1H-pyrazole-5-N- (2'aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide: A solution of 1- (4'-methoxyphenyl) -3-aminomethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide (15 mg, 0.031 mmol) in CH ₂ Cl ₂ MsCl (3.6 mg, 0.035 mmol) and Et ₃ N (4.7 mg, 0.047 mmol) were added in ₂ (1 mL). After stirring at room temperature for 2 hours, the resulting mixture was concentrated and purified by chromatography on TLC silica gel plates eluting with EtOAc-CH ₂ Cl ₂ (1: 1) to give the title compound (12 mg, 70%). DSGMS (M + H) ⁺ calcd m / z: 556.1324, found: 556.1320.

EXAMPLE 100

1- (4'-Methoxyphenyl) -3- (imidazol-1-yl) methyl-1 H -pyrazol-5-N- (2'-aminosulfonyl [1,1 '] - biphen-4-yl) carboxamide

138

- (4'-Methoxyphenyl) -3- (imidazol-1-yl) methyl-1 H -pyrazol-5-N- (2'-aminosulfonyl [1,1 '] - biphen-4-yl) carboxamide: 1- (4'-Methoxyphenyl) -3-bromomethyl-1 H -pyrazol-5-N- (2-Laminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide (30 mg, 0.055 mmol) in CH ₂ Cl ₂ (2 ml) imidazole (12 mg, 0.176 mg) was added and the resulting mixture was stirred at room temperature for 8 hours. Concentrate the mixture and purify by chromatography on TLC silica gel plates eluting with CH ₂ Cl ₂ / EtOAc (1: 3) to give the title compound. ESMS (M + Na) ⁺ m / z: 528.5.

EXAMPLE 101

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

AND EXAMPLE 102

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

- (4'-Methoxyphenyl) -3-hydroxylmethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] biphen-4-yl) carboxamide and 1- (4'-methoxyphenyl) - Preparation of 3-Trifluoroacetylhydroxylmethyl-1 H -pyrazol-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) · carboxamide: Preparation of 1- (4'-methoxyphenyl) -3-hydroxylmethyl- 1H-Pyrazole-5-N- (2'-tert-butylaminosulfonyl- [1,1'] -biphen-4-yl) carboxamide (40 mg, 0.075 mmol) was added with 25% TFA in CH ₂ Cl ₂ - (6 mL), and the mixture was Stir at room temperature for 20 hours. Concentrate the mixture and purify by preparative HPLC to give Example 101: 1- (4'-Methoxyphenyl) -3-hydroxylmethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl ) Carboxamide (8 mg, 22%): ESMS (M + H) ⁺ m / z: 479; and the compound of Example 102: 1- (4'-Ethoxyphenyl) -3-trifluoroacetyl hydroxylmethyl-1H-pyrazole-5-N- (2'aminosulfonyl- [1,1'] -biphen-4). -yl) -carboxamide (18 mg, 42%): ESMS (M + H) ⁺ m / z: 575.

EXAMPLE 103

139

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

1N- (4'-Methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-5-methylpyrazole: J

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 g, 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, the filtrate washed with water and brine (10 mL x 5), and dried over MgSO ₄ . Filtration, concentration, and purification by silica gel column chromatography eluting with hexane-CH ₂ Cl ₂ (1: 1) gave 1N- (4'-methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-5-methylpyrazole (3.17 g, 51%). %). ESMS (M + H) ⁺ m / z: 315.

1N- (4'-Methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-carboxylic acid: 1 N- (4'-methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-5-methylpyrazole (2, A solution of 54 g, 8.09 mmol) in CCl ₄ (150 mL) was added with NBS (2.88 g, 16.18 mmol), benzoyl peroxide (31 mg, 0.12 mmol) and AIBN (123 mg,

0.44 mmol), the mixture is degassed and then saturated with nitrogen. After refluxing under nitrogen for 24 hours, the mixture is cooled to 0 ° C and filtered. Concentration of the filtrate gives a brown oil. To this brown oil solution CH ₃ CN (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 h. 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 is extracted with ether and the aqueous layer is carefully acidified. HCl to pH 2 and extracted with EtOAc, the EtOAc layer was washed with brine (10 ml) and dried over MgSO _4th Filtration and concentration provided pure 1N- (4'-methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-carboxylic acid (1.2 g, 43.1%). ESMS (M + H) ⁺ m / z:

345.

140

1- (4'-Methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-1 H -pyrazol-5-N- (2 '· methylsulfonyl- [1,1'] - biphen-4-yl) carboxamide: To 1 N- To a solution of (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 stirred at room temperature for 30 min. After adding N, N-diisopropylethylamine (288 mg, 2.5 mmol), the resulting mixture was stirred for 10 min, followed by the addition of 4- (2'-methylsulfonylphenyl) aniline (265 mg, 1 mmol). The resulting mixture was stirred at 90 ° C for 16 h, diluted with EtOAc (100 mL), washed with 1N HCl (20 mL x 2), 10% NaHCO ₃ (20 mL x 2), water (10 mL), and brine (20 mL). ml x 4), dried over MgSO _4, and concentrated. Dissolve the residue in CH ₂ Cl ₂ (20 mL) for 30 min. exposed to DOWEX (1 g). The mixture was filtered and the filtrate was purified by silica gel column chromatography eluting with a solvent gradient (CH ₂ Cl ₂ to EtOAc); to give the title compound (430 mg, 73%). ESMS (M + H) ⁺ m / z: 592.

EXAMPLE 104

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

To 1- (4'-methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'-methylsulfonyl- [1,1 '] - biphen-4-yl) carboxamide (290 mg, A solution of 0.49 mmol) in MeOH (10 mL) was added aqueous NaOH (0.39 g in 5 mL water) and the mixture was stirred at room temperature for 16 h. After extraction with ether, the resulting aqueous solution is carefully acidified. HCl to pH 2 and extracted with EtOAc. The EtOAc layer was dried over MgSO ₄ , concentrated, and purified by silica gel column chromatography eluting with EtOAc; yielding the title compound (110 mg, 50%) as a white solid. ESMS (M + H) ⁺ m / z: 578.

EXAMPLE 105

1- (4-Methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'3-azo-8-methyl-1-yl) -3,3'-5'-3 '

141

To a solution of N- (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 min. N, N-Diisopropylethylamine (288 mg, 2.5 mmol) was added and the resulting mixture was stirred for 10 min followed by the addition of a solution of 4- (2'-tert-butylaminosulfonylphenyl) aniline hydrochloride (358 mg, 1 mmol). The resulting mixture was stirred at 90 ° C for 16 h. and cleaved with EtOAc (100 mL). The mixture was washed with 1N 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), 30 min. treated with DOWEX (1 g) and filtered. The filtrate was purified by silica gel column chromatography eluting with a solvent gradient (CH ₂ Cl ₂ to EtOAc) to give 1- (4'-methoxy-2'methoxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2 '). -tert-butylaminosulfonyl [1,1 '] - biphen-4-yl) carboxamide (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) carboxamide (200 mg) TFA (5 mL) was added and the resulting solution was refluxed for 2 hours. Concentrate the mixture, purify over silica gel plates, eluting with 10% EtOAc in CH ₂ Cl ₂ to give the title compound (160 mg, 87%). ESMS (M + H) ⁺ m / z: 593.

EXAMPLE 106

1- (4'-Methoxy-2'-hydroxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'-tert-butylaminosulfonyl- [1,1 '] - biphenyl) carboxamide

To 1- (4'-Methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazol-5- [(2'-tert-butylaminosulfonyl- [1,1'] -biphen-4-yl) carboxamide (350 of a solution of MeOH (5 mL) in aqueous NaOH (90 mg in 5 mL water) was added and the mixture was stirred at room temperature for 16 h. After extraction with ether, the resulting aqueous solution is carefully acidified. HCl to pH 2 and extracted with EtOAc. The EtOAc layer was dried over MgSO ₄ ,

142 was concentrated and purified by column chromatography over silica gel eluting with EtOAc; yielding the title compound (210 mg, 61.3%) as a white solid. ESMS (M + H) ⁺ m / z: 635.

EXAMPLE 107

1- (4'-Methoxy-2'-hydroxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazol-5-N- (2'aminosulfonyl- [1,1 '] - biphenyl) carboxamide

To 1- (4'-Ethoxy-2'-hydroxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazol-5-Ν (2'-tert-butylaminosulfonyl- [1, 1 '] -biphen-4-yl) carboxamide (210 mg, 0.33 mmol) was added TFA (5 mL) and the resulting mixture was refluxed for 1 h. The mixture was concentrated and purified by chromatography on silica gel TLC plates, eluting with 10% MeOH in EtOAc, to give the title compound (190 mg, 99%). ESMS (M + H) ⁺ m / z: 579.

EXAMPLE 108

1- (4'-Methoxy-2'-hydroxymethyl-phenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) -carboxamide to 1- (4) '-methoxy-2'-hydroxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5- (2'-aminosulfonylphenyl) phenyl) carboxamide (210 mg, 0.36 mmol) in THF (5 mL) at 0 ° C of NN-diisopropylethylamine (62 mg, 0.54 mmol) and isopropyl chloroformate (freshly distilled, 446 mg, 0.38 mmol) were added at room temperature and the resulting mixture was stirred at room temperature for 1.5 h. NaBH ₄ (30 mg, 0.79 mmol) was added and the mixture was stirred for 1 h. The reaction mixture was diluted with 1N HCl and stirred for 30 min. The mixture was diluted with EtOAc, the organic layer was washed with water and brine, dried over Na ₂ SO ₄ , and purified by chromatography on silica gel TLC plates, eluting with EtOAc to afford the title compound (75 mg, 37%) ). ESMS (M + Na) ⁺ m / z: 586.9.

v,

EXAMPLES 109-115

143

1N- (4'-Methoxyphenyl) -3-methylpyrazol-5-yl) ethylcarboxylate: To a solution of 4-methoxyphenylhydrazine (8.65 g, 50 mmol) in HOAc (300 mL) was added (ethyl 2-N-) at 80 ° C. (methoxy) imino-4-oxopentanoate oxime (see Example 1, 6 g, 32 mmol) was refluxed for 18 h and concentrated The residue was dissolved in EtOAc (300 mL), washed with 10% NaOH (100 mL), water (100 mL x 2) and saturated NaCl solution (20 mL x 2), dried over MgSO ₄ , concentrated and purified by column chromatography on silica gel eluting with CH ₂ Cl ₂ to give a partially purified product which was recrystallized from hexane to give the title compound ( 10.5 g, 80%) ESMS (M + H) ⁺ m / z: 261.

1N- (4'-Methoxyphenyl) -3-methylpyrazol-5-yl) carboxylic acid: 1N- (4'-Methoxyphenyl) -3-methylpyrazol-5-yl) ethylcarboxylate (5.9 g, 22.7 mmol) in THF (50 mL) was treated with 1N NaOH (50 mL) at room temperature for 24 h. The aqueous layer of the mixture is carefully acidified almost. HCl to pH 2 and extracted with EtOAc. The EtOAc layer was dried and purified by column chromatography on silica gel eluting with a solvent gradient (CH ₂ Cl ₂ to EtOAc) to give the title compound (3.7 g, 66.3%). ESMS (MH) ⁺ m / z: 245.

Preparation of Examples 109-115 by Library: To a solution of 1 N- (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 refluxed for 1.5 hours, then concentrated. The residue solution in THF (38 mL) was partitioned and poured into anilines or amines (0.1 mmol / sample / well) and DMAP (12.4 mg / well) in THF (1 mL / well) in a 96 well polyfiltronic filter plate. This polyfiltronic filter plate with the reaction mixtures is shaken at room temperature for 2 days, to each solution / well is added DOWEX (0.2 g) suspension in CH ₂ Cl ₂ (0.4 ml) and the resulting mixtures are shaken for one hour.

144 filtered, carefully collected filtrates were vacuum dried and a library of compounds was obtained.

EXAMPLE 109

1- (4'-Methoxyphenyl) -3-methyl-1H-pyrazole-5-N- (4'-sec-butyl) phenyl) -, carboxamide: ESMS (M + H) ⁺ m / z: 245.

EXAMPLE 110

1- (4'-Methoxyphenyl) -3-methyl-1H-pyrazole-5-N- (4 '- (3' -methyl-3 '-pyrazolin-5' -on2 '-yl) phenyl) carboxamide: ESMS (M + H) ⁺ m / z: 364.

EXAMPLE 111

1- (4'-Methoxyphenoyl) -3-methyl-1 H -pyrazol-5-N- (4 '- (6' -methbeozothiazol-2 'yl) phenyl) carboxamide: ESMS (M + H) ⁺ m / z : 455.

EXAMPLE 112

1- (4'-Methoxy-phenyl) -3-methyl-1H-pyrazole-5-N- (4 '- (3', 4'-dibromo-phenyl) -carboxamide: ESMS (M + H) ⁺ m / z: 364.

EXAMPLE 113

1- (4'-Methoxyphenyl) -3-methyl-1H-pyrazole-5-N- (4'-n-butylphenyl) carboxamide:

ESMS (M + H) ⁺ m / z: 464.

EXAMPLE 114

1- (4'-Methoxyphenyl) -3-methyl-1H-pyrazole-5-N- (4 '- (4' -methylpiperidio) phenyl) carboxamide: ESMS (M + H) ⁺ m / z: 405.

EXAMPLE 115

1- (4'-Methoxyphenyl) -3-methyl-1 H -pyrazol-5-N- (4 '- (2' -methylimidazol-1-yl) phenyl) carboxamide: ESMS (M + H) ⁺ m / z : 388.

EXAMPLE 116

145

3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5-N- (4-carboxy (N-methylimidazol-2-yl) phenyl) carboxamide

Part A: To 4-nitro-1- (2'-N-methylimidazole) benzene (0.58 g, 2.51 mmol) prepared from 4-nitrobenzoyl chloride and 1-methylimidazole according to .Regel, E. et al. , Liebigs Ann. Chem. (1977), 145, add ethanol (50 ml), trifluoroacetic acid (1 ml) and 10% palladium on carbon (60 mg). The mixture is hydrogenated in a Parr hydrogenator at 276 kPa for 0.5 h. The reaction mixture was filtered and concentrated. The isolated aniline salt is dissolved in water and extracted with ether. The aqueous layer was basified with 1N NaOH, extracted with ethyl acetate, dried (MgSO ₄ ) and evaporated to give 0.35 g (70%) of aniline. MS (AP +) 202.1 (M + H) &lt; + &gt;.

Part B. To 1- (4-methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-carboxylic acid (0.25 g, 0.87 mmol) in CH ₂ Cl ₂ (15 mL) was added oxalyl chloride (0.1 mL, 1 mL). , 14 mmol) and a few drops of DMF. The reaction mixture was stirred for 24 hours and then concentrated. To this chloro anhydride was added part A aniline (0.175 g, 0.87 mmol), DMAP (0.27 g, 2.2 mmol) and fresh CH ₂ Cl ₂ (20 mL) and the reaction mixture was stirred for 24 h. Concentrate the mixture, dissolve the residue in EtOAc (10 mL) and TFA (0.1 mL), and purify by reverse phase HPLC and lyophilize to give the title compound (60 mg, 11%); 1 H NMR (DMSO-d ₆ ) δ 10.97 (s, 1H), 8.30 (d, J = 8.80 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) md; DSGMS (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) carboxamide,

EXAMPLE 118

146

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

AND EXAMPLE 119

1- (4-Methoxyphenyl) -3-trifluoromethyl-1 H -pyrazol-5-N- (4- (2-carboxy (imidazol-2-yl) phenyl) carboxamide

Part A: 4-Nitro-1- (2'-N-benzylimidazoyl) benzene (0.47 g, 1.53 mmol) prepared from 4-nitrobenzoyl chloride and 1-benzylimidazole according to Regel, E. et al. Liebigs Ann. Chem. (1977), 145, EtOAc (15 mL) and tin chloride (0.86 g, 3.80 mmol) were added. The reaction mixture was refluxed for 2 hours, then stirred at room temperature for 18 hours. 0.3 g of tin chloride is added again and the reaction mixture is stirred for 3 hours. The reaction mixture was cooled to 0 ° C, quenched with 6M NaOH, extracted with EtOAc, dried (Na ₂ SO ₄ ) to give 0.4 g (95%) of an orange solid. MS (M + H) ⁺ 278.2 (AP +).

Part B: The benzyl derivative of Part A (0.229 g, 0.4 mmol) was hydrogenated in a Parr hydrogenator with EtOH (30 mL) and TFA (0.5 mL) with 30 mg of 10% Pd / C at 276 kPa, 5 or. The reaction mixture is filtered, concentrated, and purified by reverse phase HPLC to give the corresponding desired compounds mentioned above.

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), 7.55 (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 (ds, 2H), 6.00 (d, J = 4.0 Hz, 1H), 3.81 (s, 3H) md DSGMS (M + H) ⁺ C 22 H 19 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 = 8.80 Hz, 2H), 7.55 (s, 1H), 7.34 (d, J = 5.80 Hz, 2H), 7.32 (m , 5H), 7.19 (pi, 1H), 7.10 (dd, J = 2.20, 5.80 Hz,

147

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) md DSGMS (M + H) ⁺ C 24 H 34 N 5 O 5a 548.1923;

Example 119: 15 mg (6.2%) Ή 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 = 8.80 Hz, 2H), 7.41 (s, 2H), 7.31 ( m, 1H), 7.07 (m + d, J = 8.80 Hz, 3H), 3.82 (s, 3H)

md DSGMS (M + H) ⁺ C ₂₂ H ₇ F ₃ N ₅ O ₃ 456.1271.

EXAMPLE 120

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

AND EXAMPLE 121

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

Part A: To 3-trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5-carboxylic acid chloro anhydride (0.34 g, 1.11 mmol) in CH ₂ Cl ₂ (10 mL) was added paminobenzaldehyde (135 mg, 1.11 mmol) and TEA (0.155 mL, 1.11 mmol). The reaction mixture was stirred for 18 hours. followed by concentration. Purification by chromatography on silica gel. eluting with 2: 1 hexanes / EtOAc to give 0.16 g (37%) of a yellow solid. MS (ESI) (MH ⁺ ) 388.1.

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

Part B: To a cooled to -40 ° C solution of thiazole (0.1 mL, 1.43 mmol) in THF (6 mL) was added n-BuLi (0.6 mL, 1.43 mmol) and stirred for 1.5 h. . To aldehyde A (0.14 g, 0.36 mmol) in benzene (10 mL) and MeOH (5 mL) was added 4A molecular mesh and p-anisidine (44 mg, 0.36 mmol) and the mixture was refluxed. min The mixture is filtered and the imine is concentrated. to this imine, a thiazole anion is added via cannula to THF (5 mL) at -78 ° C. The reaction mixture was stirred at 0 ° C

148 for 0.5 h, then quenched with 1M KHSO ₄ (0.4 mL). The product was extracted with EtOAc and dried (MgSO ₄ ). Purification by silica gel chromatography using 1: 2 hexanes / EtOAc afforded 0.113 g (54%) of the title compound; MS (MH) ⁺ 578.1; ¹ H NMR (CDCl 3) δ 7.74 (d,

J = 3.30 Hz, 1H), 7.50 (d, J = 14.4 Hz, 2H), 7.41 (m.s, 5H), 7.27 (d, J = 3.30 Hz, 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) m.d.

1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5- (N- (4 '(2-carboxy- (4,5-dihydrothiazol-2-yl) phenyl))) carboxamide:

Part C: To a solution of Part B product (98 mg, 0.17 mmol) in acetonitrile (10 mL) at 0 ° C was added a solution of cerium ammonium nitrate (0.185 g, 0.34 mmol) in water (10 mL). The reaction mixture was stirred for 10 min. followed by concentration. The residue was dissolved in EtOAc, washed with aqueous sodium sulfite and dried (MgSO ₄ ). The product is purified by silica gel chromatography, reverse-phase HPLC and lyophilized; The title compound is obtained (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,

1 H), 7.05 (d, J = 9.20 Hz, 2H), 3.88 (s, 3H) md; MS (M + H) ⁺ 473.2 (AP +).

EXAMPLE 122

1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-N-4- (2- (4 ', 5'-dihydro-1H-imidazol-2'-yl) phenyl) carboxamide

AND EXAMPLE 123

1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (4- (N-2'aminoethylenecarboxamide) phenyl) carboxamide

Ethylenediamine (57 mg, 0.95 mmol) was added to trimethylaluminum (1.2 mL, 2M in heptane) cooled to 0 ° C, and the mixture was stirred for 15 min. Flatten

149 Suspension of previously prepared ethyl 3-trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-carboxyphenyl) carboxamide (0.2 g, 0.47 mmol) in toluene (10 mL). the mixture was heated at 50 ° C for a total of 9 hours and at room temperature for 18 hours. The reaction mixture was quenched with ice water, filtered and concentrated, the aqueous layer was extracted with CH 2 Cl 2, followed by extraction with 1N HCl, acidified, EtOAc and dried (MgSO _4). Purification by reverse phase HPLC and lyophilization afforded 56 mg (22%) of imidazoline (Example 122) and 7 mg (3%) of the open ring amide (Example 123).

EXAMPLE 122: Imidazoline: Ή NMR (DMSO-d6) 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) md; MS (ESI) 430.2 (M + H) &lt; + &gt;.

123 EXAMPLE amide ¹ H NMR (DMSO-ds) 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, 2Hz, 2H), 7.06 (d, J = 8.80 Hz, 2H), 3.82 (s, 3H), 3.51 (s, J = 5.50 Hz, 2H), 2.98 (kv, J = 5.90 Hz, 2H) md; MS (ESI)

448.2 (M + H) ⁺ .

'S

EXAMPLE 124

1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazol-5- [4- (1,4,5,6-tetrahydropyrimidin-2-yl) phenyl] carboxamide

Ethyl 3-trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-carboxyphenyl) carboxamide (0.2 g, 0.48 mmol) and 1,3-diaminopropane (70 mg, 0.95 mmol) is copolished according to the procedure described above, and purified by reverse phase HPLC and lyophilized to give 20 mg (7.5%). 1 H NMR (DMSO-d 6) δ: 11.0 (s, 1H), 10, 3 (s, 1H), 7.86 (d, J = 8.80 Hz, 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) md; DSGMS calcd for C 20 H 18 N 4 O 5 444.1646.

EXAMPLE 125

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

150

Ethyl 3-trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-carboxyphenyl) carboxamide (0.2 g, 0.48 mmol) and N-methyl-1,3- Propandiamine (0.1 mL, 0.95 mmol) was copied according to the procedure described above, purified by reverse phase HPLC and lyophilized to give 58 mg (21%). ¹ H NMR (DMSO-d ₆ ) δ: 9.70 (s) , 1H), 7.85 (d, J = 8.80 Hz, 2H), 7.62 (d, J = 9.20 Hz, 2H), 7.55 (s, 1H), 7.47 (d) , J = 9.20 Hz, 2H), 7.07 (d, J = 9.20 Hz, 2H), 3.82 (s, 3H), 3.57 (t, J = 5.50 Hz, 2H) ), 3.39 (m, 2H), 2.97 (s, 3H), 2.05 (t, J = 5.50 Hz, 2H) md

EXAMPLE 126

1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-N-1- (2-fluoro-4imidazolinophenyl) carboxamide

Part A: Oxalyl chloride (1.72 mL, 19.7 mmol) and a few drops of DMF were added to 3-fluoro-4-nitrobenzoic acid (2.81 g, 15 mmol) in CH ₂ Cl ₂ (75 mL). The reaction mixture was stirred for 6 h, evaporated and ethanol (20 mL) was added. After 18 or. ethanol was evaporated and EtOAc (30 mL) and tin chloride (13.7 g, 61 mmol) were added. The reaction mixture was refluxed for 2 h, cooled and quenched with saturated NaHCO ₃ . Extraction with EtOAc and drying (MgSO ₄ ) gives 2.7 g (97%) of aniline.

Part B: Oxalyl chloride (0.08 mL) was added to 1- (4-methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-carboxylic acid (0.21 g, 0.73 mmol) in CH ₂ Cl ₂ (15 mL). , 0.95 mmol) and a few drops of DMF. The reaction mixture was stirred for 24 hours and then concentrated. Fresh CH ₂ Cl _{2 is} mixed with this hydrochloric anhydride, DMAP (0.27 g, 2.20 mmol), and part A aniline (134 mg, 0? 73 mmol) and stirred for 18 h. The reaction mixture was washed with 1N HCl, saturated NaHCO ₃ , saturated

151

NaCl solution and dried (MgSO _4). Purification by silica gel chromatography eluting with 1: 1 hexanes / EtOAc 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 = 8, 10 Hz, 1H), 7.89 (d, J = 3.30 Hz, 1H), 7.84 (d, J = 9.60 Hz, 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 (kv, J = 7.0 Hz, 2H), 3.88 (s, 3H), 1.41 (t, J = 6.90 Hz, 3H) md

Part C: Ethylenediamine (27.6 mg, 0.46 mmol) was added to trimethylaluminium (0.57 mL, 2M heptane) cooled to 0 ° C and the mixture was stirred for 15 min. Add a suspension of ethyl 3-trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-carboxy-2-fluorophenyl) carboxamide (0.1 g, 0.23 mmol) in toluene (10 mL). The reaction mixture is heated at 50 ° C for 18 h, then quenched with ice water, filtered and concentrated, the aqueous layer is extracted with CH ₂ Cl ₂ , which is then extracted with 1N HCl, the acid layer is basified, extracted with EtOAc and dried (MgSO ₄ ). Purification by reverse-phase HPLC and lyophilization gave 26 mg (20%). ¹ H NMR (DMSO-d ₆ ) δ: 10.90 (s, 1H), 10.55 (s, 1H), 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) md; DSGMS for C ₂₁ H ₁₈ F ₄ O ₂ N ₅ found 488.1393.

