MXPA99010588A - Inhibitors of factor xa with a neutral p1 specificity group - Google Patents

Abstract

The present application describes inhibitors of factor Xa with a neutral P1 specificity group of formula (I) or pharmaceutically acceptable salt forms thereof, wherein R and E may be groups such as methoxy and halo.

Description

INHIBITORS OF THE FACTOR Xa WITH A SPECIFIC GROUPS Pl NEUTRAL FIELD OF THE INVENTION This invention relates in general to new inhibitors of factor Xa with a group of specificity Pl neutral, to pharmaceutical compositions containing them, and to methods for using them as anticoagulant agents for the treatment and prevention of rhomboembolic disorders.

BACKGROUND OF THE INVENTION WO 96/28427 discloses anti-benzamidine coagulants of the formula: wherein Z1 and Z2 are O, N (R), S or OCH2 and the central ring may be phenyl or a variety of EF .: 31743 heterocycles. The presently claimed compounds do not contain the linker Z1 or the substitution pattern of the above compounds. WO 95/13155 and the international application of PCT US96 / 07692 describe isoxazoline and isoxazole fibrinogen receptor antagonists of the formula: wherein R1 can be a basic group, U-V can be a six-membered aromatic ring, W-X can be a variety of linear or cyclic groups, and Y is an oxy group. In this way, these compounds all contain an acid functionality (ie, W-X-C (= 0) -Y). In contrast, the presently claimed compounds do not contain this acid functionality. EP 0,513,387 describes active oxygen inhibitors which are oxazoles or thiazoles of the formula: wherein X is O or S, R is preferably hydrogen, and both R1 and R3 are substituted cyclic groups, with at least one which is phenyl. The invention currently claimed does not refer to these types of oxazoles or thiazoles. WO 95/18111 deals with fibrinogen receptor antagonists containing basic terms and acids of the formula: wherein R "represents the basic term, U is an alkylene linker or heteroatom, V can be a heterocycle, and the right side portion of the molecule represents the acid term The presently claimed compounds do not contain the term basic acid of the WO 95/18111 In the United States patent number ,463,071, from Himmelsbach et al., The inhibitors of cellular aggregation are represented as with heterocycles of 5 members of the formula: *1. * 5 X3-X4 wherein the heterocycle may be aromatic and groups A-B-C and F-E-D are attached to the ring system. A-B-C can be a broad variety of substituents that include a basic group attached to an aromatic atom. The group F-E-D, however, will appear to be an acid functionality that differs from the present invention. Additionally, the use of these compounds as factor Xa inhibitors is not discussed. Baker et. al, in U.S. Patent No. 5,317,103, discusses 5-HTJ agonists which are 5-membered heteroaromatic compounds, substituted with indole of the formula: wherein R 1 may be pyrrolidine or piperidine and A may be a basic group may be a basic group including amino and amidino. Baker et al, however, does not indicate that A can be a substituted ring system similar to that contained in the heteroaromatics currently claimed. Baker et al, in WO 94/02477, discusses 5-HTJ agonists which are imidazoles, triazoles, or tetrazoles of the formula: wherein R1 represents a ring system containing nitrogen 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 can be a substituted ring system such as that contained in the heteroaromatics currently claimed. Tidwell et al, in J, Med. Chem. 1978, 21 (7), 613-623, describes a series of di a r i 1 amidine derivatives including 3,5-b s (4-amidinopheni 1) isoxazole. This series of compounds was tested against thrombin, trypsin, and pancreatic kallikrein.

The presently claimed invention does not include this type of compounds. Activated factor Xa, whose main practical role is the generation of thrombin by the limited proteolysis of prothrombin, maintains a central position that 'links the intrinsic and extrinsic activation mechanisms in the final common route of blood coagulation. The generation of thrombins, the final serine-protase in the path to generate a fibrin clot, from its precursor is amplified by the formation of the prothrombinase complex (factor Xa, factor V, Ca2 + and phospholipid) Since it is estimated that a Factor Xa molecule can generate 138 thrombin molecules (Elodi, S. Varadi, K.; Optimization of conditions for the catalytic effect of factor IXa-factor CIII Complex: Probable role of the complex in the amplification of blood coagulation. Thromb. Res, 1979, 15, 617-629), the inhibition of factor Xa may be more efficient than the inactivation of thrombin in the interruption of the blood coagulation system. Therefore, effective and specific inhibitors of factor Xa are necessary as potentially valuable therapeutic agents for the treatment of rhomboembolic disorders. In this way, it is desirable to discover new factor Xa inhibitors.

BRIEF DESCRIPTION OF THE INVENTION Accordingly, an object of the present invention is to provide novel factor Xa inhibitors with a Pl neutrality specificity group or pharmaceutically acceptable salts or prodrugs of the same. It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug thereof. It is another object of the present invention to provide a method for treating disorders that comprise administering to a host in need of treatment a pharmaceutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug. acceptable of it.

These and other objects that will become apparent during the following detailed description have been achieved by the discovery of the inventors that the compounds of the formula (I): or pharmaceutically acceptable salt forms thereof, wherein D, E, M and R, as defined below, are effective inhibitors of factor Xa.

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES [1] Thus, in a first embodiment, the present invention provides new compounds of the formula I: or stereoisomers or pharmaceutically acceptable salts thereof, wherein: ring D is pyridyl phenyl; E is selected from F, Cl Br, OH, 1-3 alkoxy, SH, C1-3 alkyl-S, S (0) R3b, S (0) 2R3a, S (0) 2NR2 a, and 0CF3 R is selected from H, F, Cl, Br, I, OR, SR, C02R, N02 and CH20R alternatively, E and R combine to form meth i lendi oxy or ethylenedioxy; M is selected from the group * ss tt J e s O or S; A is NH or NR l1a ' Z is selected from a bond, alkylene of 1-4 carbon atoms, (CH2) rO (CH2) r, (CH2) rNR3 (CH2) r, (CH2) rC (0) (CH2) r. (CH2) rC (0) 0 (CH2) r, (CH2) rOC (O) (CH2) r, (CH2) r (0) NR3 (CH2) r, CH2) rNRJC (O) (CH2) r, (CH2) rOC (0) 0 (CH2) r, CH2) rOC (O) NR (CH2) (CH2) rNR3C (0) 0 (CH2) r, (CH2) rNRA (O) NRJ (CH2) (CH2) rS (0) p (CH2) r, (CH2) rS02NRJ (CH2) r, (CH2) rNR3S02 (CH2) r, and (CH2), rNR3S02NR3 (CH2) r, with the proviso that Z does not form an NN, NO, NS, NCH20, or NCH2S bond with the M ring or the A group; RJ and R Ib are independently absent are selected from - (CH2) rR - CH = CH - R - NCH? RJ OCH2R SCH.R1", NH (CH2) 2 (CH2) tR, 0 (CH2) 2 (CH2) tR1 'and S (CH2) 2 (CH2) tR1'; alternatively Rla and Rlb when joined to the adjacent carbon atoms, together with the atoms to which they are attached, form a partially saturated, 5- to 8-membered ring substituted with 0-2 R4 and containing 0-2 heteroatoms selected from a group consisting of N, O, and S; alternatively, when Z is C (O) NH and Ri is attached to a ring carbon adjacent to Z, then Rla is a C (0) which replaces the hydrogen of the Z-measure to form a cyclic imide; R is selected from H-alkyl of 1 to 3 carbon atoms, F, Cl, Br, I, -CN, -CHO (CF2) rCF3, CH) rOR 'NR2R2 C (O) R 2c OC (O) R ', 2b 2C (CF2) rC02R'-, S (0) pR, NR' (CH2) rOR, (CH = NR ^) NRA NR2C (0) R2, NR2C (O) NHR2b, NR2C (0) 2R, 2aa, OC (0) NRz .aaRn2b C (0) NR2R2a, C (O) NR2 (CH2) rOR :, S02NR2R2a, NR S02R2b carboxylic residues of 6 to 3 carbon atoms substituted with 0-2 R4, and a heterocyclic system of 5-10 members containing 1 4 heteroatoms selected from a group consisting of N, O. and S, substituted with 0-2 R4; ,2 C R- is selected from H, CH (CH2ORJ 2 / C (0) R, C (0) NR2R2a, S (0) R2D, S (0) 2R2b, and S02NR2R2a; R2, in each occurrence is selected from H, CF3, alkyl of 1 to 6 carbon atoms, benzyl, carbocyclic residue of 3 to 6 carbon atoms substituted with 0-2 R4b and heterocyclic system of 5-6 members containing of 1-4 heteroatoms selected from the group consisting of N, O and S substituted with 0-2 R 4b R'a, in each occurrence is selected from H, CF3, alkyl of 1 to 6 carbon atoms alkyl, benzoyl, phenethyl, carbocyclic residue of 3 to 6 carbon atoms substituted with 0-2 R4b, and heterocyclic 5-6 members containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b; R: b, in each occurrence is selected from CF3, alkoxy of 1-4 carbon atoms, alkyl of 1 to 6 carbon atoms, benzyl, carboxylic residue of 3 to 6 carbon atoms substituted with 0-2 R4b and 5-6 membered heterocyclic system containing from 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4fc; R2c, in each occurrence is selected from CF3, OH, alkoxy of 1-4 carbon atoms, alkyl of 1 to 6 carbon atoms, benzyl, carboxylic residue of 3 to 6 carbon atoms substituted with 0-2 R4b and 5-6 membered heterocyclic system containing from 1 to 4 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R4b; alternatively R2 and R2a, together with the atom to which they are attached, combine to form. a partially unsaturated, saturated, 5- or 6-membered ring substituted with 0-2 R4 and containing 0-1 additional heteroatoms selected from the group consisting of N, 0, and S; R, in each occurrence is selected from H, alkyl of 1 to 4 carbon atoms, and phenyl; RJa in each occurrence is selected from H, alkyl of 1 to 4 carbon atoms and phenyl; R, 3 * b in each occurrence is selected from H, alkyl of 1 to 4 carbon atoms, and phenyl; R, 3c in each occurrence is selected from H, alkyl of 1 to 4 carbon atoms, and phenyl; A is selected from: carbocyclic residue of 3 to 10 carbon atoms substituted with 0-2 R4 and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S is substituted with 0-2 R4; B is selected from: H, Y, and X-Y; X is selected from alkylene 1-4 carbon atoms, -CR '(CR'R 2b, CH; -C (O) -C ANR1) - -CR' (NR1 R¿) - -CR '(OR') CR 'SR2) -C (O) CR' R2a_2p2a CR'R'A (O), S (0) p-, -S (OACRA-, -CR, 2AD2aaS, (O) p-, -S (0 ) 2NR'-, -NR'S (?: NR2S (O) 2CR2R2a-, CR R2SS (O) 2NR2-, -NR2S (O) 2NR2-, -C (0) NR2-, -NR2C (0) -, -C (O) NR2CR2R2a-, -NR2C (O) CR2R2a-, -CR2R2aC (O) NR2-, -CR2R2aNR2C (O) -, -NR2C (0) 0-, -OC (0) NR2-, -NR C (O ) R2-, -NR: -, -NR2CR2R2a-, -CR2R2aNR-, O, -CR2R2aO-, and OCR2R2a-; And it is selected from CH2) rNR R, with the Icondition that X-Y does not form an N-N, O-N, or S-'N link carbocyclic residue of 3 to 10 carbon atoms substituted with 0-2 R and -10 member heterocyclic clicol containing 1-4 heteroatoms selected from the group consisting of N 0, and S and substituted with 0-2 R 4a R in each occurrence, is selected from H = 0, (CH; -OR 'Cl Br C? -4 alkyl, -CN, N02 CH2) rNR'R 2'a CH2) rC (O) R "N R2C (0) R2, C (0) NR2R2a, NR'C (O NR2R2a CH (= NR2) NR2R2a CH (= NS (O) 2R5) NR2R2a, NHC (= NR ') NR'R' C (O) NHC (= NRl 2) NR2R2a, S02NR2R2a NR2S02NR2R2a NR2S02-C? -4 alkylated, NR2S02R5, S (0) pR5, CF2) rCF3, NCH? R1", OCH2R1" SCH2R ', N (CH2) 2 (CH2) tRx', ii, 0 (CH2) 2 (CH2) tR "J and S (CH2) 2 (CH2) tR | , alternatively, a R i is a 5- to 6-membered aromatic heterocycle containing 1-4 heteroatoms from the group consisting of N, O and S; I with the condition that B is H, then R is different from tetrazole, C (0) -alkoxy, and C (0 NR2R2a, R, 4a, in each occurrence, is selected from A CH2) r0R2, (CH2) r-F, (CH2) r-Br, (CH2) r-Cl alkyl, -CN. NO, 2a, 2b Ci- 2, (CH2) rNRA '(CH2) rNRA' CH2) r (O) R 2'c NR2C O) R 2b O) NR2R2a C (O) NH (CH2 2 NR2R2a, NR2C OR NR2R2a, CH (= NR 'NR2R2a, NHC (= NR2) NR2R2a, - S02NR2R2a, NR2S02NR2R2a, NR2S02-C? -4 alkyl, C (O) NHS02-C? -4 alkyl, NR2S02R5, S (0) pR5, and (CF2) rCF3; alternatively, an R4a is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from a group consisting of N, 0, and S and substituted with 0-1 R5; R, 4b, in each occurrence, is selected from H, = 0, (CH2) rOR3, F, Cl, Br, I, C? -4 alkyl, -CN, N02, CH2) rNR, 3A0J3aa, (CH2) rC (0) R \ (CH2) rC (0) 0R 3JcC, NRA (0) R, 3jaa, C (O) NR5R3a, NR3C (0) NR3R3a CH (= NR3) NR3R3a ' NH3C (= NR3) NR3R3a, S02NR R3a, NR3S02NR3R3a, NR3S02-C? -4 alkyl, NR3S02CF3, NR3S02- f eni lo, S (0) pCF3, S (0) pC? -4 alkyl, S (O) pf eni lo, y (CF2) rCF3; R, in each occurrence, is selected from CF3, alkyl of 1 to 6 carbon atoms, phenyl substituted with 0-2 R6, and benzyl substituted with 0-2 R in each occurrence, is selected from H, OH CH2) r0R 'F, Cl Br, C? -4 alkyl, CN NO 2 i CH; rNR2R2a 'CH2) rC (O) R2b, NR2C (0) R2b, NR2C (O) NR2R2a, CH (= NH) NH2, NHC (= NH) NH2, S02NR2R2a, NR2S02NR2R2a, and NR2S02C? -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; Y, t is selected from 0 and 1. [2] In a preferred embodiment, the present invention provides new compounds, wherein M is selected from the group: Z is selected from (CH2) rC (O) (CH2) r, (CH2) rC (0) 0 (CH2) r, (CH2) rC (0) NR3 (CH2) r, CH2) rS (0) p (CH2) r, and (CH2) rS02NR3 (CH2) r; and Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazole, thiadiazole, triazole, 1,2, 3-oxadiazole, 1, 2, 4 -oxadia zol, 1,2,5-oxadiazole, 1, 3, 4 -oxadia zol, 1, 2, 3 - 1 iadia zol, 1,2,4-thiadiazole, 1, 2, 5 - 1 iadia zol, 1, 3, 4 - 1 iadia zol, 1,2,3-triazole, 1, 2, 4-t-riazole, 1, 2, 5-t ria zol, 1,3,4, -triazol, benzofuran, benzot iofuran , indole, benzimidazole, benzoxazole, benzthiazole, indazole, benzisoxazole, benzisothiazole, and isoindazole; And it can also be selected from the following heterocyclic ring systems, bicyclic: K is selected from O, S, NH, and N. [3] In a more preferred embodiment, the present invention provides novel compounds of the formula Ia or Ib: the Ib where; Ring D is phenyl or pyridyl: E is selected from F, Cl, Br, and alkoxy of 1 to 3 carbon atoms; R is selected from H, F, Cl, Br, OR, and CH2OR3; M is selected from the group: is selected from (CH2) rC (0) (CH2) r and CH2) rC (O) NR3 (CH2) r; and Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazole, thiadiazole, triazole, 1,2, 3-oxadiazole, 1, 2, 4-oxadiazole, 1,2,5-oxadiazole, 1, 3, 4 -oxadia zol, 1, 2, 3- 1 iadia zol, 1,2,4-thiadiazole, 1, 2, 5- 1 iadia zol, 1 , 3, 4 - 1 iadia zol, 1,2,3-triazole, 1, 2,4-triazole, 1, 2, 5-t-riazole, 1,3,4-triazole, benzofuran, benzot iofuran, indole , benzimidazole, benzoxazole, benzthiazole, indazole, benzisoxazole, benzisothiazole, and isoindazole; [4] In an even more preferred embodiment, the present invention provides novel compounds of the formula la, wherein: ring D is phenyl; E is selected from F, Cl, Br, and OCH3 R is selected from H, F, Cl, and Br; M is selected from the group A is selected from: carbocyclic residue of 5 to 6 carbon atoms substituted with 0-2 R4, and heterocyclic system of 5-6 members containing 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4; Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, yl thiophene, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, benzimidazolyl, oxadiazole, thiadiazole, triazole, 1, 2, 3-oxadiazole, 1 , 2,4-oxadiazole, 1, 2, 5 -oxadia zol, 1, 3, 4 -oxadia zol, 1,2,3-thiadiazole, 1, 2, 4 - 1 iadia zol, 1, 2, 5- 1 iadia zol, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, and 1,3,4-triazole; R, in each occurrence, is selected from H, CF3, alkyl of 1 to 6 carbon atoms, benzyl, carbocyclic residue of 5 to 6 carbon atoms, substituted with 0-2 R by heterocyclic system of 5-6 members containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b; R'a, at each occurrence, is selected heterocyclic system from H, CF3, alkyl of 1 to 6 carbon atoms, benzyl, phenethyl, carbocyclic residue 5-6 carbon atoms substituted with 0-2 R4b, and 5-6 members containing from 1-4 heteroatoms selected from a group consisting of N, O, and S substituted with 0-2 R4b, R2b, at each occurrence, is selected from CF3, alkoxy from 1 to 4 carbon atoms, alkyl of 1 to 6 carbon atoms, benzyl, carbocyclic residue of 5-6 carbon atoms substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from from a group consisting of N, O, and S substituted with 0-2 R4b, R'c, in any occurrence, is selected from CF3, OH, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 6 carbon atoms, benzyl, carbocyclic residue of 5 to 6 carbon atoms substituted with 0-2 R4 '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 R4b; alternatively, R 'and R 2a, together with the atom to which they are attached, combine to form a selected from imidazolyl, morpholino, piperazinyl, pyridyl, and pyrrolidinyl, substituted with 0-2 R 4b R, in each occurrence, is selected from H, = 0, OR 'CH2OR' F, Cl Cl-4 alkyl, NR2R2a, CH2NR, 2ZRnA2a C (0) R c, CH2C (0) R, 2c C (0 NR2R2a CH (= NR2) NR2R2a, CH (= NS (0) 2R5) NR2R2a, S02NR2R2a, NR'SO; C? -4 alkyl, S (0) 2R5, and CF3 with the proviso that if B is H, then R4 is different from tetrazole, C (0) -alkoxy, and C (0) NR2R2a; R 4a in each occurrence, is selected from H = 0, CH2) r0R 'Cl C 2n2a 1-4 alkyl, NRA' CH2NRA ' NR, 2AD2¿bD, CH2NRA, 2'bD, (CH2) rC (0) R 2c, NRA (0) R 2b, C (0) NR'R'a, C (0) NH (CH2) 2NR2R to , NR2C (0) NR2R2a, S02NR2R2a, S (0) 2R5, and CF3; Y R4b, in each occurrence is selected from H : 0, (CH2) r0R, F, Cl, C? -4 alkyl, NR 3A3a, CH2NR, 3An3a C (0) R \ CH: C (0) RJ, C (0) OR 3c C (0) NR3R3a CH (= NR3) NR3R3a, S02NR3R3a, NR3S02-C -4 alkyl NR3S02CF3, NR3S02-phenyl, S (0) 2CF3, S (0) 2-C! -4 alkyl S (0) 2-phenyl, and CF3. [5] In an even more preferred embodiment, the present invention provides novel compounds selected from: 3-Methyl-l-phenyl-lH-pyrazole-5- (N- (2'-aminosulfonyl '[1, 1'] -bifen-4-yl) carboxyamide; 3-Methyl-l- (2-methoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide; 3-Methyl-l- (3 -metox i) phenyl-1H-pyrazole-5 (N- (2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide; 3-Methyl-1- (4-methoxy) phenyl-1H-pyrazole-5 (N- (2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide; 3-Methyl-1- (2-hydroxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide; 3-Methyl-1- (3-hydroxy) phenol-lH-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 3-Methyl-l (4-hydroxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide; 3-Methyl-1- (4-methoxy phenyl) -lH-pyrazole-5- (N- (3-fluoro- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 3-Methyl-l- (4-methoxyphenyl) -lH-pyrazole-5- (N- (3-bromo -4- (2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide; 3-Methyl-l- (4-methoxyphenyl) -lH-pyrazole-5- (N- (3-iodo- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 3-Methyl-1- (4-methoxy-phenyl) -lH-pyrazole-5- (N- (3-methyl- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 3-Methyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4-N-carboxyldimethyl-1-lamel) phenyl) -carboxyamide; 3-Methyl-l- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4-N-pyrrolidinocarbonyl) phenyl) carboxyamide; 3-Methyl-1- (4-methoxy phenyl) -lH-pyrazole-5- (N- (4-a-methyl-N-pyrrolidine) phenyl) carboxyamide; 3-Trifluoromethyl-l- (4-methoxyphenyl) -lH-pyrazole-5- (N- (2 * -aminosulfonyl- [1, 1 '] -bifen) -4-yl) carboxyamide; 3-Trifluoromethyl-l- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4-N-pyrrolidinocarbonyl) phenyl) carboxyamide; 3 - . 3 -Tri fluoromet il-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (5- (2-methanesulfonyl) phenyl) pyridin-2-yl) carboxyamide; 3-Tri fluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (5- (N-pyrrolidinocarbonyl) pyridin-2-yl) carboxyamide; 3-Methyl-l- (-me toxy phenyl) -lH-pyrazole-5- (N- (5-N-pyrrolidinocarbonyl) pyridin-2-yl) carboxyamide; 3-Methyl-1- (4-methoxy phenyl) -lH-pyrazole-5- (N- (5- (2-sulphonamide) phenyl) pyridin-2-yl) carboxyamide; 3-Methyl-1- (4-methoxyphenyl) -lH-pyrazole-5-N- (4- (N-carboxyl-3-hydroxypyrrolidine) phenyl) carboxyamide; 2-Amino-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) aminocarbonyl] thiazole; 2-Bromo-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl [1, 1 '] -bifen-4-yl) aminocarbonyl] thiazole; 2 - . 2-Chloro- - (-methoxy phenyl) -5 - [(2'-amino-fonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] thiazole; 2-Chloro-4- (4-phenoxy) -5 - [(2'-amino-sulfonyl- [1,1 '] biphen-4-yl) aminocarbonyl] thiazole; 2-Methoxy-4- (4-methoxyphenyl) -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] thiazole; 2-Tiomethyl-4- (4-methoxy phenyl) -5- [2'-aminosulfonyl '[1,1'] -bifen-4-yl) aminocarbonyl] thiazole; 2-Methylsulfoxide-4- (4-methoxy-phenyl-1) -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] thiazole; 2-Methylsulfon-4- (4-methoxyphenyl) -5 - [(2 * -aminosul fonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] thiazole; 2-Cyano-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl '[1,1'] -bifen-4-yl) aminocarbonyl] thiazole; 2-N, N-Dimethylamino-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) aminocarbonyl] thiazole; 2- (1-Pyrrole) -4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl [1, 1 '] -bifen-4-yl) aminocarbonyl] thiazole; 3- (4-Methoxy phenyl) -5- [5- (2'-amino-sulfonyl-phenyl-1-yl) -pyridin-2-yl] -aminocarbonyl-5-carbomethoxymethyl-isoxazoline; 3- (4-Methoxyphenyl) -5- [5- (2'-aminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl 1-5-carboxymethyl-1-isoxazoline; 3- (4-Methoxyphenyl) -5- [5- (2'-aminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl-5- (N-carboethoxymethyl) carboxamidomethyl-isoxazoline; 3- (4-Methoxyphenyl) -5- [5- (2'-aminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl-5- (1,2, 4-triazol-1-yl) ethyl-isoxazoline l- (4-Methoxyphenyl) -5 - [(2'-amino-sulfonyl- [1,1 '] -biferi'-4-yl) aminocarbonyl] tetrazole; 3-Methyl-1- (4-methoxy-3-chloro) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide; 3-Methyl-1- (4-trifluoromethoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; l- (3-Bromophenyl) -3-methyl-1H-pyrazole-5 - [(2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide; l- (3-Iodophenyl) -3-methyl-1H-pyrazole-5- [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 1- (3, 4-Methylenedioxanophenyl)) -3-methyl-1H-pyrazole-5- [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 1- (4-Methoxy phenyl) -3-hydroxylmethylene-1H-pyrazole-5- (4'-pyrrolidinocarbonyl) anuide; 1- (4-Methoxyphenyl) -3-formaldehyde-1H-pyrazole-5- (4'-pyrrolidinocarbonyl) anuide; 1 - (4-Methoxy-enyl) -5- (4'-pyrrolidinocarbonyl) anilide-3-pyrazolecarboxylic acid; i- (4-Methoxyphenyl) -3-methylcarboxylate-1H-pyrazole-5- (4'-pyrrolidinocarbonyl) anuide; 1- (4'-Chlorophenyl) -3-methyl-1H-pyrazo1-5- [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 1- (4'-Chlorophenyl) -3-meth i 1- lH-pi ra zol-5 - [(2'-aminosulfonyl- [1-pyridyl-l'-phenyl] -4-yl) carboxyamide; 1- (3 *, '-Dichlorophenyl) -3-met i 1-lH-pi ra zol-5- [(2'-aminosulfonyl- [1, 1'] -bifen-4-yl) carboxyamide; 1- (3'-Chlorophenyl) -3-met i 1-lH-pyrazol-5- [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 2 - . 2 - . 2-amino-4-phenyl-5- [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] thiazole; 2-Chloro-4-phenyl-5 - [(2'-aminosulfonyl- [1, 1 '] - biphen-4-yl) aminocarbonyl] thiazole; 2-Amino-4- [3- (bromo) -4- (fluoro) -phenyl] -5 - [(2'-amino-sulfonyl- [1, 1 '] -bifen-4-yl) aminocarbonyl] thiazole; 2-A ino-4- [4-fluoro-phenyl] -5 - [(2'-aminosulfonyl- [1, 1 '] - biphen-4-yl) aminocarbonyl] thiazole; 2-amino-4 - [3-bromophenyl] -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] thiazole; 2-Chloro-4- [3-bromophenyl] -5 - [(2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) aminocarbonyl] thiazole; N- (2'-Aminosulfonyl- [1, 1 '] - biphen-4-yl) -l- (4-methoxy-phenyl) -3- (methylthio) pyrazole-5-carboxyamide; l ~ (4-Methoxyphenyl) -3- (methylsulfonyl) -N- (5- (2'-meth i 1 sulphonylphenyl) pyrimid-2-yl) pyrazole-5-carboxyamide; N- (2'-Aminosulfonyl- [1, 1 '] - biphen-4-yl) -l- (4-methoxyphenyl) -3- (methylsulfonyl) -lH-pyrazole-5-carboxyamide; N- (4-Benzoylpyrrolidine) -1- (4-methoxyphenyl) -3- (methylthio) -lH-pyrazole-5-carboxyamide; i- (4-Methoxyphenyl) -N- (5- (2'-methyl-sulfonyl-phenyl-pyrimid-2-yl) -3- (methylthio) -lH-pyrazole-5-carboxyamide; N- (4-Benzoylpyrrolidine) -1- (4-methoxyphenyl) -3- (methylsulfonyl) -lH-pyrazole-5-carboxyamide; N- (2 '-Aminosulfonyl- [1, 1'] - biphen-4-yl) -l- (4-methoxy phenyl) -3- (methoxymethyl) -lH-pyrazole-5-carboxyamide; N- (2'-Aminosulfonyl- [1, 1 *] - biphen-4-yl) -l- (4-methoxyphenyl) -3-carbomethoxy-1H-pyrazole-5-carboxyamide; N- (2'-Aminosulfonyl- [1, 1 '] - biphen-4-yl) -l- (4-ethoxyphenyl) -3- (methylsulfonylmethyl) -lH-pyrazole-5-carboxyamide; 3-Trifluoromethyl-1- (4-methoxy phenyl) -lH-pyrazole-5- (N- (5- (2-methanesulfonyl) phenyl) pyrimidin-2-yl) carboxyamide; 3-Methyl-l- (4-methoxy-phenyl-1) -lH-pyrazole-5-N- (4- (N-cabobo-1-2-carbomethoxy-pyrrole-idine) phenyl) -carboxyamide; 3-Met? L-l- (4-methoxyphenyl) -lH-pyrazole-5-N- (4- (N-carboxyl-3-aminopyrrolidine) phenyl) carboxyamide; 3-Methyl-1- (4-methoxyphenyl) -lH-pyrazole-5-N- (4- (N-carboxyl-3-methoxypyrrolidine) phenyl) carboxyamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (5- (2-aminosulphyl) phenyl) pyridin-2-yl) carboxyamide; 3-Tri? Uoromethyl-1- (4-methoxy phenyl) -lH-pyrazole-5- (N- (4-amidine) phenyl) carboxyamide; 3-Trifluoromethyl-1- (4-methoxy phenyl) -lH-pyrazole-5- (N- (4- (N-pyrrolidine) formylimine) phenylcarboxyamide; 3 - . 3 - . 3 - . 3-Trifluoromet i 1-5- (N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl)) -1- (4-methoxyphenyl) pyrrole [3,4-d] pyrazole-4 , 6 - (1 H, 5H) -dione; 3-Trif luoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5-carbomethoxy- (N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl)) carboxyamide; 3-Trifluoromethyl-l- (4-methoxyphenyl) -lH-pyrazole-5-hydroxymethyl- (N- (2'-aminosulfonyl- [1, 1 '] -bifen-4-yl)) carboxyamide; 3-Tri-fluoromethyl-1- (methoxyphenyl) -lH-pyrazole-5- (N-2-fluoro (4- (N-pyrrolidine) formylimin) phenyl) carboxyamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4- (N-pyrrolidine) formyl-N- (2-propyl) methylcarbamoyl) imino) phenyl) carboxyamide; 3 -Trif luoromet i 1-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4- (N-pyrrolidine) formyl-N- (methanesulfamoyl) imino) phenyl) carboxyamide; 3-Trifluoromethyl-1- (4-methoxy phenyl) -lH-pyrazole-5- (N- ((4-amidine) phenyl) methyl) carboxyamide; 3-Trifluoromethyl-1- (4-methoxy phenyl) -lH-pyrazole-5- (N- ((4- (N-pyrrolidine) formylimine) phenyl) methyl) carboxyamide; 3-Trifluoromethyl-1- (4-methoxy phenyl) -lH-pyrazole-5- (N- ((1-benzyl) piperidin-4-yl)) carboxyamide; 3 -Tri f luoromet il-1- (4-methoxy phenyl) -lH-pyrazole-5- (N- (< 1- (pyridin-2-yl) methyl) piperidin-4-yl)) carboxyamide; 3-Tri f luoromet i 1- (4-methoxy phenyl) -lH-pyrazole-5- (N- (4- (2-methylimidazo-l-yl) phenyl) carboxyamide; 3-Methyl- (4-methoxy) phenyl-lH-pyrazol-5- (N-. {4- (5-methyl'-imidazol-1-yl}. Phenyl) -carboxyamide; 3-Methyl- (4-methoxy) phenyl-1H-pyrazole-5- (N- (4- (4-methyl-imidazol-1-yl.) Phenyl) carboxyamide; 3-Trifluoromethyl- (4-methoxy) phenyl-1H-pyrazole-5- (N-. {4 (5-carbomethoxy-imidazol-1-yl) phenyl) carboxyamide; 3-Trifluoromethyl- (4-methoxy) phenyl-1H-pyrazole-5- (N-. {(5-carboxy-imidazol-1-yl) phenyl) carboxyamide; 1- (4'-Methoxyphenyl) -3-hydroxylmethyl-lH-pyrazol-5-N- (4 '-pyrrolidinocarbonyl) phenyl) carboxyamide; 1- (4'-Methoxyphenyl) -3-formaldehyde-1H-pyrazole-5-N- ('- (pyrrolidinocarbonyl) phenyl) carboxyamide; 1- ('-methoxyphenyl) -5-N- (4') acid (pyrrolidinocarbonyl) anuide) -lH-pyrazol-3-yl-carboxylic acid; 1- (4'-Methoxyphenyl) -3-methylcarboxylate-1H-pyrazole-5-N- (4'-pyrrolidinocarbonyl) phenyl) carboxyamide; 1- ('-Methoxyphenyl) -3-cyanomethyl-1- lH-pyrazol-5-N- (4' -pyrrolidinocarbonyl) phenyl) carboxyamide; 2- (1 '- (4 *' - Methoxyphenyl) -5 '- (4"-pyrrolidinyl-one) anilide-1H-pyrazol-3'-yl) acetic acid; 1- (4'-Methoxyphenyl) -3-bromomethyl-1H-pyrazol-5-N- (2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide; 1- (4'-Methoxy phenyl) -3 -aminomet i 1-lH-pyrazol-5-N- (2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide; 1- (4'-Methoxyphenyl) -3- (N-methylsulfonylamino) methyl-lH-pyrazol-5-N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 1- (4'-Methoxyphenyl) -3- (imidazol-1-yl) methyl-1H-pyrazol-5-N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 1- (4'-Methoxyphenyl) -3-hydroxylmethyl-1H-pyrazol-5-N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 1- (4'-Methoxyphenyl) -3-trifluoroacetylhydroxylmethyl-1H-pyrazol-5-N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 1- (4'-Methoxy-2'-methoxycarbonyl phenyl) -3-trifluoromethyl-1H-pyrazol-5-N- (2'-methylsulfonyl [1,1 '] -bifen-4-yl) carboxyamide; 1- (4'-Methoxy-2'-hydroxycarbonyl-phenyl) -3-trifluoromethyl-1H-pyrazol-5-N- (2'-methylsulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 1- (4'-Methoxy-2'-methoxycarbonyl phenyl) -3-trifluoromethyl-1H-pyrazol-5-N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 1- ('-Metoxy-2' -hydroxycarbonyl phenyl) -3-trifluoromethyl-1H-pyrazol-5-N- (2'-tert-butylaminosulfonyl) - [1,1 '] -biphenyl) carboxyamide; 1- (4'-Methoxy-2'-hydroxycarbonyl-phenyl) -3-trifluoromethyl-1H-pyrazol-5-N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; l- (4'-Methoxy-2'-hydroxylmethylphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'-aminosulfonyl 1- [1,1 '] -bifen-4-yl-carboxyamide; 1- ('-methoxyphenyl) -3-methyl-lH-pyrazol-5-N- (4' -sec-butyl) pheni 1) carboxyamide 1- (4'-Methoxyphenyl) -3-methyl-lH-pyrazol-5-N- (4 '- (3"-methyl-3" -pyrazoline-5"-one-2" -yl) phenyl) carboxyamide; 1- (4'-Methoxyphenyl) -3-methyl-lH-pyrazol-5-N- (4 '- (6"-methylbenzothiazol-2" -yl) phenyl) carboxyamide; 1- (4'-Methoxyphenyl) -3-me t i 1- 1 H-pi ra zol-5-N- (3 ', 4' -dibromophenyl) carboxyamide; 1- (4'-Methoxyphenyl) -3-methyl-lH-pyrazol-5-N- (4 '-n-butyl) phenyl) carboxyamide; 1- (4'-Methoxyphenyl) -3-methyl-1H-pyrazol-5-N- (4 '- (4"-methylpiperidine) phenyl) carboxyamide; 1- ('-Methoxyphenyl) -3-methyl-l-pyrazol-5-N- (4' - (2"-methyl-1-imide zol-1" -i 1) phenyl) carboxyamide; 3-Trif luoromet i 1- (4-methoxy phenyl) -lH-pyrazole-5- (N- (4-carboxy (N-methylimidazo-2-yl) phenyl) carboxyamide; 3 - . 3 -Trif luoromet i 1-1- (4-methoxy phenyl) -lH-pyrazole-5- (N- (4-hydroxymethyl (2- (imidazol-2-yl) phenyl))) carboxyamide; 3-Trifluoromethyl-1- (4-methoxy phenyl) -lH-pyrazole-5- (N- (4-yl) phenyl))) carboxy amide; 1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5- (N- (4- (2-carboxy (imidazol-2-yl) phenyl))) carboxyamide; 3-Trifluoromethyl-l- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4- (N- (4-methoxyphenyl) amino- (2 - (thiazolyl) methyl) phenyl))) carboxyamide; 1- (4-Methoxyphenyl) -3-trifluoromethyl-lH-pyrazole-5- (N- (4- (2-carboxyl- (4,5-dihirothiazol-2-yl) phenyl))) carboxyamide; 1- (4-Methoxyphenyl) -3-tri fluorometyl-1H-pyrazol-5-N-4- (2- (4 ', 5'-dihydro-1H-imidazol-2'yl) phenyl) carboxyamide; 1- (4-Methoxy phenyl) -3-tri fluoromethyl-1H-pyrazol-5-N- (4- (N-2'-aminoethylenecarboxyamide) phenyl) carboxyamide; 1- (4-Methoxy phenyl) -3-trifluoromethyl-1H-pyrazol-5- [4 - (1, 4, 5, 6-tetrahydro-pyrimid-2-yl) -phenyl] carboxyamide; 1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazol-5- [4 - (N-meth i 1-4,5,6,6-trihydro-pi imid-2-yl) -phenyl] carboxyamide; 1- (4-Methoxyphenyl) -3-trifluoromethyl-lH-pyrazol-5-N-l- (2-fluoro-4-ymadazolinophenyl) carboxyamide; 1- (4-Methoxyphenyl) -3- 1 ri f luoromet il-H-pyrazol-5-N- 1- (2-fluoro-4-N-methylimadazolinophenyl) carboxyamide; 1- (4-Methoxyphenyl) -3-tri fluoromet i 1- lH-pi ra zo1-5- - [- (, 5-dihydro-1-N-meth i 1 -imide zo-2-yl) phenyl] carboxyamide; 1- (4-Methoxyphenyl) -3-trifluoromethyl-lH-pyrazol-5-N- [4-carbonylguanidine) phenyl] carboxyamide; 1- (4-Methoxyphenyl) -3-trifluoromethyl-lH-pyrazol-5-N- [4- (pyrimidine-2-yl) phenyl] carboxyamide; 2- (Carboxyamide) -4- [(-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide] thiazole; 2- (2-Methoxyethylamino) -4- [(4-methoxy) phenyl] -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide] thiazole; 2- (3-Hydroxypropylamino) -4- [(4-methoxy) phenyl] -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide] thiazole; 2- (2-Cyanoethylamino) -4- [(4-methoxy) phenyl] -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide] thiazole; 2- (3-Methoxypropylamino) -4- [(4-methoxy) phenyl] -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide) thiazole; 2- (N-b-Alanyl) -4- [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide] thiazole; 2- (Isopropylamino) -4- [(4-methoxy) phenyl] -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide] thiazole; 2- (1,3-Dihydroxy-2-propylamino) -4- [(4-methoxy) phenyl] -5 - [(2'-amino-sulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole; 2- [(Methoxycarbonyl) methylamino] -4- [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole; 2- (N-Glycyl) -4- [(4-methoxy) phenyl] -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide] thiazole; 1- [(4-Methoxy) phenyl] -3- (ethoxycarbonyl) -lH-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- (carboxyamido) -lH-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1- [(4-Methoxy) phenyl] -3 - [(2-hydroxyethyl) carboxyamid] -lH-pyrazol-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1- [(4-Methoxy) phenyl] -lH-pi ra zol-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide-3-hydroxamic acid; 1- [(4-Methoxy) phenyl] -3- [phenylcarboxyamido] -1H-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- [(3-hydroxypropyl) carboxyamid] -lH-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- [methylcarboxyamide] -1H-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- [(benzyl) carboxyamide] -1 H -pyraz-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- [(dimethyl) carboxyamido] -1H-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- [(phenylethyl) carboxyamido] -1H-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- [(hydroxyphenyl) carboxyamid] -lH-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- [(3-hydroxyphenyl) carboxyamido] -lH-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; l- [(4-Methoxy) phenyl] -3- [(4-hydroxyphenyl) carboxyamid] -lH-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- [(methoxycarbonyl) amino] -1H-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; l - [(4-Methoxy) phenyl] -3-amino-1H-pyrazol-5- [(2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- [methoxycarbonyl) methylamino] -5 lH-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; l- [(4-Methoxy) phenyl] -3- [(2-hydroxy) ethylamino] -1H-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] -bifen-4-10 yl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- [E-2- (methoxycarbonyl) ethenyl-1H-pyrazole-5- [(2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide; ID 1- [(4-Methoxy) phenyl] -3- [2- (methoxycarbonyl) ethyl] -1H-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- [E-2- (carboxy) ethenyl] -1H-pyrazole-5- [(2'-aminosulfonyl- [1, 1 '] -bifen-4-yl. carboxyamide; l - [(4-Methoxy) phenyl] -3- [2- (carboxy) ethyl] -lH-pyrazol-5-5- [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- [E-2- (carboxyamido) ethenyl] -1H-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; l- [(4-Methoxy) phenyl] -3- [E-2- (hydroxymethyl) ethenyl] -1H-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- [3-hydroxypropyl] -lH-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; i- [(4-Methoxy) phenyl] -3-propyl-lH-pyrazole-5- [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4-cyano-lH-pyrazole-5- [(2'-methyl-sulfonyl-3-fluoro- [1,1 '] -bifen-4-yl] carboxyamide; l - [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4- (amidine) -lH-pyrazole-5- [(2'-methylsulfonyl-3-fluoro- [1, 1 '] -bifen-4 -yl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4- (N-hydroxyamidino) -lH-pyrazole-5- [(2'-methy1 sulphon 1-3-fluoro- [1, 1] '] -bifen-4-yl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4- (ethoxycarbonyl) -lH-pyrazole-5- [(2'-methylsulfonyl-3-fluoro- [1, 1 '] -bifen-4 -yl) carboxyamide; Y, 1- [(4-Methoxy) phenyl] -3- (trifluoromethyl) -1H-pyrazole-5- [(2'-methylsulfonyl-3-fluoro- [1, 1 '] -bifen-4-yl) carboxyamide -4-carboxylic acid; [6] In a second embodiment, the present invention provides novel compounds of formula II: II or stereoisomers or pharmaceutically acceptable salts thereof, wherein; M is selected from the group Z is selected from C (0) CH2 and C (0) NR- R, is selected from H, alkyl of 1 to 3 carbon atoms, F, Cl, Br, CH (CH20) 2. CF; -CF- (CH2) rOR, NR, 2An2'a, S (0) pR, 2b, NRJCH2) rOR¿ NRA (0) R 2b, C (0) NR2R2a, C (O) NR2 (CH2) r0R2, and S02NR2R2a; R, in each occurrence, is selected from H, CF3, alkyl of 1 to 6 carbon atoms, benzyl, carbocyclic residue of 3 to 6 carbon atoms substituted with 0-2 R4, and heterocyclic system of 5-6 members containing 1-4 heteroatoms selected from a group consisting of N, O, and S substituted with 0-2 R4; R'a, in each occurrence is selected from H, CF3, alkyl of 1 to 6 carbon atoms, benzyl, carbocyclic residue of 3 to 6 carbon atoms substituted with 0-2 R4, and heterocyclic system of 5-6 members containing 1-4 heteroatoms selected from a group consisting of N, O, and S substituted with 0-2 R4; R2b, in each occurrence, is selected from CF3, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 6 carbon atoms, carbocyclic residue of 3 to 6 carbon atoms substituted with 0-2 R4, and heterocyclic system 5-6 members containing from 1-4 heteroatoms selected from a group consisting of N, 0, and S, substituted with 0-2 R4; alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a saturated or unsaturated, saturated, 5-6 membered ring substituted with 0-2 R4 containing 0-1 selected additional heteroatoms from a group consisting of N, O, and S; R, in each occurrence is selected from H, alkyl of 1 to 4 carbon atoms, and phenyl; A is selected from phenyl, pyridyl, and pyrimidyl, and A is substituted with 0-2 R4; B is selected from: H and Y; Y is selected from phenyl, pyridyl, tetrazolyl, and morpholino, and Y is substituted with 0-2 R a; R * in each occurrence is selected from F, Cl, Br C (O) NRA, 2'a and (CF2) rCF 3 ' R, in each occurrence, is selected from F, Cl, Br, I, alkyl of 1 to 4 carbon atoms, C (0) NR2R2a, S02NR2S02-C? -4 alkyl, S (0) pR5, and (CF2) rCF3; R, in each occurrence, is selected from CF3, alkyl of 1 to 6 carbon atoms, phenyl, and benzyl; p is selected from 0, 1, and 2; and r is selected from 0, 1, 2 and 3. [7] In another more preferred embodiment, the present invention provides novel compounds selected from: 3-Methyl-1-phenyl-1H-pyrazole-5- (N- (2-aminosulfonyl- [1, 1] -bifen- 4-yl) carboxyamide; 2-Amino-4-phenyl-5- [2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] thiazole; Y, 2-Chloro-4-phenyl-5- [(2'-amino-sulfonyl- [1,1 '] -biphen-4-yl) aminocarbonyl] thiazole; and pharmaceutically acceptable salts thereof In a third embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier of a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof. In a fourth embodiment, the present invention provides a novel compound for treating or preventing a rhomboembolic disorder, comprising: administering a patient in need thereof a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt of the same.