EXAMPLE 127

1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-N-1- (2-fluoro-4-N-methylimidazolinophenyl) carboxamide

N-Methylethylenediamine (52 mg, 0.71 mmol) and ethyl 3-trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-carboxy-2-fluorophenyl) carboxamide (150 mg, 0 , 35 mmol) according to the procedure of example ankstesnaime. Purification by reverse-phase HPLC after lyophilization to give 54 mg (27%). ¹ H NMR (DMSO-d ₆₎ δ: 10.90 (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)

152

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) md; MS (ESI) 462.3 (M + H) &lt; ⁺ &gt; Analysis calculated for C ₂₂ H ₁₉ F ₄ O ₂ N ₅ (TFA): C: 46.61, H: 3.53; N: 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-methylimidazo-2-yl) phenyl] carboxamide

AND EXAMPLE 129

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

Part A: To a solution of N-4'-methoxyphenyl-3-trifluoromethyl-pyrazole-5-carboxylic acid (2 g, 6.99 mmol) in dichloromethane (50 mL) was added oxalyl chloride (1.36 g, 10.48 mmol). and a few drops of DMF. The reaction mixture was stirred at room temperature for 3 hours, then evaporated to a yellowish solid which was redissolved in dichloromethane (50 mL). To this solution 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, quenched with dilute HCl (50 mL), the organic material extracted with ethyl acetate (2 x 100 mL), dried (MgSO ₄ ) and evaporated to a yellow solid. Purification of the crude copolymer product by flash chromatography on silica gel (hexane: ethyl acetate 7: 3) gives the desired copolymer precursor which is colorless crystals (1.9 g). MSGMS (ESI) m / z 420.0 (100). ¹ H NMR (CDCl 3) δ: 8.019 (d, J = 8.8, 2H), 7.617 (s, 1H), 7.480 (m, 4H), 7.158 (s, 1H), 7.03 (d, J = 8.8, 2H) 3.90 (s, 3H), 3.87 (s, 3H) md

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

Part B: The product from Part A (0.2 g, 0.048 mmol) in dichloromethane (50 mL) was treated with N ¹ -methyl ethylenediamine (0.071 g, 0.099 mmol) followed by trimethylaluminium (1.23 mL, 2.45 mmol). The reaction mixture was stirred at room temperature

153 overnight, then quenched with dilute HCl (5 mL). The product is concentrated in vacuo and then purified by preparative HPLC (acetonitrile / water, 2% TFA). Lyophilization gave colorless crystals of the desired product (0.167 g). MSGMS (ESI) m / z 444.2 (100). DSGMS: (M + H) ⁺ calcd 444.1647, found 444.1644. ¹ H NMR (DMSO-d ₆ ) δ: 11.07 (s, 1H), 10.12 (s, 1H), 7.88 (d, J = 8.8, 2H), 7.71 (d, J = 8.8, 2H), 7.63 (s, 1H), 7.47 (m, 2H), 7.06 (m, 2H), 4.05 (m, 2H), 3.89 (m , 2H), 3.82 (s, 3H), 3.09 (s, 3H) md

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

Part C: The product from Part A (150 mg, 0.358 mmol) was treated with guanidine hydrochloride (103 mg, 1.074 mmol) and trimethylaluminum (103 mg, 1.432 mmol) according to the Veinreb standard procedure described above in dichloromethane (10 mL). The mixture was stirred at room temperature for 18 hours. and quenched with 1N hydrochloric acid (5 mL). The suspension is then basified (pH 9, saturated sodium bicarbonate). The organics were extracted with dichloromethane (3 x 100 mL) and dried (Na ₂ SO ₄ ). Evaporation of the solvent, purification by reverse phase preparative HPLC and lyophilization afforded the desired acylguanidine derivative, which is colorless crystals. MSGMS (ESI) m / z 447.2 (100). DSGMS: (M + H) ⁺ calcd 447.1392, found 447.1391. ¹ H NMR (DMSO) δ: 11.20 (s, 1H), 11.00 (s, 1H), 8.33 (pi, 4H), 7.98 (d, J = 8.79, 2H), 7.88 (d, J = 8.79, 2H), 7.64 (S, 1H), 7.48 (d, J = 8.79, 2H), 7.07 (d, J = 9.16). , 2H), 3.82 (s, 3H) md

• EXAMPLE 130

1- (4-Methoxyphenyl) -3-trifluoromethyl-1 H -pyrazol-5-N- [4- (pyrimidin-2-yl) phenyl] carboxamide

Part A: Standard Suzuki coupling of 4-trifluoromethylphenylboronic acid (0.88 g, 3.77 mmol) with 2-bromopyrimidine (0.5 g, 3.144 mmol) yields the copolished product (0.47 g). MSGMS (ESI) m / z 268.1 (100). Ή NMR (CDCl ₃₎

154 δ: 8.82 (d, J = 5.1, 2H), 8.52 (d, J = 8.8, 2H), 7.96 (pi, 1H), 7.73 (d, J = 8.8, 2H), 7.23 (t, J = 4.8, 1H) md Hydrolysis of this compound followed by flash chromatography (4: 1 hexanes: ethyl acetate) affords the desired anilinopyrimidine precursor (0.24 g). . MSGMS (NH ₃ -Cl) m / z 172.2 (100). 1 H NMR (CDCl 3) δ: 8.73 (d, J = 5.1.2H), 8.28 (m, 2H), 7.06 (t, J = 5.1, 1H), 6.76 (m, 2H), 3.94 (pi, 2H) md

1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazol-5-N- [4- (pyrimidin-2-yl) phenyl] · carboxamide:

Part B: Standard coupling of the compound obtained in Part A (0.13 g, 0.77 mmol) with previously obtained trifluoromethylpyrazole acid chloro anhydride (0.22 g, 0.77 mmol carboxylic acid). yields the desired product which is purified by flash chromatography on silica gel (hexane: ethyl acetate, 1: 1) to give the title compound which is colorless crystals (0.14 g). MSGMS (ESI) m / z 440.1 (100). DSGMS: (M + H) ⁺ calcd 440.1334, found: 440.1333. 1 H NMR (DMSO-d 6) 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, 1 H), 7.07 (d, J = 9.2, 2H), 3.82 (s, 3H) md

EXAMPLE 131

2- (Carboxamide) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4yl) carboxamide] thiazole

2-Bromo-4 - [(4-methoxy) phenyl] -5- (methoxycarbonyl) thiazole: Copper (II) bromide (11.43 g, 51.2 mmol) and tert-butyl nitrite (6.0 g, 58). The mixture (2 mmol) was stirred in 200 mL of acetonitrile at 80 ° C until gas evolution ceased (about 30 min). To this solution was added 2-amino-4 - [(4-methoxy) phenyl] -5 (methoxycarbonyl) -thiazole (12.3 g, 46.55 mmol) in 100 mL of acetonitrile. The solution is stirred at 80 ° C until gas evolution ceases (about 1 hour). The mixture is 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 I} dried (MgSO ₄ ) and concentrated to give 8.95 g (59%) of the title compound which was used crude. MSGMS (ES &lt; + &gt;): 328 (M + H) &lt; + &gt;.

2-Bromo-4 - [(4-methoxy) phenyl] thiazole-5-carboxylic acid: 2-bromo-4 - [(4-methoxy) phenyl] -5- (methoxycarbonyl) thiazole (6.24 g, 19.74 mmol) ) solution of 20 ml of methanol and 20 ml of water are added lithium hydroxide monohydrate (0.91 g,

21.7 mmol). The mixture was stirred at room temperature for 1 h and lithium hydroxide monohydrate (0.91 g, 21.7 mmol) was added. After stirring for a further 1 h, the volatiles were removed in vacuo and the residue partitioned between 10% aqueous HCl. The mixture was extracted with ethyl acetate and the organic extract was washed with brine, dried (MgSO ₄₎ and concentrated. Recrystallization of the residue from chloroform / hexane gave 2.2 g (37%) of the title compound as a white solid. MSGMS (ES-): 303 (MH +).

2-tert-Butylcarboxamide-4 - [(4-methoxy) phenyl] thiazole-5-carboxylic acid: 2-bromo-4 - [(4-methoxy) phenyl] thiazole-5-carboxylic acid (2.0 g, 6.36 mmol) ) solution of 70 ml of tetrahydrofuran at -78 ° C was added dropwise tert-butyllithium (12.3 ml

1.7 M solution in hexanes, 21.0 mmol). The reaction mixture was stirred for 15 min before tert-butyl isocyanate was added dropwise. Remove the cooling bath and stir the reaction mixture to room temperature for 18 hours. The reaction mixture was quenched with 10% aqueous HCl, then diluted with ethyl acetate. The organic layer was washed with brine, dried (MgSO ₄₎ and concentrated to afford 0.9 g (43%) of the title compound which was used without further purification. MSGMS (ES-): 332.9 (MH +).

2- (tert-Butylcarboxamide) -4 - [(4-methoxy) phenyl] -5 - [(2 '- (tert-butylamino) sulfonyl- [1,1'] - biphen-4-yl) carboxamide] thiazole: To a solution of 2-tert-butyl 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 room temperature for 4 hours, after which the volatiles were removed in vacuo. Dissolve the residue in 10

156 mL of methylene chloride and 4-dimethylaminopyridine (0.36 g, 2.99 mmol) was added.

This mixture was stirred at room temperature for 15 min before 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 mixture was diluted with ethyl acetate, washed successively with 10% aqueous HCl, saturated NaHCO ₃ solution and saturated NaCl solution, dried (MgSO ₄ ), and concentrated to give 0.69 g (75%) of the title compound which was used crude. MSGMS (ES &lt; + &gt;): 643.4 (M + Na) &lt; + &gt;.

2- (tert-Butylcarboxamide) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] biphen-4-yl) carboxamide] thiazole: 2- (tert-Butylcarboxamide) -4 - [(4-methoxy) phenyl] -5 - [(2 '- (tert-butylamino) sulfonyl- [1,1'] - biphen-4-yl) carboxamide] thiazole (0.69 g, 1, A solution of 11 mmol) in 5 ml of trifluoroacetic acid was stirred at 80 ° C for 1 h. then cooled and concentrated in vacuo. Purification of the residue by preparative HPLC (C18 reverse phase column, eluting with H ₂ O / CH ₃ CN with a gradient of 0.5% TFA) and lyophilization gave 0.34 mg (53%) of the title compound as a white powder. MSGMS (ES +): 565.1 (M + H) &lt; + &gt;.

2- (carboxamido) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- ^[1,1] -biphen-4-yl) carboxamido] thiazole: 2- (tert-butylcarboxamide) -4 - Solution of [(4-methoxy) -phenyl] -5C (2 '- (tert-butylamino) sulfonyl- [1,1'] -biphen-4-yl) carboxamide] thiazole (70 mg, 0.10 mmol) 20 ml of trifluoroacetic acid are stirred at 80 ° C for 24 hours. The reaction mixture was cooled and concentrated in vacuo. Purification of the residue by preparative HPLC (C18 reverse phase column, eluting with H ₂ O / CH ₃ CN with a gradient of 0.5% TFA) and lyophilization gave 20 mg (32%) of the title compound as a white powder. MSGMS (ES &lt; + &gt;): 508.8 (M + H) &lt; + &gt;.

EXAMPLE 132

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

157 µl of a solution of 2-bromo-4 - [(4-methoxy) -phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide-thiazole (25 mg, 0.046 mmol) 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. Purification of the residue by preparative HPLC (C 18 reverse phase column, eluting with H ₂ O / CH ₃ CN with a gradient of 0.5% TFA) and lyophilization gave 10 mg (41%) of the title compound as a white powder. MSGMS (ES +): 538.9 (M + H) &lt; + &gt;.

EXAMPLE 133

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

A solution of 2-bromo-4 - [(4-methoxy) -phenyl] -5 - [(2'-aminosulfonyl- [1,1'] -biphen-4-yl) carboxamide] thiazole (50 mg, 0.092 mmol) in 3 mL of acetonitrile added

3-Hydroxypropylamine (0.5 mL, 5.5 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. Purification of the residue by preparative HPLC (C18 reverse phase column, eluting with H ₂ O / CH ₃ CN with a gradient of 0.5% TFA) and lyophilization gave 19 mg (37%) of the title compound as a white powder. MSGMS (ES +): 538.9 (M + H) &lt; + &gt;.

EXAMPLE 134

2- (2-Cyanoethylamino) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] biphen-4-yl) carboxamide] thiazole 2-bromo-4- A solution of [(4-methoxy) -phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide] thiazole (80 mg, 0.15 mmol) in 3 mL of acetonitrile was added.

3-aminopropionitrile (0.11 mL, 1.5 mmol). The resulting solution was stirred at 60 ° C for 48 hours, then cooled, filtered through a small pad of silica gel, and concentrated in vacuo. After purification of the residue by preparative HPLC (C18 reverse phase column, eluting with H ₂ O / CH ₃ CN

158% TFA gradient) and lyophilization afforded 35 mg (41%) of the title compound as a white powder. MSGMS (ES &lt; + &gt;): 534.2 (M + H) &lt; + &gt;.

EXAMPLE 135

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

A solution of 2-bromo-4 - [(4-methoxy) -phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide thiazole (80 mg, 0.15 mmol) Add 3 mL of acetonitrile

3-methoxypropylamine (0.15 mL, 1.5 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. Purification of the residue by preparative HPLC (C18 reverse phase column, eluting with H ₂ O / CH ₃ CN with a gradient of 0.5% TFA) and lyophilization gave 25 mg (31%) of the title compound as a white powder. MSGMS (ES &lt; + &gt;): 552.8 (M + H) &lt; + &gt;.

EXAMPLE 136

2- (N-3-Alanyl) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide] thiazole

2- (2- (Methoxycarbonyl) ethylamino) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl [1,1 '] - biphen-4-yl) carboxamide] thiazole: J 2-bromo To a solution of -4 - [(4-methoxy) -phenyl] -5 - [(2aminosulfonyl- [1,1 '] - biphen-4-yl) -carboxamide] thiazole (80 mg, 0.15 mmol) was added 3 mL of acetonitrile. -aminopropionate hydrochloride (0.20 g, 1.5 mmol) and N, N-diisopropylethylamine (0.26 mL, 1.5 mmol). The resulting solution was stirred at 60 ° C for 48 hours, then cooled, filtered through a small pad of silica gel, and concentrated in vacuo. Purification of the residue by preparative HPLC (C18 reverse phase column, eluting with H ₂ O / CH ₃ CN with a gradient of 0.5% TFA) and lyophilization gave 45 mg (55%) of the title compound as a white powder. MSGMS (ES &lt; + &gt;): 567.2 (M + H) &lt; + &gt;.

159

2- (N-β-Alanyl) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) · carboxamidothiazole: 2- (2- (Methoxycarbonyl) ethylamino) -4 - [(4-methoxy) phenyl] - [(2'-aminosulfonyl- [1,1]] -biphen-4-yl) carboxamide] thiazole (38 mg, 0.066 mmol) Lithium hydroxide monohydrate (5 mg, 0.13 mmol) was added in mL of tetrahydrofuran and 2 mL of water. The resulting solution was stirred at room temperature for 18 hours and then concentrated in vacuo. Purification of the residue by preparative HPLC (C18 reverse phase column, eluting with H2O / CH3CN with 0.5% TFA gradient) and lyophilization gave 32 mg (88%) of the title compound as a white powder. MSGMS (ES-): 567.2 (M-H + TFA).

EXAMPLE 137

2- (isopropylamino) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1'] -biphen-4-yl) carboxamide] thiazole 2-bromo-4 - [(4- methoxy) -phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide-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 h, then cooled, filtered through a small pad of silica gel, and concentrated in vacuo. Purification of the residue by preparative HPLC (C18 reverse phase column, eluting with H2O / CH3CN with 0.5% TFA gradient) and lyophilization gave 28 mg (37%) of the title compound as a white powder. MSGMS (ES &lt; + &gt;): 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) carboxamide] thiazole

J 2-Bromo-4 - [(4-methoxy) -phenyl] -5 - [(2'-aminosulfonyl- [1,1]] -biphen-4-yl) -carboxamidothiazole (80 mg, 0.15 mmol) of acetonitrile was added

1,3-dihydroxy-2-aminopropane (0.13 g, 1.5 mmol). The resulting solution is stirred «

After 72 hours at 0 ° C, it was cooled, filtered through a small pad of silica gel and concentrated in vacuo. After purification of the residue

160 by preparative HPLC (C18 reverse phase column, elution

H2O / CH3CN with 0.5% TFA gradient) and lyophilization gave 30 mg (37%) of the title compound as a white powder MSGMS (ES +): 555.1 (M + H) ⁺ .

EXAMPLE 139

2 - [(methoxycarbonyl) methylamino] -4 - [(4-methoxy) phenyl] -5 - [(2'aminosulfonil- [1, t] ^e -BiFi n-4-yl) carboxamido] thiazole To 2-bromo- To a solution of 4 - [(4-methoxy) -phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide] 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 mL, 1.5 mmol). The resulting solution was stirred at 60 ° C for 72 h, then at 75 ° C for a further 24 h. The reaction mixture was cooled, filtered through a small pad of silica gel, and concentrated in vacuo. Purification of the residue by preparative HPLC (C18 reverse phase column, eluting with H ₂ O / CH ₃ CN with a gradient of 0.5% TFA) and lyophilization gave 40 mg (49%) of the title compound as a white powder. MSGMS (ES &lt; + &gt;): 553.0 (M + H) &lt; + &gt;.

EXAMPLE 140

2- (N-Glycyl) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamidothiazole] 2- (2- (methoxycarbonyl) methylamino) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 T] -biphen-4-yl) carboxamide] thiazole (27 mg, 0.049 mmol) in 2 mL of tetrahydrofuran and Lithium hydroxide monohydrate (4 mg, 0.098 mmol) was added in 2 mL of water. The resulting solution was stirred at room temperature for 18 hours and then concentrated in vacuo. Purification of the residue by preparative HPLC (C18 reverse phase column, eluting with H ₂ O / CH ₃ CN with a gradient of 0.5% TFA) and lyophilization gave 16 mg (61%) of the title compound as a white powder. MSGMS (ES-): 536.8 (MH +).

161

EXAMPLE 141

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

1 - [(4-Methoxy) phenyl] -3,5-dimethylpyrazole: To a solution of 4-methoxyphenylhydrazine hydrochloride (118.7 g, 0.68 mol) in 300 ml glacial acetic acid was added 2,4-pentandione (68.0 g). , 0.68 mol). The resulting solution was stirred at 100 ° C for 18 hours, then cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate, stripped through a pad of silica gel, and concentrated to give 131 g (95%) of the title compound which was used crude. MSGMS (NH ₄ -Cl): 203.3 (M + H) ⁺ .

1 - [(4-Methoxy) phenyl] pyrazole-3,5-dicarboxylic acid: To a suspension of 1 - [(4-methoxy) phenyl] -3,5-dimethylpyrazole (131 g, 0.65 mol) in 400 mL of water was added potassium permanganate ( 410 g, 2.6 mol). This mixture was heated at 70 ° C and stirred for 1 h. The reaction mixture is filtered and the material on the filter is washed with hot water. The filtrate was acidified with HCl, then extracted twice with ethyl acetate. The combined organic extracts were washed with saturated NaCl solution, dried (MgSO ₄ ) and concentrated. The residue was triturated with chloroform to afford 39.7 g (23%) of the title compound. MSGMS (ES-): 260.9 (MH) -.

Dimethyl 1 - [(4-methoxy) phenyl] pyrazole-3,5-dicarboxylate: 1 - [(4-Methoxy) phenyl] pyrazole-3,5-dicarboxylic acid (39.7 g, 0.15 mmol), solution 300 of anhydrous methanol is cooled to 0 ° C and passed through a gas distribution tube to the solution for 15 min. bubbling gaseous HCl. Stopper the flask and stir the reaction mixture at room temperature for 24 hours. Volatiles are evaporated 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 crude. MSGMS (NH ₄ Cl): 291.2 (M + H) ⁺ . ^%

162

- [(4-Methoxy) phenyl] -5- (methoxycarbonyl) pyrazole-3-carboxylic acid: solution of dimethyl 1 - [(4-methoxy) phenyl] pyrazole-3,5-dicarboxylate (32.7 g, 110 mmol) 50 Concentrated sulfuric acid (1.50 mL, 28.2 mmol) was added in mL of dioxane and 100 mL of water. The resulting solution was stirred at 100 ° C for 18 hours, then cooled to room temperature. The reaction mixture is basified with potassium carbonate and then extracted with ether to remove the unreacted ester. The aqueous layer was acidified with HCl and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO ₄ ), and concentrated to give 19.2 g (63%) of the title compound together with 5.0 g (15%) of unreacted starting material. The title compound is used crude. MSGMS (ES-): 274.9 (MH +).

1 - [(4-Methoxy) phenyl] -3- (ethoxycarbonyl) -5- (methoxycarbonyl) pyrazole: 1 - ((4Methoxy) phenyl] -5- (methoxycarbonyl) pyrazole-3-carboxylic acid (7.50 g, 27 50 ml of thionyl chloride are stirred at 80 ° C for 1 hour, the volatiles are evaporated in vacuo, the residue is azeotropically dried by the addition and evaporation of 20 ml of toluene, and the residue is dissolved in 100 ml of tetrahydrofuran followed by diisopropylethylamine (11 8 mL, 67.9 mmol) and absolute ethanol (3.2 mL, 54.3 mmol) The reaction mixture was stirred at room temperature for 24 h and the volatiles were evaporated and the residue was dissolved in ethyl acetate, filtered through a pad of silica gel and concentrated in vacuo. 3.7 g (45%) of the title compound are obtained, which is used crude MSGMS (DCI): 305.1 (M + H) ⁺ .

1 - [(4-Methoxy) phenyl] -3- (ethoxycarbonyl) pyrazole-5-carboxylic acid: 1 - [(4-methoxy) phenyl] -3- (ethoxycarbonyl) -5- (methoxycarbonyl) pyrazole (4.0 g, A solution of 13.2 mmol) in 40 ml of tetrahydrofuran and 20 ml of water is added lithium hydroxide monohydrate (0.55 g, 13.2 mmol) in aqueous solution. The reaction mixture was stirred at room temperature for 1 h, the Tetrahydrofuran% evaporated in vacuo and the aqueous layer was extracted with ether to remove the unreacted diester. The aqueous layer is acidified

163

HCl and extracted with ethyl acetate. The organic extract is washed saturated

NaCl solution, dried (MgSO ₄ ) and concentrated to give 3.2 g (84%) of the title compound which was used crude. MSGMS (ES-): 289.0 (MH +).

1 - [(4-Methoxy) phenyl] -3- (ethoxycarbonyl) -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl] carboxamide: 1 - [(4-Methoxy) phenyl] -3- ( solution of ethoxycarbonyl) pyrazole-5-carboxylic acid (3.2 g, 11.1 mmol) in 20 ml of thionyl chloride was stirred at 80 ° C for 1 h. The volatiles were evaporated in vacuo, the residue was azeotropically dried by the addition and evaporation of 20 ml of Methylene chloride (50 mL) was added followed by triethylamine (4.6 mL, 33.3 mmol) and 4- (N-pyrrolidinocarbonyl-aniline (3.2 mL, 54.3 mmol). The reaction mixture was stirred at room temperature for 4 h. dissolved in ethyl acetate, washed with 10% aqueous HCl followed by saturated NaCl solution, dried (MgSO ₄ ), filtered through a thin pad of silica gel and concentrated to give 2.5 g (50%) of the title compound. phase column eluted with H ₂ O / CH ₃ CN with 0.5% TFA in graph dientu) and lyophilization yields the desired compound which is a white powder. MSGMS (ES &lt; + &gt;): 463.1 (M + H) &lt; + &gt;.

EXAMPLE 142

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

1 - [(4-Methoxy) phenyl] -3- (carboxamide) -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl] carboxamide-3-carboxylic acid: 1 - [(4-methoxy) phenyl ] A solution of -3 (ethoxycarbonyl) -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl] carboxamide (2.05 g, 4.43 mmol) in 10 mL of THF and 10 mL of water was added with potassium hydroxide (0 32 g, 5.76 mmol) The resulting solution was stirred at room temperature for 18 h under vacuum, and the aqueous solution was extracted with ether to remove the unreacted ester.

The 164 layer was acidified with HCl and extracted with ethyl acetate. The organic extract was washed with saturated NaCl solution, dried (MgSO ₄ ) and concentrated to give 1.1 g (57%) of the title compound which was used crude. MSGMS (ES-): 433.0 (MH +).

1 - [(4-Methoxy) phenyl] -3- (carboxamide) -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl] carboxamide: To 1 - [(4-methoxy) phenyl] -1H -Pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl] carboxamide-3-carboxylic acid (117 mg, 0.27 mmol) was added triethylamine (0.056 mL, 0.40 mmol) in 10 mL of 1: 1 THF / CH ₃ CN. and isobutyl chloroformate (0.038 mL, 0.30 mmol) After stirring at room temperature for 30 min, methanolic ammonia solution (1.34 mL of 2.0 M ammonia in methanol, 2.7 mmol) was added and the reaction mixture was stirred for 1 h. The residue is purified by preparative HPLC (C18 reverse phase column, eluted with H2O / CH3CN with 0.5% TFA gradient) and lyophilization to give 50 mg (43%) of the title compound as a white powder. ES +): 434.1 (M + H) ⁺ .