DEFINITIONS The compounds described herein can all be asymmetric. The compounds of the present invention containing an asymmetrically substituted atom can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis of optically active starting materials. Many geometric isomers of olefins, C = N double bonds, the like may also be present in the compounds described herein, and all of these stable isomers are contemplated in the present invention. The Cis and trans geometry isomers of the compounds of the present invention are described and can be isolated as a mixture of isomers or as separate isomeric forms. All racemic, diastereomeric, chiral and all isomeric, geometric forms of a structure are proposed, unless the specific stereochemical or isomeric form is specifically indicated.

The term "substituted", as used herein, means that any or more hydrogens on the designated atom are replaced with a selection of the indicated group, with the proviso that the normal valence of the designated atom is not exceeded, and that the substitution of result a stable compound. When a substituent is keto (ie, = 0), then 2 atoms are replaced in the atom. Keto substitutes are not present in the aromatic portions. The present invention is proposed to include all isotopes of atoms that occur in the following compounds. Isotopes include these atoms that have the same atomic number, but different mass numbers. By way of general example and without limitation, hydrogen isotopes include tritium and deuterium. Carbon isotopes include C-13 and C-14. When any variable (for example, R6) occurs more than once in any constituent or formula for a compound, its definition in each occurrence is independent of its definition in any other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R, then the group can optionally be substituted with up to two groups R6 and R6 in each occurrence independently selected with the definition of R6. Also, combinations of substituents and / or variables are permissible only if these combinations result in stable compounds. When a binding to a substituent is shown to cross a junction that connects two atoms in a ring, then this substituent can be attached to any atom in the ring. When a constituent is listed without indicating the atom to which this substituent was bound to the rest of the compound of a given formula, then this substituent may be attached via any atom in this substituent. Combinations of substituents and / or variables are permissible only if these combinations result in stable compounds. As used herein "alkyl of 1 to 6 carbon atoms" is proposed to include aliphatic, saturated hydrocarbon groups, both branched and straight chain having the specified number of carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl; "Alkenyl" is proposed to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds that occur at any stable point along the chain, such as ethenyl, propenyl, and the like. "Halo" or "halogen" as used herein refers to fluoro, chloro, bromo, and iodo; and "counterion" is used to represent a negatively charged, small species, such as chloride, bromide, hydroxide, acetate, sulfate, and the like. As used herein, "carbocycle" or "carbocyclic residue" is intended to mean any 3- to 7-membered stable or bicyclic, or bicyclic or tricyclic 7 to 13 membered monocyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of these carbocyclics include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl; [3.3.0] bicyclooctane, [4.3.0] biciclononane, [4.4.0] bicyclodecane (decalin), [2.2.2] bi ci clooct an, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tet rahydrona f t i lo (tetralin).

As used herein, the term "heterocyclic" or "heterocyclic system" is intended to mean a heterocyclic, bicyclic, 7- to 10-membered, monocyclic or bicyclic 5-7 membered ring that is saturated, partially unsaturated or unsaturated (aromatic), and consisting of carbon atoms and from 1 to 4 heteroatoms independently selected from a group consisting of N, O and S which includes any bicyclic group in which any of the heterocyclic rings defined above is fused to the ring of benzene. The nitrogen and sulfur heteroatoms can optionally be oxidized. The heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted at the carbon or at a nitrogen atom if the resulting compound is already stable. If specifically stated, a nitrogen in the heterocyclic can be quaternized optionally. It is preferred that when the total number of S and O in the heterocyclic exceeds one, then these heteroatoms are not adjacent to each other. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term "aromatic heterocyclic system" is intended to mean a bicyclic, bicyclic, heterocyclic 7-aromatic ring 10 members, monocyclic or bicyclic 5 to 7 members consisting of carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heterocycles include but are not imitated acridinyl, azoacinyl, benzimidazolyl, benzofuranyl, benzoturofiyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetra zolyl, benzisoxazole, benzothiazol The benzimide zal ini lo, carbazolilo, 4 aH-ca rba zol i lo, carbolinilo, cromanilo, cromenilo, cinolinilo, decahidroquinol iní lo, 2H, 6H-1,5,2-ditiazinilo, dihidrofuro [2, 3-b] tetrahydrof urane, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-inda zolyl, indolenyl, indolinyl, indole indole, indolyl, 3H-indolyl, and soben zo furani lo, i socromani lo, i soinda zol i lo, Initially, isoindolyl, isoquinolinyl, (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthymide, octylhydroquinolone, oxadia zolyl, 1,2,3-oxadia zolyl, 1, 2, -oxadiazole i, 1,2,5-oxadia zoli lo, 1, 3, 4 -oxadia zol lio, oxazolidol, oxazolyl, oxazolidil, pipmidinyl, fenant pdmi lo, fenant rol mi lo, fenanzmilo, phenot iazinyl, phenoxat and mylo, phenoxane zini, phthalazinyl, piperazinyl, piperidinyl, fteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyrazolyl, pyrazolyl, pyrazinyl, piolidooxazol, pyridoimidazole, pyridotyl, pyridinyl, pipdyl, pyridinyl, pyrrolidmyl, pyrrolinyl, 2H-pyrrolidol, pyrrolyl, quinazolinyl, quinolinyl, 4 H-quinol iz mi lo, qumoxal mi l or, quinucl ídini 1 o, tet rahidrofurani lo, t et rahidroi soqu olíni, t et rah ídroqumol mi lo, 6H-1, 2, 5- t íadia zini lo, 1, 2, 3 - t íadia zol i lo , 1,2,4-thiadiazolyl, 1, 2, 5- 1 -adiazolyl, 1,3,4-tiadiazol, thiantrenyl, thiazolyl, thienyl, thienotide, zolyl, t-inoxa, t-thiolimide zol i lo, thiophenyl, triazmyl, 1, 2, 3 - 1 na zol i lo, 1,2,4-tpazolyl, 1, 2, 5 - 1 ri a zol i lo, 1, 3, 4 -1 ría zol i lo, and xanthenyl. Preferred heterocyclics include, but are not limited to, pipdmyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl, lH-inda zolyl,, oxa zol idini lo, benzotriazolyl, benzi soxa zol ilo, oxindolyl, benzoxa zol inyl, or isatinoyl. Also included are rings operated on spiro compounds containing, for example, the above heterocyclics. The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms that are, within the scope of accurate medical judgment, suitable with use in contact with the tissues of humans and animals. without excessive toxicity, irritation, allergic response, or other problem or complication, in proportion to a reasonable risk / benefit ratio. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the described compounds wherein the parent compound is modified by making acid or basic salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of organic or mineral acids of basic residues such as amines; alkaline or organic salts of acidic residues, such as carboxylic acids; Similar. The pharmaceutically acceptable salts include the non-conventional salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic organic or inorganic acids. For example, these conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, maleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acet oxybenzoic, fumaric, toluensul phonic, methanesulfonic, ethanesulfonic , oxalic, isethionic, and the like. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acid portion by conventional chemical methods. In general, these salts can be prepared by reacting the free acid or basic forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; in general a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418, the description of which is incorporated in this way by reference. "Prodrugs" are proposed to include any covalently linked carrier that releases the active drug of origin according to formula (I) in vivo when this prodrug is administered to a mammalian subject. Prodrugs of a compound of the formula (I) are prepared by modifying the functional groups present in the compound in such a way that the modifications are cleaved either in retinal manipulation or in vivo, to the parent compound. Prodrugs include compounds of the formula (I) wherein a hydroxy, amino or sulfhydryl group is attached to any group which, when the prodrug compound of the formula (I) is administered to a mammalian subject, 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 amine functional groups in the compounds of formula (I), and the like.

"Stable compound" and "stable structure" is intended to indicate a compound that is strong enough to survive isolation to a useful degree of purity from a reaction mixture, and the formulation into an effective therapeutic agent.

SYNTHESIS The compounds of the formula I can be prepared using the reactions and techniques described below. The reactions are carried out in a solvent appropriate to the reagents and materials used and suitable for the transformation that was carried out. It will be understood by those skilled in the art of organic synthesis that the functionality present in the molecule must be consistent with the proposed transformations. This will sometimes require a judgment to modify the order of the synthetic steps to select a particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any other synthetic in this field is judicious choice of the protective use used for the protection of the reactive functional groups present in the compounds described in this invention. An authoritative explanation describing the many alternatives to trained practitioners is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).

Preparation of the compounds of FORMULA I with a five-membered heterocyclic nucleus The general syntheses for the compounds of the formula I are summarized in Schemes la-b. Ring M can be N-linked or C-linked to the ring referred to in the following scheme as D. B 'and Rf, are protected functional groups that can be converted to R, B and Rla, respectively. It is understood that group E can be protected or not or a precursor E of Formula I, depending on the demands of the chemistry involved. The compounds can also be obtained by changing the sequences of the reaction steps as described in Scheme 1. For the N-linked ring, the appropriate M-substituted amine ring is treated under conditions described in "The Chemistry of Heterocyclic Compounds" , Weissberger, A. And Taylor, EC Ed., John Wiley &Sons "or as described later in the synthesis section to give the ring M N- linked. Further modifications and deprotections give the N-linked M ring with the substituents R, Z-AB and Rla Scheme the For nitrogen heterocycle M linked Vulnerability For the M-ring, five-member C-linked, the above aniline is diazotized with nitrous acid and treated with NaBr to give the heterocyclic bromide. Treatment with n-BuLi followed by DMF gives the aldehyde that can be converted to the M ring as described in "The Chemistry of Heterocyclic Compounds, Weissberger, A. and Taylor, EC Ed., John Wiley &Sons" or as described later in the synthesis section. Other functional precursor groups such as acid, cyanide, methyl ketone, etc., can also be used to form the M ring. Additional modifications and deprotections can produce the five-membered M ring substituted with M, Z-A-B and Rla. The corresponding M-ring of six members, C-linked, can be obtained by converting the above bromide with n-butyl lithium and triisopropyl borate to give the heterocyclic boronic acid. The Suzuki coupling with the appropriate heterocyclic bromide followed by modifications and deprotections gives the six-membered M ring C-linked with R, Z-A-B and the Rla substituents.

Scheme Ib For carbon-linked heterocycle M The compounds of the present invention in which M-het erocycle is tlazole can be prepared according to the procedures described in Scheme 2. The appropriate D-ring bromide can be converted to a beta-keto ester in several ways. A preferred method comprises transmetalation with an alkylithium reagent followed by rapid increase with DMF to give the corresponding aldehyde. The addition of ethyl diazoacetate in the presence of tin (II) chloride gives the beta-keto ester directly. Other methods are available for this conversion, one of which comprises the Reformatsky reaction of the aldehyde followed by the oxidation to the beta-keto ester.

It burns 2 A second preferred method for converting the bromide to a beta-keto ester comprises palladium catalyzed coupling with (ethoxy vini 1) tributyl, followed by acid hydrolysis to give the corresponding acetyl derivative. Many methods exist for the conversion of the acetyl derivative to the beta-keto ester, a preferred method of which comprises reacting the acetyl derivative in a dialkyl carbonate in the presence of a base such as sodium hydride or lithium diisopropylamide. The beta-keto ester can be converted to the corresponding thiazole derivatives by bromination with NBS followed by cyclization with an appropriate thiourea or thioamide in a solvent such as ethanol or tetrahydrofuran. A kettle method for this conversion comprises the treatment of the beta-ester with hydroxytyloxy iodobenzene in acetonitrile which forms an intermediate alpha-tosyloxy-beta-ketoester, followed by the addition of a thiourea or thioamide to effect cyclization to the corresponding thiazole. The manipulation of the ester group of these thiazoles can give the compounds containing an appropriate Z-A-B group. Where Z = CONH, standard methods of peptide coupling with an appropriate amine can be employed, such as the reaction of the ester with an amine-derived aluminum reagent. Where Z = COCH2, the formation of acid chloride by normal methods can be followed by the addition of an appropriate zinc reagent. The Rla group in the thiazole ring can also be manipulated to provide a variety of different groups. For example, when thiourea is used as the cyclization partner, a 2-aminotia is produced. This amino group can easily be diazotized and displaced with the appropriate copper halide to give 2 -halot ia zoles. The halogen atom can then be easily displaced by a variety of carbon, nitrogen, oxygen and sulfur nucleophiles to produce a wide variety of alkyl, aryl, heteroatom and heterocyclic derivatives of Rla. The tetrazole compounds of this invention, where Z is CONH-, can be prepared as exemplified in Scheme 3. An appropriately substituted amine (E-D-NH2) is acylated with e t i 1 -oxa 1 i lo chloride. The resulting amide can be converted to tetrazole either by the methods described by Duncia (J. Org. Chem. 1991, 2395-2400) or Thomas (Synthesis 1993, 767-768, 1993). The amide can be converted to the iminoyl chloride first, and then reacted with NaN3 to form the 5-carboethoxytetrazole (J. Org. Chem. 1993, 58, 32-35 and Bioorg. & Med. Chem. Lett. 1996, 6, 1015-1020). The 5-carboethoxy tet ra zol is then coupled to an appropriate amine (BANH) by the method described by Weinreb (Tetr. Lett, 1977, 48, 4171-4174). The final deprotection as described above produces the desired product. The tetrazole compounds of this invention where Z is -CO- can also be prepared via the iminoyl chloride (Chem. Berl 1961, 94, 1116 and J. Org. Chem. 1976, 41, 1073) using an acyl chloride appropriately substituted as starting material. The acetone linker can be reduced to compounds where Z is alkyl.

Scheme 3 (CHjljAI CH2Cl, The tetrazole compounds of this invention where Z is -S02NH-, -S-, -S (O), S02-, can be prepared as exemplified in Scheme 4. The appropriately substituted partner is reacted with acid of sodium to give 5- t iot et ra zol (J. Org. Chem. 1967, 32, 3580-3592). The thio-compound can be alkylated (J. Org. Chem. 1978, 43, 1197-1200) and then oxidized to sulfoxide or sulfone. The thio-compound can also be converted to the sulfonyl chloride and then reacted with an amine to give the desired sulfonamide. The tetrazole compounds of this invention wherein Z is -O- can be prepared via the same method described in Scheme 4 by using the appropriately substituted isocyanate as the starting material.

Scheme 4 The tetrazole compounds of this invention where Z is -NH-, -NHCO-, -NHSO2 - can be prepared from 5-aminot et ra zol, which can be prepared by the Smiles re-arrangement as shown in Scheme 5. The compound prepared as described in Example 4 it is alkylated with 2-chloroacet amide. The resulting compound is then refluxed in ethanolic sodium hydroxide for the corresponding 5-aminoethereal zol (Chem. Pharm. Bull, 1991, 39, 3331-3334). The resulting 5-amino-tetrazole can then be alkylated or acylated to form the desired products.

Scheme 5 The N-linked imidazole M ring can be synthesized by the synthetic route shown in Scheme 6. The alkylation of ED-NH2 with 2-bromoet-ilacetate followed by the reaction with the Gold's reagent in the presence of a base, such as NaOMe, or LDA, forms the M ring of imidazole.

Scheme 6 The general procedure for making the M-ring of imidazole C-linked is described in Scheme 7. The aldehyde E-D-CHO of Scheme 1 can be converted to the cyano compound by treatment with hydroxyamine and then dehydration with POC13. Amidine can be obtained from the cyano compound a by the Pinner reaction, which can be cyclized with the alpha-halo ester, ketone or aldehyde to form the M ring of imidazole. The alkylation or acylation of the M ring of imidazole for further modification as described in Scheme 1.

Scheme 7 As shown in Scheme 8, the pyrazole ring M of the general formula I such as that described in Scheme 1 can be prepared by the condensation of an appropriately substituted hydrazine with a variety of diketo-esters. The condensations of this type typically give a mixture of pyrazole regioisomers which can be effectively removed via silica gel column chromatography. Hydrolysis of the esters followed by coupling with an appropriate amine can give the desired amide intermediate. Then, several substituents on the pyrazole NI can be manipulated to give a variety of benzo, heterocyclic and bicyclic compounds.

Scheme 8 ji Column chromatography then LiOH, THF water The above methodology when applied to the diketo derivatives also gives a mixture of pyrazole regioisomers. This can be manipulated additionally to give the compounds of the formula I as shown in Scheme 9.

Scheme 9 HfW OMe O '* R1a = amino or alkyl i Column or archaic chromatography Qja'diza, esterification CO tt When the ketoimidates are used for condensations with hydrazines, the corresponding pi-zol-amino-ester-esters are obtained (Scheme 9). The conversion of these intermediates to the final compounds of formula I can then be achieved by protecting the amino functionality with a suitable protecting group commonly known to those skilled in the art or by derivatization (such as a sulfonamide as in Scheme 10) then following the general synthetic strategy to prepare the compounds of this invention.

Scheme 10 as in «1 Baqueini 8 T The pyrazole ester intermediate compound can be further manipulated to the ketones by the cuprate methodology described by Knochel et al (Scheme 11). Alternatively, the ester can be reduced to either the alcohol or the aldehyde via methods known to those skilled in the art, followed by either a reductive amination with an appropriate amine to an alkyl amine or by converting alcohol to a group projection which in turn can be displaced with a number of nucleophiles to provide the intermediate compounds that in further manipulations should give the compounds of this invention.

Scheme 11 A N "" 3-CH2NHAB or CH2SAB or CH2S02AB E-D Thio compounds such as those compounds in Scheme 12 can be easily prepared by the conversion of 5-hydroxy-pyrazole to its thiol by treatment with the Esson's reagent with toluene.

Scheme 12 7T ~ "? &" AB < V y ~ QH wßsori- N & M hilquih-luro N -E D-e D-E D OndacUn The compounds of the invention wherein the M ring of pyrazole is replaced with 1, 2, 3-tria zol can be prepared as summarized in Scheme 13.

Scheme 13 B The compounds of this invention where the M ring is 1, 2, - 1 r ia zol can be easily obtained by the methodology of Huisgen et al.

(Liebigs Ann, Chem. 1962, 653, 105) by the cycloaddition of nitriliminium species (derived from the treatment of triethylamine and chlorohydrazone) and an appropriate nitrile dipovilafilo as in the Scheme 1 Scheme 14 This methodology provides a wide variety of 1, 2, 4 -triazoles with a varied substitution pattern in positions 1, 3 and 5. Alternatively, the 1, 2, -1 ría zoles can also be prepared by the methodology of Zecchi et al. (Synthesis 1986, 9, 772) via a condensation of Wittig aza (Scheme 15).

Scheme 15 R 'a = alkyl or aryl Alternatively, the 1, 2, 4 -1 ria zoles can also be prepared via the methodology of Sauer et al (Tetr. Lett 1986, 325) for the photolysis of a cyclic carbonate with an appropriate nitile (Esauema 16).

Scheme 16 R1 a = Phenyl or ester For the compounds of this invention, the esters can be converted to the intermediate amide compounds via the Weinreb methodology (Tetr. Lett, 1977, 48, 4171), that is, the condensation of an appropriate amine-aluminum complex with the ester (Scheme 17).

Scheme 17 EtOj The M-ring of isoxazoline of the general formula I in which position 4 and 5 are substituted can be prepared following the 1,3-dipolar cycloaddition methodology outlined in Scheme 18. A suitable benzyhydroximinoi chloride or heterocyclic oximinoyl chloride or the oxime when subjected to the 1,3-dipolar cycloaddition protocol with a suitable 1, 2-di substituted olefin as a dipo lillafilo should give a mixture of regioisomers. The separation of the regioisomers by column chromatography followed by the sequence of reactions as previously described should then give the compounds of choice. Optically active isoxazolines can also be obtained by enzymatic resolution in the esters in the regioisomeric esters or by the use of an appropriate chiral auxiliary in dipoylillary as described by Olsson et al (J. Org. Chem. 1988, 53, 2468). .

Scheme 18 2-cv sxa? Nic-- 3-cartx? Amide In the case of the compounds of the general formula I wherein the substrate in the cycloaddition process described in Scheme 18 uses an appropriately substituted crotonate ester. The crotonate esters can be obtained from commercial sources or can be obtained from et il-4-bromocrotonate by nucleophilic displacement reactions shown in Scheme 19.

Scheme 19 CO? R The olefins t r i their t i t uida s as dipo lofil can be obtained from the eti lpropiolato by the chemistry of the crupato (Scheme 20) according to the method described by Deslongchamps et al. (Synlett 1994, 660).

Scheme 20 R = -CO-jEt R, MßaCu. RX C0-E * The compounds of this invention with the M ring of 1, 3, 4 -tria zol can be easily obtained with the methodology of Moderhack et al. (J. Prakt.Chem. 1996, 338, 169) as in Scheme 21.

Scheme 21 KN-N H-.N-NH E-D-NCS then NaOH g ^ * - CH (OEt, and II-CHfOEt); or - < D E HNO. N-N ABB '. NaH ^ N / -CH (0E1) D-E N-N Hy r NBS then alcohol D-E sxE ation n the Outline- 1 - A Ag X = None of or H or alkyl or heteroatom 'D-E This reaction comprises the condensation of a carbazide with a commercially available, suitably substituted thiocyanate, to the cyclic thiourea derivative as previously described. The nucleophilic displacement reactions or the alkylation in the thiono intermediate then gives an intermediate thio-alkyl or aryl intermediate that can be hydrolyzed, oxidized and decarboxylated to the intermediate of 5-H-2-thio-triazole which can be effectively convert to the compounds of this invention. Alternatively, the thiono-urea intermediate can be directly oxidized to the 2-H-triazole which can then be converted to the ester and then subjected to a variety of reactions shown above, to obtain the compounds of this invention. The esters can also be converted to the amine via the re-arrangement of Hoff ann and this methodology provides a variety of analogs similar to those shown previously. The cyclic thiono-urea intermediate can also be oxidized to the sulfonyl chloride by methods shown in the above examples. This in turn can provide the sulfonamides shown in Scheme 22.

Scheme 22 Scheme 23 describes the general synthesis for pyrazoles having oxidized sulfur derivatives and thio. An appropriately substituted amine is alkylated with ethyl bromoacetate and hydrolyzed to the glycine derivative. The preparation of the N-nitroso compounds was easily achieved with sodium nitrite (J. Chem. Soc. 1935, 899). Cyclization to sindone using acetic anhydride (J. Chem. Soc. 1935, 899) was followed by the introduction of the sulfide unit using a sulfoxide as a solvent and acetyl chloride as an activation reagent (Tetr 1974, 30, 409). The photolytic cleavage of sindone in the presence of an acetylenic compound, pyrazole 1, 3, 5-t risust it as the main regioisomer (Chem. Ber. 1979, 112, 1206). These can be carried on, as described above, the final compounds containing the sulfur, sulfoxide or sulfone functionality.

Scheme 23 Where V = NO-, SO; N ^: o ZO t? Scheme 24 shows a possible synthesis of isoxazoles. The substituted benzaldehydes are reacted with hydroxylamine then chlorinated to give the hydrominoyl chloride according to the procedure of (J. Org. Chem. 1980, 45, 3916). The preparation of the nitrile oxide in situ with triethylamine and the cycloaddition with a substituted alkane gives a mixture of regioisomeric isoxazoles as shown by H. Kawakami (Chem. Lett 1987, 1, 85). The preparation of the disubstituted alkene is achieved by the nucleophilic attack of the alkenyl anion on an electrophile as shown by Jungheim et al (J. Org. Chem. 1987, 57, 4007). Alternatively, the hydroxy iminoyl chloride of the Rla piece can be made and reacted with an appropriately substituted alkyne to give another set of regioisomeric isoxazoles that can be chromatographically separated.

Scheme 24 where V = N02, S02NR2 or C02Me, synthetic precursor to -ZAB An alternative procedure that produces only one regioisomer is described in Scheme 25. The methylated form of V can be deprotonated and silized, cloning against carbon chloride or flowering with difluorodibromomethane under the catalysis of trioethylborane gives the compound dihal geminal as shown by Sugimoto (Chem. Lett., 1991, 1319). The conjugate addition, mediated by cuprate, gives the desired alkene as Harding (J. Org. Chem. 1978, 43, 3874. Alternatively, it can be acylated with an acid chloride to form a ketone as in Andrews (Tetr. Lett, 1991, 7731) followed by diazomethane to form the phenol-ether Each of these compounds can be reacted with a hydroxyiminoyl chloride in the presence of triethylamine to give a somatic isoxazole regioi as shown by Stevens (Tetr. Lett, 1984, 4587).

Scheme 25 1) LDA 2) TBD SCI > A * X (R1a) 2C-iL.? ^ A 3, CC or CF2Br2 ^ ^? _ C | or F Where Y = OMe, C l or F V = N02, S02NR2 or C02Me, synthetic precursor to -Z-A-B When the core substituent Rla is CH2Q, the synthesis is shown in Scheme 26.

After being treated with LDA, the ketone starting material reacts with PhSS02Ph to give the phenylthiolated compound which reacts with hydrazine in acetic acid to form a pyrazole derivative. The pyrazole ester reacts with an amine or amidine (previously treated with AlMe3) to provide amide. Oxidation of sulfide with mCPBA gives the corresponding sulfone. Deprotonation of the sulfone with base, followed by entrapment with an electrophile (Q-X) and treatment with Sml2 provided the desired compound after deprotection.

Scheme 26 NH,; "O x Scheme 27 shows other synthesis methods for Rla = CH2Q or COQ. The protection of the hydroxyl group of hydroxyacetone with a benzyl halide and the treatment with a base and CO (CO: Et) 2 gives the t-carbonate compound. Reflux with NH OMe »HCl in pyridine and ethanol in the presence of 3A molecular sieves gives the oxime. The cyclization of the oxime with E-D-NHNH2 provided the pyrazole, which can be converted into the corresponding amide by reacting it with an amine or aniline (previously activated with AlMe3). The desbenci 1 aci on by catalytic hydrogenation provides the alcohol. The alcohol is converted to the tosylate with TsCl, followed by replacement with a nucleophile to provide the desired compound. The alcohol can also be oxidized to the corresponding aldehyde or acid, or is further converted to the ester or amide.

Scheme 27 E-D-NHNH; HOAc Preparation of compounds of FORMULA I with a six-membered heterocyclic nucleus Scheme 28 describes the synthesis of compounds wherein M is a benzene ring and v is a nitro, protected sulfonamide or ester group and precursor of group Z of formula I. Group V is placed in an appropriately substituted phenol either by nitration as shown by Poirier et al. (Tetrahedron 1989, 45 (5), 1415), sulfonylation as shown by Kuznetsov (Akad, Nauk SSSR Ser. Khim 1990, 8, 1888) or carboxylation by Sartorio et al. (Synthesis 1988, 10, 763). Bromination with triphenylphosphine and bromine (J. Am. Chem. Soc. 1964, 86, 964) gives the desired bromide. Suzuki coupling with the appropriate boronic acid provides the substituted pyridine, desired.

Scheme 28 Scheme 29 to 32 describe the synthesis of the compounds wherein M is pyridine. Each Scheme represents a different substitution pattern for the pyridine ring. In Scheme 29, a suitably protected aldehyde is subjected to base catalyzed condensation with an activated ester to then give the deprotection of the desired aldehyde. reflux with ammonium chloride as shown by Dornow and Ische (Chem. Ber, 1956, 89, 876) provides the pyridinol which is treated with bromine with POBr 3 (Tjeenk et al., Rec., Trav. Chim. 1948, 67, 380 ) to give the desired 2-bromopyridine. Suzuki coupling with the appropriate boronic acid provides the substituted pyridine, desired.

Scheme 29 The treatment of a 5-ethoxoxoxol appropriately substituted with alkene as shown by Kondrat'eva et al. (Dokl Akad, Nauk SSSR 1965, 164, 816) provides a pyridine with substituent V in the para position. Bromination at position 3 as shown by van der Does and Hertog (Rec.Trav. Khim.Pays-Bas 1965, 84, 951) followed by coupling with boronic acid catalysed with palladium gives the substituted pyridine, desired.

Scheme 30 Scheme 31 describes a synthesis of a third substitution pattern in a pyridine ring. The appropriate tricarbonyl compound that can be prepared by methods described in Scheme 29 is treated with ammonium chloride to form the pyridinol which is subsequently brominated. Palladium catalyzed coupling provides the desired substituted pyridine.

Scheme 31 Rlb Scheme 32 takes a dicarbonyl compound, suitably substituted, and by the chemistry illustrated in Schemes 29 and 31, reacts with ammonium chloride. Bromination gives the 3-bromopyridine which in the palladium catalyzed coupling provides the substituted pyridine, desired.

Scheme 32 Schemes 33 to 35 describe the synthesis of the compounds wherein M is pyrazine. Each Scheme represents a different substitution pattern for the pipeline. In Scheme 33, an active ester is reacted with an appropriately substituted α-keto-aldehyde and hydrazine as shown by Schmidt and Druey (Helvo, Chim Acta 1954, 37, 134 and 1467). The conversion of pyridazinone to the bromide using P0Br3 and palladium catalyzed coupling provides the desired substituted pyridazine.

Scheme 33 : i NH-NK- pi? - KaEE c- N-T ^ R 10 E- D- B I OK1:. ^ - \ Kl c E -0; v.- \ _,; K) - V CHO 2) POBr, > = (P jPlíPd X Br V N? -. CO-. O V In Scheme 34, the glyoxal can react under basic conditions with an activated ketone and subsequently bromide / dehydrobromat to give the desired ketoaldehyde. Alternatively, a protected ketone can react with an activated aldehyde, undergo bromination / dehydrobromination, be deprotected and oxidized to give the regioisomeric ketoaldehyde. Cyclization as shown by Sprio and Madonia (Ann Chim 1958, 48, 1316) with hydrazine followed by palladium catalyzed coupling provides the appropriate substituted pyridazine.

Scheme 34 By analogy, Scheme 34, in Scheme 35 an aldehyde can be reacted with an activated ketone, brominated, dehydrobrominated and deprotected to give the desired ketone. Alternatively, a regioisomeric acetone can be placed through the same reaction sequence to produce an isomeric keto-to-ldehyde. Reaction with hydrazine followed by palladium catalyzed coupling provides the desired substituted pyridazine.

Scheme 35 Schemes 36 and 37 describe the synthesis of the compounds wherein M is pyrimidine. Each Scheme represents a different substitution pattern for the pyrimidine ring. In Scheme 36, a condensation with an appropriately substituted acid chloride and an activated ester followed by conjugate reduction by tin hydride (Moriya et al., J. Org. Chem. 1986, 51, 4708) gives the compound of 1, 4 -dicarboni lo, desired. Cyclisation with formamidine or a substituted amidine followed by bromination gives the desired pyrimidine regioi somé rica. Palladium catalyzed coupling provides the desired substituted pyrimidine.