EXAMPLE 143

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

To a solution of 1 - [(4-methoxy) phenyl] -1H-pyrazo [5 - [(4- (N-pyrrolidinecarbonyl) phenyl] carboxamide-3-carboxylic acid (110 mg, 0.25 mmol) in 5 mL acetonitrile was added triethylamine (0.053 mL, 0.38 mmol) and iso-butyl chloroformate (0.036 mL, 0.28 mmol) and stirred at room temperature for 30 min, ethanolamine (0.06 mL, 1.01 mmol) was added. The residue was purified by preparative HPLC (C18 reverse phase column, eluted with H ₂ O / CH ₃ CN with 0.5% TFA gradient) to give 80 mg (67%) of the title compound after lyophilization. which is a white powder MSGMS (ES +): 478.0 (M + H) ⁺ .

EXAMPLE 144

165

1 - [(4-Methoxy) phenyl] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl] carboxamide-3-hydroxamic acid to 1 - [(4-methoxy) phenyl] -1H- To a solution of pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl] carboxamide-3-carboxylic acid (100 mg, 0.23 mmol) in 5 mL of acetonitrile was added triethylamine (0.064 mL, 0.46 mmol) and isobutyl chloroformate (0.030 mL, 0.23 mmol) After stirring at room temperature for 30 min, hydroxylamine hydrochloride (16 mg, 0.23 mmol) was added and the reaction mixture was stirred for 1 h before the volatiles were evaporated and the residue was purified by preparative HPLC (C18). reverse phase column, eluted with H ₂ O / CH ₃ CN with 0.5% TFA gradient), and lyophilized to give 28 mg (27%) of the title compound as a white powder MSGMS (ES-): 562.1 (M-). H + TFA) '.

EXAMPLE 145

1 - [(4-Methoxy) phenyl] -3- [phenylcarboxamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl] carboxamide

To a solution of 1 - [(4-methoxy) phenyl] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl] carboxamide-3-carboxylic acid (100 mg, 0.23 mmol) in 5 mL of acetonitrile was added triethylamine (0.064 mL). (0.46 mmol) and isobutyl chloroformate (0.030 mL, 0.23 mmol) and stirred at room temperature for 30 min, add aniline (0.02 mL, 0.23 mmol) and stir the reaction for 1 h, then The residue was purified by preparative HPLC (C18 reverse phase column, eluting with H ₂ O / CH ₃ CN with a gradient of 0.5% TFA) to afford, after lyophilization, 22 mg (19%) of the title compound as a white powder. (ES +)? 510.2 (M + H) ⁺ .

EXAMPLE 146

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

166 µl of a solution of 1 - [(4-methoxy) phenyl] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl] carboxamide-3-carboxylic acid (100 mg, 0.23 mmol) Triethylamine (0.064 mL, 0.46 mmol) and iso-butyl chloroformate (0.030 mL, 0.23 mmol) were added to 5 mL of acetonitrile, and 3-hydroxypropylamine (0.02 mL, 0.23 mmol) was added with stirring at room temperature for 30 min. After stirring for 1 h, the volatiles were evaporated to give a residue which was purified by preparative HPLC (C18 reverse phase column, eluting with H ₂ O / CH ₃ CN with 0.5% TFA gradient) to give 38 mg (30%) of the desired product as lyophilized. of the compound which is a white powder MSGMS (ES +): 510.2 (M + H) ⁺ .

EXAMPLE 147

1 - [(4-Methoxy) phenyl] -3- [methylcarboxamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl] carboxamide

To a solution of 1 - [(4-methoxy) phenyl] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl] carboxamide-3-carboxylic acid (100 mg, 0.23 mmol) Triethylamine (0.096 mL, 0.69 mmol) and iso-butyl chloroformate (0.033 mL, 0.25 mmol) were added in acetonitrile and methylamine hydrochloride (23 mg, 0.35 mmol) was added with stirring at room temperature for 30 min. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with H ₂ O / CH ₃ CN with 0.5% TFA gradient) to give po5 mg (15%) of the title compound after lyophilization, which is a white powder MSGMS (ES +): 448.2 (M + H) ⁴ .

EXAMPLE 148

1 - [(4-Methoxy) phenyl] -3 - [(beryzyl) carboxamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl] carboxamide 1 - [(4-methoxy) phenyl] -1H To a solution of -pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl] carboxamide-3-carboxylic acid (100 mg, 0.23 mmol) in 5 mL of acetonitrile was added triethylamine (0.096 mL, 0.69 mmol) and isobutylchloroformate (0.033 mL, 0.25 mmol) and after stirring at room temperature for 30 min, add

167 Benzylamine hydrochloride (49 mg, 0.35 mmol). The reaction mixture is stirred under stirring and then the volatiles are evaporated. The residue is purified by preparative

HPLC (C18 reverse phase column, eluting with H ₂ O / CH ₃ CN with a gradient of 0.5% TFA) and lyophilization gave 19 mg (16%) of the title compound as a white powder. MSGMS (ES &lt; + &gt;): 524.2 (M + H) &lt; + &gt;.

EXAMPLE 149

1 - [(4-Methoxy) phenyl] -3 - [(dimethyl) carboxamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl] carboxamide] 1 - [(4-methoxy) phenyl] -1H To a solution of -pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl] carboxamide-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) After stirring at room temperature for 30 min, aqueous dimethylamine (0.040 mL of a 40% aqueous solution, 0.80 mmol) was added and the reaction mixture was stirred for 1 h, then the volatiles were evaporated and the residue was purified by preparative HPLC (0.25 mmol). C18 reverse phase column eluted with H ₂ O / CH ₃ CN (0.5% TFA gradient) and lyophilized to afford 20 mg (19%) of the title compound as a white powder MSGMS (ES +): 462.2 (M +). H) ⁺ .

EXAMPLE 150

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

To a solution of 1 - [(4-methoxy) phenyl] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl] carboxamide-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), and after stirring at room temperature for 30 min, phenethylamine (0.043 mL, 0.80 mmol) was added and the reaction mixture was stirred for 1 h, followed by volatile matter. The residue is purified by preparative HPLC (C 18 reverse phase column, eluting with H ₂ O / CH ₃ CN, 0.5% TFA).

168) and lyophilization yields 15 mg (12%) of the title compound as a white powder. MSGMS (ES &lt; + &gt;): 538.2 (M + H) &lt; + &gt;.

EXAMPLE 151

1 - [(4-Methoxy) phenyl] -3 - [(2-hydroxyphenyl) carboxamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl] carboxamide] 1 - [(4-methoxy) phenyl] - To a solution of 1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl] carboxamide-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) After stirring at room temperature for 30 min, 2-hydroxyaniline (75 mg, 0.69 mmol) was added and the reaction mixture was stirred for 1 h before the volatiles were evaporated and the residue was purified by preparative HPLC (C18 reverse phase column eluted with H2O / CH3CN with a gradient of 0.5% TFA) and lyophilized to give 10 mg (8%) of the title compound as a white powder MSGMS (ES +): 526.1 (M + H) ⁺ .

EXAMPLE 152

1 - [(4-Methoxy) phenyl] -3 - [(3-hydroxyphenyl) carboxamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl] carboxamide] 1 - [(4-methoxy) phenyl] - To a solution of 1H-pyrazole-5 - [(4- (N-pyrrolidinecarbonyl) phenyl) carboxamide-3-carboxylic acid (100 mg, 0.23 mmol) in 5 mL of acetonitrile was added triethylamine (0.096 mL, 0.69 mmol) and isobutylchloroformate (0.033 mL, 0.25 mmol), and after stirring at room temperature for 30 min, 3-hydroxyaniline (75 mg, 0.69 mmol) was added and the reaction mixture was stirred for 1 h before the volatiles were evaporated. preparative HPLC (C18 reverse phase column eluting with H ₂ O / CH ₃ CN with 0.5% TFA gradient) and lyophilization yielded 12 mg (10%) of the title compound as a white powder. MSGMS (ES +): 526, 1 (M + H) ⁺ .

FIGURE 153

169

1 - [(4-Methoxy) phenyl] -3 - [(4-hydroxyphenyl) carboxamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl] carboxamide] 1 - [(4-methoxy) phenyl] - To a solution of 1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl] carboxamide-3-carboxylic acid (100 mg, 0.23 mmol) in 5 mL of acetonitrile was added triethylamine (0.096 mL, 0.69 mmol) and iso-butyl chloroformate ( 0.033 mL, 0.25 mmol) After stirring at room temperature for 30 min, 4-hydroxyaniline (75 mg, 0.69 mmol) was added and the reaction mixture was stirred for 1 h before the volatiles were evaporated and the residue was purified by preparative HPLC (C18 reverse phase). column eluted with H ₂ O / CH ₃ CN with 0.5% TFA gradient) and lyophilized to give 12 mg (10%) of the title compound as a white powder MSGMS (ES +): 548.1 (M + Na) ⁺ .

FIGURE 153

1 - [(4-Methoxy) phenyl] -3 - [(methoxycarbonyl) amino] -1 H -pyrazol-5 - [(2'aminosulfonyl- [1,1 T] -biphen-4-yl) carboxamide

1 - [(4-Methoxy) phenyl] -3 - [(methoxycarbonyl) amino] -5- (methoxycarbonyl) · pyrazole: 1 - [(4-methoxy) phenyl] -5- (methoxycarbonyl) pyrazole-3-carboxylic acid A solution of (3.0 g, 10.9 mmol) in 50 mL of acetone at 0 ° C was added triethylamine (1.66 mL, 11.9 mmol) followed by isobutyl chloroformate (1.14 mL, 11.9 mmol). . The resulting mixture was stirred for 30 min. and a solution of aqueous sodium azide (2.82 g, 43.4 mmol) was added. The reaction mixture was stirred at 0 ° C for 1 h. The reaction mixture was then diluted with ethyl acetate and washed with a saturated NaCl solution. The organic solution was dried (MgSO ₄ ) and concentrated in vacuo. The residue was dissolved in 50 mL of toluene and stirred at 100 ° C for 1 h. The volatiles were removed in vacuo and the residue was dissolved in methanolic sodium methoxide (5 mL of 25% sodium methoxide in methanol, 21 mmol) and stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (MgSO ₄₎ and concentrated in vacuo. The residue is purified by flash chromatography (eluting with 1: 1)

170 hexanes / ethyl acetate) to give 1.1 g (33%) of the title compound as a solid. MSGMS (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) carboxamide: J ( A solution of 2'-tert-butylaminosulfonyl- [1,1 '] -biphen-4-yl) amino (0.90 g, 2.95 mmol) in 20 mL of methylene chloride was added dropwise at room temperature with trimethylaluminum (8.85 mL of 2.0 M). solution in toluene, 17.68 mmol). The resulting solution is stirred until gas evolution ceases (Ί5 min). 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 h, then cooled to room temperature and quenched with saturated aqueous NH ₄ Cl. After dilution with ethyl acetate, the organic layer was washed with 10% aqueous HCl, saturated aqueous NaHCCb and brine, then dried (MgSO _4), filtered through silica gel and concentrated in vacuo cover film. Recrystallization of the solid residue from hexanes / ethyl acetate gives 1.4 g (82%) of the title compound. MSGMS (ES +): 577.9 (M + H) &lt; + &gt;.

1 - [(4-Methoxy) phenyl] -3 - [(methoxycarbonyl) amino] -1H-pyrazole-5 - [(2 '· aminosulfonyl- [1,1'] - biphen-4-yl) carboxamide: 1- [(4-Methoxy) phenyl] -3 [(methoxycarbonyl) amino] -1H-pyrazol-5 - _[(2'-tert: butiiaminosulfonil- [1,1 '] - biphen4-yl) carboxamide (0.40 g, A solution of 0.69 mmol) in 5 mL of trifluoroacetic acid was stirred and refluxed for 20 min, then cooled to room temperature and concentrated in vacuo. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with H2O / CH3CN with 0.5% TFA gradient) to give, after lyophilization, 200 mg (56%) of the title compound as a white powder. MSGMS (ES &lt; + &gt;): 521.8 (M + H) &lt; + &gt;.

EXAMPLE 155

1 - [(4-Methoxyijienyl] -3-amino-1 H -pyrazol-5 - [(2'-aminosulfonyl- [1,1 '] - biphen4-yl) carboxamide

171 | 1 - [(4-methoxy) phenyl] -3 - [(methoxycarbonyl) amino] -1 H -pyrazol-5 - [(2'aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide (O, Potassium hydroxide (2.0 g, 35 mmol) was added to a solution of 22 g (0.42 mmol) in 10 mL of 1: 1 water / methanol. The resulting mixture was stirred at 70 ° C for 4 h, then cooled to room temperature and acidified with aqueous HCl. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with brine, dried (MgSO ₄₎ and concentrated in vacuo. The residue was purified by preparative HPLC (C18 reverse phase column, eluted with H ₂ O / CH ₃ CN in 0.5% TFA gradient) to give, after lyophilization, 75 mg (38%) of the title compound as a white powder. MSGMS (ES +): 463.8 (M + H) &lt; + &gt;.

156 EXAMPLE

1 - [(4-Methoxy) phenyl] -3 - [(methoxycarbonyl) methylamino] -1H-pyrazol-5 - [(2'aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide - [(4-methoxy) phenyl] -3-amino-1 H -pyrazol-5 - [(2'-tert-butylaminosulfonyl [1,1 '] - biphen-4-yl) carboxamide (1.0 g, 1.92 mmol) ) solution of sodium bicarbonate (0.24 g, 2.88 mmol) and methyl bromoacetate (0.22 mL, 2.30 mmol) in 10 mL of DMF. The resulting mixture was stirred at 85 ° C for 16 h. Since the reaction is not complete, additional portions of sodium bicarbonate (0.48 g, 5.76 mmol) and methyl bromoacetate (0.22 mL, 2.30 mmol) are added and the reaction mixture is stirred at 95 for 6 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic solution was washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue was dissolved in 5 ml of trifluoroacetic acid and stirred under reflux for 20 minutes, then cooled to room temperature and concentrated in vacuo. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with H ₂ O / CH ₃ CN with 0.5% TFA gradient) and lyophilization to give 450 mg (44%) of the title compound as a white powder. MSGMS (ES &lt; + &gt;): 536.0 (M + H) &lt; + &gt;.

172

FIGURE 157

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

1 - [(4-Methoxy) phenyl] -3- [N-glycyl] -1H-pyrazol-5 - [(2'-aminosulfonyl- [1,1 '] - biphen4-yl) carboxamide: 1 - [ (4-Methoxy) phenyl] -3 - [(methoxycarbonyl) -methylamino] -1 H -pyrazol-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide (0.40 g, Lithium hydroxide monohydrate (0.13 g, 2.98 mmol) was added to a solution of 0.75 mmol) in 10 mL of 1: 1 methanol / water. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was acidified with aqueous HCl and diluted with ethyl acetate. The organic extract was washed with saturated NaCl solution, dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with H ₂ O / CH ₃ CN with a gradient of 0.5% TFA) to give, after lyophilization, 200 mg (51%) of the title compound as a white powder. MSGMS (ES &lt; + &gt;): 522.0 (M + H) &lt; + &gt;.

1 - [(4-Methoxy) phenyl] -3 - [(2-hydroxy) ethylamino] -1H-pyrazol-5 - [(2'aminosulfonyl- [1,1'-biphen-4-yl) carboxamide: J 1- [(4-Methoxy) phenyl] -3- [N-glycyl] -1 H -pyrazol-5 - [(2'-aminosulfonyl- [1,1]] -biphen-4-yl) carboxamide (0.14 g, 0.27) triethylamine (0.038 mL, 0.27 mmol) and ethyl chloroformate (0.026 mL, 0.27 mmol) were added at -20 ° C. This mixture is stirred for 30 min, then sodium borohydride (20 mg, 0.54 mmol) is added in a minimum amount of water. The reaction mixture was stirred with slow warming to room temperature for 1 h, then quenched with 10% aqueous HCl. After dilution with ethyl acetate, the organic layer is washed with brine, dried (MgSO ₄ ) and concentrated in vacuo, the residue is purified by preparative HPLC (C18 reverse phase column, eluting with H ₂ O / CH ₃ CN with 0.5% TFA gradient) and freeze drying. 35 mg (26 *%) of the title compound as a white powder. MSGMS (ES &lt; + &gt;): 507.9 (M + H) &lt; + &gt;.

173

FIGURE 158

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

1 - [(4-Methoxy) 1-enyl] -3- (hydroxymethyl) -1H-pyrazole-5- (methoxycarbonyl) pyrazole: 1 - [(4-methoxy) phenyl] -1H-pyrazole-5- (methoxycarbonyl) A solution of pyrazole-3-carboxylic acid (2.4 g, 8.69 mmol) in 50 mL of tetrahydrofuran at -20 ° C was added triethylamine (1.21 mL, 8.69 mmol) and ethyl chloroformate (0.83 mL, 8.69 mmol). This mixture was stirred for 30 min, then sodium borohydride (0.66 mg, 17.4 mmol) was added in a minimum amount of water. The reaction mixture was stirred slowly with warming to room temperature for 1 h, then quenched with 10% aqueous HCl. After dilution with ethyl acetate, the organic layer was washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by flash chromatography (eluting with 3: 2 ethyl acetate / hexane) to give 1.4 g (61%) of the title compound. MSGMS (DCI): 263.3 (M + H) &lt; + &gt;.

1 - [(4-Methoxy) phenyl] -3- (hydroxymethyl) -1H-pyrazole-5 - [(2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide: J (2 A solution of tert-butylaminosulfonyl- [1,1,1-biphen-4-yl) amino (1.44 g, 4.73 mmol) in 40 mL of methylene chloride was added dropwise at room temperature to a solution of trimethylaluminum (14.2 mL of 2.0 M in toluene). , 4 mmol). The resulting solution is stirred until gas evolution ceases (-15 min). 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 for 16 h, then cooled to room temperature and quenched with saturated aqueous NH ₄ Cl. After dilution with ethyl acetate, the organic layer was washed with 10% aqueous HCl, saturated aqueous NaHCO ₃ and saturated NaCl solution, dried (MgSO ₄ ), filtered through a pad of silica gel and concentrated in vacuo. Recrystallization of the solid residue from hexanes / ethyl acetate gives 1.7 g (68%) of the title compound. LRMS (ES +): 557.1 (M + Na). ⁴

174

1 - [(4-Methoxy) phenyl] -3- (carboxaldehyde) -1H-pyrazole-5 - [(2'-tert-butylaminosulfonyl [1,1 '] - biphen-4-yl) carboxamide: oxalyl chloride ( Dimethylsulfoxide (0.54 mL, 7.63 mmol) was added at -78 ° C in 20 mL of methylene chloride (0.33 mL, 3.81 mmol). The mixture was stirred for 15 min, then 1 - [(4-methoxy) phenyl] -3- (hydroxymethyl) -1H-pyrazole-5 - [(2'-tert-butylaminosulfonyl- [1,1 '] was added. ] -biphen-4-yl) carboxamide (1.70 g, 3.18 mmol) in 10 mL of methylene chloride. The reaction mixture was stirred allowing to warm slowly to room temperature for 2 hours. Triethylamine (2.21 mL, 15.90 mmol) was added and the reaction mixture was stirred at room temperature for 30 min. The mixture was diluted with ethyl acetate, and the organic layer was washed with 10% HCl, saturated aqueous NaHCO ₃ and brine, dried (MgSO ₄ ), filtered through a pad of silica gel and concentrated under vacuum to give 1.3 g (76%) of the title compound can be used unpurified. MSGMS (ES &lt; + &gt;): 533.2 (M + H) &lt; + &gt;.

1 - [(4-Methoxy) phenyl] -3- [E-2- (methoxycarbonyl) ethenyl] -1H-pyrazole-5 - [(2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide: 1 - [(4-methoxy) phenyl] -3 (carboxaldehyde) -1H-pyrazole-5 - [(2'-tert-butylamino-sulfonyl- [1,1 '] - biphen-4-yl) carboxamide To a solution of (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 room temperature for 18 hours. The volatiles were evaporated 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. MSGMS (ES &lt; + &gt;): 589.1 (M + H) &lt; + &gt;.

1 - [(4-Methoxy) phenyl] -3- [E-2- (methoxycarbonyl) ethenyl] -1H-pyrazol-5 - [(2'aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide : 1 - [(4-Methoxy) phenyl] -3- [E-2 (methoxycarbonyl) ethenyl] -1H-pyrazole-5 - [(2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4yl) ) -Carboxamide (1.2 g, 2.04 mmol) solution in 10 ml of trifluoroacetic acid was stirred at reflux for 20 min, then cooled to room temperature and concentrated in vacuo. The residue is purified

175 by preparative HPLC (C 18 reverse phase column, eluted

H ₂ O / CH ₃ CN with 0.5% TFA gradient) and lyophilization yields 1.0 g (90%) of the title compound as a white powder. MSGMS (ES &lt; + &gt;): 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) carboxamide] 1 - [(4-Methoxy) phenyl] -3- [E-2- (methoxycarbonyl) ethenyl] -1H-pyrazol-5 - [(2'-aminosulfonyl- [1,1]] -biphen-4-yl) carboxamide (35 mg, 0.065 mmol) in 20 ml absolute ethanol at room temperature was added 10% palladium on carbon as a catalyst (3.5 mg). The mixture is stirred under a hydrogen gas pressure of 101.3 kPa for 3 hours, then filtered through a pad of celite and concentrated in vacuo. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with H ₂ O / CH ₃ CN with a gradient of 0.5% TFA) to give, after lyophilization, 15 mg (42%) of the title compound as a white powder. MSGMS (ES &lt; + &gt;): 534.9 (M + H) &lt; + &gt;.

160 EXAMPLE

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

J 1 - [(4-methoxy) phenyl] -3- [E-2- (methoxycarbonyl) ethenyl] -1H-pyrazol-5 - [(2'aminosulfonyl- [1,1'] -biphen-4-yl) carboxamide (1.2 g, 2.25 mmol) of lithium hydroxide monohydrate (0.19 g, 4.5 mmol) was added in 20 mL of 1: 1 methanol / water at room temperature. The mixture was stirred for 3 hours, then acidified with aqueous HCl and diluted with ethyl acetate. The organic solution was washed with a saturated NaCl solution, dried (MgSO ₄ ), and concentrated in vacuo. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with H ₂ O / CH ₃ CN with a gradient of 0.5% TFA) to afford 1.0 g (83%) of the title compound as a white powder after lyophilization. MSGMS (ES-): 516.8 (MH +).

176

EXAMPLE 161

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

To 1 - [(4-methoxy) phenyl] -3- [E-2- (carboxy) ethenyl] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4- il) A solution of carboxamide (40 mg, 0.077 mmol) in 20 mL of absolute ethanol at room temperature was added 10% palladium on carbon as a catalyst (20 mg). The mixture is stirred under a hydrogen gas pressure of 101.3 kPa for 3 hours, then filtered through a pad of celite and concentrated in vacuo. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with H ₂ O / CH ₃ CN with a gradient of 0.5% TFA) to give, after lyophilization, 10 mg (25%) of the title compound as a white powder. MSGMS (ES +): 520.9 (M + H) ⁺ .

EXAMPLE 162

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

J 1 - [(4-methoxy) phenyl] -3- [E-2- (carboxy) ethenyl] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) ) A solution of carboxamide (140 mg, 0.27 mmol) in 10 mL of acetonitrile was added triethylamine (0.11 mL, 0.81 mmol) and isobutyl chloroformate (0.039 mL, 0.30 mmol). After stirring at room temperature for 30 min, methanolic ammonia solution (0.27 mL of 2.0 M ammonia in methanol, 0.54 mmol) was added. The reaction mixture was stirred for 16 hours, after which the volatiles were evaporated. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with H ₂ O / CH ₃ CN with a gradient of 0.5% TFA) to give, after lyophilization, 35 mg (25%) of the title compound as a white powder. MSGMS (ES &lt; + &gt;): 517.9 (M + H) &lt; + &gt;.

EXAMPLE 163

v.

177

1 - [(4-Methoxy) phenyl] -3- [E-2- (hydroxymethyl) ethenyl] -1H-pyrazol-5-I (2'aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide

J 1 - [(4-methoxy) phenyl] -3- [E-2- (carboxy) ethenyl] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4- il) A solution of carboxamide (1.0 g, 1.93 mmol) in 20 mL of tetrahydrofuran at -20 ° C was added triethylamine (0.27 mL, 1.93 mmol) and isobutyl chloroformate (0.25 mL, 1.93 mmol). ). This mixture was stirred for 30 min, then sodium borohydride (0.22 g, 5.78 mmol) was added in a minimum amount of water. The reaction mixture was stirred with slow warming to room temperature for 1 h, then quenched with 10% aqueous HCl. After dilution with ethyl acetate and the organic layer was washed with brine, dried (MgSO ₄₎ and concentrated in vacuo. The residue was purified by preparative HPLC (C 18 reverse phase column, eluting with H ₂ O / CH ₃ CN with a gradient of 0.5% TFA) to give, after lyophilization, 0.5 g (52%) of the title compound as a white powder. MSGMS (ES &lt; + &gt;): 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) carboxamide

AND EXAMPLE 165

1 - [(4-Methoxy) phenyl] -3-propyl-1 H -pyrazol-5 - [(2'-aminosulfonyl- [1,1 '] - biphen4-yl) carboxamide

To 1 - [(4-methoxy) phenyl] -3- [E-2- (hydroxymethyl) ethenyl] -1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4- il) A solution of carboxamide (40 mg, 0.08 mmol) in 20 mL of methanol at room temperature was added 10% palladium on carbon as catalyst (4 mg). The mixture is stirred under a hydrogen gas pressure of 101.3 kPa for 3 hours, then filtered through a pad of celite and concentrated in vacuo. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with H ₂ O / CH ₃ CN with a gradient of 0.5% TFA) to give, after lyophilization, 15 mg (38%) of Example 164 as a white solid.