Scheme 36 S- -3IOHÍ- - N o -b - ¡a (Phy) ^ Using similar chemistry, Scheme 37 shows how an amidine can be condensed with a 1,3-dicarbonyl compound and subsequently brominated at position 5 (J. Het Chem. 1973, 10, 153) to give a bromopyrimidine regioisomer. ica, specific. Palladium catalyzed coupling provides the desired pyrimidine.

Scheme 37 Using the same ketoaldehyde from Scheme 37, cyclization with appropriately substituted 1,2-diamine (Chimia 1967, 21, 510) followed by aromatization (Helv. Chim. Acta 1967, 50, 1754) provides a regioi mixture of pyrazine as illustrated in Scheme 38 The bromination of the hydrobromide salt (US Patent Number 2,403,710) produces intermediate compound for the palladium-catalyzed coupling step which occurs as-shown above.

Scheme 38 PA 'OHG O 1IH3N KH, / 7- ^ »E-D-S-OK: - / 7- if N- - ^ N N ~ K K V 2: CuC« Cr20, \ = - P; P) 4? C = 3; K2r / Br: e- "V Na2CO: E ~ DV Schemes 39 and 40 describe the synthesis of the compounds wherein M is 1, 2, 3 - 1 ria zin.In Scheme 39, a vinyl bromide is palladium coupling to a molecule containing the Rlb substituent Allylic bromination followed by displacement with acid provides the cyclization precursor Triphenylphosphine mediated cyclization (J. Org. Chem. 1990, 55, 4724) gives the 1-aminopyrazole subsequently joke with N-bromosuccinimide The re-arrangement mediated with lead tetraacetate as shown by (Ann 1985, 1732) provides the desired regioisomeric 1, 2, 3- 1 zina.Palladium-catalyzed coupling provides to the substituted triazine.

Scheme 39 In Scheme 40, an alkene is brominically brominated and the bromide is displaced to give a regioisomer of the azide in Scheme 39. Following the same reaction sequence as shown above, cyclization provides 1-aminopyrazole. Bromination followed by rearrangement mediated by lead tetraacetate gives 1, 2, 3-t riazine. The palladium catalyzed coupling provides the other desired triazine.

Scheme 40 Schemes 41 and 42 describe the synthesis of the compounds wherein M is 1, 2, 4-tine zine. In Scheme 41, a nitrile is converted using hydrazine to give the hydrazone which is condensed with an α-ketoester to give the trizinone as shown by Paudler and Lee (J. Org. Chem. 1971, 36, 3921). Bromination as shown by Rykowski and van der Pias (J. Org. Chem. 1987, 52, 71) followed by palladium catalyzed coupling provides the desired 1, 2, 4 -1 RNA.

Scheme 41 In Scheme 42, to achieve the opposite regioisomer, the reaction Scheme shown above is modified by the substitution of a protected a-ketoester. This allows the more nucleophilic nitrogen to attack the functionality of the ester that establishes the opposite regiochemistry. Deprotection and thermal cyclization gives the triazinone which is brominated as shown above. Palladium catalyzed coupling provides the other desired 1,2,4-triazine.

Scheme 42 4 i POB:.

Scheme 43 describes the synthesis of the compounds wherein M is 1, 2, 3, 4-tetra z ina. Lithiation of a vinyl bromide, tin transmetalation, palladium catalyzed carbonylation and hydrazone formation provides a diene for a subsequent Diels-Alder reaction as shown by Carboni and Lindsey (J. Am. Chem. Soc. 1959, 81, 4342). The reaction with dibenzyl azodicarboxylate followed by catalytic hydrogenation to debenzylate and decarboxylate should give, after bromination, the desired 1, 2, 3, 4-tetraethylazine. The desired coupling with palladium provides the desired substitution.

Scheme 43 Preparation of the compounds of FORMULA I that contain a Bicyclic nucleus Schemes 44 and 45 illustrate the preparation of benzopyrazole and intermediates of the indole nucleus useful for the synthesis of the compounds of the formula I. The pyrazole N-oxide initiating in Scheme 44 can be obtained by a method summarized in Chem. Ber. (1926) 35-359. The pyrazole N-oxide can be reduced by any number of methods including triphenylphosphine in reflux toluene followed by hydrolysis of the nitrile substituent to a carboxylic acid with base to give the benzopyrazole intermediate which can be coupled in the usual manner to give a compound of the title of formula I.

Scheme 44 The starting imidazole of Scheme 45 can be obtained via Fischer's indole synthesis (Org Syn, Col. Vol. III 725) from an appropriately substituted phenylazine and acetophenone. Further elaboration using normal synthetic methods include the introduction of a 3-formyl group by treatment with POCl3 in DMF, optional protection of NH indole with the SEM group (TSMCH2CH20CH2C1, NaH, DMF) and the oxidation of the aldehyde to a carboxylic it is now ready for transformation to the compounds of formula I.

Scheme 45 Preparation of an AB group of FORMULA I The compounds of this invention, wherein B is either a carbocyclic or heterocyclic residue as defined in Formula I, are coupled to A as shown generically and by the specific example in Schemes 46 and 47, respectively. Either of both A and B can be substituted with 0-2 R. W is defined as a suitable protected nitrogen, such as NO: or NHBOC; a protected sulfur, such as S-tBu or SMOM; or a methyl ester. The halogen-metal exchange of bromine in bromine-B with n-butyl lithium, rapid quenching with triisopropyl borate and acid hydrolysis yields the required boronic acid, B-B (OH) 2. The W-A-Br subunit can already be linked to the M ring before the Suzuki coupling reaction. Deprotection provides the complete subunit.

Scheme 46 B-Br 1) n-BuLi 2) (iPrOJ3B 3) HCl W-A-B Scheme 47 describes a typical example of how the AB subunit is prepared for binding to the M ring. 4-bromoani 1 ina is protected as a BOC derivative and that coupled to 2- (terbutylamino) sulphonyl phenyl boronic acid under the conditions of Suzuki 2- (t-Butylamino) sulfonyl phenyl boronic acid is prepared by the method described by Rivero (Bioorg, Med Chem. Lett, 1994, 189). Deprotection with TFA can provide the aminobi phen-4-yl compound. The phene-aminobi is then coupled to the ring-in-core structures as described below.

Scheme 47 When B is defined as X-Y, the following description applies. Groups A and B are available either from commercial sources, known in the literature or are easily synthesized by adapting standard procedures known to those skilled in the art of organic synthesis. The required reactive functional groups attached to the analogues of A and B are also available either from commercial sources, known in the literature, easily synthesized by the adaptation of standard procedures known to those skilled in the art of synthesis. In the tables that follow the chemistry required to effect the air coupling is summarized.

Table A: Preparation of the Amide Esters, Urea, Sulfonamide and Sulfamide bonds between A and B If A contains: then to give the following substituent Y reactive product AXY is: A-NHR2 as a C1C (0) -Y A-NR2-C (0) -Y substituent a secondary NH C1C (0) -Y AC (0) -And as part of a ring of the chain A-OH as a C1C (0) -Y AC (0) -Y substituent A-NHR2 as a C1C (0) -CR2R2a-Y A-NR2-C ( 0) -replacer CR2R2a_? a secondary NH C1C (0) -CR2R2a-Y AC (0) -CR2R2a- Y as part of a ring of the A-OH chain as a C1C (0) -CR2R2a-Y AOC (0) -CR2R2a -Y substituent A -NHR2 as a C1C (0) -CNR2-Y A-NR2-C (0) -substituent CR2R2a_? The chemistry of Table A can be carried out in aprotic solvents such as a chlorocarbon, pyridine, benzene or toluene, at temperatures ranging from -20 ° C to the reflux point of the solvent with or without a tri-alkylamine base.

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

The coupling chemistry of Table B can be carried out by a variety of methods. The Grignard reagent required for Y is prepared from Y-halogen analogue in dry ester, dimethoxyethane or tetrahydrofuran at 0 ° C at the reflux point of the solvent. This Grignard reagent can be reacted directly under very controlled conditions, which is low temperature (-20 ° C or lower) and with a large excess of acid chloride or with the copper bromide complex of dimethyl sulphide, catalytic or t oiquiomét rico, the dimethyl sulfide as a solvent or a variant thereof. Other available methods include the transformation of the Grignard reagent to the cadmium reagent and the coupling according to the Carson and Prout method (Org Syn. Col. Vol. 3 601, 1955) or the coupling mediated by Fe (acac) 3 according to Fiandanesse et al. (Tet. Lett., 4805, 1984), or a coupling mediated by manganese (II) catalysis (Cahiez and Laboue, Tet. Lett., 33 (31), 4437, 1992). Table C Preparation of ether and thioether bonds between A and B.

The ether and thioether bonds of Table C can be prepared by reacting the two components in a polar aprotic solvent such as acetone, dimethylformamide or dimethyl sulfoxide in the presence of a base such as potassium carbonate, sodium hydride or t- butoxy potassium at a temperature that varies from the environment to the point of reflux of the solvent used.

Table D: Preparation of SO-and-S02- bonds from thioether of Table C.

The thioethers of Table C serve as a convenient starting material for the preparation of the sulfoxide and sulfone analogues of Table D. A combination of wet alumina and Oxone can provide reliable reagents for the oxidation of the thioether to the sulfoxide as shown by Greenhalgh ( Syn. Lett., 235, 1992). The sulfone can be prepared according to the Satoh method (Chem. Lett., 381, 1992) using chloroperbenzoic acid.

Other features of the invention will become apparent in the course of the following descriptions of the exemplary embodiments that are given for illustration of the invention and are not intended to limit the same.

EXAMPLES The abbreviations used in the examples are defined as follows: "° c" for degrees Celsius, "d" for doublet, "dd" for doublet of doublets, "eq" for equivalent or equivalents, "ESMS" for mass spectroscopy by electrowelding , "H" for hydrogen or hydrogens, "h" for hour or hours, "g" for gram or grams, "m" for multiplet, "M" for molar, "mg" for milligram or milligrams, "MHz" for megahertz , "min" for minute or minutes, "mL" for milliliter or milliliters, "MS" for mass spectroscopy, "nmr" or "NMR" for nuclear magnetic resonance spectroscopy, "t" for triplet, "TLC" for chromatography thin layer, "BOP" for benzotriazole-1-yloxy-tris- (dimethylamino) phosphonium hexafluorosphate, "DMAP" for dimethylaminopyridine, "DME" for dimethoxyethane, "EDAC" for l- (3-dimethylaminopropyl) -3 hydrochloride -et? lcarbodimide, "LAH" for aluminum and lithium hydride, "NBS" for N-bromosuccinimide, "PyBrop" for hexafluorophosphate-tris-pyrrolidine-phosphonium, "TBAF" for fluoride tetrabutylammonium rod, "TBS-C1" for t-butyldimethylsilyl chloride, and "TEA" for triethylamine.

EXAMPLE 1 3-Methyl-l-phenyl-lH-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - bi en-4-yl)) carboxyamide Ethyl 2-N- (methoxy) imino-4-oxopentanoate: a mixture of ethyl pentanoate-2,4-dione (24.5 g, 154.9 mmol) and methioxamine acid chloride (13.58 g, 162.6 mmol) in ethanol (100 g. mL) was allowed to stand on activated 3 A molecular sieves (75 g) at room temperature for 18 hours. After the removal of the molecular sieves by filtration, dichloromethane (100 mL) was added and the reaction was filtered. The resulting solution was evaporated and the residue was applied to a column of silica gel. The title compound was isolated in a homogeneous form by elution with hexane: ethyl acetate 5: 1 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 g). mL) and 2-methoxyethanol (5 mL) were heated at 105 ° C for 5 hours. The reaction was evaporated, dissolved in ethyl acetate and washed with 0.2 N HCl, then with water. The solution was dried (Na2SO4), evaporated and the residue was applied to a column of silica gel. The illusion with a 10: 1 to 5: 1 gradient of hexane: ethyl acetate gave 160 mg of ethyl 3-methyl-1-phenyl-lH-pyrazolecarboxylate; LRMS (M + H) + m / z: 231. 3-methyl-l-phenyl-lH-pyrazole-5- (N- (2 '-Nt-butylaminosulfonyl- [1,1'] -bifen-4-yl)) carboxyamide: At 0 ° C, the 4- ( 2-Nt-butylaminosulfonyl) phenyl) aniline (0.22 g, 0.73 mmol) in dichloromethane (10 mL) was added a solution of trimethylaluminum (2.0 M in hexane, 5 eq, 1.75 mL). This mixture was stirred for 15 minutes then ethyl 3-methyl-1-phenyl-1H-pyrazolecarboxylate (0.16 g, 0.69 mmol) in dichloromethane (5 mL) was added. The reaction was allowed to warm to room temperature and was stirred for 18 hours. This mixture was rapidly cooled with water, then diluted with ethyl acetate and the layers were separated, dried and evaporated. The residue was applied to a column of silica gel and the title compound was isolated by gradient elution with a 3: 1 to 1: 1 mixture of hexane: ethyl acetate. 150 mg of 3-methyl-1-phenyl-1H-pyrazole-5- (N- (4- (2'-Nt-butylaminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide; HRMS ( M + H) + cal.m / z: 489. 196038, obs: 489. 194346. 3-methyl-1-phenyl-1H-pyrazole-5- (N- (2'-amino-sulfonyl- [1,1 '] - biphen-4-yl)) carboxyamide: To a solution of 150 mg of 3-methyl- l-Phenyl-lH-pyrazole-5- (N- (4- (2'-Nt-butylaminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide in trifluoroacetic acid (15 mL) was little heated for 1 hour. hour.

The reaction was evaporated taken up in ethyl acetate and washed with IN sodium hydroxide solution. The organic solution was dried and evaporated to give 140 mg of the product. Further purification of 3-methyl-1-phenyl-1H-pyrazole-5- (N- (4- (2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide was carried out by HPLC using the Gradient elution with a mixture of water: acetonitrile with trifluoroacetic acid 0. 05% in an inverted phase C18 column (60 A); HRMS (M + H) + cale, m / z: 433.133438, obs .: 433.131005.

EXAMPLE 2 3-Methyl-1- (2-methoxy) phenyl-1H-β-irazol-5- (N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide This compound was prepared by the same methodology described for Example 1 with 2-methoxyphenyl-hydrazine • HCl substituted by phenyl hydrazine. 3-Methyl-1- (2-methoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide was obtained; HRMS (M + H ) + cale.m / z: 463.144002, obs: 463.144162.

EXAMPLE 3 3-Methyl-1- (3-methoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide This compound was prepared by the same methodology described for Example 1 with 3-methoxyphenyl-hydrazine »HCl substituted by phenyl hydrazine. 3-Methyl-1- (2-methoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; HRMS (M + H) + cale, m / z: 463.144002, obs: 463.144301.

EXAMPLE 4 3-Methyl-1- (4-methoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide This compound was prepared by the same methodology described for Example 1 with 4-methoxyphenyl-hydrazine »HCl substituted by phenyl-hydrazine. 3-Methyl-1- (2-methoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide was obtained; HRMS (M + H ) + cale, m / z: 463.144002, obs: 463.141980.

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

EXAMPLE 6 3-Methyl-1- (3-hydroxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide The product of Example 3, 3-Methyl-l- (3-methoxy) phenyl-lH-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide was treated according to the procedure described for Example 5 to give the title compound: HRMS (M + H) + cale, m / z: 449.128352, obs: 449.127'620 EXAMPLE 7 3-Methyl-1- (4-hydroxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide The product of Example 4, 3-methyl-1- (4-methoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide was treated with according to the procedure described for Example 5, to give the title compound; HRMS (M + H) + cale, m / z: 449.128352, obs: 449.127304.

EXAMPLE 8 3-Methyl-l- (4-methoxyphenyl) -lH-pyrazole-5- (N- (3-fluoro- (2 * - aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide 3-Methyl-l- (4-methoxyphenyl) -lH-pyrazolecarboxylic acid: A mixture of ethyl 3-methyl-l- (4-methoxyphenyl) -lH-pyrazolecarboxylate (0.01997 mol, 5.197 g) and potassium hydroxide (3.362 g, 3.0 eq.) In ethanol (70 mL) was stirred at room temperature for 5 hours. The solvent was removed in vacuo and the residue was taken up in water. This was extracted with methylene chlorine (3 x) to remove the unreacted starting material. The aqueous was made acidic (pH 3) by the dropwise addition of concentrated HCl at 0 ° C, to give white acid precipitation. The solid acid was obtained by filtration and pumped for several hours for drying. This procedure gave 4.23 g of pure product (91%); p.f .: 161.8 ° C. 2-Fluoro-4- (2-aminosulfonylphenyl) aniline: A mixture of 2-fluoro-4-bromoaniline (0.01 mol, 2.51 g), boronic acid (2.57 g, 1.0 eq.), Sodium carbonate (3.18 g, 3.0 eq.), And tetrakis (triphenylphosphine) palladium (0) (0.23 g, 0.02 eq.) In tetrahydrofuran (100 mL) and water (50 mL) was stirred at room temperature for 30 minutes while pumping nitrogen to remove the oxygen. This 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 and the residue was taken up in water, then extracted with ethyl acetate (3 x); the ethyl acetate extracts were washed with brine, dried (MgSO 4), and evaporated. This residue was purified by flash chromatography on a column of silica gel (150 g) eluted with 2.5: 1 hexane: ethyl acetate to give 1.976 g of the pure product (61%). 3-Methyl-l- (4-methoxyphenyl) -lH-pyrazole-5- (N- (3-fluoro-4- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide: A The solution of 3-methyl-1- (4-methoxyphenyl) -lH-pyrazolecarboxylic acid (0.001 mole, 0.232 g) in dry acetonitrile (10 mL) was added thionyl chloride (0.3 mL, 4.0 eq.). The reaction medium was heated to 50 ° C for 1 hour, then allowed to cool to room temperature and stirred for 1 hour.The solvent and extra thionyl chloride were removed in vacuo and the residue was pumped for several hours to dry further. To this dry residue was added a mixture of 2-fluoro-4- ((2-Nt-butylsulfonamido) phenyl) aniline (0.322 g, 1.0 eq.) And triethylamine (0.14 mL, 1.0 eq .; 2.0 eq. HCl) in dry methylene chloride (10 mL) This reaction mixture was allowed to stir at room temperature for 2 hours.The reaction mixture was evaporated and purified by flash chromatography on a column of silica gel (50 g) eluted with hexan or: ethyl acetate 3: 1 to give 0.301 g of the pure product with t-butyl sulfonamide sulfonamide (56%). This product was treated with trifluoroacetic acid at 55 ° C for 2 hours for the deprotection of sulfonamide to give 0.287 g of pure product (86%) after purification by reverse phase HPLC; HRMS (M + H) + cale. 481.134581, found 481.133650 for the title compound.

EXAMPLE 9 3-Methyl-l- (4-methoxyphenyl) -lH-pyrazole-5- (N- (3-bromo-4- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide 2-Bromo-4- (2-aminosulfonylphenyl) aniline: This compound was prepared by the method described for 2-fluoro-4- (2-aminosulfonylphenyl) aniline described in EXAMPLE 8 when starting with 2,4-dibromoaniline instead of 2-fluoro-4-bromoaniline. 3-Methyl-l- (4-methoxyphenyl) -lH-pyrazole-5- (N- (3-bromo-4- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide: This compound was prepared with the same method for EXAMPLE 8 by coupling with 2-bromo-4- ((2-Nt-butylsulfonamido) phenyl) aniline in place of 2-fluoro-4- ((2-Nt-butylsulfonamido) phenyl) Aniline The title compound was obtained as a pure product after purification by reverse phase HPLC, HRMS (M + H) + ca. 541.054513, found 541.055340.

EXAMPLE 10 3-Methyl-l-4- (4-methoxyphenyl) -lH-pyrazole-5- (N- (3-iodo- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide 2-Iodo-4- (2-aminosulfonylphenyl) aniline: This compound was prepared by the method described for 2-fluoro-4- (2-aminosulfonylphenyl) aniline described in EXAMPLE 8 when starting with 2-iodo-4-bromoaniline in place of 2-fluoro-4-bromoaniline. 3-Methyl-l- (4-methoxyphenyl) -lH-pyrazole-5- (N- (3-iodo- (2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide: This compound is prepared by the same methods described for EXAMPLE 8 by coupling with 2-iodo-4- ((2-Nt-butylsulfonamido) phenyl) aniline in place of 2-fluoro-4- ((2-Nt-butylsulfonamido) phenyl) aniline The title compound was obtained as pure product after purification by reverse phase HPLC HRMS (M + H) + ca. 589.040654, found 589.039223.

EXAMPLE 11 3-Methyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (3-methyl- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide 2-Methyl -4- (2-aminosulfonylphenyl) aniline: This compound was prepared by the method described for 2-fluoro-4- (2-aminosulfonylphenyl) aniline described in EXAMPLE 8 when starting with 2-methyl-4-bromoaniline instead of 2 -fluoro-4-bromoaniline. 3-Methyl-l- (4-methoxyphenyl) -lH-? Irazol-5- (N- (3-methyl- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide: This compound was prepared by the same methods described for EXAMPLE 8 by coupling with 2-methyl-4- ((2-Nt-butylsulfonamido) phenyl) aniline in place of 2-fluoro-4- ((2-Nt-butylsulfonamido) phenyl) Aniline The title compound was obtained as the pure product after purification by reverse phase HPLC HRMS (M + H) + ca. 477.159652, found 477.159337.

EXAMPLE 12 3-Methyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4-N-carboxyldimethylamine) phenylcarboxyamide 4- (N-Carboxyldimethylamine) aniline: A 2-fold excess of pure dimethylamine (ca. 0.73 g) was added to a solution of 0 ° C of p-nitrobenzoyl chloride (1.5 g, 8.1 mmol) in dichloromethane (50 mL ). The reaction was then evaporated to dryness and the residue was dissolved in ethyl acetate. The solution was washed with IN hydrochloric acid and brine, then dried, evaporated to give 4- (N-carboxyldimethylamine) nitrobenzene. This material was reduced under a mixture of hydrogen gas (50 psi) in methanol (100 mL) in the presence of palladium catalyst in 10% carbon (100 mg). After about 2 hours, the reduction was determined; the reaction was purged with nitrogen gas the catalyst was removed by filtration through a pad of Celite. The solvent was evaporated to give the title compound. 3-Methyl-l- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4-N-carboxyldimethylamine) phenyl) carboxyamide: This compound was prepared by the same methods described for EXAMPLE 8 when coupling with 4- (N-carboxyldimethylamine) aniline in place of 2-fluoro-4- ((2-Nt-butylsulfonamido) phenyl) aniline and then omitting the final step of deprotection with trifluoroacetic acid. The title compound was obtained as a pure product after purification by inverted phase HPLC; HRMS (M + H) + cale. 379.177016, found 379.176235.

EXAMPLE 13 3-Methyl-l- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4-N-pyrrolidinocarbonyl) phenyl) carboxyamide 4- (N-Pyrrolidinocarbonyl) aniline: A 2-fold excess of pure pyrrolidine (1.15 g, 16.2 mmol) was added to a solution of 0 ° C of p-nitrobenzoyl chloride (1.5 g, 8.1 mmol) in dichloromethane (50 g). mL). The reaction was then evaporated to dryness and the residue was dissolved in ethyl acetate. The solution was washed with IN hydrochloric acid solution and brine, then dried and evaporated to give 4- (N-pyrrolidinocarbonyl) nitrobenzene. This material was reduced under the atmosphere of hydrogen gas (50 psi) in methanol (100 mL) in the presence of 10% palladium on carbon catalyst (100 mg). After about 2 hours, the reduction is finished; The reaction was purged with nitrogen gas and the catalyst was removed by filtration through a pad of Celite. The solvent was evaporated to give the title compound. 3-Methyl-l- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4-N-pyrrolidinocarbonyl) phenylcarboxyamide: This compound was prepared by the same methods described for EXAMPLE 8 when coupling with 4- (N -pyrrolidinocarbonyl) aniline instead of 2-fluoro-4- ((2-Nt-butylsulfonamido) phenyl) aniline and then by omitting the final step of deprotection with trifluoroacetic acid.The title compound was obtained as pure product after purification by inverted phase HPLC; HRMS (M + H) + ca. 404.184841, found 404.182119.

EXAMPLE 14 3-Methyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4-a-methyl-N-pyrrolidine) phenyl) carboxyamide 4- (α-N-pyrrolidine) methylaniline: To pyrrolidine (0.67 g, 0.79 mL, 9.4 mmol) in chloroform (50 mL) was added 4-nitrobenzyl bromide (2.03 g, 9.4 mmol) and sodium carbonate (2 g). The reaction was refluxed for 2 hours, then stirred at room temperature for 18 hours. Water was added to the reaction mixture, then the layers were divided. The chloroform layer was dried and evaporated to give 1.55 g of the N-alkylation product; LRMS (M + H) + m / z: 207.2. The reduction of the nitro group in the material prepared above was effected 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 was diluted with IN sodium hydroxide solution and extracted with ethyl acetate (3 x). The extracts were washed with brine, dried and evaporated to give 1.23 g of 4- (a-N-pyrrolidino) ethylaniline; LRMS (M + H) + m / z: 177.2. 3-Methyl-l- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4-a-methyl-N-pyrrolidino) phenyl) carboxyamide: A mixture of 3-Methyl-1- (4-methoxyphenyl) acid ) -lH-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 was added. The reaction was allowed to thaw at room temperature and was stirred for 18 hours. The reaction was diluted with IN sodium hydroxide, then extracted with ethyl acetate. The extracts were washed with brine, dried and evaporated. This material was purified by HPLC using gradient elution with a mixture of water: acetonitrile with 0.05% trifluoroacetic acid on an inverted phase C18 column (60 A) to give the title compound (70 mg); LMRS (M + H) + m / z: 391.2.