178 powder. MSGMS (ES +): 506.9 (M + H) &lt; + &gt;. 8 mg (20%) of the compound of Example 165 is also obtained as a white powder. MSGMS (ES &lt; + &gt;): 490.9 (M + H) &lt; + &gt;.

EXAMPLE 166

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

1 - [(4-Methoxy (phenyl)] - 3- (trifluoromethyl) -4-cyano-1H-pyrazole-5- (2-furyl) · pyrazole: 2-Furoylacetonitrile (0.91 g, 6.73 mmol) sodium hydroxide (2.5 ml of a 21% w / w solution in ethanol, 6.73 ml) was added to 20 ml of absolute ethanol followed by 2,2,2-trifluoroacetoyl bromide-N- (4-methoxyphenyl) hydrazone (2.0 g) The mixture was stirred at room temperature for 4 hours, and the volatiles were evaporated in vacuo and the residue was dissolved in ethyl acetate, washed with water and brine, dried (MgSO ₄ ) and concentrated to give a residue which was purified by recrystallization from hexane / ethyl acetate. , 1 g (49%) of the title compound.

1 - [(4-Methoxy (phenyl)] - 3- (trifluoromethyl) -4-cyano-pyrazole-5-carboxylic acid: 1 - [(4-methoxy (phenyl)] - 3- (trifluoromethyl) -4-cyano To a solution of 5- (2-furyl) pyrazole (0.68 g, 2.04 mmol) in 4: 4: 6 carbon tetrachloride / acetonitrile / water was added sodium periodate (196 mg, 9.2 mmol) and ruthenium (III) chloride monohydrate (42 mg, 0.20 mmol) The resulting biphasic reaction mixture was stirred vigorously at room temperature for 24 hours, quenched with 10% aqueous HCl and diluted with ethyl acetate.The organic layer was washed with saturated NaCl solution, dried (MgSO ₄ ), filtered through a pad of celite and The residue is dissolved in 1: 1 hexanes / ethyl acetate and extracted with saturated aqueous Na ₂ CO ₃ (2 times). The combined aqueous extracts are acidified and extracted with ethyl acetate.These ethyl acetate extracts are washed with saturated NaCl solution, dried (MgSO ₄ ) and concentrated. g (67%) of the title compound as a solid MSGMS (ES-): 310.0 (MH). ^'%

179

T - [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4-cyano-1 H -pyrazol-5 - [(2'-methylsulfonyl-3-fluoro [1,1 '] - biphen-4-yl) ) Carboxamide: To a solution of 1 - [(4-methoxy (phenyl)] -3- (trifluoromethyl) -4-cyano-pyrazole-5-carboxylic acid (0.41 g, 1.32 mmol) in 20 mL of methylene chloride is added oxalyl chloride ( 0.17 ml, 1.98 mmol) and 2 drops of dimethylformamide The reaction mixture was stirred at room temperature for 6 hours, then the volatiles were evaporated in vacuo, the residue was dissolved in 20 ml of methylene chloride and 4-dimethylaminopyridine (0.48 g, The reaction mixture was stirred for 10 min 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 room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and the organic solution was washed with 10% aqueous HCl, saturated aqueous NaHCO _3, brine, dried (MgSCų) cover film was filtered through a silica and concentrated to give 0.6 g (81%) of what they want nginis, which is a tan solid. MSGMS (ES &lt; + &gt;): 581.3 (M + Na) &lt; + &gt;.

EXAMPLE 167

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

AND EXAMPLE 168

1 - [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4- (N-hydroxyamidino) -1H-pyrazole-5 [(2'-methylsulfonyl-3-fluoro [1,1 '] - biphen-4) -yl) carboxamide 1 - [(4-ethoxy) phenyl] -3- (trifluoromethyl) -4-cyano-1H-pyrazole-5 - [(2'-methylsulfonyl-3-fluoro- [1,1'j] -Biphen-4-yl) carboxamide (100 mg, 0.18 mmol) in 5 mL of 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 h. The reaction mixture was diluted with water and ethyl acetate. The organic layer was washed with saturated NaCl solution, dried (MgSO ₄ ) and concentrated to a solid. The residue was dissolved in 10 mL of absolute ethanol, cyclohexene (1 mL), 20% palladium hydroxide on carbon (50 mg) and acetic acid (0.02 mL, 0.36 mmol) were added. Received

The mixture was stirred at 80 ° C for 6 hours. The reaction mixture was cooled, filtered through a pad of celite and concentrated in vacuo. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with H ₂ O / CH ₃ CN with a gradient of 0.5% TFA) to give, after lyophilization, mg (16%) of Example 167 as a white powder. MSGMS (ES +):

576.2 (M + H) ⁺ . 15 mg (12%) of the compound of Example 168 which is a white powder are also obtained. MSGMS (ES &lt; + &gt;): 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-) il) carboxamide

T - [(4-Methoxy (phenyl)] - 3- (trifluoromethyl) -4- (ethoxycarbonyl) -5- (2-furyl) pyrazole: Ethyl 3- (2-furyl) -3-ketopropionate (2, To a solution of 45 g, 13.4 mmol) in 20 mL of absolute ethanol was added sodium ethoxide (4.6 mL of a 21% w / w solution in 12.2 mL) followed by 2,2,2-trifluoroacetoyl bromide-N- (4-methoxyphenyl) hydrazone (1.82 g, 6.1 mmol) This mixture was stirred at room temperature for 4 h and the volatiles were evaporated in vacuo and the residue was dissolved in ethyl acetate, washed with water and saturated NaCl solution, dried (MgSO ₄ ) and concentrated. ethyl acetate to give 1.4 g (61%) of the title compound MSGMS (ES +);

381.2 (M + H) ⁺ .

1 - [(4-Methoxy (phenyl)] - 3- (trifluoromethyl) -4- (ethoxycarbonyl) -pyrazole-5-carboxylic acid: 1 - [(4-methoxy (phenyl)] - 3- (trifluoromethyl) -4- ( ethoxycarbonyl) -5- (2-furyl) pyrazole (1.0 g, 2.63 mmol) in 4: 4: 6 carbon tetrachloride / acetonitrile / water was added sodium periodate (2.5 g, 11.8 mmol) and ruthenium (III). chloride monohydrate (11 mg, 0.05 mmol) The resulting biphasic reaction mixture was stirred vigorously at room temperature for 24 h, the reaction mixture was diluted with 10% aqueous HCl and diluted with ethyl acetate, the organic layer was washed with saturated NaCl solution, dried (MgSO ₄ ), filtered Celite and concentrate

181 is dissolved in 1: 1 hexanes / ethyl acetate and extracted with saturated aqueous solution

Well ₂ CO ₃ (2 times). The combined aqueous extracts were acidified and extracted with ethyl acetate. These ethyl acetate extracts were washed with saturated NaCl solution, dried (MgSO ₄ ) and concentrated to give 0.5 g (53%) of the title compound as a solid. MSGMS (ES-): 357.0 (MH +). ,

1 - [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4- (ethoxycarbonyl) -1H-pyrazole-5 - [(2'-methylsulfonyl-3-fluoro [1,1 '] - biphenyl) 4-yl) carboxamide: A solution of 1 - [(4-methoxy (phenyl)] -3- (trifluoromethyl) -4- (ethoxycarbonyl) -pyrazole-5-carboxylic acid (0.5 g, 1.4 mmol) in 10 mL Methylene chloride is added oxalyl chloride (0.18 mL, 2.1 mmol) and 2 drops of dimethylformamide, The reaction mixture is stirred at room temperature for 6 hours, then the volatiles are evaporated in vacuo and the residue is dissolved in 20 mL of methylene chloride followed by (0.51 g, 4.2 mmol) The reaction mixture was stirred for 10 min and (2'-methylsulfonyl-3-fluoro- [1,1'-biphen-4-yl) -amine hydrochloride (0.42 g, 1 mmol) was added. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate and the organic solution was washed with 10% aqueous HCl, saturated aqueous NaHCO ₃ , brine, dried (MgSO ₄ ), filtered through a pad of silica gel, 6g (70%) of the compound of Example 169 as a solid. A portion of this material was purified by preparative HPLC (C18 reverse phase column, eluting with H ₂ O / CH ₃ CN with a gradient of 0.5% TFA) to give, after lyophilization, the title compound as a white powder. MSGMS (ES &lt; + &gt;): 628.1 (M + Na) &lt; + &gt;.

EXAMPLE 170

1 - [(4-Methoxy) phenyl] -3- (trifluoromethyl) -1H-pyrazole-5 - [(2'-methylsulfonyl-3-fluoro [1, T] -biphen-4-yl) carboxamide-4-carboxylic acid

J 1 - [(4-methoxy) phenyl] -3- (trifluoromethyl) -4- (ethoxycarbonyl) -1H-pyrazole-5 - [(2'-methylsulfonyl-3-fluoro [1,1 '] - biphen-4) -yl) carboxamide (0.30 g, 0.49 mmol) in v * 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 h, then

182 was 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, eluted with H2O / CH3CN with 0.5% TFA gradient) to give 150 mg (53%) of the title compound as a white powder after lyophilization. MSGMS (ES-); 576.2 (MH) +.

Table 183

Structure A Structure B Structure c

For example, R. E M _R 1a A-B 1 - Structure A ch ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 2 2-CH ₃ O Structure A ch ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 3 3-CHsO Structure A ch ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 4 4-CH3O Structure A ch ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 5 2-OH Structure A ch ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 6th 3-OH Structure A ch ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 7th 4-OH Structure A ch ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 8th 4-CH3O Structure A ch ₃ 2'-H ₂ NSO ₂ -3-F-biphen-4-yl 9th 4-CH3O Structure A ch ₃ 2'-H ₂ NSO ₂ -3-Br-biphen-4-yl 10th 4-CH3O Structure A ch ₃ 2'-H ₂ NSO ₂ -3-l-biphen-4-yl 11th 4-CH3O Structure A ch ₃ 2'-H ₂ NSO ₂ -3-methylbiphen-4-yl 12th 4-CH3O Structure A ch ₃ 4 - ((CH ₃ ) ₂ NC (O)) C ₆ H ₄ 13th 4-CH3O Structure A ch ₃ 4- (N-pyrrolidinocarbonyl) CsH ₄ 14th 4-CH3O Structure A ch ₃ 4- (N-pyrrolidinomethyl) C ₆ H ₄ 15th 4-CH3O Structure A cf ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 16th 4-CH3O Structure A cf ₃ 4- (N-pyrrolidinocarbonyl) C6H ₄ 17th 4-CH3O Structure A - cf ₃ 5- (2'-CH ₃ SO ₂ -C ₆ H ₄ ) pyrid-2-yl 18th 4-CH3O Structure A cf ₃ 5- (N-pyrrolidinocarbonyl) pyridine 2-il 19th 4-CH3O Structure A ch ₃ 5- (N-pyrrolidinocarbonyl) pyridine 2-il 20th 4-CH3O Structure A ch ₃ 5- (2'-H ₂ NSO ₂ -C ₆ H ₄ ) pyrid-2-yl 21st 4-CH3O Structure A ch ₃ 4- (3'-HO-N-pyrrolidinocarbonyl) C ₆ H ₄ 22nd 4-CH3O Structure of F nh ₂ 2'-H ₂ NSO ₂ -biphen-4-yl

184

23rd 4-CH ₃ O Structure of F Br 2'-H ₂ NSO ₂ -biphen-4-yl 24th 4-CH3O Structure of F Cl 2'-H ₂ NSO ₂ -biphen-4-yl 25th 4-HO Structure of F Cl 2'-H ₂ NSO ₂ -biphen-4-yl 26th 4-CH3O Structure of F CH ₃ O 2'-H ₂ NSO ₂ -biphen-4-yl 27th 4-CH3O Structure of F CH ₃ S. 2'-H ₂ NSO ₂ -biphen-4-yl 28th 4-CH3O Structure of F CH3SO 2'-H ₂ NSO ₂ -biphen-4-yl 29th 4-CH3O Structure of F CH3SO2 2'-H ₂ NSO ₂ -biphen-4-yl 30th 4-CH3O Structure of F CN 2'-H ₂ NSO ₂ -biphen-4-yl 31st 4-CH3O Structure of F (CH ₃ ) ₂ N 2'-H ₂ NSO ₂ -biphen-4-yl 32 4-CH3O Structure of F pyrrol-1-yl 2'-H ₂ NSO ₂ -biphen-4-yl 33 4-CH3O Structure of E CH ₂ CO ₂ CH ₃ 5- (2'-H ₂ NSO ₂ -C ₆ H ₄ ) pyrid-2-yl 34 4-CH3O Structure of E ch ₂ co ₂ h 5- (2'-H ₂ NSO ₂ -C ₆ H ₄ ) pyrid-2-yl 35 4-CH3O Structure of E (a) 5- (2'-H ₂ NSO ₂ -C ₆ H ₄ ) pyrid-2-yl 36 4-CH3O Structure of E (b) 5- (2'-H ₂ NSO ₂ -C ₆ H ₄ ) pyrid-2-yl 37 4-CH3O Structure D - 2'-H ₂ NSO ₂ -biphen-4-yl 38 4-CH3O, 3-CI Structure A ch ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 39 4-CF3O Structure A ch ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 40 3-Br Structure A ch ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 41 3-I Structure A ch ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 42 3,4-OCH ₂ O Structure A ch ₃ 4- (N-pyrrolidinocarbonyl) C ₆ H ₄ 43 4-CH3O Structure A ch ₂ oh 4- (N-pyrrolidinocarbonyl) C ₆ H ₄ 44 4-CH3O Structure A CHO 4- (N-pyrrolidinocarbonyl) C ₆ H ₄ 45 4-CH3O Structure A co ₂ h 4- (N-pyrrolidinocarbonyl) C ₆ H ₄ 46th 4-CH3O Structure A co ₂ ch ₃ 4- (N-pyrrolidinocarbonyl) CeH ₄ 47 4-CI Structure A ch ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 48 4-CI Structure A ch ₃ 5- (2'-H ₂ NSO ₂ -C ₆ H ₄ ) pyrid-2-yl 49 3,4-diCl Structure A ch ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 50 3-CI Structure A ch ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 51 - Structure of F nh ₂ 2'-H ₂ NSO ₂ -biphen-4-yl 52 - Structure of F Cl 2'-H ₂ NSO ₂ -biphen-4-yl 53 3-Br, 4-F Structure of F nh ₂ 2'-H ₂ NSO ₂ -biphen-4-yl 54 4-F Structure of F nh ₂ 2'-H ₂ NSO ₂ -biphen-4-yl 55 3-Br Structure of F nh ₂ 2'-H ₂ NSO ₂ -biphen-4-yl 56 3-Br Structure of F Cl 2'-H ₂ NSO ₂ -biphen-4-yl 57 4-CH3O Structure A CH ₃ S. 2'-H ₂ NSO ₂ -biphen-4-yl 58 4-CH3O Structure A ch ₃ so ₂ 5- (2'-CH ₃ CO ₂ -C ₆ H ₄ ) pyrimidin-2-yl 59 4-CH3O Structure A ch ₃ so ₂ 2'-H ₂ NSO ₂ ; biphen-4-yl 60 4-CH3O Structure A CH ₃ s 4- (N-pyrrolidinocarbonyl) C ₆ H ₄ 61 4-CH3O Structure A CH ₃ s 2'-CH ₃ SO ₂ -biphen-4-yl 62 4-CH3O Structure A CH3SO2 4- (N-pyrrolidinocarbonyl) C6H ₄

> 5.

185

63 4-CH ₃ O Structure A CH3OCH2 2'-H ₂ NSO ₂ -biphen-4-yl 64 4-CH3O Structure A CH ₃ OC (O) 2'-H ₂ NSO ₂ -biphen-4-yl 65 4-CH3O Structure A CH3SO2CH2 2'-H ₂ NSO ₂ -biphen-4-yl 66 4-CH3O Structure A cf ₃ 5- (2'-CH ₃ SO ₂ -C ₆ H ₄ ) pyrimidin-2-yl 67 4-CH3O Structure A ch ₃ 4- (2'-CH ₃ CO ₂ - pyrrolidinocarbonyl) C ₆ H ₄ 68 4-CH3O Structure A cf ₃ 4- (3'-H ₂ N-pyrrolidinocarbonyl) C ₆ H ₄ 69 4-CH3O Structure A ch ₃ 4- (3'-CH ₃ O-pyrrolidinocarbonyl) C ₆ H ₄ 70 4-CH3O Structure A cf ₃ 5- (2'-H ₂ NSO ₂ -C ₆ H ₄ ) pyrid-2-yl 71 4-CH3O Structure A cf ₃ 4-amidinophenyl 72 4-CH3O Structure A cf ₃ 4- (N-pyrrolidino-C (= NH) C ₆ H ₄ 73 4-CH3O - cf ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 74 4-CH3O Structure B 3-CF3, 5-CO2CH3 2'-H ₂ NSO ₂ -biphen-4-yl 75 4-CH3O Structure B CFA-3, 5- (CH _{2) 2} OH 2'-H ₂ NSO ₂ -biphen-4-yl 76 4-CH3O Structure A cf ₃ 4- (N-pyrrolidino-C (== NH) C ₆ H ₄ 77 4-CH3O Structure A cf ₃ 4- (N-pyrrolidino-C (= NCO ₂ -butyl)) C ₆ H ₄ 78 4-CH3O Structure A cf ₃ 4- (N-pyrrolidino-C (= N) SO ₂ CH ₃ ) -C ₆ H ₄ 79 4-CH3O Structure A cf ₃ 4-amidinophenylmethyl 80 4-CH3O Structure A cf ₃ 4- (N-pyrrolidino-C (= NH ₂ )) C ₆ H ₄ -CH ₂ - 81 4-CH3O Structure A cf ₃ N-benzyl-piperidin-4-yl 82 4-CH3O Structure A cf ₃ N- (Pyrid-2-ylmethyl) piperidin-4- ilas 83 4-CH3O Structure A cf ₃ 4- (2'-methylimidazolyl) C ₆ H ₄ 84 4-CH3O Structure A cf ₃ 4- (5'-methylimidazolyl) C6H ₄ 85 4-CH3O Structure A cf ₃ 4- (4'-methylimidazolyl) C ₆ H ₄ 86 4-CH3O Structure A cf ₃ 4- (5'-CH ₃ C (O) -imidazolyl) C ₆ H ₄ 87 4-CH3O Structure A cf ₃ 4- (5'-karboksiimidazolil) C6H ₄ 88 4-CH3O Structure A ' cf ₃ 4- (5'-CH ₃ NHC (O) -imidazolyl) C ₆ H ₄ 89 4-CH3O Structure A cf ₃ 4- (5'-H ₂ NC (O) -imidazolyl) C ₆ H ₄ 90 4-CH3O Structure A cf ₃ 4- (5'-CH ₃ NHC (O) -imidazolyl) C ₆ H ₄ 91 4-CH3O Structure A ch ₂ oh 4- (N-pyrrolidinocarbonyl) C ₆ H ₄ 92 4-CH3O Structure A CHO 4- (N-pirqlidinokarbonil) C6H ₄ 93 4-CH3O Structure A CO ₂ H 4- (N-pyrrolidinocarbonyl) C ₆ H ₄ 94 4-CH3O Structure A co ₂ ch ₃ 4- (N-pyrrolidinocarbonyl) C6H ₄ 95 4-CH3O Structure A ch ₂ cn 4- (N-pyrrolidinocarbonyl) C6H ₄

186

4-CH ₃ O Structure A CH ₂ CO ₂ H 4-CH ₃ O Structure A CH ₂ Br 4-CH ₃ O Structure A CH ₂ NH ₂ 4-CH ₃ O Structure A ch ₂ nh ₂ - 4-CH ₃ O Structure A so ₂ ch ₃ ch ₂ - 4-CH ₃ O Structure A imidazole CH ₂ OH 4-CH ₃ O Structure A ch ₂ - 4-CH ₃ O, Structure A OC (O) CF ₃ cf ₃ 2-CO ₂ Me 4-CH ₃ O, Structure A cf ₃ 2-CO ₂ H 4 -CH ₃ O, ' Structure A cf ₃ 2-CO ₂ CH ₃ 4 -CH ₃ O, Structure A cf ₃ 2-CO ₂ H 4 -CH ₃ O, Structure A cf ₃ 2-CO2H 4-CH ₃ O, Structure A cf ₃ 2-CH ₂ OH 4-CH ₃ O Structure A ch ₃ 4-CH ₃ O Structure A ch ₃ 4-CH ₃ O Structure A ch ₃ 4-CH ₃ O Structure A ch ₃ 4-CH ₃ O Structure A ch ₃ 4-CH ₃ O Structure A ch ₃ 4-CH ₃ O Structure A ch ₃ 4-CH ₃ O Structure A cf ₃ 4-CH ₃ O Structure A cf ₃ 4-CH ₃ O Structure A cf ₃ 4-CH ₃ O Structure A cf ₃ 4-CH ₃ O Structure A cf ₃ 4-CH ₃ O Structure A cf ₃ 4-CH ₃ O Structure A cf ₃ 4-CH ₃ O Structure A cf ₃ 4-CH ₃ O Structure A cf ₃ 4-CH ₃ O Structure A cf ₃

4- (N-pyrrolidinocarbonyl) C ₆ H ₄

2'-H ₂ NSO ₂ -biphen-4-yl

2'-H ₂ NSO ₂ -biphen-4-yl

2'-H ₂ NSO ₂ -biphen-4-yl

2'-H ₂ NSO ₂ -biphen-4-yl

2'-H ₂ NSO ₂ -biphen-4-ifas

2'-H ₂ NSO ₂ -biphen-4-yl

2'-CH 3 S ₂ biphen-4-yl

2'-CH 3 S ₂ biphen-4-yl

2'-H ₂ NSO ₂ -biphen-4-yl

2'-t-Bu-HNSO _2- biphen-4-yl

2''H ₂ NSO ₂ -Biphen-4-yl

2'-H ₂ NSO ₂ -biphen-4-yl

4-sec-butyl-phenyl

4- (3'-methyl-3'-pyrazol-5'-on2'-yl) C ₆ H ₄

4- ^(6? -Metilbenzotiazol-2-yl) C ₆ H ₄

3,4-dibromophenyl

4-Butylphenyl

4- (4-methylpiperidinyl) C ₆ H ₄

4- (2'-methylimidazolyl) C6H ₄

4- (N-methylimidazol-2-ylcarbonyl) C ₆ H ₄

4- (imidazol-2-ylhydroxymethyl) C ₆ H ₄

4- (N-benzylimidazole-2-ilhidroksimetil) C6H ₄

4- (imidazol-2-ylcarbonyl) C ₆ H ₄ [(thiazol-2-yl) (4'-CH ₃ OC ₆ H ₄ NH) CH ₂ ] C ₆ H ₄

4- (2'-thiazol-2'-ylcarbonyl) C _s H ₄

4- (2'-imidazolin-2'-yl) C ₆ H ₄

4- (H ₂ N (CH ₂ ) ₂ NHC (O)) C ₆ H ₄

4- (1 ', 4', 5 ', 6'-tetrahydropyrimidin-2-yl) C ₆ H ₄

4- (N-methyl-1 ', 4', 5 ^, .6 '