EXAMPLE 15 3-Trifluoromethyl-1- (4-methoxyphenyl) -l-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide 3-trifluoromethyl-5-methyl -l- (4-oxyphenyl) -lH-pyrazole: A mixture of 1,1-trifluoro-2,4-pentanedione (0.02 mol, 2.4 mL) and 4-methoxyphenyl-hydrazine HCL (4.54 g, 1.3 eq .) in 2-methoxyethanol (100 mL) and acetic acid (30 mL) was refluxed for 6 hours.The reaction mixture was evaporated and purified by flash chromatography on a column of silica gel (400 g). it was eluted with hexane: ethyl acetate 4: 1 to give 4.5 g of the pure product (88%) 3-Trifluoromethyl-5-hydroxymethyl-1- (4-methoxyphenyl) -1H-pyrazole: A mixture of 3-trifluoromethyl-5-methyl-1- (4-methoxyphenyl) -lH-pyrazole (0.01756 mol, 4.5 g), N-bromosuccinamide (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 the solid impurities and washed with carbon tetrachloride (100 mL). The filtrate was evaporated and purified by flash chromatography on a silica gel column (400 g) and eluted with hexane: ethyl acetate 4: 1 to give 3.826 g of the pure product (65%). This material was treated with calcium carbonate (2,637 g, 1.5 eq.) In dioxane (80 mL) and water (20 mL) at 55-60 ° C for 18 hours. The reaction mixture was evaporated and purified by flash chromatography on a column of silica gel (400 g) eluted with hexane: ethyl acetate 4: 1 to give 1198 g of the pure product (39%). Recrystallization from a mixture of benzene: hexane gave an analytically pure sample; p.f. 79.0 ° C; CHNF: theory% C 52.95,% H 4.07,% N 10.29,% F 20.94, found% C 52.88; % H 3.98; % N 10.11; % F 20.62.

Acid-3-trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5-carboxylic acid: To the solution of 3-trifluoromethyl-5-hydroxymethyl-1- (4-methoxyphenyl) -lH-pyrazole (4.4007 mmol, 1.198 g) in acetonitrile (20 mL) and water (20 L) was added sodium periodate (1977, 2.1 eq.) and several crystals of ruthenium chloride (III) at 0 ° C. This reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered through Celite to remove the white solid impurity and the filter cake was washed with acetonitrile: water 1: 1. The filtrate was evaporated in vacuo and the residue was taken up in water. The aqueous layer was made acidic (pH 3) by dropwise addition of concentrated HCL at 0 ° C, all was extracted with ethyl acetate (3 x); the ethyl acetate extracts were washed with brine, dried (MgSO 4), and evaporated to give 1.13 g of the pure product (90%). 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (2'-Nt-butylaminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide: A 300 mg of acid 3 -trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5-carboxylic acid (1.05 mmol) in dichloromethane (10 mL) at 0 ° C was added a solution of oxalyl chloride in dichloromethane (2M, 1.5 equivalents, 1.58 mmol 0.8 mL) and one drop of dimethylformamide After 4 h the reaction was finished, the solvent was evaporated and the acid chloride was taken to the next reaction The material prepared above was dissolved in dichloromethane (20 mL) and then added over a period of 15-20 minutes to a 0 ° C solution of 4- (2-Nt-butylaminosulfonyl) phenyl) aniline (1.2 equivalents, 1.25 mmol, 0.365 g), pyridine (10 equivalents, 12.5 mmol, 0.99 g , 1.0 mL) and N, N-dimethylaminopyridine (1.2 equivalents, 1.25 mmol, 0.155 g) in dichloromethane (20 mL). The reaction was maintained at 0 ° C low until thin layer chromatography indicated that all of the starting acid chloride was consumed. The reaction was evaporated, then the residue was dispersed in IN hydrochloric acid solution. The suspension was extracted with ethyl acetate; the extracts were washed with IN hydrochloric acid solution (2 x), then dried and evaporated. 660 mg of the desired product were obtained; LRMS (M + Na) + m / z: 594.5. 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide: 3-Trifluoromethyl-1- ( -methoxyphenyl) -lH-pyrazole-5- (N- (2'-Nt-butylaminosulfonyl- [1,1 '] -bifen-4-yl carboxyamide (0.66 g) was dissolved in trifluoroacetic acid (20 mL) and heated The reaction was evaporated, then dissolved in ethyl acetate and washed with 1N sodium hydroxide in solution (2x) and brine.This solution was dried and evaporated to 0.48 g of the crude product. it was made analytically pure by first subjecting it to flash chromatography with a column of 200 g of silica gel and elution with hexane: ethyl acetate 2: 1 and finally recrystallizing the homogeneous chromatography product from chloroform 0.262 g of the compound were obtained of the title, mp: 237.3; CHNSF: theory% C 55.81,% H 3.718,% N 10.85,% S 6.218,% F 11.03, found% C 56.02,% H 3.77,% N 10.51,% S 5.84,% F 11.29 .

EXAMPLE 16 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4-N-pyrrolidinocarbonyl) phenyl) carboxyamide 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4-N-pyrrolidinocarbonyl) phenyl) carboxyamide: 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole- 5-carboxylic acid (500 mg) was dissolved in anhydrous CH2C12 (25 mL) with thionyl chloride (0.257 mL). This mixture was stirred at room temperature for 24 hours. The volatile products were removed under reduced pressure and the solution was dried under vacuum. 4- (N-Pyrrolidinocarbonyl) aniline (0.369 g) was dissolved in anhydrous CH2C12, 30 mL) and cooled to 0 ° C. Anhydrous pyridine (1.43 mL), and DMAP (0.259 g) were added and the mixture was stirred for 15 minutes. The acid chlorine prepared was dissolved in anhydrous CH2C12 (5 mL) and added dropwise to the reaction mixture. The reaction was warmed to room temperature and stirred overnight. The mixture was concentrated in vacuo. Purification was done on silica gel using ethyl acetate: hexane (1: 1) as the eluent yielding 325 mg (95% purity by HPLC). LRMS (M + H) + = 459 C23H2? N403F3. HRMS for C23H2? N403F3 (M + H) + cale 458.156576, found 458.156478. 1H NMR (CDC13) d 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 17 3-Trifluoromethyl -1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (5- (2-methanesulfonyl) phenyl) pyridine-2-yl) carboxyamide 3-trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (5- (2-ethanesulfonyl) phenyl) pyridin-2-yl) carboxyamide: This material was prepared according to the methods described by EXAMPLE 15 with the exception that during the coupling step the 2-amino-5- (2-Nt-butylaminosulfonyl) phenyl) pyridine was replaced by 4- (2-Nt-butylaminosulfonyl) phenyl) aniline. Purification by HPLC using gradient elution with a mixture of water: acetonitrile with 0.05% trifluoroacetic acid on an inverted phase C18 (60 A) column gave a pure sample of the title compound; LRMS (M + H) + m / z. 517, (M + Na) + m / z: 539.

EXAMPLE 18 3-Trifluoromethyl -1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (5-N-pyrrolidinocarbonyl) pyridine-2-yl) carboxyamide 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. The mixture was added with N-methylmorpholine (3.31 g, 32.7 mmol) and HBTU (6.2 g, 16.4 mmol). The reaction was allowed to warm to room temperature and was stirred for 18 hours. The reaction was diluted with IN sodium hydroxide and extracted with ethyl acetate. The product was purified by flash chromatography using 10% methanol in chloroform as the eluent; 1.65 g of the product were used; LRMS (M + H) + m / z: 192. 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (5-N-pyrrolidinocarbonyl) pyridine-2-yl) carboxyamide: This material was prepared according to the methods described for EXAMPLE 15 with the exception that during the coupling step the 2-amine-5- (N-pyrrolidinocarbonyl) pyridine was replaced by 4- (2-Nt-butylaminosulfonyl) phenyl) aniline. Purification by HPLC using gradient elution with a mixture of water: acetonitrile with 0.05% trifluoroacetic acid on an inverted phase C18 (60 A) column gave a pure sample of the title compound; LRMS (M + H) + m / z: 460.2.

EXAMPLE 19 3-Methyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (5-N-pyrrolidinocarbonyl) pyridine-2-yl) carboxyamide 3-Methyl-l- (4-methoxyphenyl) -lH-pyrazole-5- (N- (5-N-pyrrolidinocarbonyl) pyridine-2-yl) carboxyamide: To a solution of 3-methyl-1- (4- methoxyphenyl) -1H-pyrazolecarboxylic acid (1.02 g, 4.4 mmol) in dichloromethane (20 mL) at 0 ° C was added 4.4 mL of a 2M solution of oxalyl chloride in dichloromethane followed by a drop of dimethylformamide. After 2 hours, the solvent was removed and 1.12 g of acid chloride was obtained. This material was taken to 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 a solution of dichloromethane (10 mL) of acid chloride prepared previously (0.5 g, 2.0 mmol). The reaction was allowed to thaw at room temperature and evaporated. The product was isolated by flash chromatography with 10% chloroform in methanol. Purification by HPLC using gradient elution with a mixture of water: acetonitrile with 0.05% trifluoroacetic acid on an inverted phase C18 (60 A) column gave a pure sample of the title compound; HRMS (M + H) + cale, m / z: 405.180090, obs: 405.180328.

EXAMPLE 20 3-Methyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (5- (2-sulfonamide) phenyl) pyridin-2-yl) carboxyamide This compound was prepared by the methodology described for EXAMPLE 19 with the exception that in the coupling step, 2-amino-5- (2- (Nt-butylsulfonamide) phenyl) pyridine was used instead of 2-amino-5- ( N-pyrrolidinocarbonyl) pyridine. The resulting product was filtered into trifluoroacetic acid (20 mL) for 18 hours, after which the solvent was removed by distillation under reduced pressure. Purification of the pure product by HPLC using gradient elution with a mixture of water: acetonitrile with 0.05% trifluoroacetic acid on an inverted phase C18 (60 A) column gave a pure sample of the title compound; HRMS (M + H) + cale, m / z: 464.139251, obs: 464.138485.

EXAMPLE 21 3-Methyl-1- (4-methoxyphenyl) -lH-pyrazole-5-N- (4- (N-carboxyl-3-hydroxypyrrolidine) phenyl) carboxyamide 4- (N-Carboxyl-3-t-butyldimethylsilyloxypyrrolidine) aniline: To acid chloride of 3-hydroxypyrrolidine (1.63 g, 14.9 mmol) and triethylamine (1.51 g, 14.9 mmol) in dichloromethane (50 mL) at 0 ° C, a solution of p-nitrobenzoyl chloride (2.5 g, 12.4 mmol) was added. ) in dichloromethane (50 mL).

The reaction was evaporated to dryness and the residue was dissolved in ethyl acetate. This solution was washed with IN hydrochloric acid solution and brine, then dried and evaporated to give 2.22 g of product; LRMS (M + H) + m / z: 237. A solution of tetrahydrofuran (75 mL) of the material prepared above (2.2 g 9.4 mmol), t-butyldimethylsilyl chloride (1.54 g, 10.2 mmol) and imidazole (0.89 g, 13.0 mmol) was cooled to 0 ° C and stirred for 72 hours. The reaction mixture was filtered and evaporated. It was dissolved in ethyl acetate and washed with water and brine, dried and evaporated. Flash chromatography using hexane: ethyl acetate 2: 1 gave 2: 7 g of pure product; LRMS (M + H) + m / z: 351. The material prepared above (2.07 g) was reduced under an atmosphere of hydrogen gas (50 psi) in methanol (100 mL) in the presence of 10% palladium catalyst on carbon (200 mg). After about 2 hours, the reduction is finished; The reaction was purged with nitrogen gas and the catalyst was removed by filtration through a pad of Celite. The solvent was evaporated to give 1.75 g of 4- (N-carboxyl-3-t-butyldimethylsilyloxypyrrolidine) aniline; LRMS (M + H) + m / z: 321. 3-Methyl-l- (4-methoxyphenyl) -lH-pyrazole-5-N- (4- (N-carboxyl-3-hydroxypyrrolidine) phenyl) carboxyamide: This compound was prepared by the methodology described for EXAMPLE 19 with the except that in the coupling step, 4- (N-carboxyl-3-t-butyldimethylsilyloxypyrrolidine) aniline was used in place of 2-amino-5- (N-pyrrolidinocarbonyl) pyridine. The protecting group of t-butyldimethylsilyl was removed by treatment with 2 equivalents of tetrabutylammonium fluoride in tetrahydrofuran. The solvent was evaporated, the residue was dissolved in ethyl acetate and washed with water. After drying and removal of the solvent, the crude product was purified by HPLC using gradient elution with a mixture of water: acetonitrile with 0.05% trifluoroacetic acid on an inverted phase C18 (60 A) column gave a pure sample of the compound of Title; HRMS (M + H) + cale, m / z: 420.179756, obs: 420.175589.

EXAMPLE 22 2-Amino-4- (4-methoxyphenyl) -5 - [(2'-amino-sulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -iazole 1- (4-Methoxyphenyl) -1 '- (4-bromophenyl) aminocarbonyl acetone: 4-Methoxyacetophenone (3.00 g, 19.97 mmol) was dissolved in 60 mL of THF followed by the addition of LDA (2.0 M in THF, 10.0 mL, 20 mmol) and stirred at room temperature for 1 hour. 4-Bromophenylisocyanate (3.95 g, 19.97 mmol) was added and the reaction was allowed to stir at room temperature overnight. The solution was acidified with 10% HCl and the solution was diluted with 300 mL EtOAc. The solution was washed with brine (300 mL), dried over MgSO 4, filtered through a plug of silica and the volatiles were removed in vacuo The product was isolated by recrystallization from hot ethyl ether (3.08 g, 44%). ). 2-Amino-4- (-methoxyphenyl) -5- (4-bromophenyl) -iazole: L- (4-Methoxyphenyl) -1 '- (4-bromophenyl) aminocarbonyl acetone (3.08 g, 8.84 mmol) and hydroxy (tosyloxy) iodobenzene (3.46 g, 8.84 mmol) were combined in 100 mL of acetonitrile and refluxed for 45 minutes followed by the addition of thiourea (0.673 g, 8.84 mmol) and refluxed for 4 hours. The volatiles were removed in vacuo the residue was triturated with MeOH (1.68 g, 47%) MS (NH3-DCI) 404.0 (M + H) + 2-Amino-4- (4-methoxyphenyl) -5 - [(2'-tert-butylaminosulfonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] thiazole: 2-amino-4- (4- methoxyphenyl) -5- (-bromophenyl) thiazole (1.68 g, 4.15 mmol), sodium carbonate (0.88 g8.31 mmol), tetrabutylammoniobromide (0.134 g, 0.415 mmol) and 2- (tert-butylaminosulfonyl) phenyl boronic acid (1.50 g, 5.82 mmol) were combined in a solution containing benzene: acetonitrile: water 1: 1: 4 and I degas with N2 for 15 minutes. After purging with N2 tetrakistriphenylphosphine palladium (0) was added and the reaction mixture was heated to reflux overnight. The solution was diluted with EtOAc, placed in a separatory funnel and washed with three 150 mL portions of brine. The organic products were dried over MgSO4, filtered through a plug of silica gel and the volatiles were removed in vacuo. The residue was dissolved in a minimum amount of hot CHC13, the product was triturated with Et20 and isolated (1.59 g, 71.3%) by vacuum filtration. MS (NH3-DCI) 537.2 (M + H) +. 2-Amino-4- (4-methoxyphenyl) -5 - [(2'-amino-sulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -iiazole: 2-amino-4- (-methoxyphenyl) - 5- [(2'-Tert-butylaminosulfonyl- [1,1 '] -biphen- -yl) aminocarbonyl] thiazole (1.59 g, 2.96 mmol) was dissolved in 20 mL of TFA and heated to reflux for 1 hour. The volatiles were removed in vacuo and the title compound was purified by preparative HPLC. MS (NH3-DCI) 481.1 (M + H) +.

EXAMPLE 23 2-Bromo-4- (4-methoxyphenyl) -5 - [(2'-amino-sulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -iazole Methyl-3- (methoxyphenyl) -3-oxopropianate: Bis- (trimethylsilyl) amine (158.2 mL, 0.750 mol) was dissolved in 150 mL of THF and cooled to -78 ° C with the aid of a dry ice bath. /acetone. N-butyl lithium (2.5 M in hexane, 300 mL, 0.750 mol) was introduced via cannula into the system and stirred at that temperature for 20 minutes. 4-Methoxy-acetophenol (51.20 g, 0.340 mol) was added via a solid addition funnel and stirred at -78 ° C for 3 hours. Dimethylcarbonate (87.0 mL, 1.02 mol) was added via cannula and the system was allowed to stir overnight with heating at room temperature. The solution was acidified with 10% HCl, diluted with 1 liter of EtOAc and washed three times with 400 L of 10% HCl. The organic products were dried over MgSO 4, filtered through a plug of silica gel and the volatiles were removed in vacuo. The title compound was obtained as a viscous brown oil (65.09 g, 91.7%) MS (NH3-DCI) 347.9 (M + H) +. 2-Amino-4- (4-methoxyphenyl) -5- (carbomethoxy) iazole: Methyl-3- (methoxyphenyl) -3-oxopropianate (33.34 g, 95.75 mmol) and hydroxy (tosyloxy) iodobenzene (37.55 g, 95.75 mmol) in 350 mL of acetonitrile and refluxed for 45 minutes, followed by the addition of thiourea (7.29 g, 95.75 mmol) and refluxed for 2 hours. The volatiles were removed in vacuo and the residue was dissolved in 50/50 EtOAc / Hexane and passed through a plug of silica gel. Once the impurities were eluted, the product was recovered by elution with 100% EtOAc and the volatiles were removed in vacuo. The title compound was 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: Cupric bromide (11.42 g, 51.17 mmol) and tert-butyl nitrite (6.93 mL, 58.16 mmol) were combined in 75 mL of acetonitrile were heated to reflux until the gas emission was stopped. 2-Amino-4- (4-methoxyphenyl) -5- (4-bromophenyl) thiazole (12.3 g, 46.55 mmol) was added to the acetonitrile solution and heated to reflux until the gas emission was stopped. The solution was diluted with 300 mL of EtOAc and washed repeatedly with 250 mL of a saturated NaC03 solution. The organic products were dried over MgSO4, filtered through a plug of silica gel and the volatiles were removed in vacuo. The residue was purified by preparative HPLC to yield the title compound as a brown solid, 8.95 g (57%) MS (NH3-DCI) 328.0 (M + H) +. 2-Bromo-4- (4-methoxyphenyl) -5 - [(2'-tert-butylaminosulfonyl- [1, 1 '] -bifen-4-yl) aminocarbonyl] -iiazole: To a solution of (2 '-ter-butylated inosulfonyl- [1, 1'] -bifen-4-yl) amine (2.57 g, 8.47 mmol) in 50 mL of methylene chloride at 25 ° C was added trimethylaluminum (12.7 mL of a solution 2.0 M in toluene, 25.41 mmol) dropwise. The resulting solution was allowed to stir until no more gas emission was observed (approximately 15 minutes). To this solution was added 2-bromo-4- (4-methoxyphenyl) -5- (4-bromophenyl) thiazole (2.94 g, 9.31 mmol) and stirred at reflux for 2 hours. The solution was rapidly cooled with NH 4 Cl, diluted with 200 mL of EtOAc and washed 2 times with 200 mL portions of brine. The organic products were dried over MgSO4, filtered through a plug of silica and the volatiles were removed in vacuo to yield the title compounds as a golden solid (5.0 g, 98%) MS (HN3-DCI) 600.3 (M + H) +. 2-Bromo-4- (4-methoxyphenyl) -5 - [(2'-amino-sulfonyl- [1,1 '] -biphen-4-yl) aminocarbonyl] thiazole: The deprotection with trifluoroacetic acid used in the last step of Example 1 with 2-bromo-4- (4-methoxyphenyl) -5 - [(2'-t-butylaminosulfonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] thiazole (1.00 gm, 1.66 mmol), composed of the title. It was isolated as a white solid by preparative HPLC, HPLC, MS (ESI) 543.8 (M + H) +.

EXAMPLE 24 2-Chloro-4- (4-methoxyphenyl) -5 - [(2'-amino-sulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -iazole.

Using methods similar to Example 2 with the exception that SUC2 is used in place of CuBr2 is used in the diazotization and halogenation of 2-amino-4- (4-methoxyphenyl-5 (4-bromophenyl) thiazole to give the corresponding 2- chloro-4- (4-methoxyphenyl) -5- (4-bromophenyl) thiazole The final product, 2-chloro-4- (4-methoxyphenyl) -5- [2'-aminosulfonyl- [1,1 '] - bifen-4-yl) aminocarbonyl] thiazole, was isolated as a white solid by preparative HPLC; MS (NH3-DCI) 500.3 (M + H) +.

EXAMPLE 25 2-Chloro-4- (4-phenoxy) -5 - [(2'-amino-sulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole 2-Chloro-4- (4-phenoxy) -5 - [(2'-amino-sulfonyl- [1,1 '] -biphen-4-yl) aminocarbonyl] -iazo: 2-Chloro-4- (4-methoxyphenyl) -5- [(2'-amino-sulfonyl- [1, 1 '] -bifen-4-yl) aminocarbonyl] thiazole (0.40 g, 8 mmol) was dissolved in 5 mL of CH2C12 and cooled to 0 ° C, followed by addition of BC13 (1.0 M solution in CH2Cl2, 4.8 mL, 4.8 mmol) and allowed to stir 72 hours at room temperature. The solution was cooled with 10% HCl and the volatile products were removed in vacuo. The title compound was purified by preparative HPLC, MS (NH3-DCI) 485.9 (M + H) + EXAMPLE 26 2-Methoxy-4- (4-methoxyphenyl) -5 - [(2'-amino-sulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -iazole The 2-methoxy-4- (4-methoxyphenyl) ) -5- [(2'-Amino-sulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -iazole: 2-Chloro-4- (4-methoxyphenyl) -5- [(2'-aminosulfonyl [ 1,1 '] -bifen-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 heated to reflux; The addition is monitored by TLC. The title compound was isolated as a white solid by preparative HPLC, MS (ESI) 518.0 (M-Na) +.

EXAMPLE 27 2-Tiomethyl-4- (4-methoxyphenyl) -5 - [(2'-amino-sulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole 2-Tiomethyl-4- (4-methoxyphenyl) -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] thiazole: 2-chloro-4- (4-methoxyphenyl) ) -5- [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] thiazole (0.700 g, 1.4 mmol) and sodium thiomethoxide (0.490 g, 7.0 mmol) were refluxed at 50 ° C. mL of THF and the reaction was checked by TLC (approximately 4 h). The volatiles were removed in vacuo and the title compound was purified by preparative HPLC. MS (ESI) 534.0 (M + H) +.

EXAMPLES 28 and 29 2-Methylsulfoxida-4- (4-methoxyphenyl) -5 - [(2'-amino-sulfonyl- [1,1 '] -biphen-4-yl) aminocarbonyl] -iole and 2-methylsulfone-4- (4 -methoxyphenyl) -5- [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] thiazole 2-Thiomethyl-4- (4-methoxyphenyl) -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] thiazole (0.54 g, 1.05 mmol) and Oxone® (1.94 g, 3.16 mmol) were dissolved in 300 mL of a 50/50 methanol / water solution and stirred at room temperature for 72 hours. The solution was diluted with 400 mL of EtOAc and washed with three 200 mL portions of brine. The organic layers were dried over MgSO4, filtered through a plug of silica gel, the volatiles were removed in vacuo and the residue was purified by preparative HPLC. EXAMPLES both 28 and 29 were recovered from HPLC purification 2-Methylsulfoxida-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) aminocarbonyl ] thiazole MS (ESI) 527.9 (M + H) + 2-Methylsulfone-4- (4-methoxyphenyl) -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] thiazole MS (ESI) 543.9 (M + H) +.

EXAMPLE 30 2-Cyano-4- (4-methoxyphenyl) -5 - [(2'-amino-sulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole 2-Cyano-4- (4-methoxyphenyl) -5 - [(2'-amino-sulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole: 2-methylsulfone-4- (4-methoxy-phenyl) -5- [(2'-Amino-sulfonyl- [1,1 '] -biphen-4-yl-aminocarbonyl] thiazole (0.500 g, 0.920 mmol) and sodium cyanide (0.225 g, 4.60 mmol) were combined in 35 mL of DMF and stirred at room temperature overnight followed by heating for several hours at 70 ° C. The solution was dissolved in 300 mL of EtOAc and washed with three 200 mL pons of brine, dried over MgSO4, filtered at room temperature. through a plug of silica and the volatiles were removed in vacuo.The title compound was isolated with a white solid by preparative HPLC, MS HPLC (ESI) 490.9 (M + H) +.

EXAMPLE 31 2-N, N-Dimethylamino-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] thiazole 2-N, N-Dimethylamino-4- (4-methoxyphenyl) -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] thiazole: 2-chloro-4- ( 4-methoxyphenyl) -5 - [(2'-amino-sulfonyl- [1,1 '] -biphen-4-yl) aminocarbonyl] thiazole (0.200 g, .4 mmol) and dimethyl-amine (40% solution in water, 1.00 mL, 2.0 mmol) were stirred at room temperature in 50 mL of THF overnight. The volatiles were removed in vacuo and the title compound was purified by preparative HPLC, MS (ESI) 509.0 (M + H) +.

EXAMPLE 32 2- (1-Pyrrole) -4- (4-methoxyphenyl) -5 - [(2'-amino-sulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole 2- (1-pyrrole) -4- (4-methoxyphenyl) -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] thiazole: 2-amino-4- ( 4-methoxyphenyl) -5 - [(2'-amino-sulfonyl- [1,1 '] -biphen-4-yl) aminocarbonyl] thiazole (0.050 g, 0.104 mmol) and 2,5-dimethoxy tetrahydrofuran (0.015 mL, 0.114 mmol ) were refluxed in 20 mL of acetic acid for 1 hour. The volatiles were removed in vacuo and the title compound was purified by preparative HPLC, MS (ESI) 531.0 (M + H) +.

EXAMPLE 33 3- (4-Methoxyphenyl) -5- [5- (2'-amino-sulfonyl-phenyl-1-yl) -pyridin-2-yl] -aminocarbonyl-5-carbomethoxymethyl-isoxazoline 4-Methoxybenzaldehyde-oxime: 4-methoxybenzaldehyde (10.0 g, 73.4 mmol) was dissolved in 200 mL of ethanol.

A solution of hydroxyamine hydrochloride was added (6.38 g, 91.8 mmol) in 50 mL of H2O followed by a solution of sodium acetate (12.1 g, 146.8 mmol) in 50 mL of H20. The mixture was stirred at room temperature under N2 for 12 hours. The ethanol was removed in vacuo and the aqueous mixture was extracted with EtOAc. The EtOAc solution was washed with brine, dried over MgSO4 and concentrated to give 12. 8 g of light yellow oil. NMR XH showed that it was 80% pure (92% yield). This material was taken in the next step without further purification (CDC13: d 2.15 (S, 1 HOUR); 3.83 (s, 3H); 6.92 (d, 2H); 7.50 (d, 2H); 8.10 (s, 1 HOUR) . 3- (4-Methoxyphenyl) -5-carbomethoxy-methyl-isoxazoline-5-ylcarboxylic acid: 4- Methoxybenzaldehyde oxime (5.00 g, 33.1 mmol) and itaconic monomethyl ester (5.72 g, 39.7 mol) were added together with 200 mL of THF. Bleach was added to the previous mixture (84 mL of 0.67M aqueous solution), dropwise at room temperature. The reaction mixture was then stirred at room temperature under N2 for 12 hours. The THF was removed in vacuo. The aqueous mixture was acidified with aqueous HCl and extracted with EtOAc. The EtOAc solution was washed with brine, dried over MgSO4, concentrated, and chromatographed with 10-30% MeOH in CH2C12 of silica gel to give 5.58 g of the desired product (58%) obtained. 1 H NMR (DMS0-d 6): d 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- [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 (64.0 mmol) of thionyl chloride for 1 hour under N2. The solvent was removed in vacuo. The residual thionyl chloride was removed by adding toluene and then evaporating to dryness. The resulting solid was dissolved in 100 mL of CH2C12 and 2-amino-5- [(2'-t-butylaminosulfonyl) phenyl] pyridine (1.57 g., 5.15. mmol) was added followed by N, N-dimethylpyridine (0.94 g, 7.73 mmol). The reaction mixture was stirred at room temperature and the reaction was finished in less than 30 minutes. The mixture was diluted in CH2C12 and the solution was washed with water and brine. It was dried over MgSO and concentrated. The crude product mixture was chromatographed on silica gel eluted with methylene chloride / ethyl acetate (9: 1) to give 2.55 g of the desired product (68%). MS (ESI) 581.1, (M + H); 603.1, (M + Na). 3- (4-Methoxyphenyl) -5-N- [2 * -aminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl-5-carbomethoxymethyl-isoxazoline: 3- (4-Methoxyphenyl) -5-N- [ 2'-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 N2 for 22 hours. The TFA was removed in vacuo, and the crude product was purified by chromatography (on silica gel eluted with ethyl acetate and 5% methanol in CH2C12) to give 1.10 g of the desired product (97%). MS (ES +) 525.0, (M + H); 547.0, (M + Na).

EXAMPLE 34 3- (4-Methoxyphenyl) -5- [5- (2'-amino-sulfonyl-phenyl-1-yl) pyridin-2-yl] aminocarbonyl-5-carboxymethyl-isoxazoline The 3- (4-methoxy phenyl) -5-N- [2'-amino-sulfonyl-phenyl-1-yl) pyridin-2-yl] aminocarbonyl-5-carbomethoxymethyl-isoxazoline (0.95 g, 1.78 mmol) was dissolved in 20 mL of THF The aqueous LiOH (2.3 mL of 1M solution) was added. The mixture was stirred at room temperature under N2 for 1.5 h. The THF was removed in vacuo, the residue was diluted with H20 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 MgSO4, and concentrated to a light yellow foam (0.85 g, 94%). MS (ES +) 511.0, (M + H); 533.0, (M + Na).

EXAMPLE 35 3- (4-Methoxyphenyl) -5- [5- (2'-aminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl-5- (N-carbomethoxymethyl) carboxamidomethyl-isoxazoline 3- (4-Methoxyphenyl) -5- [5- (2'-amino-sulfonyl-phenyl-1-yl) pyridin-2-yl] aminocarbonyl-5-carboxymethyl-isoxazoline (0.20 g, 0.39 mmol) was dissolved in 20 mL of EtOAc and 5 L of DMF. To this was added methyl glycine ester hydrochloride (49.0 mg, 0.039 mmol), TBTU (0.13 g, 0.39 mmol), and Et3N (0.16 mL, 1.17 mmol). The mixture was stirred at room temperature under N2 for 22 hours. It was diluted with H20 and extracted with EtOAc. The EtOAc solution was washed with brine, dried over MgSO4, concentrated, and chromatographed with 5% MeOH in CH2C12 on silica gel to give 0.11 g of the desired product (49%). MS (ES +) 582.0, (M + H); 604.0, (M + Na).

EXAMPLE 35 3- (4-Methoxyphenyl) -5- [5- (2'-amino-sulfonyl-phenyl-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-isoxazoline-5-ylcarboxylic acid: 1, 2, 4-Tetrazole (5.05 g, 73.0 mmol) was added and K2C03 (11.23 g, 81.3 mmol) together with 100 mL of DMF. Methyl 2- (bromomethyl) acrylate (13.0 g, 72.6 mmol) was added. The mixture was stirred at room temperature under N2 for 4 h. The mixture was poured into water and extracted with EtOAc. The combined organic solution was washed with brine, dried over MgSO4, and then 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-l-ylmethyl) acrylate were added. (1.50 g, 8.97 mol) together with 100 mL of CH2C12. To the previous mixture was added bleach (23 mL of 0.67 M aqueous solution) dropwise at room temperature. The reaction mixture was then stirred at RT under N2 for 12 h. The mixture was diluted with CH2Cl2 and washed with water and brine. Dry over MgSO4, concentrate, chromatograph with 30-100% EtOAc in CH2Cl2 on silica gel to give 1.81 g of the desired product (66%). The above ester (1.81 g) is dissolved in 25 mL of THF and LiOH. aqueous (7.2 mL of 1M solution) was added. The mixture was stirred at room temperature under N2 for 0.5 h. The THF was removed in vacuo. The aqueous mixture was diluted in H20 and extracted with EtOAc. The resulting aqueous solution was acidified and then extracted with EtOAc. The white precipitate formed was filtered and dried (1.30 g) at NMR (DMSO-d6): d 3.75 (g, 2H); 3.78 (s, 3H); 4.74 (q, 2H); 6.98 (d, 2H); 7.53 (d, 2H); 7.92 (s, 1H); 8.51 (s, 1H); 13.75 (s, 1H). 3- (4-Methoxyphenyl) -5-N- [2'-t-butylaminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl-5- (1, 2,4-triazol-1-yl) methyl-isoxazoline: 3- (4-Methoxyphenyl) -5- (1, 2, -triazol-1-yl) methyl-isoxazoline-5-ylcarboxylic acid (0.30 g, 1.03 mmol) was refluxed with 20 mL of acetonitrile and 0.75 mL (10.3 mmol) of thionyl chloride for 1 hour under N2. The solvent was removed in vacuo. The residual thionyl chloride was removed by adding toluene and then evaporating to dryness. The resulting solid was dissolved in 20 mL of CH2C1 and 2-amino-5- [(2'-t-butylaminosulfonyl) phenyl] pyridine (0.25 g, 0.82 mmol) was added followed by N, N-dimethylpyridine (0.15 g, 1.24 mmol). The reaction mixture was stirred at room temperature and the reaction was completed in less than 30 minutes. The mixture was diluted with CH2C12 and the solution was washed with water and brine. Dried over MgSO,] and concentrated. The crude product mixture was chromatographed on silica gel eluted with a 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- [2'-aminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl-5- (1,2,4-triazol-1-yl) methyl-isoxazoline: 3- (4-Methoxyphenyl) -5-N- [2'-t-butylaminosulfonylphenyl-1-yl) pyridine-2-yl] aminocarbonyl-5- (1,2,4-triazol-1-yl) methyl- isoxazoline (0.24 g, 0.41 mmol) was dissolved in 5 mL of TFA and stirred at room temperature under N2 for 12 hours. The TFA was removed in vacuo, in crude product and purified by chromatography on silica gel diluted with ethyl acetate to give 0.19 g of the desired product (87%). MS (ES +) 534.0, (M + H); 556.0, (M + Na).

EXAMPLE 37 1- (4-Methoxyphenyl) -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] tetrazole 1- (4-Methoxyphenyl) -5-Carboethoxy-tetrazole: 4-Methoxyaniline (20.0 g, 0.16 mol) and triethylamine (26.3 mL, 0.19 mol) were dissolved in CH2C12 (200 mL). Ethyl oxalyl chloride (18.1 mL, 0.16 mol) was added dropwise. The mixture was stirred at room temperature under N2 for 15 minutes. It was diluted with CH2C12 and washed with water and brine. The CH2C12 solution was dried over MgSO4 and concentrated to a tan solid (34.7 g, 96%) MS (DCI-NH3) 224, (M + H); 241, (M + NH4). The above amide (34.0 g, 0.15 mol) was refluxed for 20 h with a solution of triphenylphosphine (56.6 g, 0.22 mol) in 500 mL of CC14 (The solution was stirred at 0 ° C for 15 minutes before it was will add the amide). The reaction mixture was cooled and hexane was added. The precipitate was completely filtered. The filtrate was concentrated to a solid. Then it was dissolved in 400 mL of CH3CN and NaN3 (10.0 g, 0.15 mol) was added. The mixture was stirred at room temperature under N2 for 12 hours. The solvent was removed. The solid was dissolved in EtOAc and washed with water and brine. It was dried over MgSO4 and concentrated, and chromatographed on silica gel (eluted with CH2C12) to give 27.7 g of the desired product (58%). MS (DCI-NH3) 249, (M + H), 266 (M + NH4). 1- (4-Methoxyphenyl) -5- [(2'-t-butylaminosulfonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] tetrazole: 2'-t-Butylaminosulfonyl-4-amino- was dissolved [1, 1 '] -bifen-4-yl (1.84 g, 6.04 mmol) in 100 mL of anhydrous CH2CI, and trimethylaluminum (15.2 mL of 2.0 M solution in heptane) was slowly added. The mixture was stirred at room temperature under N for 15 minutes, and 1- (4-methoxyphenyl) -5-Carboethoxy-tetrazole (1.50 g, 6.04 mmol) was added. The reaction mixture was stirred at room temperature under N2 for 18 hours. The reaction was rapidly cooled carefully with 0.1N aqueous HCL. It was diluted with CH2C12 and washed with water and brine. The organic solution was then dried over MgSO4, concentrated and chromatographed on silica gel (10% EtOAc / CH2C12) to give 1.20 g of the desired product (39%). MS (ESI) 507.0 (M + H) +. 1- (4-Methoxyphenyl) -5- [(2'-amino-sulfonyl- [1,1 '] -biphen-4-yl) aminocarbonyl] tetrazole: 1- (4-Methoxyphenyl) -5- [(2'-t butylamine sulfonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] tetrazole (1.20 g, 2.37 mmol) was dissolved in 10 mL of TFA. The mixture was refluxed under N2 during h. The TFA was removed in vacuo. The crude mixture was purified by inverted phase HPLC to give 0.12 g of the desired product (11%) MS (ESI) 451.0 (M + H) +.

EXAMPLE 38 3-Methyl-1- (4-methoxy-3-chloro) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide This compound was prepared by the same methodology described for Example 1 with 4-methoxy-3-chlorophenyl-hydrazine • HCl substituted by phenyl hydrazine. 3-Methyl-1- (4-trifluoromethyl) phenyl-1H-pyrazole-5- (N- (4- (2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide was obtained; HRMS (M + H) + cale.m / z: 497.1050, obs: 497.1045.

EXAMPLE 39 3-Methyl-1- (4-trifluoromethoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide This compound was prepared by the same methodology described for EXAMPLE 1 with 4-trifluoromethoxyphenyl-hydrazine • HCl substituted by phenyl hydrazine. 3-Methyl-1- (4-trifluoromethyl) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide was obtained; HRMS (M + H) + cale.m / z: 517.1170, obs: 517.1176.

EXAMPLE 40 1- (3-Bromophenyl) -3-methyl-1H-pyrazol-5- [2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide This compound was prepared by the same methodology described for Example 1 with 3-bromophenyl-hydrazine • HCl substituted by phenyl-hydrazine. L- (3-bromophenyl) -3-methyl-1H-pyrazol-5- [2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide was obtained; HRMS (M + H) + cale. 511.043949; found: 511.043295.

EXAMPLE 41 1- (3-Iodophenyl) -3-methyl-1H-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide This compound was prepared by the same methodology described for Example 1 with 3-iodophenyl-hydrazine • HCl substituted by phenyl hydrazine. L- (3-iodophenyl) -3-methyl-1H-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide was obtained; HRMS (M + H) + cale. 559.030090; found: 559.027878.

EXAMPLE 42 1-3- (3, 4-Methylenedioxanophenyl) -3-, methyl-lH, pyrazole-5- [2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide.

This compound was prepared by the same methodology described in Example 1 with 3-methylenedioxanophenyl-hydrazine. HCl replaced by phenyl hydrazine. L- (3,4-methylenedioxanophenyl) -3-methyl-1H-pyrazole-5- [2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide was obtained; HRMS (M + H) + cale. 477.123267; found 477.124553.

EXAMPLE 43 1- (4-Methoxyphenyl) -3-hydroxylmethylene-lH-pyrazole-5- (4'-pyrrolidinocarbonyl) anuide 1- (4-Methoxyphenyl) -3-hydroxylmethylene-1H-pyrazole-5-ethylcarboxylate: To a solution of 1- (4-methoxyphenyl) -3-methyl-1H-pyrazole-5-ethylcarboxylate (1.58 g 7.1 mmol) and Benzoyl peroxide (73 mg, 4% mmol) and the mixture was degassed and then filled with nitrogen. The mixture was then refluxed for 18 hours under nitrogen, cooled to room temperature, diluted with CH2C12 (100 mL), washed with 10% NaOH (20 mL x 3), water (20 mL x 3), and brine (10 mL x 2), and dried over MgSO4. The filtration concentration gave a crude bromide (2.4 g). To a solution of the crude bromide in aqueous DMSO (75%, 40 mL) was added Cu0, (1.5 g, 10.5 mmol), and the mixture was stirred at 60 ° C for 2 hours. The mixture was filtered to remove excess Cu20, and the filtrate was extracted with ethyl ether. The ether layer was washed with brine (10 ml x 5) and dried over MgSO4. Filtration and concentration, followed by purification in flash chromatography with EtOAc-CH2C12 (1 to 1) gave 1- (4-methoxyphenyl) -3 -hydroxylmethylene-lH-pyrazole-5-ethylcarboxylate (1.5 g, 81%). LRMS (M + H) + m / z: 277. 1- (4-Methoxyphenyl) -3-hydroxylmethylene-1H-pyrazole-5- (4'-pyrrolidinecarbonyl) anuide: To a solution of 4- (4'-pyrrolidinocarbonyl) aniline (390 mg, 2.05 mmol) in CH2C12 (20 mL) was added ALMe3 (2M in hexanes, 3 mmol) at 0 ° C. After the mixture stirred at room temperature for 15 minutes, a solution of l- (4-methoxyphenyl) -3-hydroxylmethylene- was added thereto. lH-pyrazole-5-ethylcarboxylate (560 mg, 2.05 mmol) in CH2C1 (5 mL), and the resulting mixture was stirred overnight. The mixture was quenched with water (5 L), and filtered through a pad of celite to remove the Al (OH) 3 The filtrate was washed with water and brine, and dried over MgSO4. Filtration, concentration and purification by flash chromatography by EtOAc-CH2Cl2 gave 1- (4-methoxyphenyl) -3-hydroxylmethylene-1-H-pyrazole-5- (4'-pyrrolidinocarbonyl) anuide (570 mg, 67% yield ) ESMS (M + Na) + m / z: 443. HRMS (M + H) + cale, m / z: 420.1798, obs: 420.1771.

EXAMPLE 44 1-4-Methoxyphenyl) -3-formaldehyde-1H-pyrazole-5- (4'-pyrrolidinocarbonyl) anuide.

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 MnO2 (435 mg, 15 mg). eq.), and the resulting mixture was refluxed for 12 hours. The mixture was filtered to remove excess Mn02, and the filtrate was concentrated to give 1- (4-methoxyphenyl) -3-formaldehyde-1H-pyrazole-5- (4'-pyrrolidinocarbonyl) anuide as a solid in near yield. quantitative. LRMS (M + H) + m / z: 419.

EXAMPLE 45 1- (4-Methoxyphenyl) -5- (4'-pyrrolidinocarbonyl) anilide-3-pyrazolecarboxylic acid A solution of AgN03 (34 mg, 0.2 mmol) in H20 (0.5 mL) was added NaOH (16 mg, 0.4 mmol) and then added to a solution of 1- (4-methoxyphenyl) -3-formaldehyde-1H-pyrazole -5- (4'-pyrrolidinocarbonyl) anuide (42 mg, 0.1 mmol) in MeOH (0.5 mL) at 0 ° C. After, the resulting mixture was stirred at temperature for 30 minutes, the mixture was carefully acidified with concentrated HCl (35 μL) at pH about 2, and concentrated to give a residue, which was purified by flash chromatography to give 1- (methoxyphenyl) -5- (4'-pyrrolidinocarbonyl) -nuuide-3-pyrazolecarboxylic acid (25 mg , 58%). ESMS (M + Na) + m / z: 456.9 EXAMPLE 46 1- (4-Methoxyphenyl) -3-methylcarboxylate-1H-pyrazole-5- (4'-pyrrolidinocarbonyl) anuide To a solution of 1- (4-methoxyphenyl) -3-formaldehyde-1H-pyrazole-5- (4'-pyrrolidinocarbonyl) anuide (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 Mn02 (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, dried over MgSO4. The solution was filtered, concentrated and purified by flash chromatography with EtOAc to give l- (4-Methoxyphenyl) -3-methylcarboxylate-1H-pyrazole-5- (4'-pyrrolidinocarbonyl) anuide (38 mg, 85% yield ). ESMS (M + Na) + M / Z: 471.

EXAMPLE 47 1- (4'-Chlorophenyl) -3-methyl-lH-pyrazole-5- [. { 2 '-aminosulfonyl- [1,1'] -bifen-4-yl-carboxamide.

This compound was prepared by the same methodology described for EXAMPLE 1 with 4-chlorophenyl hydrazine • HCl substituted by phenyl hydrazine. L- (4'-chlorophenyl) -3-methyl-lH-pyrazole-5- [. { 2 '-aminosulfonyl- [1,1'] -bifen-4-yl-carboxamide; HRMS (M + H) +: cale. 467.094465; found 467.093532.

EXAMPLE 48 1- (4'-Chlorophenyl) -3-methyl-1H-pyrazole-5- [. { 2 '-aminosulfonyl- [1-pyridyl-l' phenyl] 4-yl) carboxyamide.

This compound was prepared by the same methodology described for EXAMPLE 8 with 4-chlorophenyl-hydrazine • HCl substituted by phenyl-hydrazine and 2-amino-5- (2-N-t-butylaminosulfonylphenyl) pyridine was used in the coupling step. The title compound was obtained; HRMS (M + H) +: cale. 468.089714; found 468.088873.

EXAMPLE 49 1- (3 ', 4' -Dichlorophenyl) -3-methyl-lH-pyrazole-5- [. { 2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide.

This compound was prepared by the same methodology described for Example 1 with 3,4-dichlorophenyl-hydrazine • HCl substituted by phenyl hydrazine. The title compound was obtained; HRMS (M + H) +: cale. 501.055493; found 501.053920.

EXAMPLE 50 1- (3'-Chlorophenyl) -3-methyl-1H-pyrazol-5- [2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide. This compound was prepared by the same methodology described for EXAMPLE 1 with 3-chlorophenyl-hydrazine • HCl substituted by phenyl-hydrazine. The title compound was obtained; HRMS (M + H) +: cale. 467.094465: found 467.091517.

EXAMPLE 51 2-Amino-4-phenyl-5- [. { 2 '-aminosulfonyl- [1,1'] -bifen-4-yl) aminocarbonyl] thiazole 2-Amino-4-phenyl-5-carboethoxythiazole: To a solution of 3-phenyl-3-oxopropionate (5.0 g, 26.0 mmol) in 100 mL of acetonitrile was added hydroxy (toxyloxy) iodobenzene (11.2 g, 28.6 mmol). The resulting suspension was stirred at 65 ° C for 1 hour at which time the reaction was a homogeneous mixture. Thiourea (2.2 g, 28.6 mmol) was added and stirring was continued at 65 ° C for 2 hours. The mixture was cooled and concentrated, and the residue was taken up in ethyl acetate, washed with N2CO3 and brine, dried (MgSO4) and concentrated. The residue was triturated with ethyl ether to give 4. 9 g (70%) of the title compound as a yellow solid NMR A (CDCl 3) d, 7.65 (m, 2 H), 7.39 (m, 3 H), 5.98 s broad 2 H), 4.18 (q, 2 H), 1.22 ( t, 3H) 2-Amino-4-phenyl-5- [(2'-tert-butylaminosulfonyl- [1,1 '] -biphen-4-yl) aminocarbonyl] thiazole: To a solution of (2'-tert-butylaminosulfonyl- [1, 1 '] -bifen-4-yl) amine (0.68 g, 2.22 mmol) in 15 mL of methylene chloride at 25 ° C was added trimethylaluminum (3.3 mL of a 2.0 M solution in toluene, 6.68 mmol) dropwise , the resulting solution was allowed to stir until no more gas emission was observed (approximately 15 minutes). To this solution was added 2-amino-4-phenyl-5-carboethoxythiazole (0.30 g, 1.11 mmol) in 5 mL of methylene chloride. The resulting solution was stirred at 40 ° C for 16 hours and then cooled to 25 ° C and quenched by the addition of aqueous, saturated NH 4 Cl. After dilution with ethyl acetate, the organic layer was washed with aqueous HCl, 10% saturated aqueous NaHCO3 and brine was dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (elution with hexanes / ethyl acetate 1: 1) to give 0.3 g (54%) of the title compound as a solid. 2-Amino-4-phenyl-5- [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] thiazole: A solution of 2-amino-4-phenyl-5- [2'] -tert-butylaminosulfonyl- [1,1 '] - bifen-4-yl) aminocarbonyl] thiazole (80 mg, 0.16 mmol) in 3 mL of trifluoroacetic acid was stirred at reflux for 20 minutes and then cooled to room temperature and concentrated in vacuo. The residue was purified by preparative HPLC (C18 inverted phase column, elution with a H 2 O / CH 3 CN, gradient with 0.5% TFA) and lyophilized to give 50 mg (71%) of the title compound as a white powder. MS (ESI) 451.0 (M + H) +.

EXAMPLE 52 2-Chloro-4-phenyl-5- [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] thiazole 2-Chloro-4-phenyl-5- [(2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole: To a solution of copper (II) chloride (54 mg, 0.4 mmol) in 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 '] -bifen-4-yl) aminocarbonyl] thiazole (200 mg , 0.4 mmol). The agitation to 80 ° C was continued for 1 hour, at which time the gas emission ceased. The reaction was cooled to room temperature, diluted with ethyl acetate, washed with 10% aqueous HCl, saturated aqueous NAHO3, and brine dried (MgSO) and concentrated to give 0.2 g (95%) of the title compound which was used without purification MS (ESI) 526.1 / 528.0 (M + H) +. 2-Chloro-4-phenyl-5- [(2'-amino-sulfonyl- [1,1 '] -biphen-4-yl) aminocarbonyl] thiazole: A solution of 2-chloro-4-phenyl-5- [(2 '-ter-butylaminosulfonyl- [1,1'] -bifen-4-yl) aminocarbonyl] thiazole (100 mg, 0.19 mmol) in 5 mL of trifluoroacetic acid was stirred at reflux for 20 minutes and then cooled to room temperature and it was concentrated in vacuo. The residue was purified by preparative HPLC (C18 inverted phase column, elution with a gradient of H20 / CH3CN with 05% TFA) and lyophilized to give 50 mg (56%) of the title compound as a white powder. MS (ESI) 469.9 / 471.9 (M + H) + EXAMPLE 53 2-Amino-4- [3- (bromo) -4- (fluoro) -phenyl] -5- [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] thiazole 3- [3- (Bromo) -4- (fluoro) -phenyl] -3-oxopropionate methyl: To a suspension of sodium hydride (1.1 g of suspension 60% mineral oil, washed in hexane, 27.6 mmol) in 50 mL of tetrahydrofuran was added dimethyl carbonate (2.3 mL, 27.6 mmol) and 3 '-bromo-4' -fluoroacetophenone (3.0 g, 13.8 mmol). The resulting suspension was stirred at 65 ° C for 1 hour and then cooled to room temperature. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried (MgSO 4) and concentrated in vacuo. The residue was purified by flash chromatography (elution with hexane / ethyl acetate 3: 1) to give 1.0 g (26%) of the title compound XH NMR (CDC13) (data for keto-tautomer) d 8.15 (dd, 1H ), 7.87 (m, 1H), 7.2 (m, 1H), 3.95 (s, 2H), 3.73 (s, 3H). 2-Amino-4- [3- (bromo) -4- (fluoro) -phenyl] -5-carbomethoxythiazole: Following the procedure described in procedure 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 compound of title A NMR (CDC13) d 7.97 (m, 1H), 7.90 s broad, 2H), 7.68 (m, 2H), 3.61 (s, 3H). 2-Amino-4- [3- (bromo) -4- (fluoro) -phenyl] -5- [2 '-suninosulfonyl-tl, 1'] -bifen-4-yl) aminocarbonyl] thiazole: Following the procedures described in EXAMPLE 51, 2-amino-4- [3- (bromo) -4- (fluoro) -phenyl] -5-carbomethoxythiazole (0.25 g, 0.75 mmol) was converted into the title compound in a powder white after purification by HPLC. NMR A (CDC13) d 9.95 (s, 1H), 7.98 (d, 1H), 7.94 (dd, 1H), 7.65-7.55 (, 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 (+ H) +.