187 tetrahydropyrimidin-2-yl) C ₆ H ₄

126 4-CH3O Structure A CF ₃ 4- (T, 4 ', 5', 6'-Tetrahydropyrimidin-2-yl) -2-F-C ₆ H ₄ 127 4-CH3O Structure A cf ₃ 4- (N-CH ₃ -4'-imidazolin-2'-yl) - 2-PC ₆ H ₄ 128 4-CH3O Structure A cf ₃ 4- (N-CH ₃ -4'-imidazolin-2'-yl) C ₆ H ₄ 129 4-CH3O Structure A cf ₃ 4- (guanidino carbonyl) C6H ₄ 130 4-CH3O Structure A cf ₃ 4- (pyrimidin-2-yl) phenyl 131 4-CH3O Structure of F C (O) NH ₂ 2'-H ₂ NSO ₂ -biphen-4-yl 132 4-CH3O Structure of F NH (CH ₂ ) ₂ - ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 133 4-CHaO Structure of F NH (CH ₂ ) ₃ OH 2'-H ₂ NSO ₂ -biphen-4-yl 134 4-CH3O Structure of F NH (CH ₂ ) ₂ CN 2'-H ₂ NSO ₂ -biphen-4-yl 135 4-CH3O Structure of F NH (CH ₂ ) ₃ -. and ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 136 4-CH3O Structure of F NH (CH ₂ ) ₂ - co ₂ h 2'-H ₂ NSO ₂ -biphen-4-yl 137 4-CH3O Structure of F NH-i-Pr 2'-H ₂ NSO ₂ -biphen-4-yl 138 4-CH3O Structure of F NHCH (CH ₂ - OH) ₂ 2'-H ₂ NSO ₂ -biphen-4-yl 139 4-CH3O Structure of F nhch ₂ co ₂ - ch ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 140 4-CH3O Structure of F nhch ₂ co ₂ h 2'-H ₂ NSO ₂ -biphen-4-yl 141 4-CH3O Structure A co ₂ c ₂ h ₅ 4- (N-pyrrolidinocarbonyl) C ₆ H ₄ 142 4-CH3O Structure A conh ₂ 4- (N-pyrrolidinocarbonyl) C ₆ H ₄ 143 4-CH3O Structure A C (O) NH- (CH ₂ ) ₂ OH 4- (N-pyrrolidinocarbonyl) C ₆ H ₄ 144 4-CH3O Structure A CONHOH 4- (N-pyrrolidinocarbonyl) C ₅ H ₄ 145 4-CH3O Structure A CONHCsHs 4- (N-pyrrolidinocarbonyl) C ₆ H ₄ 146 4-CH3O Structure A CONH (CH ₂ ) ₃ - OH 4- (N-pyrrolidinocarbonyl) C ₆ H ₄ 147 4-CH3O Structure A CONHCH ₃ 4- (N-pyrrolidinocarbonyl) C ₆ H ₄ 148 4-CH3O Structure A conhch ₂ - C _s H ₅ 4- (N-pyrrolidinocarbonyl) C6H ₄ 149 4-CH3O Structure A CON (CH ₃ ) ₂ 4- (N-pyrrolidinocarbonyl) C _s H ₄ 150 4-CH3O Structure A CONH- (CH ₂ ) ₂ C ₆ H ₅ 4- (N-pyrrolidinocarbonyl) C ₆ H ₄ 151 4-CH3O Structure A CONH-2-OH-C ₆ H ₄ 4- (N-pyrrolidinocarbonyl) C ₆ H ₄ 152 4-CH3O Structure A CONH-3-OH-C ₆ H ₄ 4- (N-pyrrolidinocarbonyl) C6H ₄ 153 4-CH3O Structure A CONH-4-OH-C ₆ H ₄ 4- (N-pyrotidinocarbonyl) C ₆ H ₄ 154 4-CH3O Structure A nhco ₂ ch ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 155 4-CH3O Structure A nh ₂ 2'-H ₂ NSO ₂ -biphen-4-yl 156 4-CH3O Structure A nhch ₂ - 2'-H ₂ NSO ₂ -biphen-4-yl

188

157 4-CH ₃ O Structure A CO ₂ CH ₃ NH (CH ₂ ) ₂ OH 2'-H ₂ NSO ₂ -biphen-4-yl 158 4-CH3O Structure A CH = CH- 2'-H ₂ NSO ₂ -biphen-4-yl 159 4-CH3O Structure A CO ₂ CH ₃ ch ₂ ch ₂ - 2'-H ₂ NSO ₂ -biphen-4-yl 160 4-CH3O Structure A CO2CH3 ch = chco ₂ H CH ₂ CH ₂ CO ₂ H 2'-H ₂ NSO ₂ -biphen-4-yl 161 4-CH3O Structure A 2'-H ₂ NSO ₂ -biphen-4-yl 162 4-CH3O Structure A CH = CH- 2'-H ₂ NSO ₂ -biphen-4-yl 163 4-CH3O Structure A conh ₂ CH = CH- 2'-H ₂ NSO ₂ -biphen-4-yl 164 4-CH3O Structure A CH ₂ OH (CH ₂ ) ₃ OH 2'-H ₂ NSO ₂ -biphen-4-yl 165 4-CH3O Structure A (CH ₂ ) ₂ CH ₃ 2'-H ₂ NSO ₂ -biphen-4-yl 166 4-CH3O Structure C 3-CF ₃ , 4-CN 2'-CH ₃ SO ₂ -3-F-biphen-4-yl 167 4-CH3O Structure C 3-CF3, 2'-CH ₃ SO ₂ -3-F-biphen-4-yl 168 4-CH3O Structure C Of 4-amidine 3-CF3, 2'-CH ₃ SO ₂ '3-F-biphen-4-yl 169 4-CH3O Structure C 4-amidino-OH 3-CF ₃ , 2'-CH ₃ SO ₂ -3-F-biphen-4-yl 170 4-CH3O Structure C 4-CO ₂ C ₂ H ₅ 3-CF 3, 2'-CH ₃ SO ₂ -3-F-biphen-4-yl 4-CO2H

(a) -CH ₂ C (O) NHCH ₂ CO ₂ CH ₃ (b) - (1,2,4-triazole (-1-yl) CH ₂

The following tables are representative examples of the present invention. Each entry in each table is considered to be paired with each formula at the beginning of the table. For example, Example 1 in Table 2 is considered to be paired with ai-f _{9 for} each formula.

Table 189

= CH ₃ a ₂ R ^1a = CF 3 aa R ^1a = SCH3 a4 R ^1a = SOCH3 a5 R ^1a = SO2CH ₃ ae R ^1a = Cl a7 R ^1a = Br ag R ^1a = CO2CH ₃ a ₉ R ^1a = CH ₂ OCH ₃ b ₂ R ^1a = CF3 b3 R ^la = SCH3 b ₄ R ^1a = SOCHa b5 R ^1a = SO2CH ₃ b ₆ R ^1a = Cl b7 R ^1a = Br b8 R ^1a = CO2CH3 b9 R ^1a = CH2OCH ₃ c ₂ R ^1a = CF3 c3 R ^1a = SCH3 c ₄ R ^1a = SOCHa c5 R ^1a = SO2CH ₃ c ₆ R ^1a = Cl c7 R ^la = Br c8 R ^1a = CO2CH3 c9 R ^la = CH2OCH ₃

d, R ^1a = CH ₃ = CH ₃ d ₂ R ^1a = CF3 d3 R ' ^a = SCH3 d ₄ R ^1a = SOCH3 d5 R ^1a = SO2CH ₃ d ₆ R ^la = Cl d7 R ^1a = Br dg R ^1a = CO2CH ₃ dg R ^1a = CH ₂ OCH ₃

e ₂ R ^1a = CF3 e3 R ^1a = SCH3 e ₄ R ^1a = SOCH3 e5 R ^la = SO2CH ₃ e ₆ R ^1a = Cl e7 R ^1a = Br ea R ^1a = CO2CH3 e9 R ^1a = CH2OCH ₃ f ₂ R ^1a = CF3 f3 R ^1a = SCH3 f ₄ R ^1a = SOCH3 f5 R ^1a = SO2CH ₃ f ₆ R ^la = Cl f7 R ^1a = Br f3 R ^1a = CO2CH3 f9 R ^1a = CH2OCH ₃

190

For example, A B 1 phenyl 2- (aminosulfonyl) phenyl 2 phenyl 2- (methylaminosulfonyl) phenyl 3 phenyl 1-Pyrrolidinocarbonyl 4 phenyl 2- (methylsulfonyl) phenyl 5 phenyl 4-morpholine group 6th phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 7th phenyl 4-morpholinocarbonyl 8th 2-pyridyl 2- (aminosulfonyl) phenyl 9th 2-pyridyl 2- (methylaminosulfonyl) phenyl 10th 2-pyridyl 1-Pyrrolidinocarbonyl 11th 2-pyridyl 2- (methylsulfonyl) phenyl 12th 2-pyridyl 4-morpholine group 13th 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 14th 2-pyridyl 4-morpholinocarbonyl 15th 3-pyridyl 2- (aminosulfonyl) phenyl 16th 3-pyridyl 2- (methylaminosulfonyl) phenyl 17th 3-pyridyl 1-Pyrrolidinocarbonyl 18th 3-pyridyl 2- (methylsulfonyl) phenyl 19th 3-pyridyl 4-morpholine group 20th 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 21st 3-pyridyl 4-morpholinocarbonyl 22nd 2-pyrimidyl 2- (aminosulfonyl) phenyl 23rd 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 24th 2-pyrimidyl 1-Pyrrolidinocarbonyl 25th 2-pyrimidyl 2- (methylsulfonyl) phenyl 26th 2-pyrimidyl 4-morpholine group 27th 2-pyrimidyl 2- (1 '-CF ₃ -theirazol-2-yl) phenyl 28th 2-pyrimidyl 4-morpholinocarbonyl 29th 5-pyrimidine (as 2- (aminosulfonyl) phenyl 30th 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 31st 5-pyrimidyl 1-Pyrrolidinocarbonyl 32 5-pyrimidyl 2- (methylsulfonyl) phenyl 33 5-pyrimidyl 4-morpholine group 34 5-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 35 5-pyrimidyl 4-morpholinocarbonyl 36 2-Cl-phenyl 2- (aminosulfonyl) phenyl 37 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 38 2-Cl-phenyl 1-Pyrrolidinocarbonyl 39 2-Cl-phenyl 2- (methylsulfonyl) phenyl 40 2-Cl-phenyl 4-morpholine group 41 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-ii) phenyl 42 2-Cl-phenyl 4-morpholinocarbonyl 43 2-F-phenyl 2- (aminosulfonyl) phenyl 44 2-F-phenyl 2- (methylaminosulfonyl) phenyl 45 2-F-phenyl 1-Pyrrolidinocarbonyl

191

2-F-phenyl 2- (methylsulfonyl) phenyl 2-F-phenyl 4-morpholine group 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-morpholine group 2,5-diF-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 2,5-diF-phenyl 4-morpholinocarbonyl phenyl 2- (N-pyrrolidinylmethyl) phenyl phenyl 2- (N-piperidinyl-methyl) phenyl phenyl 2- (N-morpholino-methyl) phenyl phenyl 2- (N, N'-methylmorpholino-methyl) phenyl phenyl 2- (N-pyridine-methyl) phenyl phenyl 2- (N-4- (N, N'-dimethylamino) -pyridine- methyl) phenyl phenyl 2- (N-azatanylmethyl) phenyl phenyl 2- (N-azetidinylmethyl) phenyl phenyl 2- (N-piperazinyl-methyl) phenyl phenyl 2- (N, N'-BOC-piperazinyl-methyl) phenyl phenyl 2- (N-imidazolyl-methyl) phenyl phenyl 2- (N-methoxy-N-methylamino-methyl) phenyl phenyl 2- (N-pyridonyl-methyl) phenyl phenyl 2- (N- (N ', N'-dimethylhydrazinyl-methyl) phenyl phenyl 2- (amidinyl) phenyl phenyl 2- (N-guanidinyl) 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- (amidinyl-methyl) phenyl phenyl 2- (2-imidazolidinylmethyl) phenyl phenyl 2- (N- (2-aminoimidazolyl) -methyl) phenyl phenyl 2-Dimethylaminoimidazol-1-yl phenyl • 2- (3-aminophenyl) phenyl 2- (3-pyrrolidinylcarbonyl) phenyl 2-Glycinoyl phenyl 2- (imidazol-1-ylacetyl) 2-pyridyl 2- (N-pyrrolidinylmethyl) phenyl 2-pyridyl 2- (N-piperidinyl-methyl) phenyl 2-pyridyl 2- (N-morpholino-methyl) phenyl 2-pyridyl 2- (N, N'-methylmorpholine-methyl) phenyl 2-pyridyl 2- (N-pyridine-methyl) phenyl 2-pyridia 2- (N-4- (N, N'-dimethylamino) -pyridine- methyl) phenyl

192

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

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- (N-azatanylmethyl) 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-pyridonyl-methyl) phenyl

2- (N- (N ', N'-dimethylhydrazinyl-methyl) phenyl

2- (amidinyl) phenyl

2- (N-guanidinyl) phenyl

2- (imidazolyl) phenyl

2- (imidazolidinyl) phenyl

2- (2-imidazolidinylsulfonyl) phenyl

2- (2-Pyrrolidinyl) phenyl

2- (2-piperidinyl) phenyl

2- (amidinyl-methyl) phenyl

2- (2-imidazolidinylmethyl) phenyl

2- (N- (2-aminoimidazolyl) methyl) phenyl

2-Dimethylaminoimidazol-1-yl

2- (3-aminophenyl)

2- (3-pyrrolidinylcarbonyl)

2-Glycinoyl

2- (imidazol-1-ylacetyl)

2- (N-pyrrolidinylmethyl) phenyl

2- (N-piperidinyl-methyl) phenyl

2- (N-morpholino-methyl) phenyl

2- (N, N'-methylmorpholine-methyl) phenyl

2- (N-pyridine-methyl) phenyl

2- (N-4- (N, N'-dimethylamino) -pyridinomethyl) phenyl

2- (N-azatanylmethyl) phenyl

2- (N-azetidinyl-methyl) phenyl

2- (N-piperazinyl-methyl) phenyl

2- (N, N'-BOC-piperazinyl-methyl) phenyl

2- (N-imidazolylmethyl) phenyl

2- (N-methoxy-N-methylamino-methyl) phenyl

2- (N-pyridonylmethyl) phenyl

2- (N '- (N', N'-dimethylhydrazinyl-methyl) phenyl

2- (amidinyl) phenyl

2- (N-guanidinyl) phenyl

2- (imidazolyl) phenyl

2- (imidazolidinyl) phenyl

2- (2-imidazolidinylsulfonyl) phenyl

2- (2-pyrrolidinyl) phenyl

2- (2-piperidinyl) phenyl

2- (amidinyl-methyl) phenyl

2- (2-imidazolidinylmethyl) phenyl

2- (N- (2-aminoimidazolyl) -methyl) phenyl

193

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-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-Dimethylaminoimidazol-1-yl

2- (3-aminophenyl)

2- (3-pyrrolidinylcarbonyl)

2-Glycinoyl

2- (imidazol-1-ylacetyl)

2- (N-pyrrolidinylmethyl) phenyl

2- (N-piperidinyl-methyl) phenyl

2- (N-morpholino-methyl) phenyl

2- (N, N'-methylmorpholine-methyl) phenyl

2- (N-pyridine-methyl) phenyl

2- (N-4- (N, N'-dimethylamino) -pyridinomethyl) phenyl

2- (N-azatanylmethyl) phenyl

2- (N-azetidinylmethyl) phenyl

2- (N-piperazinyl-methyl) phenyl

2- (N, N'-BOC-piperazinyl-methyl) phenyl

2- (N-imidazolyl-methyl) phenyl

2- (N-methoxy-N-methylamino-methyl) phenyl

2- (N-pyridonyl-methyl) phenyl

2- (N- (N ', N'-dimethylhydrazinyl-methyl) phenyl

2- (amidinyl) phenyl

2- (N-guanidinyl) phenyl.

2- (imidazolyl) phenyl

2- (imidazolidinyl) phenyl

2- (2-imidazolidinylsulfonyl) phenyl

2- (2-pyrrolidinyl) phenyl

2- (2-piperidinyl) phenyl

2- (amidinyl-methyl) phenyl

2- (2-imidazolidinylmethyl) phenyl

2- (N- (2-aminoimidazolyl) -methyl) phenyl

2-Dimethylaminoimidazol-1-yl

2- (3-aminophenyl)

2- (3-pyrrolidinylcarbonyl)

2-Glycinoyl

2- (imidazol-1-ylacetyl)

2- (N-pyrrolidinylmethyl) phenyl

2- (N-piperidinyl-methyl) phenyl

2- (N-morpholino-methyl) phenyl

2- (N, N'-methylmorpholine-methyl) phenyl

2- (N-pyridine-methyl) phenyl

2- (N-4- (N, N'-dimethylamino) -pyridinomethyl) phenyl

2- (N-azatanylmethyl) phenyl

2- (N-azetidinylmethyl) phenyl

2- (N-piperazinyl-methyl) phenyl

2- (N, N'-BOC-piperazinyl-methyl) phenyl

2- (N-imidazolyl-methyl) phenyl

2- (N-methoxy-N-methylamino-methyl) phenyl

194

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

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

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

2-F-phenyl

2-F-phenyl

2.5-diF-phenyl

2- (N-pyridonyl-methyl) phenyl

2- (N- (N ', N'-dimethylhydrazinyl-methyl) phenyl

2- (amidinii) phenyl

2- (N-guanidinyl) phenyl

2- (imidazolyl) phenyl

2- (imidazolidinyl) phenyl

2- (2-imidazolidinylsulfonyl) phenyl

2- (2-pyrrolidinyl) phenyl

2- (2-piperidinyl) phenyl

2- (amidinyl-methyl) phenyl

2- (2-imidazolidinylmethyl) phenyl

2- (N- (2-aminoimidazolyl) -methyl) phenyl

2-Dimethylaminoimidazol-1-yl

2- (3-aminophenyl)

2- (3-pyrrolidinylcarbonyl)

2-Glycinoyl

2- (imidazol-1-ylacetyl)

2- (N-pyrrolidinylmethyl) phenyl

2- (N-piperidinyl-methyl) phenyl

2- (N-morpholino-methyl) phenyl

2- (N, N'-methylmorpholine-methyl) phenyl

2- (N-pyridine-methyl) phenyl

2- (N-4- (N, N'-dimethylamino) -pyridinomethyl) phenyl

2- (N-azatanylmethyl) phenyl

2- (N-azetidinylmethyl) phenyl

2- (N-piperazinyl-methyl) phenyl

2- (N, N'-BOC-piperazinyl-methyl) phenyl

2- (N-imidazolylmethyl) phenyl

2- (N-methoxy-N-methylamino-methyl) phenyl

2- (N-pyridonyl-methyl) phenyl

2- (N- (N ', N'-dimethylhydrazinyl-methyl) phenyl

2- (amidinyl) phenyl

2- (N-guanidini) phenyl

2- (imidazolyl) phenyl

2- (imidazolyl) 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-Dimethylaminoimidazol-1-yl

2- (3-aminophenyl)

2- (3-Pyrrolidinylcarbonyl)

2-Glycinoyl 2- (imidazol-1-ylacetyl) 2- (N-pyrrolidinylmethyl) phenyl

195

232 2,5-diF-phenyl 2- (N-piperidinylmethyl) phenyl 233 2,5-diF-phenyl 2- (N-morpholino-methyl) phenyl 234 2,5-diF-phenyl 2- (N, N'-methylmorpholine-methyl) phenyl 235 2,5-diF-phenyl 2- (N-pyridine-methyl) phenyl 236 2,5-diF-phenyl 2- (N-4- (N, N'-dimethylamino) -pyridine- methyl) phenyl 237 2,5-diF-phenyl 2- (N-azatanylmethyl) phenyl 238 2,5-diF-phenyl 2- (N-azetidinylmethyl) phenyl 239 2,5-diF-phenyl 2- (N-piperazinyl-methyl) phenyl 240 2,5-diF-phenyl 2- (N, N'-BOC-piperazinyl-methyl) phenyl 241 2,5-diF-phenyl 2- (N-imidazolyl-methyl) phenyl 242 2,5-diF-phenyl 2- (N-methoxy-N-methylamino-methyl) phenyl 243 2,5-diF-phenyl 2- (N-pyridonyl-methyl) phenyl 244 2,5-diF-phenyl 2- (N- (N ', N'-dimethylhydrazinyl-methyl) phenyl 245 2,5-diF-phenyl 2- (amidinyl) phenyl 246 2,5-diF-phenyl 2- (N-guanidinyl) phenyl 247 2,5-diF-phenyl 2- (imidazolyl) phenyl 248 2,5-diF-phenyl 2- (imidazolidinyl) phenyl 249 2,5-diF-phenyl 2- (2-imidazolidinylsulfonyl) phenyl 250 2,5-diF-phenyl 2- (2-pyrrolidinyl) phenyl 251 2,5-diF-phenyl 2- (2-piperidinyl) phenyl 252 2,5-diF-phenyl 2- (amidinyl-methyl) phenyl 253 2,5-diF-phenyl 2- (2-imidazolidinylmethyl) phenyl 254 2,5-diF-phenyl 2- (N- (2-aminoimidazolyl) -methyl) phenyl 255 2,5-diF-phenyl 2-Dimethylaminoimidazol-1-yl 256 2,5-diF-phenyl 2- (3-aminophenyl) 257 2,5-diF-phenyl 2- (3-pyrrolidinylcarbonyl) 258 2,5-diF-phenyl 2-Glycinoyl 259 2,5-diF-phenyl 2- (imitates dye! -1 -ii acetyl)

table

196

For example, A B 1 phenyl 2- (aminosulfonyl) phenyl 2 phenyl 2- (methylaminosulfonyl) phenyl 3 phenyl 1-Pyrrolidinocarbonyl 4 phenyl 2- (methylsulfonyl) phenyl 5 phenyl 4-morpholine group 6th phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 7th phenyl 4-morpholinocarbonyl 8th 2-pyridyl 2- (aminosulfonyl) phenyl 9th 2-pyridyl 2- (methylaminosulfonyl) phenyl 10th 2-pyridyl 1-Pyrrolidinocarbonyl 11th 2-pyridyl 2- (methylsulfonyl) phenyl 12th 2-pyridyl 4-morpholine group 13th 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 14th 2-pyridyl 4-morpholinocarbonyl 15th 3-pyridyl 2- (aminosulfonyl) phenyl 16th 3-pyridyl 2- (methylaminosulfonyl) phenyl 17th 3-pyridyl 1-Pyrrolidinocarbonyl 18th 3-pyridyl 2- (methylsulfonyl) phenyl 19th 3-pyridyl 4-morpholine group 20th 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 21st 3-pyridyl 4-morpholinocarbonyl 22nd 2-pyrimidyl 2- (aminosulfonyl) phenyl 23rd 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 24th 2-pyrimidyl 1-Pyrrolidinocarbonyl

197

2-pyrimidyl

2-pyrimidyl

2-pyrimidyl

2-pyrimidine

5-pyrimidyl

5-pyrimidyl

5-pyrimidyl

5-pyrimidyl

5-pyrimidyl

5-pyrimidyl

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 phenyl phenyl phenyl

2- (methylsulfonyl) phenyl

4-morpholine group

2- (1 '-CF ₃ -tetrazol-2-yl) phenyl

4-morpholinocarbonyl

2- (aminosulfonyl) phenyl

2- (methylaminosulfonyl) phenyl

1-Pyrrolidinocarbonyl

2- (methylsulfonyl) phenyl

4-morpholine group

2- (1 '-CF ₃ -tetrazol-2-yl) phenyl as

4-Morpholinocarbonyl 2- (aminosulfonyl) phenyl 2- (methylaminosulfonyl) phenyl

1-Pyrrolidinocarbonyl

2- (methylsulfonyl) phenyl

4-morpholine group

2- (1 '-CF ₃ -tetrazol-2-yl) phenyl

4-morpholinocarbonyl

2- (aminosulfonyl) phenyl

2- (methylaminosulfonyl) phenyl

-pyrrolidinocarbonyl

2- (methylsulfonyl) phenyl

4-morpholine group

2- (1 '-CF ₃ -tetrazol-2-yl) phenyl

4-morpholinocarbonyl

2- (aminosulfonyl) phenyl

2- (methylaminosulfonyl) phenyl

1-Pyrrolidinocarbonyl

2- (methylsulfonyl) phenyl

4-morpholine group

2- (1 '-CF ₃ -tetrazol-2-yl) phenyl

4-morpholinocarbonyl

2- (N-pyrrolidinylmethyl) phenyl

2- (N-piperidinyl-methyl) phenyl

2- (N-morpholino-methyl) phenyl

2- (N, N'-methylmorpholine-methyl) phenyl

2- (N-pyridino-methyl) phenyl • 2- (N-4- (N, N'-dimethylamino) -pyridinomethyl) phenyl

2- (N-azatanylmethyl) phenyl

2- (N-azetidinylmethyl) phenyl

2- (N-piperazinyl-methyl) phenyl

2- (N, N'-BOC-piperazinyl-methyl) phenyl

2- (N-imidazolyl-methyl) phenyl

2- (N-methoxy-N-methylamino-methyl) phenyl

2- (N-pyridonyl-methyl) phenyl

2- (N- (N ', N'-dimethylhydrazinyl-methyl) phenyl

2- (amidinyl) phenyl

198 phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl 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-pyridyl

3-pyridyl 3-pyridyl 3-pyridyl 3-pyridyl

2- (N-guanidinyl) phenyl

2- (imidazolyl) phenyl

2- (imidazolidinyl) phenyl

2- (2-imidazolidinylsulfonyl) phenyl

2- (2-pyrrolidinyl) phenyl

2- (2-piperidinyl) phenyl

2- (amidinyl-methyl) phenyl

2- (2-imidazolidinylmethyl) phenyl

2- (N- (2-aminoimidazolyl) -methyl) phenyl

2-Dimethylaminoimidazol-1-yl

2- (3-aminophenyl)

2- (3-pyrrolidinylcarbonyl)

2-Glycinoyl

2- (imidazol-1-ylacetyl)

2- (N-pyrrolidinylmethyl) phenyl

2- (N-piperidinyl-methyl) phenyl

2- (N-morpholino-methyl) phenyl

2- (N, N'-methylmorphonylthio-methyl) phenyl

2- (N-pyridine-methyl) phenyl

2- (N-4- (N, N'-dimethylamino) -pyridinomethyl) phenyl

2- (N-azatanylmethyl) phenyl

2- (N-azetidinylmethyl) phenyl

2- (N-piperazinyl-methyl) 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- (N- (N '. N'-dimethylhydrazinyl-methyl) phenyl

2- (amidinyl) phenyl

2- (N-guanidinyl) phenyl

2- (imidazolyl) phenyl

2- (imidazolidinyl) phenyl

2- (2-imidazolidinylsulfonyl) phenyl

2- (2-pyrrolidinyl) phenyl

2- (2-piperidinyl) phenyl

2- (amidinyl-methyl) phenyl

2- (2'-imidazolidinyl-methyl) phenyl

2- (N- (2-aminoimidazolyl) -methyl) phenyl

2-Dimethylaminoimidazol-1-yl

2- (3-aminophenyl)

2- (3-pyrrolidinylcarbonyl)

2-Glycinoyl

2- (imidazol-1-ylacetyl)

2- (N-pyrrolidinylmethyl) phenyl

2- (N-piperidinylmethyl) phenyl

2- (N-morpholino-methyl) phenyl

2- (N, N'-methylmorpholine-methyl) phenyl

199

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-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- (N-pyridine-methyl) phenyl

2- (N-4- (N, N'-dimethylamino) -pyridinomethyl) phenyl

2- (N-azatanylmethyl) phenyl

2- (N-azetidinylmethyl) phenyl

2- (N-piperazinyl-methyl) phenyl

2- (N, N'-BOC-piperazinylmethyl) phenyl

2- (N-imidazolylmethyl) phenyl

2- (N-methoxy-N-methylamino-methyl) phenyl

2- (N-pyridonyl-methyl) phenyl

2- (N- (N ', N'-dimethylhydrazinyl-methyl) phenyl

2- (amidinyl) phenyl

2- (N-guanidini) phenyl

2- (imidazolyl) phenyl

2- (imidazolidinyl) phenyl

2- (2-imidazolidinylsulfonyl) phenyl

2- (2-pyrrolidinyl) phenyl

2- (2-piperidinyl) phenyl

2- (amidinyl-methyl) phenyl

2- (2-imidazolidinylmethyl) phenyl

2- (N- (2-aminoimidazolyl) -methyl) phenyl

2-Dimethylaminoimidazol-1-yl

2- (3-aminophenyl)

2- (3-pyrrolidinylcarbonyl)

2-Glycinoyl

2- (imidazol-1-ylacetyl)

2- (N-pyrrolidinylmethyl) phenyl

2- (N-piperidinyl-methyl) phenyl

2- (N-morpholino-methyl) phenyl

2- (N, N'-methylmorpholine-methyl) phenyl

2- (N-pyridine-methyl) phenyl

2- (N-4- (N, N'-dimethylamino) -pyridinomethyl) phenyl

2- (N-azatanylmethyl) phenyl

2- (N-azetidinylmethyl) phenyl

2- (N-piperazinyl-methyl) phenyl

2- (N, N'-BOC-piperazinyl-methyl) phenyl

2- (N-imidazolyl-methyl) phenyl

2- (N-methoxy-N-methylamino-methyl) phenyl

2- (N-pyridonyl-methyl) phenyl

2- (N- (N ', N'-dimethylhydrazinyl-methyl) phenyl

2- (amidinyl) phenyl

2- (N-guanidinyl) phenyl

2- (imidazolyl) phenyl

2- (imidazolidinyl) phenyl

2- (2-imidazolidinylsulfonyl) phenyl

2- (2-pyrrolidinyl) phenyl

2- (2-piperidinyl) phenyl

200

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-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

2- (amidinyl-methyl) phenyl

2- (2-imidazolidinylmethyl) phenyl

2- (N- (2-aminoimidazolyl) -methyl) phenyl

2-Dimethylaminoimidazol-1-yl

2- (3-aminophenyl)

2- (3-pyrrolidinylcarbonyl)

2-Glycinoyl

2- (imidazol-1-ylacetyl)

2- (N-pyrrolidinylmethyl) phenyl

2- (N-piperidinyl-methyl) phenyl

2- (N-morpholino-methyl) phenyl

2- (N, N'-methylmorpholino-methyl) phenyl

2- (N-pyridine-methyl) phenyl

2- (N-4- (N, N'-dimethylamino) -pyridinomethyl) phenyl

2- (N-azatanylmethyl) phenyl

2- (N-azetidinylmethyl) phenyl

2- (N-piperazinyl-methyl) -phenyl

2- (N, N'-BOC-piperazinyl-methyl) phenyl

2- (N-imidazolyl-methyl) phenyl

2- (N-methoxy-N-methylamino-methyl) phenyl

2- (N-pyridonyl-methyl) phenyl

2- (N- (N ', N'-Dimethylhydrazinyl-methyl) phenyl

2- (amidinyl) phenyl

2- (N-guanidinyl) phenyl

2- (imidazolyl) phenyl

2- (imidazolidinyl) phenyl

2- (2-imidazolidinylsulfonyl) phenyl

2- (2-pyrrolidinyl) phenyl

2- (2-piperidinyl) phenyl

2- (amidinyl-methyl) phenyl

2- (2-imidazolidinylmethyl) phenyl

2- (N- (2-aminoimidazolyl) -methyl) phenyl

2-Dimethylaminoimidazol-1-yl

2- (3-aminophenyl)

2- (3-pyrrolidinylcarbonyl)

2-Glycinoyl

2- (im idazol-1-lacetate as)

2- (N-pyrrolidinylmethyl) phenyl

2- (N-piperidinyl-methyl) phenyl

2- (N-morpholino-methyl) phenyl

2- (N, N'-methylmorpholine-methyl) phenyl

2- (N-pyridine-methyl) phenyl

2- (N-4- (N, N'-dimethylamino) -pyridinomethyl) phenyl

2- (N-azatanylmethyl) phenyl

2- (N-azetidinylmethyl) phenyl

2- (N-piperazinyl-methyl) phenyl

201

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

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

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

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

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

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- (N, N'-BOC-piperazinyl-methyl) phenyl

2- (N-imidazolyl-methyl) phenyl

2- (N-methoxy-N-methylamino-methyl) phenyl

2- (N-pyridonyl-methyl) phenyl

2- (N- (N ', N'-dimethylhydrazinyl-methyl) phenyl

2- (amidinyl) phenyl

2- (N-guanidinyl) phenyl

2- (imidazolyl) phenyl

2- (imidazolidinyl) phenyl

2- (2-imidazolidinylsulfonyl) phenyl

2- (2-pyrrolidinyl) phenyl

2- (2-piperidinyl) phenyl

2- (amidinyl-methyl) phenyl

2- (2-imidazolidinylmethyl) phenyl

2- (N- (2-aminoimidazolyl) -methyl) phenyl

2-Dimethylaminoimidazol-1-yl

2- (3-aminophenyl)

2- (3-pyrrolidinylcarbonyl)

2-Glycinoyl

2- (imidazol-1-ylacetyl)

2- (N-pyrrolidinylmethyl) phenyl

2- (N-piperidinyl-methyl) phenyl

2- (N-morpholino-methyl) phenyl

2- (N, N'-methylmorpholine-methyl) phenyl

2- (N-pyridine-methyl) phenyl

2- (N-4- (N, N'-dimethylamino) -pyridinomethyl) phenyl

2- (N-azatanylmethyl) phenyl

2- (N-azetidinylmethyl) phenyl

2- (N-piperazinyl-methyl) phenyl

2- (N, N'-BOC-piperazinyl-methyl) phenyl

2- (N-imidazolyl-methyl) phenyl

2- (N-methoxy-N-methylamino-methyl) phenyl

2- (N-pyridonyl-methyl) phenyl

2- (N- (N ', N'-Dimethylhydrazinyl-methyl) phenyl

2- (amidinyl) phenyl

2- (N-guanidinyl) phenyl. 2- (imidazolyl) phenyl

2- (imidazolidinyl) phenyl

2- (2-imidazolidinylsulfonyl) phenyl

2- (2-pyrrolidinyl) phenyl

2- (2-piperidinyl) phenyl

2- (amidinyl-methyl) phenyl

2- (2-imidazolidinylmethyl) phenyl

2- (N- (2-aminoimidazolyl) -methyl) phenyl

2-Dimethylaminoimidazol-1-yl

2- (3-aminophenyl)

2- (3-pyrrolidinylcarbonyl)

202

258

259

2,5-diF-phenyl

2,5-diF-phenyl

2-Glycinoyl

2- (imidazole-1)

-ylacetyl)

v.

Table 203

= CH ₃ a ₂ R ^1a = CF3 a3 R ^la = SCH3 a4 R ^1a = SOCH3 a5 R ^1a = SO2CH ₃ ae R ^1a = Cl a7 R ^1a = Br ag R ^la = CO2CH ₃ a ₉ R ^la = CH ₂ OCH ₃ b ₂ R ^1a = CF3 b3 R ^1a = SCH3 b ₄ R ^1a = SOCH3 b5 R ^1a = SO2CH ₃ b ₆ R ^1a = Cl b? R ^1a = Br b8 R ^1a = CO2CH ₃ b ₉ R ^la = CH ₂ OCH ₃ c ₂ R ^1a = CF3 c3 R ^1a = SCH3 c ₄ R ^1a = SOCHs c5 R ^1a = SO2CH ₃ c ₆ R ^1a = Cl c7 R ^1a = Br c8 R ^1a = CO2CH3 c9 R ^1a = CH2OCH ₃

d, R ^1a = CH ₃ = ch ₃ d ₂ R ^1a = CF3 d3 R ^la = SCH3 d ₄ R ^1a = SOCH3 d5 R ^la = SO2CH ₃ d ₆ R ^la = Cl d7 R ^1a = Br d8 R ^la = CO2CH3 d9 R ^1a = CH ₂ OCH ₃

e ₂ .R ^1a = CF3 e3 R ^1a = SCH3 e ₄ R ^1a = SOCH3 e5 R ^1a = SO2CH ₃ e ₆ R ^1a = Cl e7 R ^1a = Br e8 R ^1a = CO2CH3 e9 R ^1a = CH2OCH ₃

N4 f, R ^1a f ₂ R ^1a = CF3 f3 R ^1a = SCH3 f ₄ R ^1a = SOCH3 f5 R ^la = SO2CH ₃ fe R ^la = Cl f7 R ^1a = Br f8 R ^1a = CO2CH3 f9 R ^1a = CH2OCH ₃

For example, A

204 phenyl phenyl phenyl phenyl

2-F-phenyl

2-F-phenyl

2-F-phenyl

2-F-phenyl phenyl phenyl phenyl phenyl phenyl

2-F-phenyl

2-F-phenyl

2-F-phenyl

2-F-phenyl

2-F-phenyl

2-Cl-phenyl

2-Cl-phenyl

2-Cl-phenyl

2-Cl-phenyl

2-Cl-phenyl

2- (Me) ₂ N-phenyl

2- (Me) ₂ N-phenyl

2- (Me) ₂ N-phenyl

2- (Me) ₂ N-phenyl

2- (Me) ₂ N-phenyl phenyl phenyl phenyl

2-F-phenyl

2-F-phenyl

2-F-phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl

2-F-phenyl

2-F-phenyl

2-F-phenyl

2-F-phenyl

2-F-phenyl

2 - ((Me) ₂ N-methyl) phenyl 2 - ((Me) NH-methyl) phenyl 2- (H ₂ N-methyl) phenyl 2-HOCH ₂ -phenyl 2 - ((Me) ₂ N-methyl) phenyl 2 - ((Me) NH-methyl) phenyl 2- (H ₂ N -methyl) phenyl 2-HOCH ₂ -phenyl 2-methylimidazol-1-yl 2-ethylimidazol-1-yl 2 - ((Me) ₂ N -methyl) imidazol-1-yl 2-CH ₃ SO ₂ -imidazol-1-yl 2-CH ₃ OCH ₂ -imidazol-1-yl 2-methylimidazol-1-yl 2-ethylimidazol-1-yl 2 - (( Me) ₂ N-Methyl) imidazol-1-yl 2-CH ₃ SO ₂ -imidazol-1-yl 2-CH ₃ OCH ₂ -imidazol-1-yl 2-methylimidazol-1-yl 2-ethylimidazol-1-yl 2 - ((Me) _2N-methyl) imidazol-1 -ilas 2-CH ₃ S0 ₂ -imidazol-1 -ilas 2-CH ₃ OCH ₂ -imidazol-1-yl, 2-methylimidazol-1-yl, 2-ethylimidazol -1-yl 2 - ((Me) ₂ N -methyl) imidazol-1-yl 2-CH ₃ SO ₂ -imidazol-1-yl 2-CH ₃ OCH ₂ -imidazol-1-yl N-methylimidazol-2-yl ilas

4-methylimidazol-5-yl

5-CF ₃ -pyrazof-1-yl

N-methylimidazol-2-yl

4-methylimidazol-5-yl

5-CF ₃ -pyrazol-1-yl guanidine group

2-Thiazolin-2-ylamine

N-Methyl-2-imidazolin-2-yl

N-Methyl-1,4,5,6-tetrahydropyrimidin-2-yl

N-Methylimidazol-2-ylthiol t-butoxycarbonylamine (N-pyrrolidino) formylimino group (N-pyrrolidino) formyl-Nmethanesulfamoyl) imino group guanidine group

2-Thiazolin-2-ylamine

N-Methyl-2-irididazolin-2-yl

N-Methyl-1,4,5,6-tetrahydropyrimidin-2-yl

N-methylimidazol-2-ylthio

205

48 2-F-phenyl t-butoxycarbonylamine 49 2-F-phenyl (N-pyrrolidine) formyliminogroup 50 2-F-phenyl (N-pyrrolidino) formyl-N- methanesulfamoyl) iminogroup 51 2-CH3O-phenyl (N-pyrrolidine) formyliminogroup 52 2-CH ₃ O-phenyl (N-pyrrolidino) formyl-N-

methanesulfamoyl) iminogroup Table

H

Λ / B A

O

CH,

B

For example,

phenyl phenyl phenyl

2 - ((Me) ₂ N -methyl) phenyl

2 - ((Me) NH-methyl) phenyl

2- (H ₂ N -methyl) phenyl

206 phenyl

2-F-phenyl

2-F-phenyl

2-F-phenyl

2-F-phenyl phenyl phenyl phenyl phenyl phenyl

2-F-phenyl

2-F-phenyl

2-F-phenyl

2-F-phenyl

2-F-phenyl

2-Cl-phenyl

2-Cl-phenyl

2-Cl-phenyl

2-Cl-phenyl

2-Cl-phenyl

2- (Me) ₂ N-phenyl

2- (Me) ₂ N-phenyl

2- (Me) ₂ N-phenyl

2- (Me) ₂ N-phenyl

2- (Me) ₂ N-phenyl phenyl phenyl phenyl

2-F-phenyl

2-F-phenyl

2-F-phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl 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-HOCH ₂ -phenyl 2 - ((Me) ₂ N-methyl) phenyl 2 - ((Me) NH-methyl) phenyl 2- (H ₂ N-methyl) phenyl 2-HOCH ₂ -phenyl 2-methylimidazol-1 -yl 2-ethylimidazol-1-yl 2 - ((Me) ₂ N -methyl) imidazol-1-yl 2-CH ₃ SO ₂ -imidazol-1-yl 2-CH ₃ OCH ₂ -imidazol-1-yl 2 -methylimidazol-1-yl 2-ethylimidazol-1-yl 2 - ((Me) ₂ N -methyl) imidazol-1-yl 2-CH ₃ SO ₂ -imidazol-1-yl 2-CH ₃ OCH 2 -imidazol-1 -yl 2-methylimidazol-1-yl 2-ethylimidazol-1-yl 2 - ((Me) ₂ N -methyl) imidazol-1-yl 2-CH ₃ SO ₂ -imidazol-1-yl 2-CH ₃ OCH ₂ -imidazol-1-yl 2-methylimidazol-1-yl 2-ethylimidazol-1-yl 2 - ((Me) ₂ N -methyl) imidazol-1-yl 2-CH ₃ SO ₂ -imidazol-1-yl 2- CH ₃ OCH ₂ -imidazol-1-yl N-methylimidazol-2-yl

4-methylimidazol-5-yl

5-CF ₃ -pyrazol-1-yl

N-methylimidazol-2-yl

4-methylimidazol-5-yl

5-CF ₃ -pyrazol-1-yl guanidine group

2-Thiazolin-2-ylamine

N-Methyl-2-imidazolin-2-yl

N-Methyl-1,4,5,6-tetrahydropyrimidin-2-yl

N-Methylimidazol-2-ylthiol t-butoxycarbonylamine (N-pyrrolidino) formylimino (N-pyrrolidino) formyl-Nmethanesulfamoyl) iminoguanidine

2-Thiazolin-2-ylamine

N-Methyl-2-imidazolin-2-yl

N-Methyl-1,4,5,6-tetrahydropyrimidin-2-yl

N-Methylimidazol-2-ylthio t-butoxycarbonylamine (N-pyrrolidino) formylimino (N-pyrrolidino) formyl-N

207 methanesulfamoyl) iminogroup

2-CH ₃ O-phenyl (N-pyrrolidino) formyliminogroup

2-CH ₃ O-Phenyl (N-pyrrolidino) formyl-N-methanesulfamoyl) imino

208

table

no R ⁴ = OCH ₃ h R ⁴ =

Ci R ⁴ = OCH ₃ and ₃ c ₂ R ⁴ = CO ₂ CH ₃

d. R ⁴ = OCH ₃ d ₂ R ⁴ = CO2CH3 e2 ^R4 = CO2CH ₃ f ₂ R ⁴ = CO ₂ CH ₃ c ₃ ^R4 = CH2OCH3 d3 ^R4 = CH2OCH ₃ e ₃ R ⁴ = CH2OCH3 f3 ^R4 = CH2OCH ₃ c ₄ R ⁴ = CH3 c5 ^R4 = CF3 _C6 ^R4 = Cl d ₄ R ⁴ = CH 3 and d5 R ⁴ = CF 3, d ₆ R ⁴ = c e ₄ R ⁴ = CH 3 and e5 ^R4 = CF3 e ₆ R ⁴ = Cl f ₄ R ⁴ = CH 3 fs R ⁴ = CF 3 fe R ⁴ = Cl

₃ g OCH ₂ R ⁴ = CO2CH3 g3 ^R4 = CH2OCH ₃ g ₄ ⁴ R = CH3 g5 ^R4 = CF3 h ₂ = R ⁴ R ⁴ CO2CH3 h3 = CH2OCH ₃ H ₄ R ⁴ = CH 3 and R ⁴ h5 = CF3

1 ₂ R ⁴ = CO ₂ CH ₃

1 ₃ R ⁴ = CH ₂ OCH ₃

1 ₄ R ⁴ = CH ₃

1 ₅ R ⁴ = CF ₃ j ₂ R ⁴ = sCO ² CH ₃ j ₃ R ⁴ = C H ₂ OCH ₃ j ₄ R ⁴ = CH ₃ j s R ⁴ = CF 3

209 g ₆ R ⁴ = Cl g? R ⁴ = F h ₆ R ⁴ = Cl h ₇ R ⁴ = F i ₆ R ⁴ = Cl iz R ⁴ = F j ₆ R ⁴ = Cl j ₇ R ⁴ = F

210 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 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 5-pyrimidyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-Cl-phenyl 2-O-phenyl 2-Cl-phenyl 2-. F-phenyl 2-F-phenyl 2-F-phenyl 2-F-phenyl

2- (aminosulfonyl) phenyl

2- (methylaminosulfonyl) phenyl

2-Pyrrolidinocarbonyl

2- (methylsulfonyl) phenyl

4-morpholine group

2- (1 '-CF ₃ -tetrazol-2-yl) phenyl

4-morpholinocarbonyl

2- (aminosulfonyl) phenyl

2- (methylaminosulfonyl) phenyl

2-Pyrrolidinocarbonyl

2- (methylsulfonyl) phenyl

4-morpholine group

2- (1 '-CF ₃ -tetrazol-2-yl) phenyl

4-morpholinocarbonyl

2- (aminosulfonyl) phenyl

2- (methylaminosulfonyl) phenyl

2-Pyrrolidinocarbonyl

2- (methylsulfonyl) phenyl

4-morpholine group

2- (1 '-CF ₃ -tetrazol-2-yl) phenyl

4-morpholinocarbonyl

2- (aminosulfonyl) phenyl

2- (methylaminosulfonyl) phenyl

2-Pyrrolidinocarbonyl

2- (methylsulfonyl) phenyl

4-morpholine group

2- (1 '-CF ₃ -tetrazol-2-yl) phenyl

4-morpholinocarbonyl

2- (aminosulfonyl) phenyl

2- (methylaminosulfonyl) phenyl

2-Pyrrolidinocarbonyl

2- (methylsulfonyl) phenyl

4-morpholine group

2- (1 '-CF ₃ -tetrazol-2-yl) phenyl

4-morpholinocarbonyl

2- (aminosulfonyl) phenyl

2- (methylaminosulfonyl) phenyl

2-Pyrrolidinocarbonyl

2- (methylsulfonyl) phenyl

4-morpholine group

2- (1 '-CF ₃ -tetrazol-2-yl) phenyl

4-morpholinocarbonyl

2- (aminosulfonyl) phenyl _K

2- (methylaminosulfonyl) phenyl

2-Pyrrolidinocarbonyl

2- (methylsulfonyl) phenyl

211

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

4-morpholine group

2- (1 '-CF 3 -tetrazol-2-yl) phenyl

4-morpholinocarbonyl

2- (aminosulfonyl) phenyl

2- (methylaminosulfonyl) phenyl

2-Pyrrolidinocarbonyl

2- (methylsulfonyl) phenyl

4-morpholine group

2- (1 '-CF 3 -tetrazol-2-yl) phenyl

4-morpholinocarbonyl v

212

and ₃

c ₂ R ⁴ = CO ₂ CH ₃ d ₂ R ⁴ = CO ₂ CH ₃ e ₂ R ⁴ = CO ₂ CH ₃ f ₂ R ⁴ = CO ₂ CH ₃ c ₃ R ⁴ = CH ₂ OCH ₃ d ₃ R ⁴ = CH ₂ OCH ₃ e ₃ R ⁴ = CH ₂ OCH ₃ f ₃ R ⁴ = CH ₂ OCH ₃ c ₄ R ⁴ = CH ₃ d ₄ R ⁴ = CH ₃ e ₄ R ⁴ = CH ₃ f ₄ R ⁴ = CH ₃ c ₅ R ⁴ = CF ₃ d ₅ R ⁴ = CF ₃ e ₅ R ⁴ = CF ₃ f ₅ R ⁴ = CF ₃ c ₆ R ⁴ = Cl d ₆ R ⁴ = Cl e ₆ R ⁴ = Cl f ₆ R ⁴ = Cl c ₇ R ⁴ = F d ₇ R ⁴ = F e ₇ R ⁴ = F f ₇ R ⁴ = F

g ₂ och ₃ R ⁴ = CO2CH3 g3 ^R4 = CH2OCH ₃ g ₄ ⁴ R = CH3 g5 ^R4 = CF3 h ₂ = R ⁴ R ⁴ CO2CH3 h3 = CH2OCH ₃ H ₄ R ⁴ = CH 3 and R ⁴ h5 = CF3

1 ₂ R ⁴ = CO ₂ CH ₃

1 ₃ R ⁴ = CH ₂ OCH ₃

1 ₄ R ⁴ = CH ₃

1 ₅ R ⁴ = CF ₃ j ₂ R ⁴ = CO ² CH ₃ j ₃ R ⁴ = CH ₂ OCH ₃ j ₄ R ⁴ = CH ₃ j ₅ R ⁴ = CF 3

213 g ₆ R ⁴ = Cl g? R ⁴ = F h ₆ R ⁴ = Cl i6 ^R4 = CI j6 ^R4 H ₇ R ⁴ = F i7 ^R4 = F J7 ei = R ⁴ = F

214 phenyl phenyl phenyl phenyl

2-F-phenyl

2-F-phenyl

2-F-phenyl

2-F-phenyl phenyl phenyl phenyl phenyl phenyl

2-F-phenyl

2-F-phenyl

2-F-phenyl

2-F-phenyl

2-F-phenyl

2-Cl-phenyl

2-Cl-phenyl

2-Cl-phenyl

2-Cl-phenyl

2-Cl-phenyl

2- (Me) ₂ N-phenyl

2- (Me) ₂ N-phenyl

2- (Me) ₂ N-phenyl

2- (Me) ₂ N-phenyl

2- (Me) ₂ N-phenyl phenyl phenyl phenyl

2-F-phenyl

2-F-phenyl

2-F-phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl

2-F-phenyl

2-F-phenyl

2-F-phenyl

2 - ((Me) ₂ N-methyl) phenyl 2 - ((Me) NH-methyl) phenyl 2- (H ₂ N-methyl) phenyl 2-HOCH ₂ -phenyl 2 - ((Me) ₂ N-methyl) phenyl 2 - ((Me) NH-methyl) phenyl 2- (H ₂ N -methyl) phenyl 2-HOCH ₂ -phenyl 2-methylimidazol-1-yl 2-ethylimidazol-1-yl 2 - ((Me) ₂ N -methyl) imidazol-1-yl 2-CH ₃ S0 ₂ -imidazol-1 -ilas 2-CH ₃ OCH ₂ -imidazol-1-yl, 2-methylimidazol-1-yl, 2-chloroimidazol-1 -ilas 2 - (( me) _2N-methyl) imidazol-1-yl 2-CH ₃ S0 ₂ -imidazol-1 -ilas 2-CH ₃ OCH ₂ -imidazol-1 -ilas 2-methylimidazol-1-yl, 2-chloroimidazol-1 -ilas 2 - ((Me) _2N-methyl) -ilas lmidazol-1 2-CH ₃ S0 ₂ -imidazol-1 -ilas 2-CH ₃ OCH ₂ -imidazol-1 -ilas 2-methylimidazol-1-yl, 2-ethylimidazol -1 -ilas 2 - ((Me) _2N-methyl) imidazol-1 -ilas 2-CH ₃ S0 ₂ -imidazol-1 -ilas 2-CH ₃ OCH ₂ -imidazol-1-yl, N-methylimidazol-2- ilas

4-methylimidazol-5-yl

5- CF ₃ -pyrazole-Vilas

N-methylimidazol-2-yl

4-methylimidazol-5-yl

5-CF ₃ -pyrazol-1-yl guanidine group

2-Thiazolin-2-ylamine

N-Methyl-2-imidazolin-2-yl

N-Methyl-1,4,5,6-tetrahydropyrimidin-2-yl

N-Methylimidazol-2-ylthiol t-butoxycarbonylamine (N-pyrrolidino) formylimino (N-pyrrolidino) formyl-Nmethanesulfamoyl) imino group guanidine 2-thiazolin-2-ylamine N-methyl-2-imidazolin-2-yl

215

46th 2-F-phenyl N-Methyl-1,4,5,6-tetrahydropyrimidin-2-yl 47 2-F-phenyl N-methylimidazol-2-ylthio 48 2-F-phenyl t-butoxycarbonylamine 49 2-F-phenyl (N-pyrrolidine) formyliminogroup 50 2-F-phenyl (N-pyrrolidino) formyl-N- methanesulfamoyl) iminogroup 51 2-CH ₃ O-phenyl (N-pyrrolidine) formyliminogroup 52 2-CH ₃ O-phenyl (N-pyrrolidino) formyl-N-

methanesulfamoyl) iminogroup

OPPORTUNITIES

The compounds of the present invention are useful as anticoagulants for the treatment or prophylaxis of thromboembolic disorders in mammals. As used herein, "thromboembolic disorders includes arterial and venous cardiovascular or cerebrovascular thromboembolic disorders, including, for example, persistent angina, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, paralysis, atherosclerosis, thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral artery thrombosis, 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 efficacy of the compounds of the present invention as factor Xa inhibitors was determined using purified human factor Xa and a synthetic substrate. The rate of hydrolysis of the chromogenic substrate S2222 (Kabi Pharmacia, Franklin, OH) catalyzed by factor Xa in the absence and presence of the compound of the present invention was measured. Hydrolysis of the substrate results in the release of pNA, which was controlled spectrophotometrically by measuring the increase in optical density at 405 nm. The decrease in the rate of change of the optical density at 405 nm in the presence of an inhibitor indicates that the enzyme is inhibited. The results of this test are expressed as the constant of the inhibitor

216

Factor Xa assays were performed in 0.10 M sodium phosphate buffer, pH 7.5 containing 0.20 M NaCl and 0.5% PEG 8000, and the substrate hydrolysis Michael constant Km was determined at 25 ° C using Lineweaver and Burk. 'o method. K values were determined by reacting 0.2-0.5 nM human factor Xa (Enzyme Research Laboratories, South Bend, IN) with substrate (0.20 mM - 1 mM) with the addition of an inhibitor. Reactions were run for 30 min. and velocities (time dependence of change in optical density) were measured for 25-30 min. interval. K, the following equation was used to calculate the values:

(v ₀ -v _s ) / v _s = l / (Ki (1 + S / K _m )) where:

v ₀ is the rate of the control reaction in the absence of inhibitor: v _s is the rate of inhibitor in the presence of:

I is the concentration of inhibitor;

K is the dissociation constant of the enzyme: inhibitor complex;

S is the substrate concentration;

Km is Michael's constant.