EXAMPLE 54 2-Amino-4- [4-fluorophenyl] -5 - [(2'-amino-sulfonyl- [1, 1 '] biphen-4-yl-aminocarbonyl thiazole.

Following the procedures described in Example 51, 4 '-fluoroacetophenone was converted to the title compound, 2-amino-4- [4-fluorophenyl] -5- [2'-aminosulfonyl- [1, 1'] -bifen- 4-yl) aminocarbonyl] thiazole A NMR (CDC13) d (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) +.

EXAMPLE 55 2-Amino-4- [3-bromophenyl] -5 - [(2'-amino-sulfonyl- [1, 1 '] -bifen-4-yl) aminocarbonyl] thiazole Following the procedures described in example 51, the 3'-bromoacetophenone was converted to the title compound, 2-amino-4- [3-bromophenyl] -5- [2'-aminosulfonyl- [1, 1 '] -bifen -4-yl) aminocarbonyl thiazole. A NMR (CDC13) d (9.95 (s, 1H), 7.98 (d, 1H), 7.81 (s, 1H), 7.60-745 (m, 6H), 7.30-7.22 (m, 4H), 7.18 (s broad) , 2H), 5.4 (broad s, 2H), MS (ESI) 528.8 / 530.8 (M + H) +.

EXAMPLE 56 2-Chloro-4- [3-bromophenyl] -5 - [(2'-amino-sulfonyl- [1,1 '] -biphen-4-yl) aminocarbonyl] thiazole Following the procedures described in Example 52, 2-amino-4- [3-bromophenyl] -5- [2-tert-butyl-aminosulfonyl- [1, 1 '] -bifen-4-yl) aminocarbonyl] thiazole was 2-Chloro-4- [3-bromophenyl] -5- [2'-aminosulfonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] thiazole was converted to the title compound. MS (ESI) 547.9 / 549.8 (M + H) +.

EXAMPLE 57 N- (2 'Aminosulfonyl- [1,1'] -bifen-4-yl) -1- (4-methoxyphenyl) -3- (methylthio) pyrazole-5-carboximide.

Ethyl N- (4-methoxyphenyl) glycine: To a solution of 15.00 g (122 mmol) of p-anicidine in 100 mL of DMF under N2 was added 23.50 g (141 mmol) of ethyl bromoacetate and 14.95 g (141 mmol). of anhydrous sodium carbonate. The mixture was heated at 70 ° C for 16 hours and then cooled to room temperature. Water (500 mL) was added and the mixture stirred vigorously until a precipitate formed. The solid was collected and washed with 100 mL of water, then dried in vacuo to give 19.59 g (88%) of the desired compound as a gray solid. XH NMR (CDC13) d 6.81 (d, J = 8.8, 2H), 4.24 (q, J = 7.0, 2H); 4.10 (s, 1H), 3.876 (s, 2H); 3.75 (s, 3H); 1.27 (t, J = 7.0, 3H).

N- (4-methoxy-phenyl) glycine: To a solution of 19.59 g (108 mmol) of ethyl-N- (4-methoxy-phenyl) glycine in 100 mL of THF under N2 was added 5.44 g (130 mmol) of nitroxide of lithium monohydrate in 5 mL of water. After 15 hours, the mixture was reduced to 1/2 of the original volume in vacuo and acidified with concentrated hydrochloric acid to pH 3 and a precipitate formed. The solid was collected and washed with 100 mL of water, then dried in vacuo to give 9.92 g. (51%) of the desired compound as a completely white solid. A NMR (CDC13) d 6.68 (d, J = 8.8, 2H), 6.49 (d, J = 8. 8, 2H), 3.73 (s, 2H), 3.64 (s, 3H); 2.49 (br s, 2H).

N- (4-Methoxyphenyl) -N-nitrosoglycine: Sodium nitrite (3.97 g, 57.5 mmol) in 10 mL of water was added to a suspension of N- (4-methoxyphenyl) glycine (9.92 g, 54.7 mmol) in 50 g. mL of water under N2. This was allowed to stir at room temperature until the solution was clarified, in about 6 hours. The solution was acidified with concentrated hydrochloric acid to ph3 and a precipitate formed. The solid was collected and washed with 50 mL of water, dried in vacuo to give 11.50 g (100%) of the desired compound as a white solid. A NMR (CDC13) d 7.17 (d, H = 8.8, 2H), 6.70 (d, H = 8.8, 2H), 4.30 (s, 3H), 2.29 (br s, 1H). 1- (4-Methoxyphenyl) -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 was heated to 70 ° C for 14 hours. The reaction mixture was cooled and then poured into 300 mL of ice water. After stirring for 30 minutes to decompose the excess acetic anhydride, the reaction mixture was filtered to provide 11.50 g (100%) of a thick, clear oil A NMR (CDC13) d 7.65 (d, J = 9.2, 2H), 7.08 (d, J = 9.2, 2H), 6.63 (s, 1H), 3.91 (s, 3H). MS (NH3-CI) m / z 193.3 (M + H) +. l- (3-Cyanophenyl) -4-oxy-5-methylthio-1,2,3-oxadiazole: L- (4-methoxyphenyl) -4-oxy-1,2,3-oxadiazole (2.03 g, 10.6 mmol ) was dissolved in 26 L of dry DMSO and cooled to 0 ° C. Acetyl chloride (1.66 g, 21.1 mmol) was added very slowly. Via a syringe below the surface of the liquid under N2. The reaction mixture was allowed to stir at room temperature for 14 hours. The reaction mixture was diluted with 100 mL of Et20, washed twice with 24 mL of aqueous NaHCO3, then saturated three times with 25 mL of water to remove the DMSO. The organic extract was dried with MgSO.j and concentrated in vacuo to give 1.83 g of a red solid which was used without further purification. MS (NH3-CI) m / z 239.2 (M + H) +.

Methyl 1- (4-methoxyphenyl) -3-methylthio-pyrazole-5-carboxylate: Crude 1- (4-methoxyphenyl) -4-oxy-5-methylthio-l, 2,3-oxadiazole (1.83 g, 7.68 mmol) and methyl propiolate (6.45 g, 76.8 mmol) were dissolved in 10 mL of CH2C12 and the quartz reaction vessel was purged with N2. The reaction mixture was radioed in a Rayonet RPR-100 photochemical reactor for 14 hours. The crude product was concentrated in vacuo and then chromatographed with 20% EtOAc / hexanes on silica to provide 1.06 g (49%) of a yellow solid. H NMR (CDC13) d 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 (NH3-CI) m / z 279.2 (M + H) +.

N- (2'-t-Butylaminosulfonyl- [1,1 '] -bifen-4-yl) -1- (4-methoxyphenyl) -3-methylthio-pyrazole-5-carboxamide: Trimethyl aluminum (1.4 mL, 2.0 M in heptane, 2.8 mmol) to 2 '0-t-butylaminosulfonyl-4-amino- [1,1'] bifen-4-yl (215 mg, O.tl mmol) in CH2C12 (5 mL). After stirring at room temperature, under N2 for 75 minutes, a solution of 1- (4-methoxyphenyl) -3-methylthio-pyrazole-5-carboxylate (197 g, 0.71 mmol) in CH2C12 (2 mL) was added and The resulting solution was stirred 70 hours. The reaction was rapidly cooled carefully by the dropwise addition of HCL, diluted with H20 and extracted into CH2Cl2-. The organic layer was dried over Na2SO4 filtered and evaporated. The crude product was chromatographed on silica gel (30-40% EtOAc / hexanes) to give the desired product (357 mg, 92%). A NMR (CDCI3) d 8.14 (d, 1H, J = 7.7), 7.50 (m, 9H), 7.27 (m, 1H), 7.01 (d, 2H, J = 8.8) 6.83 (s, 1H), 3.87 ( s, 3H) .3.57 (s, 1H), 2.59 (s, 3H), 1.01 (s, 9H).

N- (2 'Aminosulfonyl- [1,1'] -bifen-4-yl) -1- (4-methoxyphenyl) -3-methylthio-pyrazole-5-carboxamide: N '(2'-t-butylaminosulfonyl- [1,1 '] biphen-4-1] -1- (4-methoxyphenyl) -3-methylthio-pyrazole-5-carboxamide (328 mg, 0.60 mmol) was stirred in TDA (5 mL) for 17 hours. The solvent was evaporated and the crude product was chromatographed on silica gel (50% EtOAc / hexanes) to yield a yellow solid (267 mg, 91%) .A NMR (CDCl 3) d 10.62 (s, 1H), 7.98 (dd) , 1H J = 7.7, J '= 1.5), 7.62 (d, 2H, J = 8.8), 7.55 (m, 2H), 7.30 (m, 5H), 7.22 (s, 2H), 6.98 (m, 3H) , 3.76 (s, 3H), 2.51 (s, 3H).

EXAMPLE 58 1- (4-Methoxyphenyl) -3- (methylsulfonyl) -N- (5- (2'-methylsulfonylphenyl) pyrimid-2-yl) pyrazole-5-carboxamide 2-methylthiophenylboronic acid: 2-Bromothioanisole (29.0 g) was dissolved , 143 mmol) in dry THF (400 mL) and cooled to minus 75 ° C. N-BuLi (62.0 mL, 2.5 in hexane, 155 mmol) was added over 50 minutes. After stirring for 25 minutes, triisopropyl borate (46 mL, 199 mmol) was added over 35 minutes. The cold bath was removed and the reaction was stirred at room temperature for 16 hours. The resulting solution was cooled in ice baths, and 6 M HCl (100 mL) was added. This mixture was stirred at room temperature for 5 hours and approximately half of the original volume was concentrated. The concentrated solution was divided between Et20 and water. The organic layer was extracted with 2M NaOH, which was subsequently reacted with 6M HCl and extracted several times with Et20, dried over Na2SO4, filtered, and evaporated to yield a beige solid. (20.4 g, 85%). A NMR (CDC13): d 8.01 (dd, 1H, J = 7.3, J '= 1.4), 7.53 (dd, 1H, J = 7.7, J = 1.1), 7.43 (td, 1H, J = 7.3, J * = 1.8), 7.34 (td, 1H, J = 7.3, J = 1.5), 6.22 (s, 2H), 2.50 (s, 3H). 2- [Bis (tert-butoxycarbonyl) amino] -5-bromopyrimidine: Sodium hydride (5.06 g, 60%, 127 mmol) was added in two portions 2-amino-5-bromopyrimidine (10.0 g, 57 mmol) in THF dry (500 mL) at 0 ° C. After stirring for 30 minutes, di-t-butyl dicarbonate (27.6 g, 126 mmol) was added. The resulting mixture was refluxed 17 hours, cooled carefully with water, and concentrated. The concentrated mixture was diluted with EtOAc and extracted with water. The combined aqueous layers were extracted with EtOAc. All organic layers were combined, dried over NA2SO4, filtered and evaporated. The crude product was chromatographed on silica gel (10-15% EtOAc / hexanes) to yield the desired product (15.48 g, 72%), NMR (CDCl 3): d 8.78 (s, 2H), 1.47 (s, 18H ). 2- [Bis (tert-butoxycarbonyl) amino] -5- (2'-methylthiophenyl) pyrimidine: 2- [Bis (tert-butoxycarbonyl) amino] -5-bromopyrimidine (2.00 g, 5.3 mmol) was dissolved in benzene (130 mL). 2-Methylthiophenylboronic acid (2.24 g, 13.3 mmol), aqueous sodium carbonate (13 mL, 2.0 M, 26 mmol), tetrabutyl ammonium bromide (86 mg, 0.26 mmol), and bis (triphenylphosphine) palladium chloride ( II) (190 mg, 0.27 mmol), of the resulting mixture was first purged with vacuum and argon, then refluxed 17 hours. The cooled mixture was diluted with EtOAc and water. The layers were separated and the organic layer was dried over Na2SO4 then filtered and evaporated. The crude product was chromatographed on silica gel (50% EtOAc / hexane), evaporated, and chromatographed a second time on silica gel (30-50% EtOAc / hexanes) to yield the desired product (2.13 g. 96%) A NMR (CDC13): d 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'-methylsulfonyl) pyrimidine: 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, an Oxone solution (5.49 g) was generated by dilution to 27 mL with water. A portion of this solution (17 mL, 5.6 mmol) was removed and adjusted to pH 4.2. with saturated Na3P04 solution (4.7 mL). This mixture was added to the reaction and stirred 23 hours at room temperature. The resulting mixture was diluted with water and extracted with CH3. The organic extracts were combined, washed with water and brine, dried over NA2SO, filtered, and evaporated. The crude product was chromatographed on silica gel (50-100% EtOAC / hexanes) to produce the sulfone. (1.28 g, 56%). XH NMR (CDC13): d 8.81 (s, 2H) 8.28 (dd, 1H, J = 7.6, J '= 1.4) 7.72 (m, 2H), 7.39 (dd, 1H, J = 7.3, J' = 1.4) , 2.76 (s, 3H), 1.50 (s, 18H). 2-Amino-5- (2'-methylsulfonyl) pyrimidine hydrochloride: The 2- [Bis (tert-butoxycarbonyl) amino] -5- (2'-methylsulfonylphenyl) pyrimidine (1.28 g, 2.8 mmol) was dispersed in HCl / dioxane (10 mL, 4.0 M) and stirred 20 hours at room temperature, . The resulting mixture was filtered with Et20 and filtered to yield a white solid (772 mg, 95%). A NMR (CDC13 + few drops of MeoD): d 8.53 (s, 2H), 8.22 (dd, 1H, J = 7.7, J * = 1.8), 7.77 (m, 2H), 7.40 (dd, 1H, J = 7.4, J '= 1.5), 2.94 (s, 3H).

Methyl 1- (4-methoxyphenyl) -3-methylsulfonyl-pyrazole-5-carboxylate: M-CPBA (1.18 g, 57-86%, minutes, 3.9 mmol) was added to 1- (4-methoxyphenyl) -3- methylthio-pyrazole-5-carboxylic acid methyl ester (434 mg, 1.6 mmol) in CH2C12 (40 L) and stirred at room temperature for 24 hours. Additional m-CPBA (600 mg, 57-86%, minutes, 1.9 mmol) was added and stirred 2.5 days. The reaction was extracted with saturated Na 2 SO 3 and saturated NaHCO 3. The organic layer was dried over Na 2 SO 4, filtered and evaporated. The crude product was chromatographed on silica gel (40% EtAc / hexanes) to yield the desired product (416 mg, 86%). A NMR (CDC13): d 7.46 (s, 1H), 7.36 (d, 2H, J = 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- (Methoxyphenyl) -3-methylsulfonyl-pyrazole-5-carboxylic acid: A solution of lithium hydroxide was added (1.3 mL, 1.0, 1.3 mmol) was added to a suspension of methyl l- (4-methoxyphenyl) -3-methylsulfonyl-pyrazole-5-carboxylate (272 mg, 0.88 mmol) in MeOH (10 mL) and stirred at room temperature 17 hours. The resulting mixture was concentrated and partitioned between EtOAc and H20. The extracted organic layer was removed, and the aqueous extract was acidified with 1M HCl and extracted twice with EtOAc. The organic extracts of this extraction. were combined, dried over Na2SO4 filtered, and evaporated to yield the product (266 mg.) A NMR (CDC13 + few drops of MeOD): d 7.45 (s, lH), 7.38 (dd, 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 * -ethylsulfonyl) pyrimid-2-yl) pyrazole-5-carboxamide: Oxalyl chloride (120 u, 1.4 mmol) and dry FMF (2 drops) at room temperature to 1- (4-methoxyphenyl) -3-methylsulfonyl-pyrazole-5-carboxylic acid (2.62 mg, 0.88 mmol) in dry CH2C12. (5.mL) and stirred 2 hours under N2. The resulting solution was evaporated and placed briefly under high vacuum before dissolving in CH2C12 (2 mL). This solution was added for 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 CH2C12 (3 mL). The resulting solution was stirred at room temperature under N2 for 23 hours, diluted with CH2Cl2, extracted with H2O, dried over Na2SO4, filtered and evaporated. The crude product was chromatographed on silica gel (75-100% EtOAc / hexanes) to yield a white, impure solid, which was taken up in toluene and filtered to yield the clean product (191 mg, 41%). A NMR (CDC13): d 8.65 (s, 2H,) 8.62 (s, 1H), 8.24 (d, 1H, J = 7.0), 7.71 (M, 2h), 7.47 (D, 2h, J = 6.6), 6.98 (d, 2H, J = 8.8), 3.85 (s 3H), 3.30 (s, 3H), 2.80 (s, 3H).

EXAMPLE 59 N- (2 '-Aminosulfonyl- [1,1'] -bifen-4-yl) -1- (4-methoxyphenyl) -3- (methylsulfonyl) -lH-pyrazole-5-carboxamide.

N- (2'-t-Butylaminosulfonyl- [1,1 '] - biphen-4-yl) -1- (4-methoxyphenyl) -3 (methylsulfonyl) -lH-pyrazole-5-carboxamide. Trimethyl aluminum (930 μL, 2.0 M in heptane, 1.86 mmol) was added to 2 '-t-butylamine-sulfonyl- [1,1'] -bifen-4-yl (142 mg, 0.47 mmol) in CH2C12 (5 mL). After stirring at room temperature under N2 for 60 minutes, a solution of methyl 1- (4-methoxyphenyl) -3-methylsulfonyl-pyrazole-5-carboxylate (145 mg, 0.47 mmol) in CH2C12 (2 mL) was added. and the resulting solution was stirred for 51 hours. The reaction was rapidly cooled carefully by the dropwise addition of 0.1 M HCl, diluted with H0, and extracted twice in CHC12. The organic layer was dried over NaSO 4, filtered and evaporated to yield the desired product (277 mg, 100%). A NMR (CDC13): d 8.21 (bs, 1H,) 8.16 (dd, 1H, J = 7.6 J '= 1.1), 7. 57 (m, 3H), 7.46 (m, 5H), 7.39 (s, 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'] -bifen-4-yl) -1- (4-methoxyphenyl) -3- (methylsulfonyl) -lH-pyrazole-5-carboxamide: The N- (2 ') -t-butylaminosulfonyl- [1,1 '] -bifen-4-yl) -1- (4-methoxyphenyl) -3- (methylsulfonyl) -lH-pyrazole-5-carboxamide. (274 mg, 0.47 mmol) was stirred in TFA (5 mL) for 74 hours. The solvent was evaporated. The crude product was recrystallized from CHCl3 to yield a white solid (236 mg, 95%) A NMR (CDCI3 + few drops of MeOD): d 8.13 (d, 1H, J = 7.7), 7.67 (d, 2H, J = 8.4), 7.59 (t, 1H, J = 6.3), 7.46 (, 6H), 7.32 (d, 1H, J = 8.5) 7.00 (d, 2H, J = 9.2), 3.86 (s, 3H), 3.31 (s, 3H).

EXAMPLE 60 N- (4-Benzoylpyrrolidino) -1- (4-methoxyphenyl) -3- (methylthio-lH-pyrazole-5-carboxamide. 1- (4-Methoxyphenyl) -3-methylthio-lH-pyrazole-5-carboxylic acid: A solution of lithium hydroxide (4.5 mL, 1.0 M, 4.5 mmol) was added to its suspension of l- (4-methoxyphenyl) Methyl-3-methylthio-lH-pyrazole-5-carboxylate (840 mg, 3.0 mmol) in MeOH (30 mL) and stirred at room temperature for 21 hours. The resulting mixture was concentrated and partitioned between EtOAc and H2O, the organic layer was removed, and the aqueous layer 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 yield clean product (784 mg, 98%). A NMR (CDCl 3): d 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: Oxalyl chloride (140 μL, 1.6 mmol) and dry DMF (2 drops) were added at room temperature. environment to 1- (4-methoxyphenyl) -3-methylthio-1H-pyrazole-5-carboxylic acid (275 mg, 1.0 mmol) in dry CH2C12 (8 mL) and stirred for 100 minutes under N2. The resulting solution was evaporated and placed briefly under high vacuum before redissolving in CH2C12 (8 mL). (4-Aminobenzoyl) pyrrolidine (198 mg, 1.0 mmol) was added, followed by 4-dimethylaminopyridine (190 mg, 1.6 mmol): The resulting mixture was stirred at room temperature for 17 hours, diluted with CH2C12 and extracted with H20. . The aqueous extract was extracted with CH2Cl2, the combined extracts were extracted with brine. The organic layer was dried over Na 2 SO 4, filtered and evaporated. The crude product was chromatographed on silica gel (75-100% EtOAc / hexanes) to yield the desired product. (464 mg, 100%) A NMR (CDC13): d 7.91 (brs, 1H), 7.44 (s, 4H), 7.39 (d, 2H, J = 8.8), 6.97 (d, 2H, H = 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), 2.91 (m, 4H).

EXAMPLE 61 1- (4-Methoxyphenyl-N- (5- (2'-methylsulfonylphenyl) pyrimid-2-yl-3- (methylthio) -lH-pyrazole-5-carboxamide. 1- (4-Methoxyphenyl-N- (5- (2'-methylsulfonylphenyl) pyrimid-2-yl-3- (methylthio) -lH-pyrazole-5-carboxamide: trimethylaluminum (1.5 mL, 2.0 M in heptane, 3.0 mmol) to 2-amino-5- (2'-methylsulfonylphenyl) pyrimidine hydrochloride (208 mg, 0.73 mmol) in CH2C12. (5 mL) After stirring at room temperature under N2 for 75 minutes, a solution of methyl l- (4-methoxyphenyl) -3-methylthio-1H-pyrazole-5-carboxylic acid methyl ester (203 mg, 0.73 mmol) was added. ) in CH2C12 (2 mL) and the resulting solution was stirred for 70 hours. The reaction was rapidly cooled carefully by the dropwise addition of 1M HCl, diluted with 1M HCl, extracted with CH2C12. The organic layer was dried over Na 2 SO 4, filtered and evaporated. The crude product was chromatographed on silica gel (50-100% EtOAc / hexanes) to yield the desired product (101 mg, 28%). This material was combined with 19 mg of another reaction and purified by preparative HPLC on an inverted phase C-18 column (30-100% MeCN / H2O / 0.05% TFA) to yield a white powder (11 mg). A NMR (CDC13): d 8.67 (2, 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 62 N- (4-Benzoylpyrrolidino) -1- (4-methoxyphenyl) -3- (methylsulfonyl) lH-pyrazole-5-carboxamide N- (4-Benzoylpyrrolidino) -1- (4-methoxyphenyl) -3- (methylsulfonyl) lH-pyrazole-5-carboxamide. N- (4-Benzoylpyrrolidino) -1- (4-methoxyphenyl) -3- (methylthio) 1H-pyrazole-5-carboxamide (200 mg, 0.46 mmol) was dissolved in MeOH (6 mL). A solution of Oxone (561 mg, 0.91 mmol) in H20 (3 mL) was added, and the resulting mixture was stirred at room temperature under Ar for 17 hours. The reaction was diluted with H20 and extracted twice with CHCl3. The combined organic extracts were dried over NA2SO4, filtered and evaporated. The crude product was purified by preparative HPLC on an inverted phase C-18 column (10-70% MeCN / H2O / 0.05% TFA) to produce a white powder. (200 mg, 93%). XH NMR (CDC13): d 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 (, 4H) EXAMPLE 63 N- (2 '-Aminosulfonyl- [1,1'] -bifen-4-yl) -1- (4-methoxyphenyl) -3- (methoxyphenyl) -lH-pyrazole-5-carboxamide 3- (Bromoethyl) -1- (4-methoxyphenyl) -lH-pyrazole-5-carboxylate and ethyl 3- (dibromomethyl) -1- (4-methoxyphenyl) -l-pyrazole-5-carboxylate: 1- (4-methoxyphenyl) -3-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (2.00 g, 7.83 mmol) was dissolved in 30 mL of CC14 and N-bromosuccinimide (3.06 g, 17.2 mmol) and benzoyl peroxide was added (02.02). g, 0.08 mmol). The reaction mixture was heated for 48 hours then cooled to room temperature. The succinimide was filtered and the solvent was evaporated. The reaction mixture was chromatographed on silica (20% EtOAc / hexane) to give 0.94 g. (36%) of the monobromide. 1 H NMR (CDC13): d 7.34 (d, J = 8.8, 2H); 7.07 (s, 1H); 6.96; (d, JI = 8.8, 2H); 4.53 (s, 2H); 4.24 (q, J = 7.0 2H); 3.85 (s, 3H); 1.27 (t, J = 7.0 3H); The dibromide (0.34 g, 10%) was also isolated. A NMR (CDC13): d 7.34 (d, J = 9.1.2H); 6.73 (s, 1H); 4.26 (q, J = 7.0, 2H); 3.85 (s, 3H); 1.29 (t, J = 7.0, 3H). 1- (4-Methoxyphenyl) -3- (methoxymethyl) -lH-pyrazole-5-carboxylic acid: 3- (bromomethyl) -1- (4-methoxyphenyl) -1H-pyrazole-5-carboxylic acid ethyl ester (0.50 g , 1.47 mmol) was dissolved in 12 mL of 0.5 M NaOMe in methanol and heated to reflux for 14 hours. The reaction mixture was cooled and refluxed to 1/10 volume of the original. The reaction mixture was dissolved in 30 ml of water and extracted with EtOAc. The aqueous mixture was acidified with IN HCl and extracted with EtOAc to give 0.236 g (61%) of the desired product. A mixture of ethyl and methyl esters (approximately 0.05 g) was found in the first EtOAc extract. A NMR (CDC13): d 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-Butylaminosulfonyl- [1,1 '] - biphen-4-yl) -1- (4-methoxyphenyl) -3- (methoxymethyl) -lH-pyrazole-5-carboxamide: Oxalyl chloride was added / 460 mg, 3.6 mmol) and dry DMF (2 drops) at room temperature to 1 (4-methoxyphenyl) -3- (methoxymethyl) -lH-pyrazole-5-carboxylic acid (236 mg, 0.90 mmol) in dry CH2C1. (5 mL) and stirred 2 hours under N2. The resulting solution was evaporated and placed briefly under high vacuum before redissolving in CH2C12 (2 mL). This solution was added over a few minutes to a mixture of 2'-t-butylaminosulfonyl-4-amino- [1- 1 '] - biphen-4-yl (288 mg, 0.945 mmol) in 5 mL of CH2CL2. The resulting solution was stirred at room temperature under N2 for 23 hours, diluted with CH2C12, extracted with H2O, dried over Na2SO4, filtered and evaporated. The crude product was chromatographed on silica gel (EtOAc at % / hexanes) to yield a white solid (110 mg, 22%), MS (ESI) m / z 5781.0 (M + Na).