Using the procedure described above, it has been found that many of the compounds of the present invention have a K <15 μΜ, thus confirming that the compounds of the present invention are potent factor Xa inhibitors.

The antithrombotic effect of the compounds of the present invention may be demonstrated in a rabbit arterial-venous (AV) shunt model. This model uses 2-3 kg rabbits anesthetized with a mixture of xylazine (10 mg / kg i.m.) and ketamine (50 mg / kg i.m.). An AV shunt filled with saline is connected between the femoral artery and the femoral vein cannula. The AV shunt unit consists of a piece of 6 cm tube containing a piece of silk thread. Exposure of the running blood to the silky thread causes the formation of a large thrombus. After forty minutes, the shunt is disconnected and the thrombus thread is weighed. Testing agents (i.v., i.p., s.c. or orally) are administered prior to the shunt opening. The percentage inhibition of thrombus formation is determined for each test group. By linear regression

217 estimated ID ₅₀ values (dose which produces 50% inhibition of thrombus formation).

Compounds of formula (I) may also be useful as inhibitors of serine proteases, most notably human thrombin, plasma calicrine and plasmin. Because of this inhibitory effect, these compounds may be useful in the prevention and treatment of physiological reactions (coagulation and inflammation) catalyzed by said class of enzymes. More specifically, these compounds are useful as medicaments for the treatment of diseases resulting from increased thrombin activity, such as myocardial infarction, and as reagents used as anticoagulants in the processing of blood into plasma for diagnostic or other commercial purposes.

Some of the compounds of the present invention have been shown to be direct acting inhibitors of the serine protease, thrombin, because they are capable of inhibiting the cleavage of low molecular weight substrates in a thrombin-purified system. According to Kettner et al. J. Biol. Chem. 265, 18289-18297 (1990) (given as literature), their inhibition constants were determined in vitro. In these experiments, hydrolysis of the chromogenic substrate S2238 (Helena Laboratories, Beaumont, TX), which is mediated by thrombin, was followed spectrophotometrically. Addition of an inhibitor to the test mixture results in a decrease in optical density, indicating inhibition of thrombin. Human thrombin (Enzyme Research Laboratories, South Bend, IN) at 0.2 nM in 0.10 M sodium phosphate buffer, pH 7.5, 0.20'NaCl, and 0.5% PEG was incubated with various substrates. at concentrations of 0.20 to 0.02 mM. After 25-30 min. thrombin activity was measured by measuring the increase in optical density at 405 nm, which increases with substrate hydrolysis. Inhibition constants were obtained from the inverse dependence of the reaction rate on substrate concentration using the standard Lineweaver and Burk method. Using the procedure described above, some compounds of the present invention were evaluated and found to have a K i less than 15 μΜ, thereby confirming that the compounds of the present invention are potent thrombin inhibitors.

218

The compounds of the present invention may be used alone or in combination with one or more additional therapeutic agents. Such therapeutic agents include other anticoagulants or anticoagulants, antiplatelet or platelet inhibitors, thrombin inhibitors, or thrombolytic or fibrinolytic agents.

The mammal is administered a therapeutically effective amount of the compound. "A therapeutically effective amount is an amount of a compound of Formula I which, when administered to a mammal alone or in combination with an additional therapeutic agent, effectively prevents or ameliorates the thromboembolic disorder or retards the progression of the disease.

The term "administered in combination" or "combination therapy" means that a mammal being treated is administered simultaneously a compound of Formula I and one or more additional therapeutic agents. When administered in combination, each component may be received at the same time or one after the other in any order and at any time interval. Thus, each component can be taken individually but close enough to each other over time to achieve the desired therapeutic effect. Other anticoagulants (or anticoagulant agents) that may be used in combination with the compounds of the present invention include warfarin and heparin, as well as other factor Xa inhibitors such as those described in the preceding section of this disclosure.

As used herein, the term "anti-platelet agents" (or "platelet inhibiting agents") refers to agents that inhibit platelet function, such as inhibiting their aggregation, adhesion or granular secretion. Such agents include, but are not limited to, various known non-steroidal anti-inflammatory drugs (NSAIDS), such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and piroxicam, including their pharmaceutically acceptable forms. Of the NSAIDS, aspirin (acetylsalicylic acid or ASA) and piroxicam are the most suitable. Another suitable antiplatelet agent is ticlopidine, including its

219 pharmaceutically acceptable salts and prodrug forms thereof. Ticlopidine is a suitable compound because of its low gastrointestinal effects. Still other suitable platelet inhibitors include IIb / IIIa antagonists, thromboxane A2 receptor antagonists and thromboxane A2 synthetase inhibitors, and pharmaceutically acceptable salts or prodrug forms thereof.

As used herein, the term "thrombin inhibitors (or" anti-thrombin agents) means inhibitors of the serine protease thrombin. Inhibition of thrombin stops various processes mediated by thrombin, such as thrombin-mediated platelet activation (such as platelet aggregation and / or granular secretion of plasminogen activator inhibitor-1 and / or serotonin) and / or fibrin formation. Many thrombin inhibitors are known to those skilled in the art and it is contemplated that these inhibitors may be used in combination with the compounds of the present invention. Such inhibitors include, but are not limited to, borarginine derivatives, borpeptides, heparins, hirudin, and argatroban, including their pharmaceutically acceptable salts and their prodrug forms. Borarginine derivatives and borpeptides include the N-acetylic and peptide derivatives of boric acid such as the C-terminal α-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and their respective isothiouronium analogs. As used herein, the term "hirudin" includes suitable hirudin analogues called hiruloges, such as disulfatohirudin. Borpeptide thrombin inhibitors include compounds described by Kettner et al., U.S. Pat. Patent No. 5,187,157; and European Patent Application Publication Number 293881 A2, which are incorporated by reference. Other suitable borarginine derivatives and borpeptide thrombin inhibitors are those described in PCT Application Publication Number 92/07869 and European Patent Application Publication Number 471651 A2, which are incorporated by reference.

As used herein, the term "thrombolytic (or fibrinolytic) agents" (or "thrombolytic or" fibrinolytic ") means agents that dissolve blood clots (thrombi). Such agents include tissue plasminogen activator, anistreplase, urokinase or streptokinase, including pharmaceutically acceptable

220 salts or their prodrug forms. As used herein, the term "anistreplase" refers to an anisoylated plasminogen streptokinase activator complex, such as that described in European Patent Application No. No. 028,489, the disclosure of which is incorporated herein by reference. As used herein, the term "urokinase refers to both double and single chain urokinase, also called prourokinase.

The use of the compounds of formula I in combination with such additional therapeutic agents may be much more beneficial than the administration of one of these compounds or single agents, and this may be because it will permit their administration at lower doses. Reducing doses will also reduce the potential side effects and thus extend the safety margins.

The compounds of the present invention are also suitable as standards or as reference compounds, for example as a quality standard or control in assays or assays that are related to factor Xa inhibition.

Such compounds may be provided in the form of commercial kits, for example, for use in assays for factor Xa drugs. For example, a compound of the present invention can be used as a reference in a test comparing its known activity with a compound of unknown activity.

This assures the experimenter that his test has been properly performed and provides a basis for comparison, especially when the test compound is a derivative of the reference compound. The compounds of the present invention can be used to test their efficacy in new assays or methodologies.

The compounds of the present invention may also be used in diagnostic assays related to factor Xa. For example, the presence of factor Xa in an unknown sample can be determined by adding the chromogenic substrate S2222 to a series of solutions containing the test sample and, if necessary, one of the compounds of the present invention. If pNA formation is observed in the solutions containing the test sample and no pNA is formed in the presence of the compound of the invention, it can be concluded that the sample contains factor Xa.

DOSAGE AND PHARMACEUTICAL FORM

221

The compounds of the present invention may be administered in oral dosage forms such as tablets, capsules (and tablets and capsules may be sustained or delayed action), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. They can also be administered by intravenous (bolus or infusion), intraperitoneal, subcutaneous or intravenous administration, in all cases using dosage forms known to those skilled in the art of pharmacy. They may be administered alone, but will generally be administered with a pharmaceutically acceptable carrier selected depending upon the mode of administration selected and usual pharmaceutical practice.

The dosage regimen of the compounds of the present invention will, of course, depend on known factors such as the pharmacodynamic characteristics of the particular agent and the route of administration: species, age, sex, health status, medical condition and weight of the recipient; the nature and degree of the symptoms; the type of compatible treatment; frequency of treatment; administration, patient's kidney and liver function, and desired effect. The therapist or veterinarian may determine and prescribe an effective amount of the drug that will prevent, treat, or arrest the progression of thromboembolic disease.

According to the general guidelines, the daily dose of each active ingredient, when used to achieve the intended effects, should be from 0.001 to 1000 mg / kg body weight, preferably from 0.01 to 100 mg / kg body weight per day, and preferably from 1.0 up to 20 mg / kg / day. For intravenous administration, the preferred dosage range should be about 1 to about 10 mg / kg / min. allowing at constant speed. The compounds of the present invention may be administered as a single daily dose, or the total daily dose may be administered two, three or four times daily.

The compounds of the present invention may be administered intranasally by topical application with suitable intranasal diluents or by transdermal administration using transdermal patches on the skin. When used in the form of transdermal delivery systems, more appropriate dosing throughout the dosing regimen will, of course, be continuous over alternating dosing.

»%

These compounds are usually used in admixture with suitable pharmaceutical diluents, excipients or carriers (all of

222 herein referred to as pharmaceutical carriers) suitably selected according to the intended dosage form, such as oral tablets, capsules, elixirs, syrups, etc., and in accordance with conventional pharmaceutical practice.

For example, for oral administration in the form of a tablet or capsule, the active ingredient may be mixed with an oral, non-toxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, mannitol, and etc,; for oral administration in liquid form, the drug components may be admixed with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Additionally, suitable binders, lubricants, disintegrating agents and coloring agents may be added to the mixture if desired or desired. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, sweeteners in corn, natural and synthetic doses such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, propylene glycol, waxes and the like.

The lubricants used in such dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrating agents include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum and the like.

The compounds of the present invention may also be used in the form of liposomal delivery systems, such as small unicellular vesicles, large unicellular vesicles and multilamellar vesicles. Liposomes can be made from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

The compounds of the present invention may also be coupled with soluble polymers as targeted drug carriers. Such polymers may be polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide phenol, polyhydroxyethiaspartamide amidphenol, or polyethylene oxide polylysine substituted with palmitoyl moieties. In addition, the compounds of the present invention may be coupled with biodegradable grade polymers suitable for the manufacture of a controlled release drug, e.g.

223 polyacetic acid, polyglycolic acid, copolymers of polyacetic and polyglycolic acid, polyepsilone caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacetates and hydrogel-bound or amphipathic block copolymers.

Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 mg to about 100 mg of active ingredient per unit dosage form. In these pharmaceutical compositions, the active ingredient is generally present in an amount of from about 0.5% to about 96% by weight, based on the total weight of the composition.

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 be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products that release the drug over hours. Compressed tablets may be sugar-coated or film-coated to mask the unpleasant taste and weathering, or enteric-coated to provide selective gastrointestinal disintegration.

Liquid oral dosage forms may contain coloring and flavoring agents to assist the patient.

Non-carrier parenteral solutions usually include water, a suitable oil, saline, aqueous dextrose (glucose) and related sugars and glycols such as propylene glycol or polyethylene glycols. Preferably parenteral solutions contain a water-soluble salt of the active ingredient, suitable stabilizing agents and, if necessary, buffering agents. Suitable stabilizing agents include antioxidants, such as sodium bisulfite, sodium sulfite, or ascorbic acid, alone or in combination. Citric acid and its salts and EDTA sodium are also used. In addition, parenteral solutions may contain protective substances such as benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol.

224

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical

Sciences, Mack Publishing Company, which is a standard reference in this field.

Typical pharmaceutical dosage forms suitable for administration of the compounds of this invention may be formulated as follows:

Capsules

Multiple unit capsules can be made by filling standard double-sided hard gelatin capsules, each containing 100 mg of the active ingredient powder, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

Soft gelatine capsules

A mixture of the active ingredient in edible oil such as soybean oil, cottonseed oil or olive oil can be prepared and injected into the gelatin using a positive-boost pump to obtain soft gelatine capsules containing 100 mg of the active ingredient. These capsules should be washed and dried.

Pills

Tablets may be prepared by conventional means so that the unit dose contains 100 mg of the 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. Appropriate coatings may be applied to increase acceptability or delayed absorption.

Solutions for injection

Parenteral injectable compositions may be prepared by mixing 1.5% by weight of the active ingredient with 10% v / v propylene glycol and water. The solution must be rendered isotonic by the addition of sodium chloride and sterilized.

Suspensions

Aqueous oral suspensions may be prepared so that each 5 ml contains 100 mg of finely divided active ingredient.

225 ingredients, 200 mg sodium carboxymethylcellulose, 5 mg sodium benzoate, 1.0 g sorbitol solution (U.S.P), and 0.025 mL vanillin.

When the compounds of the present invention are combined with other anticoagulant agents, the daily dose may be, for example, about 0.1-100 mg of a compound of formula I and about 1-7.5 mg of a second anticoagulant per kilogram of patient body weight. For dosage unit forms, the compound of the present invention may generally be present in a dosage unit of 5-10 mg and a second anticoagulant in a dosage unit of 1-5 mg.

When the compounds of Formula I are used in combination with an antiplatelet agent, a typical daily dosage may be from about 0.01 mg to about 25 mg of the compound of formula I and from about 50 mg to about 150 mg of the antiplatelet agent, preferably from about 0.1 mg to about 1 mg. approximately 1-3 mg of anti-platelet agent per kilogram of patient body weight.

When a compound of Formula I is used in combination with a thrombolytic agent, a typical daily dose may be about 0.1 to 1 mg of a compound of Formula I per kilogram of patient body weight, and for thrombolytic agents, the usual dose of a thrombolytic agent alone may be reduced by about 70. -80% when administered with a compound of formula I.

When two or more of the above-mentioned second therapeutic agents are used in combination with a compound of Formula I, the amount of each component in a typical daily dose and in a typical dosage form can generally be reduced compared to the usual dose of this agent alone due to additive or synergistic effects. when used in combination.

If the combination is presented as a single unit dose, there is the potential for chemical interaction between the individual components of the combination. For this reason, when the compound of Formula I and the second therapeutic agent are combined in a single dosage unit, they are formulated so that while the active ingredients are combined in a single dosage unit, physical contact between the active ingredients is minimized (that is, reduced). For example, one active ingredient may be enteric-coated. One of the active ingredients may be coated with an enteric coating

In addition to minimizing contact between the active components of the combination, it is also possible to control the release of one of these components into the gastrointestinal tract so that one of these components is not excreted in the stomach but secreted in the intestine. One of the active ingredients may also be coated with a substance that provides sustained release throughout the gastrointestinal tract and. also minimizes physical contact between the active ingredients of the combination. In addition, an enteric coating may be applied to the sustained release component so that the release of this component occurs only in the gut. Another strategy could be a product-combination 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 low viscosity hydroxypropylmethylcellulose (HPMC) or other appropriate material known in the art. it is even better to distinguish between the active components. Polymer plating serves to form an additional barrier for interaction with another component.

These and other ways of minimizing contact between the product-combination components of the present invention, whether used in a single dosage form or in separate forms, but at the same time and in the same manner, are readily apparent to those skilled in the art.

It is understood that various modifications and variations are possible in light of the above description. It is to be understood, therefore, that the present invention may be practiced otherwise than as specifically described herein.

Claims (10)

DEFINITION OF INVENTION 1. A compound of formula I: (l) in which: D is a phenyl or pyridyl ring; E is selected from F, Cl, Br, I, OH, C ^ -alkoxy, SH, Ci- ₃ alkyl, S (O) R ^3b, S (O) 2 R ^3a, S (O) 2NR R ^{2 2a} and OCF ₃ ; R is selected from H, F, Cl, Br, I, OR ³ , SR ³ , CO ² R ³ , NO 2 and CH ₂ OR ³ ; otherwise E and R together form a methylenedioxy or ethylenedioxy group; M is selected from the group: R ^1a Rla m n R ^1a Rla P o v, 228 229 tt R ⁴ rr J ^a is NH or NR ^1a ; Z is selected from (CH ₂ ) _r C (O) (CH ₂ ) r from C 1-4 alkylene, (CH ₂ ) _r O (CH ₂ ) r, (CH ₂ ) _r NR ³ (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 C (O) (CH 2) r, (CH ₂ ) _r OC (O) O (CH ₂ ) _r , (CH ₂ ) r C O (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, (CH ₂ ) _r NR ³ SO ₂ (CH _{2) r,} and (CH _{2) r} NR ³ SO 2 NR ³ (CH 2) _r, provided that z does not NN. N-0, NS, NCH ₂ N, NCH ₂ O or NCH ₂ S bonding with M ring or A group; R ^1a and R ^1b are absent or independently selected from - (CH ₂ ) _r -R ¹ , -CH = CH-R ¹ , NCH ₂ R ^1, OCH2R ¹ SCH2R ¹ ', NH (CH2) 2 (CH2) tR = ^1', O (CH 2) ₂ (CH ₂₎ r, ^r, and S (CH _{2) 2} (CH _{2) t} R ¹ alternatively, R ^1a and R ^1b , when attached to adjacent carbon atoms, together with the atoms to which they are attached form a 5-8 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R ⁴ and which has 0-2 heteroatoms selected from the group consisting of N, O and S; alternatively, when Z is C (O) NH and R ^1a is attached to a carbon atom adjacent to Z, fai R ^1a is C (O), which replaces Z amide hydrogen to form a cyclic imide; 230 R ¹ is selected from H, C 1-3 alkyl, F, Cl, Br, I, -CN, -CHO, (CF 2) r CF 2, (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) ROR ² SO ² NR ² R ^2a , NR ² SO ² R ^2b , C ₃ . _6- carbocyclic moieties substituted with 0-2 R ⁴ and 5- to 10-membered heterocyclic systems containing from 1 to 4 heteroatoms selected from the group consisting of N, O and S, and substituted with 0-2 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 is in} each case selected from H, CF ₃ , Ci. _6- alkyl, benzyl, C ₃ . ₆ carbocyclic radicals substituted with 0-2 R ^4b substituents and 5-6 membered heterocyclic systems containing 1-4 heteroatoms selected from the group consisting of N, O and S and 0-2 substituents R ^4b ; R ^{2a is in} each case selected from H, CF ₃ , C ₆ alkyl, benzyl, phenethyl, C ₃ . an e-carbocyclic moiety substituted with 0-2 R ^4b substituents and a 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from the group consisting of N, O and S and 0-2 substituted R ^4b ; R ^2b in any event, is selected from CF _3, C _t - ₄ -alkoxy, C. ₆ alkyl, benzyl, C ₃ -6 carbocyclic residue substituted with 0-2 R ^4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O and S, and having 0-2 substituent R ^4b ; R ^{2c is in} each case selected from CF ₃ , OH, Ci. ₄ -alkoxy, C,. ₆ alkyl, benzyl, C ₃ . _{A 6-} carbocyclic residue substituted with 0-2 R ^4b , and 5-6 membered heterocyclic systems containing 1-4 heteroatoms selected from the group consisting of N, O and S and substituted with 0-2 R ^4b ; alternatively, R ² and R ^2a together with the atom to which they are attached form 5- or A 6- membered saturated, partially saturated or unsaturated ring substituted with 0-2 R ^4b and having 0-1 additional heteroatoms selected from the group consisting of N, O and S; R ^{3 is} at each occurrence selected from H, C _1-4 alkyl and phenyl; R ^{3a is in} each case selected from H, Ci. _4- alkyl and phenyl; 231 R ^{3b is in} each case selected from H, Ci. _4- alkyl and phenyl; R ^{3c is in} each case selected from Ci. _4- alkyl and phenyl; A is selected from: C3-10 carbocyclic residues substituted with 0-2 R @ ⁴ and 5- to 10-membered heterocyclic systems containing from 1 to 4 heteroatoms selected from the group consisting of N, O and S, and substituted with 0-2 R ⁴ ; B is selected from: Y and Χ-Υ; X is selected from C b ₄ alkylene, -CR ² (CR ² R ^2b ) (CH 2) r, -C (O) -, -C (= NR ¹ ) -, -CR ² (NR ^r R ² ) -, -CR ² (OR ² ) -, -CR ² (SR ² ) -, -C (O) CR ² R ^2a -, -CR ² R ^2a C (O) -, -S (O) p -, -S (O) ² R PCR ^2a -, -CR ² R ^2a S (O) p-, -S (O) 2NR ² -, -NR ² S (O) 2, -NR ² S (O) ² R 2CR ^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: (CH ₂ ) _r NR ² R ^2a , provided that Χ-Y does not form an NN, 0-N or SN bond, a C 3-10 carbocyclic residue substituted with 0-2 R ^4a and 5- to 10-membered heterocyclic systems containing from 1 to 4 heteroatoms selected from the group consisting of N, O and S, and substituted with 0-2 R ^4a ; R ^{4 is} at each occurrence selected from H, = O, (CH ² ) r OR ² , F, Cl, Br, I, CV 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 , CH (= NS ( O) 2R 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 SO2-CM-alkyl, NR ² SO 2 R ^5, S (O) PR ^5, (CF 2) _r CF _3, NCH ₂ R ^1, OCH2R ¹ SCH2R ^1, N (CH2) 2 (CH2) tR = ^1, O (CH 2 ) ₂ (CH ₂ ) _t R ¹ 'and S (CH ₂ ) ₂ (CH ₂ ) _t R ¹ '; alternatively, one R ⁴ is a 5-6 membered aromatic heterocycle containing 1-4 heteroatoms selected from the group consisting of N, O and S; R ^{4a is} at each occurrence selected from H, = O, (CH ₂ ) _r OR ² , (CH ² ) _r -F, (CH ₂ ) _r -Br, (CH ₂ ) r -Cl, I, C 1-6 alkyl, - CN, NO _2, (CH _{2) r} NR ² R ^2a, (CH 2) RNA 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 , 232 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 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 of R ^4a is a 5-6 membered aromatic heterocycle having 1-4 heteroatoms selected from the group consisting of N, O and S and substituted with 0-1 R ⁵ ; R ^{4b is} at each occurrence selected from 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, NR ³ C (= 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 Ci. _4- alkyl, S (O) _p -phenyl and (CF ₂ ) _r CF ₃ ; R ^{5 is} at each occurrence selected from CF ₃ , C _1-6 alkyl, phenyl substituted with 0-2 R ^5s and benzyl substituted with 0-2 R ⁶ ; R ^{6 is} at each occurrence selected from 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 SO2-C ₁ . Alkyl ₄ : 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; stereoisomers thereof, or pharmaceutically acceptable salts thereof. 2. A compound according to claim 1, wherein M is selected from the group consisting of: R ^1a R ^1a 233 nn is selected from (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) p (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 V »* * for systems with 0-2 substituents R ^4a : 234 phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazole, thiadiazole, 1,2,3-triazole, 1,2,3 , 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, benzothiazole, indazole, benzisoxazole, benzisothiazole and isoindazole; Y may also be selected from the following bicyclic heterocyclic ring systems: K is selected from O, S, NH and N. A compound according to claim 2, b is la or Ib: characterized in that its formula (la) in which: Ring D is phenyl or pyridyl: E is selected from F, Cl, Br and Ci. _3- alkoxy groups; R is selected from H, F, Cl, Br, OR ³ and CH ₂ OR ³ ; M is selected from the group: \ l a f 235 B-A R ^1a bb Z is selected from (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 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-oxo 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, benzothiazole, indazole such as benzisoxazole, dczisothiazole and isoindazole. 4. A compound according to claim 3 wherein: Ring D is phenyl; 236 E is selected from F, Ci, Br and OCH 3; R is selected from H, F, Cl and Br; M is selected from the group: A is selected from: Cs-e-carbocyclic moieties substituted with 0-2 R ⁴ and 5-6 membered heterocyclic systems containing 1-4 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 heterocyclic systems substituted with 0-2 R ^4a : phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, 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; R ^{2 is in} each case selected from H, CF ₃ , Ci. _6- alkyl, benzine, C ₅ -carbocyclic radicals substituted with 0-2 R ^4b and 5-6 membered heterocyclic systems containing 1-4 heteroatoms selected from the group consisting of N, O and S containing 0- 2 substituents R ^4b ; R ^{2a is in} each case selected from H, CF ₃ , Ci. _6- alkyl, benzo, phenethyl, C ₅ . A 6-carbocyclic residue substituted with 0-2 R ^4b and 5-6 membered 237 heterocyclic systems containing 1-4 heteroatoms selected from the group consisting of N, O and S substituted with 0-2 R ^4b ; R ^{2b is in} each case selected from CF ₃ , Ci. ₄ -alkoxy, Ci-6-alkyl, benzyl, C ₅ -6 carbocyclic residue substituted with 0-2 R ^4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O and S substituted with 0-2 R ^4b ; R ^{2c is in} each case selected from CF _3l OH, Ci. ₄ -alkoxy, Ci- ₆ alkyl, benzyl, C ₅ -6 carbocyclic residue substituted with 0-2 R ^4b, and 5-6 membered heterocyclic systems containing 1-4 heteroatoms selected from the group consisting of N, O and S substituted with 0-2 R ^4b ; alternatively, R ² and R ^2a together with the atom to which they are attached form a ring selected from imidazolyl, morpholine, piperazinyl, pyridyl and pyrrolidinyl substituted with 0-2 R ^4b substituents; R ^{4 is} at each occurrence selected from 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 -O 1-4 alkyl. , S (O) 2 R ⁵ and CF 3, provided that when B is H then R ⁴ is not tetrazole, C (O) -alkoxy and C (O) NR ² R ^2a ; R ^4a in any case, is selected from H, = 0, (CH2) ROR ^2, F, Cl, Ci.4 alkyl, NR ² R ^2a, CH2NR ² R ^2a, NR ² R ^2b, R ^2b CH2NR ² ( 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 ; and R ^{4b is} at each occurrence selected from 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 SO ² -C. _4- alkyl, NR ³ SO ₂ CF ₃ , NR ³ SO ² phenyl, S (O) ₂ CF ₃ , S (O) ₂ -Ci. _4- alkyl, S (O) _2- phenyl and CF ₃ . 5. A compound according to claim 1 wherein it is selected from: 3-Methyl-1-phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] -biphen-4-yl) carboxamide: 238 3-Methyl-1- (2-methoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen4-yl) carboxamide; 3-Methyl-1- (3-methoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen4-yl) carboxamide; 3-Methyl-1- (4-methoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1'-biphen4-yl) carboxamide); 3-methyl-1- (2-hydroxy) phenyl-1 H -pyrazol-5- (N- (2'-aminosulfonyl- [1 J '] - biphen4-yl) carboxamide; 3-Methyl-1- (3-hydroxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] -biphen-4-yl) carboxamide: 3-Methyl-1- (4-hydroxy) phenyl-1 H -pyrazol-5- (N- (2'-aminosulfonyl- [1,1 T] -biphen4-yl) carboxamide; 3-Methyl-1- (4-methoxy-phenyl) -1H-pyrazole-5- (N- (3-f) -fluoro- (2'-aminosulfonyl [1,1'] -biphen-4-yl) -carboxamide; 3-methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (3-bromo-4- (2'-aminosulfonyl [1,1 '] -biphen-4-yl) carboxamide); 3-methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (3-iodo- (2 ^: -aminosulfonyl [1,1 '] -biphen-4-yl) carboxamide); 3-methyl-1- (4-methoxyphenyl) -1H-pyrazole · 5- (N- (3-methyl- (2 ^, 3-methylsulfonyl- [1,1 '] - biphen-4-yl) carboxamide); 3-methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-N-carboxyldimethylamino) phenyl) carboxamide; 3-methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-N-pyrrolidinocarbonyl) phenyl) carboxamide; 3-methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-a-methyl-N-pyrrolidino) phenyl) carboxamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 T] biphen-4-yl) carboxamide; 3-trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-N-pyrrolidinocarbonyl) -phen) carboxamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (5- (2-methanesulfonyl) phenyl) pyridin-2-yl) carboxamide; 3-trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazol-5- (N- (5-N-pyrrolidinocarbonyl) pyridin-2-yl) carboxamide; 3-methyl-1- (4-methoxyphenyl) -1H-pyrazol-5- (N- (5-N-pyrrolidinocarbonyl) pyridin-2-yl) carboxamide; 3-methyl-1- (4-methoxyphenyl) -1H-pyrazol-5- (N- (5- (2sulfonamido) phenyl) pyridin-2-yl) carboxamide; 3-methyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (N-carboxyl-3-hydroxypyrrolidino) phenyl) carboxamide; 2-amino-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - benzen-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; 239 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-metilsulfoksid-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- _[1> 1 '] - biphen-4-yl) aminokarboniljtiazolo; 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]] -biphen4-yl) aminocarbonyl] thiazole; 2- (1-pyrrolo) -4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole; 3- (4-Methoxyphenyl) -5- [5- (2'-aminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl-5-carbomethoxymethylisoxazoline; 3- (4-methoxyphenyl) -5- [5- (2'-aminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl-5-carboxymethylisoxazoline; 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- (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) carboxamide; 3-methyl-1- (4-trifluoromethoxy) phenyl) -1H-pyrazole-5- (N- (2'-aminosylphonyl [1,1 '] - biphen-4-yl) carboxamide; 1- (3-Bromophenyl) -3-methyl-1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide: 1- (3-iodophenyl) -3-methyl-1 H -pyrazol-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide; 1- (3,4-methylenedioxyanophenyl) -3-methyl-1H-pyrazole-5 - [(2'-aminosulfonyl [1,1 '] - biphen-4-yl) carboxamide; 1- (4-methoxyphenyl) -3-hydroxylmethylene-1H-pyrazole-5- (4'pyrrolidinocarbonyl) anilide; 1- (4-methoxyphenyl) -3-formaldehyde-1H-pyrazole-5- (4'-pyrrolidinocarbonyl) anilide; 1- (4-methoxyphenyl) -5- (4'-pyrrolidinocarbonyl) anilide-3-pyrazolecarboxylic acid; 1- (4-methoxyphenyl) -3-methylcarboxylate-1H-pyrazole-5- (4'pyrrolidinocarbonyl) anilide; 1- (4'-Chlorophenyl) -3-methyl-1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide; 1- (4'-chlorophenyl) -3-methyl-1H-pyrazole-5 - [(2'-aminosulfonyl- [1-pyridyl-1'-phenyl] -4-yl) carboxamide; 1- (3 ', 4'-Dichlorophenyl) -3-methyl-1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1'] - biphen4-yl) carboxamide; 240 1- (3'-chlorophenyl) -3-methyl-1H-pyrazole-5 - [(2'-aminosulfonyl- [1,1 '] -biphen-4-yl) carboxamide; 2-amino-4-phenyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4yl) 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-bromfenii] -5 - [(2'-aminosulfonyl- [1 _t 1 '] - biphen-4-yl) aminokarboniljtiazolo; 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-carboxamide; 1- (4-methoxyphenyl) -3- (methylsulfonyl) -N- (5- (2'-methylsulfonylphenyl) pyrimidin-2-yl) pyrazole-5-carboxamide; N- (2'-aminosulfonyl) - [1,1 '] - biphen-4-yl) -1- (4-methoxyphenyl) -3- (methylsulfonyl) 1H-pyrazole-5-carboxamide; N- (4-benzoylpyrrolidino) -1- (4-methoxyphenyl) -3- (methylthio) -1H-pyrazole-5-carboxamide; 1- (4-Methoxyphenyl) -N- (5- (2'-methylsulfonylphenyl) pyrimidin-2-yl) -3- (methylthio) -1H-pyrazole-5-carboxamide: N- (4-benzoylpyrrolidino) -1- (4-methoxyphenyl) -3- (methylisulfonyl) -1H-pyrazole-5-carboxamide; N- (2'-aminosulfonyl) - [1,1 '] -biphen-4-yl) -1- (4-methoxyphenyl) -3 (methoxymethyl) -1H-pyrazole-5-carboxamide; N- (2'-aminosulfonyl) - [1,1 '] - biphen-4-yl) -1- (4-methoxyphenyl) -3-carbomethoxy-1H-pyrazole-5-carboxamide; N- (2'-aminosulfonyl) - [1,1 '] - biphen-4-yl) -1- (4-methoxyphenyl) -3 (methylsulfonylmethyl) -1H-pyrazole-5-carboxamide; 3-Trifluoromethyl-1- (4-methoxyphenH) -1H-pyrazole-5- (N- (5- (2-methanesylphonyl) phenyl) pyrimidin-2-yl) carboxamide; 3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5-N- (4- (N-carboxyl-2-carbomethoxypyrrolidino) phenyl) carboxamide; 3-Methyl-1- (4-methoxyphenyl) -1H-pyrazole-5-N- (4- (N-carboxy-3-aminopyrrolidino) phenyl) carboxamide; 3-methyl-1- (4-methoxyphenyl) -1H-pyrazole-5-N- (4- (N-carboxyl-3-methoxypyrrolidino) phenyl) carboxamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (5- (2-aminosulfonyl) phenyl) pyridin-2-yl) carboxamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-amidino) phenyl) carboxamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (N-pyrrolidino) formylimino) phenyl) carboxamide; ^% 3-Trifluoromethyl-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl)) - 1- (4-methoxyphenyl) pyrrolo [3,4-d] pyrazole-4,6 - (1H, 5H) -dione; -A 241 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5-carborriethoxy- (N- (2'aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5-hydroxymethyl- (N- (2'aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N-2-fluoro (4- (N-pyrrolidino) formylimino) phenyl) carboxamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (N-pyrrolidino) formylN - ((2-propyl) methylcarbamoyl) imino) phenyl) carboxamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazol-5- (N- (4- (N-pyrrolidino) formyl-N- (methanesulfamoyl) imino) phenyl) carboxamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N - ((4-amidino) phenyl) methyl) carboxamide; 3-trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N '((4- (N-pyrrolidino) formylimino) phenyl) methyl) carboxamide; 3-trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazol-5- (N - ((1-benzyl) piperidin-4-yl) carboxamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazol-5- (N - ((1-pyridin-2-yl) methyl) piperidin-4-yl) carboxamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (2-methylimidazol-1-yl)) phenyl) carboxamide; 3-methyl- (4-methoxy) phenyl-1H-pyrazol-5- (N- {4- (5-methylimidazol-1-yl} phenyl) carboxamide; 3-methyl- (4-methoxy) phenyl-1 H -pyrazol-5- (N- {4- (4-methylimidazol-1-yl} phenyl) carboxamide; 3-Trifluoromethyl- (4-methoxy) phenyl-1H-pyrazol-5- (N- {4- (5-carbomethoximidazol-1-yl} phenyl) carboxamide; 3-Trifluoromethyl- (4-methoxy) phenyl-1H-pyrazole-5- (N- {4- (5-carboxyimidazol-1-yl} phenyl) carboxamide; 1- (4'-methoxyphenyl) -3-hydroxymethyl-1H-pyrazole-5- (N- (4'pyrrolidinocarbonyl) phenyl) carboxamide; 1- (4'-methoxyphenyl) -3-formaldehyde-1H-pyrazole-5- (N- (4 '(pyrrolidinocarbonyl) phenyl) carboxamide; 1- (4'-methoxyphenyl) -5-N- (4 '- (pyrrolidinocarbonyl) anilide-1H-pyrazol-3-ylcarboxylic acid; 1- (4'-methoxyphenyl) -3-methylcarboxylate-1H-pyrazole-5-N- (4'pyrrolidinocarbonyl) phenyl) carboxamide; 1- (4'-methoxyphenyl) -3-cyanomethyl-1H-pyrazole-5-N- (4'-pyrrolidinocarbonyl) phenyl) carboxamide; 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) carboxamide; 1- (4'-methoxyphenyl) -3-aminomethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,5] biphen-4-yl) carboxamide; 1- (4'-Methoxyphenyl) -3- (N-methylsulfoneHarrin) methyl-1H-pyrazole-5-N- (2'aminosulfonyl- [1,1'] -biphen-4-yl) carboxamide; 1- (4'-Methoxyphenyl) -3- (imidazol-1-yl) methyl-1H-pyrazol-5-N- (2'aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide; 242 1- (4'-methoxyphenyl) -3-hydroxylmethyl-1 H -pyrazol-5-N- (2'-aminosulfonyl [1,1 '] - biphen-4-yl) carboxamide; 1- (4'-Methoxyphenyl) -3-trifluoroacetylhydroxylmethyl-1H-pyrazole-5-N- (2'aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide; 1- (4'-Methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'-methylsulfonyl- [1,1 '] - biphen-4-yl) carboxamide; 1- (4'-Methoxy-2'-hydroxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'-methylsulfonyl- [1,1 '] - biphen-4-yl) carboxamide; 1- (4'-Methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide; 1- (4'-Methoxy-2'-hydroxycarborylphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'-tert-butylaminosulfonyl- [1,1 '] - biphenyl) carboxamide; 1- (4'-Methoxy-2'-hydroxycarbonyl-phenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'-amino-sulfonyl- [1,1 '] - biphen-4-yl) -carboxamide; 1- (4'-Methoxy-2 ^: -hydroxylmethylphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide: 1- (4'-Methoxyphenyl) -3-methyl-1H-pyrazole-5-N- (4 '- (3' -methyl-3 '-pyrazolin-5on-2' -yl) phenyl) carboxamide; 1- (4'-methoxyphenyl) -3-methyl-1H-pyrazole-5-N- (4 '- (6' -methylbenzothiazol-2''yl) phenyl) carboxamide; 1- (4'-Methoxyphenyl) -3-methyl-1H-pyrazole-5-N- (4 '- (4' -methylpiperidino) phenyl) carboxamide: 1- (4'-methoxyphenyl) -3-methyl-1H-pyrazole-5-N- (4 '- (2-methylimidazol-1-yl) phenyl) carboxamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-carboxy (N-methylimidazol-2-yl) phenyl) carboxamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-hydroxymethyl- (2 (imidazol-2-yl) phenyl))) carboxamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-hydroxymethyl- (2- (1-benzylimidazol-2-yl) phenyl))) carboxamide; 1- (4-methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5- (N- (4- (2-carboxyl (imidazol-2-yl) phenyl))) carboxamide; 3-trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4- (N- (4-methoxyphenyl) amino- (2-thiazolyl) methyl) phenyl))) carboxamide; 1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5- (N- (4- (2-carboxy- (4,5-dihydrothiazol-2-yl) phenyl))) carboxamide; 1- (4-methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-N-4- (2- (4 ', 5'-dihydro-1 H -imidazol-2'-yl) phenyl) carboxamide; 1- (4-methoxyphenyl) -3-trifluoromethyl-1H-pyrazol-5- [4- (1,4,5,6-tetrahydropyrimidin-2-yl) phenyl] carboxamide; 1- (4-methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5- [4- (N-methyl-4,5,6-trihydropyrimidin-2-yl) phenyl] carboxamide; 1- (4-methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-N-1- (2-fluoro-imidazoline-phenyl) -carboxamide; 1- (4-methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-N-1- (2-fluoro-4-N-methylimidazolinophenyl) carboxamide; 1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazol-5-N- [4- (4,5-dihydro-1-N-methylimidazol-2-yl) phenyl] carboxamide; Λ 243 1- (4-Methoxyphenyl) -3-trifluoromethyl-1 H -pyrazol-5-N- [4- (pyrimidin-2-yl) phenyl] carboxamide; 2- (carboxamide) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4yl) carboxamide] thiazole; 2- (2-methoxyethylamino) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] biphen-4-yl) carboxamide] thiazole; 2- (3-hydroxypropylamino) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl [1,1 '] - biphen-4-yl) carboxamide] thiazole; 2- (2-cyanoethylamino) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] biphen-4-yl) carboxamide] thiazole; 2- (3-methoxypropylamino) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl [1,1 '] - biphen-4-yl) carboxamide] thiazole; 2- (N-b-alanyl) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4yl) carboxamide] thiazole; 2- (isopropylamino) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen4-yl) carboxamide] thiazole; 2- (1,3-dihydroxy-2-propylamino) -4 - [(4-methoxy) phenyl] -5 - [(2'aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide] thiazole; 2 - [(methoxycarbonyl) methylamino] -4 - [(4-methoxy) phenyl] -5 - [(2'aminosylphonyl- [1,1 '] - biphen-4-yl) carboxamide] thiazole; 2- (N-glycyl) -4 - [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4yl) carboxamide] thiazole; 1 - [(4-methoxy) phenyl] -3- (ethoxycarbonyl) -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxamide; 1 - [(4-methoxy) phenyl] -3- (carboxamide) -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxamide; 1 - [(4-methoxy) phenyl] -3 - [(2-hydroxyethyl) carboxamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxamide; 1 - [(4-methoxy) phenyl) -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxamide-3-hydroxamic acid; 1 - [(4-methoxy) phenyl] -3- [phenylcarboxamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxamide; 1 - [(4-methoxy) phenyl] -3 - [(3-hydroxypropyl) carboxamide] -1H-pyrazole-5 - [(4 (N-pyrrolidinocarbonyl) phenyl) carboxamide; 1 - [(4-methoxy) phenyl] -3- [methylcarboxamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxamide; 1 - [(4-methoxy) phenyl] -3 - [(benzyl) carboxamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxamide; 1 - [(4-methoxy) phenyl] -3 - [(dimethyl) carboxamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxamide; 1 - [(4-methoxy) phenyl] -3 - [(phenylethyl) carboxamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxamide; 1 - [(4-methoxy) phenyl] -3 - [(2-hydroxyphenyl) carboxamide] -1H-pyrazole-5 - [(4 (N-pyrrolidinocarbonyl) phenyl) carboxamide; 1 - [(4-methoxy) phenyl] -3 - [(3-hydroxyphenyl) carboxamide] -1H-pyrazole-5 - [(4- (N-pyrrolidinocarbonyl) phenyl) carboxamide; 1 - [(4-methoxy) phenyl] -3 - [(4-hydroxyphenyl) carboxamide] -1H-pyrazole-5 - [(4 (N-pyrrolidinocarbonyl) phenyl) carboxamide; 244 1 - [(4-methoxy) phenyl] -3 - [(methoxycarbonyl) amino] -1H-pyrazole-5 - [(2'aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide; 1 - [(4-methoxy) phenyl] -3-amino-1 H -pyrazol-5 - [(2'-aminosulfonyl- [1,1 '] - biphen4-yl) carboxamide; 1 - [(4-methoxy) phenyl] -3 - [(methoxycarbonyl) methylamino] -1 H -pyrazol-5 - [(2'aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide; 1 - [(4-methoxy) phenyl] -3 - [(2-hydroxy) ethylamino] -1H-pyrazol-5 - [(2'aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide; 1 - [(4-methoxy) phenyl] -3- [E-2- (methoxycarbonyl) ethenyl] -1H-pyrazole-5 - [(2'aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide ; 1 - [(4-methoxy) phenyl] -3- [2- (methoxycarbonyl) ethyl] -1H-pyrazole-5 - [(2'aminosulfonyl- [1,1 '] -biphen-4-yl) carboxamide: 1 - [(4-methoxy) phenyl] -3- [E-2- (carboxy) ethenyl] -1H-pyrazole-5 - [(2'aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide ; 1 - [(4-methoxy) phenyl] -3- [2- (carboxy) ethyl] -1H-pyrazole-5 - [(2'-aminosulfonyl [1,1 '] - biphen-4-yl) carboxamide; 1 - [(4-methoxy) phenyl] -3- [E-2- (carboxamide) ethenyl] -1H-pyrazole-5 - [(2'aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide ; 1 - [(4-methoxy) phenyl] -3- [E-2- (hydroxymethyl) ethenyl] -1H-pyrazole-5 - [(2'aminosulfonyl- [1,1 '] - biphen-4-yl) carboxamide ; 1 - [(4-methoxy) phenyl] -3- (3-hydroxypropyl) -1H-pyrazole-5 - [(2'-aminosulfonyl [1,1 '] - biphen-4-yl) carboxamide; 1 - [(4-methoxy) phenyl] -3-propyl-1 H -pyrazol-5 - [(2'-aminosulfonyl- [1,1 T] -biphen4-yl) carboxamide; 1 - [(4-methoxy) phenyl] -3- (trifluoromethyl) -4-cyano-1H-pyrazole-5 - [(2'-methylsulfonyl-3-fluoro [1,1 '] - biphen-4-yl) carboxamide; 1 - [(4-methoxy) phenyl] -3- (trifluoromethyl) -4- (amidino) -1H-pyrazole-5 - [(2'-methylsulfonyl-3-fluoro [1,1 '] - biphen-4-) (il) carboxamide: 1 - [(4-methoxy) phenyl] -3- (trifluoromethyl) -4- (N hydroxyamidino) -1H-pyrazole-5 [(2'-methylsulfonyl-3-fluoro- ^[1,1] -bifen- 4-yl) carboxamide; 1 - [(4-methoxy) phenyl] -3- (trifluoromethyl) -4- (ethoxycarbonyl) -1H-pyrazole-5 - ^[(2! Methylsulfonyl-3-fluoro- [1,1 '] - biphen-4- il) carboxamide; and 1 - [(4-methoxy) phenyl] -3- (trifluoromethyl) -1H-pyrazole-5 - [(2'-methylsulfonyl-3fluoro- [1,1 '] - biphen-4-yl) carboxamide-4 a carboxylic acid and its pharmaceutically acceptable salts. 6. Compound of Formula II: (N) where: M is selected from the group: % Λ 245 N-N 'B Cl, Br, CH (CH ₂ OR ² ) ₂ , (CF ₂ ) _r CF ₃ , 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, Ci. _3- alkyl, F, (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 ^2a , C (O) NR ² (CH ²⁾ r R ² and SO ² NR ² R ^2a ; R ^{2 is in} each case selected from H, CF ₃ , Ci. ₆ alkyl, benzyl, C ₃ .6karbociklinės residue substituted with 0-2 R ^4, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0- 2 substituents R ⁴ ; R ^{2a is} at each occurrence selected from H, CF ₃ , C ₆ -alkyl, benzyl, C 3-6 carbocyclic moieties substituted with 0-2 R ⁴ , and 5-6 membered heterocyclic systems containing 1-4 heteroatoms selected from groups consisting of N, O and S substituted with 0-2 R ⁴ ; R ^{2b is in} each case selected from CF ₃ , Ci. ₄ -alkoxy groups, Ci. _6- alkyl, C ₃ . e-carbocyclic radicals substituted with 0-2 R ⁴ and 5-6 membered heterocyclic systems containing 1-4 heteroatoms selected from the group consisting of 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 5-6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R ⁴ having 0-1 additional heteroatoms selected from the group consisting of consisting of N, O and S: R ^{3 is in} each case selected from H, Ci. _4- alkyl and phenyl; A is selected from phenyl, pyridyl and 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 morpholine, and Y is substituted with 0-2 R ^4a ; % R ^{4 is} at each occurrence selected from F, Cl, Br, I, C (O) NR ² R ^2a and (CF ₂ ) _r CF ₃ ; 246 R ^{4a is} at each occurrence selected from F, Cl, Br, I, C 1-4 alkyl, C (O) NR ² R ^2a , SO ² NR ² R ^2a , NR ² SO ² -Cl. _4- alkyl, S (O) _P R ⁵ and (CF ₂ ) _r CF ₃ ; R ^{5 is in} each case selected from CF ₃ , Ci. _6- alkyl, phenyl and benzyl; p is selected from 0, 1 and 2; and r is selected from 0, 1,2 and 3; stereoisomers or pharmaceutically acceptable salts thereof. 7. A compound according to claim 6, wherein it is selected from: 3-methyl-1-phenyl-1H-pyrazole-5- (N- (2-aminosulfonyl- [1,1 '] - biphen-4yl) carboxamide; 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-4yl) aminocarbonyl] thiazole; and pharmaceutically acceptable salts thereof. 8. 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 for use in therapy. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a thromboembolic disorder.