N- (2 '-Aminosulfonyl- [1,1'] -bifen-4-yl) -1- (4-methoxyphenyl) -3- (methoxymethyl) -lH-pyrazole-5-carboxamide: The N- (2 ') -t-butylaminosulfonyl- [1,1 '] -bifen-4-yl) -1- (4-methoxyphenyl) -3- (methoxymethyl) -lH-pyrazole-5-carboxamide (110 mg, 020 mmol) was dissolved in 5 mL of TDA and stirred at room temperature for 16 hours. The solvent was removed and the product was purified by preparative HPLC on an inverted phase C-18 column (10-90% MeCN / H 2 O / 0.05% TFA) to yield a white powder (94 mg, 95%). A NMR (CDC13): d 8.15, (d, J = 8.1, 1H); 7.73 (br 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, 2 H); 4.59 (s, 2H); 4.26 (br s, 2H); 3.86 (s, 3H); 3.49 (s, 3H). HRMS m / z 493.1546 (M + H.) EXAMPLE 64 N- (2 'Aminosulfonyl- [1,1'] -bifen-4-yl) -1-4-methoxyphenyl) -3-carbomethoxy-1H-pyrazole-5 -carboxamide. 3-Formyl-1- (4-Methoxyphenyl) -lH-pyrazole-5-carboxylic acid: Ethyl 3- (dibromomethyl) -1- (4-methoxyphenyl) -lH-pyrazole-5-carboxylate (0.34 g, 0.813 mmol) was dissolved in 2 L of THF and lithium hydroxide was dissolved (34 mg, 0.816 mmol). ) in 0.5 mL. of water and was added to the methanolic solution. After the solution at room temperature for 16 hours the solvent was evaporated, the residue was dissolved in 10 mL of water, acidified with IN HCl and extracted with EtOAc to give 66 mg (33%) of the desired product after evaporation. . A NMR (CDC13): d 10.96 (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).

N- (2'-t-butylaminosulfonyl- [1,1 '] -bifen-4-yl) -formyl-1- (4-methoxyphenyl) -lH-pyrazole-5-carboxamide: Oxalyl chloride (20 mL) was added and dry DMF (2 drops) at room temperature to 3-formyl (4-methoxyphenyl) -1H-pyrazole-5-carboxylic acid (66 mg, 0.25 mmol) in CH2Cl2 (2 mL) and stirred 2 hours under N The solution The resultant was evaporated and placed briefly under high vacuum before redissolving in CH2C12 (2 mL). This solution was added over a few minutes to a mixture of 2'-t-butylaminosulfonyl-4-amino- [1, 1 '] biphen-4-yl (51 mg, 0.17 mmol) in 2 mL of CH2C12. The resulting solution was stirred at room temperature under N2 for 23 hours, diluted with CH2Cl2, extracted with H2O, filtered and evaporated. The crude product was chromatographed on silica gel (30% EtOAc / hexanes) to give a white solid. (16.2 mg, 11%). A NMR (CDCl 3): d 10.09 (s, 1H); 8.16 (d, J = 8.1, 1H); 7.77 (br s, 1H); 7.56 (m, 3H); 7.49 (, 4H); 7.40 (m, 1H); 7.25 (m, 2H); 7.04 (d, J = 8.8, 2H); 3.89 (s, 3H); 3.61 (br s, 1H); 1.02 (s, 9H).

N- (2'-t-Butylaminosulfonyl- [12,1 '] -bifen-4-yl) -3-carbomethoxy-1- (4-methoxyphenyl) -lH-pyrazole-5-carboxamide: The N- (2') -t-butylaminosulfonyl- [1, 1 '] -bifen-4-yl) -3-formyl-1- (4-methoxyphenyl) -lH-pyrazole-5-carboximide (16.2 mg, 0.03 mmol), KCN (6.9 mg , 0.11 mmol), activated manganese oxide (100 mg), and acetic acid (1.7 μL, 0.03 mmol). It was dissolved / suspended in 1 mL of methanol and stirred at room temperature for 24 hours. The reaction mixture was filtered through celite and evaporated to 14 mg (82%) of the desired product. X H NMR (CDCl 3): d 8.16 (d, J = 8.1, 1 H); 7.67 (br 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'] -bifen-4-yl) -3-carbomethoxy-1- (4-methoxyphenyl) -lH-pyrazole-5-carboxamide: The N- (2'-t- Butylaminosulfonyl- [1,1 '] -bifen-4-yl) -3-carbomethoxy-1- (4-methoxyphenyl) -lH-pyrazole-5-carboxamide (14 mg, 0.02 mmol) was dissolved in 2 mL TFA and stirred at room temperature for 16 hours. The solvent was removed and the product was purified by preparative HPLC on an inverted phase C-18 column (10-90% MeCN / H20 / 0.05% TFA) to produce a white powder. (9 mg, 81%). A NMR (CDC13): d 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 (br s, 2H); 3.99 (s, 3H); 3.87 (s, 3H). HRMS m / z 507.1260 M A).

EXAMPLE 65 N- (2 'Aminosulfonyl- [1,1'] -bifen-4-yl) -1- (4-methoxyphenyl) -3- (methylsulfonylmethyl) -lH-pyrazole-5-carboxamide. 1- (methoxyphenyl) -3- (methylsulfonylmethyl) -lH-pyrazole-5-carboxylic acid ethyl ester: 3- (bromomethyl) -1- (4-methoxy-phenyl) -1H-pyrazole-5-carboxylate (0.4440 g, 1.31 mmol ) was dissolved in 10 mL of THF with potassium diomethoxide (0.248 g, 2.88 mmol) and heated to reflux for 14 hours. The reaction mixture was cooled and reduced to an original volume of 1/10. The reaction mixture was dissolved in 20 mL of water and extracted with EtOAc and oxidized with air for 24 hours to give 0.358 g of a crude mixture. The product was purified by preparative HPLC on an inverted phase C-18 column (10.90% MeCN / H 2 O / 0.05% TFA) to yield a white powder 47 mg (11%) of the desired product. A NMR (CDC13): d 7.32 (d, J = 8.8, 2H); 7.18 (s, 1H); 6.97 (d, J = 8.8, 2H); 4.37 (s, 2H); 4.25 (q, 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- (methylsulfonylmethyl) -lH-pyrazole-5-carboxamide: Trimethyl-aluminum was added (0.41 mL, 2.0 M in heptane, 0.83 mmol) was added to 2 't-butylaminosulfonyl-4-amino- [1,1'] bifen-4-yl (50.6 mg, 0.166 mmol) in CH2CL2 (5 mL).

After stirring at room temperature under N2, for 75 minutes, a solution of ethyl l- (4-methoxyphenyl) -3- (methylsulfonylmethyl) -lH-pyrazole-5-carboxylic acid ethyl ester (47 mg, 0.139 mmol) was added. in CH2C12 (2 mL) and the resulting solution was stirred 70 hours. The resulting reaction was carefully cooled by the dropwise division of 1M HCl, diluted with H2O and extracted with CH2C12.

The organic layer was dried over Na 2 SO 4, filtered and evaporated. The crude product was purified with preparative HPLC on an inverted phase C-18 column (10-90% MeCN / H 2 O / 0.05% TFA) to produce the desired product. A NMR (CDC13): d 8.16 (d, J = 8.1, 1H); 7.76 (br s, 1H); 7.49 (, 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 *] -bifen-4-yl) -1- (4-methoxyphenyl) -3- (methylsulfonylmethyl) -lH-pyrazole-5-carboxamide: The N- (2'- t-butylaminosulfonyl- [1,1 '] -bifen-4-yl) -1- (4-methoxyphenyl) -3- (methylsulfonylmethyl) -lH-pyrazole-5-carboxamide (80 mg, 0.15 mmol) was dissolved in 2 mL of TFA and stirred at room temperature for 16 hours. The solvent was removed and the product was purified by preparative HPLC on an inverted phase C-18 column (10-90% MeCN / H20 / 0.05% TFA) to yield a white powder (47 mg, 58%) A NMR ( CDCl 3): d 8.16 (d, J = 8.1, 1H); 8.06 (br s, 1H); 7.60 (m, 4H); 7.44 (m, 4H); 7.33 (m, 1H); 7.09 (br s, 1H); 7.01 (d, J = 9.1, 2H); 4.43 (s, 2H); 4.38 (br s, 2H); 3.87 (s, 3H); 2.97 (s, 3H). HRMS m / z 541.1137 (M + H), EXAMPLE 66 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (5- (2-methanesulfonyl) phenyl) pyrimidine-2-yl) carboxamide. 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (5- (2-methanesulfonyl) phenyl) pyrimidine-2-yl) carboxamide. This material was prepared according to the methods described for Example 15 with the exception that during the coupling step the 2-amino-5- (2-methanesulfonyl) phenyl) pyrimidine was replaced by 4- (2-Nt-butylaminosulfonyl) phenyl) aniline. Purification by HPLC using gradient elution with a mixture of water: acetonitrile with 0.05% trifluoroacetic acid on an inverted phase C-18 column (60 A) gave a pure mixture of the title compound; HRMS (M + H) + cale. m / z: 518,110987, obs: 518. 108715.

EXAMPLE 67 3-Methyl-1- (4-methoxyphenyl) -lH-pyrazole-5-N- (4- (N-carboxyl-2-carbomethoxypyrrolidino) phenyl) carboxyamide N- (4-Nitrobenzoyl) -2-carbomethoxy-pyrrolidine: A 2-carbomethoxy-pyrrolidine (d, 1-proline-methyl ester, 1.64 g, 12. 7 mmol) with pyridine (10.1 g, 12.7 mmol) in CH2C12 (100 ml) at 0 ° C was added 4-nitrobenzoyl chloride (2.36 g, 17.7 mmol) in CH2C12 (25 ml) dropwise. The reaction was allowed to warm to room temperature and was stirred 18 h. The reaction was evaporated and applied to a flash column and eluted with a gradient of Hexane: EtOAc 2: 1 to Hexane: EtOAc 1: 2. 1.3 g of the title compound were isolated; LRMS (M + H) + m / z = 279.

N- (4-Aminobenzoyl) -2-carbomethoxy-pyrrolidine: N- (4-Nitrobenzoyl) -2-carbomethoxy-pyrrolidine (0.54 g, 1.94 mmol) in MeOH (50 mL) with 10% Pd-C (0.10 g) was stirred under an atmosphere of H2 gas (50 psi) for 4 hours. The reaction was filtered through a plug of Celita® and evaporated to give 0.41 g of the aniline; LRMS (M + H) + m / z = 249. 3-Methyl-l- (4-methoxyphenyl) -lH-pyrazole-5-N- (4- (N-carboxyl-2-carbomethoxypyrrolidino) phenyl) carboxyamide: This compound was prepared by the methodology described in EXAMPLE 19 with the except that in the coupling step N- (4-aminobenzoyl) -2-carbomethoxy pyrrolidine was used in place of 2-amino-5- (N-pyrrolidinocarbonyl) pyridine. The solvent was evaporated, the residue was dissolved in ethyl acetate and washed with water. After drying and removal of the solvent the crude product was purified by HPLC using gradient elution with a mixture of water: acetonitrile with 0.05% trifluoroacetic acid on a C18 column (60 A) of inverted phase to give a pure sample of the compound of the Title; mp 46 ° C, HRMS (M + H) + cale, m / z: 462.190320, obs: 642.188795.

EXAMPLE 68 3-Methyl-1- (4-methoxyphenyl) -lH-pyrazole-5-N- (4- (N-carboxyl-3-aminopyrrolidino) phenyl) carboxyamide 3-Methyl-l- (4-methoxyphenyl) -lH-pyrazole-5-N- (4- (N-carboxyl-3-azidopyrrolidino) phenyl) carboxyamide: At 3-methyl-1- (4-methoxyphenyl) - lH-pyrazole-5-N- (4- (N-carboxyl-3-hydroxypyrrolidino) phenyl) carboxyamide (prepared in EXAMPLE 21, 0.14 g, 0.33 mmol) with Et3N (0.05 g, 0.5 mmol) in CH3C12 was added chloride of methanesulfonyl (0.057 g, 0.05 mmol). After 18 h, the reaction mixture was terminated; evaporated, dissolved in EtOAc, washed with IN HCl, dried and evaporated. 0.21 g of the methanesulfonate were obtained; LRMS (M + S02CH3) + m / z = 403.

The methanesulfonate prepared above (0.17 g, 0.35 mmol) and sodium azide (0.11 g, 1.76 mmol) in DMF (10 ml) was heated at 60 ° C for 4 hours. Brine was added to the cold reaction mixture and the suspension was extracted with EtOAc (3x). The combined extracts were washed with water (5x), dried (MgSO 4), and evaporated to give 0.10 g of the azide; LRMS (M-N2) + m / z = 418. 3-Methyl-l- (4-methoxyphenyl) -lH-pyrazole-5-N- (4- (N-carboxyl-3-aminopyrrolidino) phenyl) carboxyamide: The azide of the foregoing (0.10 g, 0.22 mmol) in MeOH (20 ml) with 10% Pd-C was stirred with an atmosphere of H2 gas (1 atmosphere). After 2 hours the reaction was purged with N2, filtered through a pad of Celita®, and evaporated. The crude product was purified by HPLC using gradient elution with a mixture of water: acetonitrile with 0.05% trifluoroacetic acid on an inverted phase C18 column (60 A) to give a pure sample of the title compound; p.f. 133 ° C, HRMS (M + H) + cale, m / z: 420.203565, obs: 420.203373.

EXAMPLE 69 3-Methyl-1- (4-methoxyphenyl) -lH-pyrazole-5-N- (4- (N-carboxyl-3-methoxypyrrolidino) phenyl) carboxyamide N- (N-carboxyl-3-methoxypyrrolidino) aniline: To the acid chloride of 3-hydroxypyrrolidine (1.63 g, 14.9 mmol) and triethylamine (1.51 g, 14.9 mmol) in dichloromethane (50 ml) at 0 ° C was added a Solution of p-nitrobenzoyl chloride (2.5 g, 12.4 mmol) in dichloromethane (50 ml). The reaction was evaporated to dryness and the residue was dissolved in ethyl acetate. This solution was washed with brine IN hydrochloric acid solution, then dried and evaporated to give 2.22 g of the product; LRMS (M + H) + m / z: 237.

To a suspension of NaH (0.16 g of a 60% suspension in mineral oil, 6.89 mmol) in THF (30 ml) was added dropwise a solution of the hydroxy compound prepared above (0.65 g, 2.75 mmol) in THF ( 10 ml). The reaction was cooled to 0 ° C and methyl iodide (0.43 g, 3.03 mmol) was added. The reaction was stirred at room temperature for 24 hours. The reaction was diluted with Et20 and washed with 0.5N NH4C1, and brine, then dried and evaporated to give the methyl ether (0.47 g); LRMS (M + H) + m / z = 251.

Methyl ether (0.42 g, 1.68 mmol) in MeOH (50 ml) with 10% Pd-C (0.05 g) was stirred under an atmosphere of H2 gas (1 atmosphere) for 3 hours. The reaction was purged with N2, and filtered through a pad of Celita® and evaporated to give 0.28 g of the aniline; LRMS (M + H) + m / z = 221. 3-Methyl-l- (4-methoxyphenyl) -lH-pyrazole-5-N- (4- (N-carboxyl-3-methoxypyrrolidino) phenyl) carboxyamide: This compound was prepared by the methodology described for EXAMPLE 19 with the except that in the coupling step, 4- (N-carboxyl-3-methoxypyrrolidino) aniline was used in place of 2-amino-5- (N-pyrrolidinocarbonyl) pyridine. The solvent was evaporated, the residue was dissolved in ethyl acetate and dried with water. After drying and removal of the solvent, the crude product was purified with HPLC using gradient elution with a mixture of water: acetonitrile with 0.05% trifluoroacetic acid on a C18 column (60 A) of inverted phase to give a pure sample of the compound of the title; p.f. 40.2 ° C, HRMS (M + H) + cale, m / z: 434.195406, obs: 434.194469.

EXAMPLE 70 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (5- (2-aminosulfonyl) phenyl) pyridin-2-yl) carboxyamide 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (5- (2-aminosulfonyl) phenyl) iridin-2-yl) carboxyamide: This material was prepared according to the methods described by EXAMPLE 15 with the exception that during the coupling step the 2-amino-5- (2-Nt-butylaminosulfonyl) phenyl) pyridine was replaced by 4- (2-Nt-butylaminosulfonyl) phenyl) aniline. The t-butylsulfonamide group was removed by heating the reflux coupling product in TFA for 1 hour, then stirring the TFA by distillation in vacuo. Purification of the final product was by HPLC using elution gradient with a mixture of water: acetonitrile with 0.05% trifluoroacetic acid in a C18 column (60 a) inverted phase to give a pure sample of the title compound; HRMS (M + H) + cale. m / z: 518.110986, obs: 518.112930.

EXAMPLE 71 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4-amidino) phenyl) carboxyamide • TFA 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4-cyano) phenyl) carboxyamide: A 3-Trifluoromethyl-5-methyl-1- (4-methoxyphenyl) -lH-pyrazole (EXAMPLE 15, 0.6 g, 2.1 mmol) in CHCl2 (20 ml) at 0 ° C oxalyl chloride was added in CH2C12 (2 M solution, 1.6 ml, 3.15 mmol) followed by a few drops of DFM. The reaction was allowed to warm to room temperature and was stirred at 18 hours. The reaction was evaporated and pumped for several hours to remove the last traces of HCl. The acid chloride was combined with p-aminobenzonitrile (0.3 g, 2.52 mmol) and DMAP (0.77 g, 6.3 mmol) in CH2C12 (40 ml) and stirred at room temperature for 18 hours. The reaction was evaporated and then partitioned between 1 N HCl and EtOAc. The EtOAc layer was dried and evaporated to give 0.79 g of the crude product. The additional purification was carried out by MPLC with a 20 g column of flash silica, eluting with Hexane: EtOAc 3: 1 and collecting 25 ml fractions. The desired 0.45 g of nitrile was obtained as fractions 30-65; p.f. 188.2. HRMS (M + H) + cale, m / z: 386.099081, obs: 386.098101. 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4- (O-methyl) formimino) phenyl) carboxyamide • HCl: An anhydrous HCl gas stream was passed through a Solution of 3-trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4-cyano) phenyl) carboxyamide (225 mg, 0.58 mmol) in dry MeOAc (25 mL) and dry MeOH (5 mL). ml) at 0 ° C until saturation. After a further passage for 18 hours at 10 ° C, the sealed flask was deselled and the solvent was removed by distillation in vacuo. The residue was repeatedly evaporated with dry Et20, then pumped for several hours to remove the last traces of HCl. 3-Trifluoromethyl-l- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4-amidino) phenyl) carboxyamide • TFA: The amidate (0.58 mmol) prepared above was dissolved in dry MeOH (10 ml) and NH 4) 2 CO 3 (0.32 g, 3.33 mmol) was added. The mixture was stirred at room temperature for 18 hours, then evaporated to dryness. Purification of the crude product was by HPLC using gradient elution with a mixture of water: acetonitrile with trifluoroacetic acid at 0.05% on a C18 column (60 A) of inverted phase to give a pure sample of the title compound; p.f. 232.5, HRMS (M + H) + cale, m / z: 404.133435, obs: 404.132331.

EXAMPLE 72 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4- (N-pyrrolidino) formylimino) phenyl) carboxyamide • TFA 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4- (N-pyrrolidino) formylimino) phenyl) carboxyamide • TFA: 3-trifluoromethyl-1- (4-methoxyphenyl) - lH-pyrazole-5- (N- (4- (0-methyl) formylimino) phenyl) carboxyamide • HCl (EXAMPLE 71, 0. 58 mmol) prepared above was dissolved in dry MeOH (10 ml) and pyrrolidine (0.12 g, 1.74 mmol) was added.

This mixture was stirred at room temperature for 18 hours, then evaporated to dryness. Purification of the final product was by HPLC using gradient elution with a mixture of water: acetonitrile with 0.05% trifluoroacetic acid on an inverted phase C18 (60 A) column to give a pure sample of the title compound; p.f. 89.5, HRMS (M + H) + cale, m / z: 458.180385, obs: 458.183032.

EXAMPLE 73 3-Trifluoromethyl-5- (N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl)) -1- (4-methoxyphenyl) pyrrolo [3,4-d] pyrazole-4 6- (1H, 5H) -dione 1,1, 1-Trifluoroacetaldehyde-N- (4-methoxyphenyl) hydrazone: A mixture of 1,1-trifluoroacetaldehyde-ethyl-hemiacetal (4.2 g, 34.17 mmol) and 4-methoxyphenylhydrazine • HCl (4.97 g, 28.48 mmol ) in EtOH (100 ml) s refluxed, then cooled to room temperature when all components were dissolved. The reaction was evaporated to dryness to give 5.34 g of a black oil which was used in the next step without further purification; LRMS (M + H) + m / z = 219.2. 1,1, 1-Trifluoroacetoyl-bromide-N- (4-methoxyphenyl) hydrazone: To the black oil (0.87 g, 4 mmol) produced above in DMF (25 ml) at 0 ° C was added N-bromosuccinimide (0.72 g, 4 mmol) as a portion. The reaction was terminated in 2 h (TLC, 3: 1 Hexane: EtOAc). The reaction was diluted with brine and extracted with EtOAc. The extracts were washed with brine (5x), and dried (MgSO 4) and evaporated to give 0.69 g of the product as a black oil. This material was used without further purification. 4- (2-Nt-Butylaminosulfonyl) phenyl) bromomaleimide: Bromomaleic anhydride (0.29 g, 1.65 mmol) was added to 4- (2-Nt-butylaminosulfonyl) phenyl) aniline (0.5 g, 1.65 mmol) in THF (10 mL) . After 1 hour the solution was cooled to 0 ° C and N-methylmorpholine (0.2 g, 1.98 mmol) was added followed by isobutylchloroformate (0.27 g, 1.98 mmol). The reaction was allowed to warm to room temperature and stirred 18 hours. The reaction was evaporated, dissolved in EtOAc, washed with 1N HCl, dried and evaporated. the product was purified by MPLC using a 200 g column in flash silica and eluting with "Hexane: EtOAc 3: 1 and 25 ml fractions were collected.The crude product (0.39 g) was isolated from the 35-65 fractions.; HRMS (M + H) + cale, m / z: 462.024890, obs: 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: A mixture of 1,1-trifluoroacetoyl-bromide-N- (4-methoxyphenyl) hydrazone (0.68 g, 2.29 mmol) and 4- (2-Nt-butylaminosulfonyl) phenyl) bromomalimide (0.2 g, 0.4 mmol) with Et3N (0.35 g, 3.45 mmol) in toluene was heated to reflux for 3 hours. The reaction was diluted in EtOAc, washed with IN HCl, dried (MgSO4) and evaporated to give 0.35 g of the crude product. The product was isolated using MPLC by eluting the raw material from a column of flash silica gel (200 g) with Hexane: EtOAc 3: 1 and collecting 25 ml fractions. Fractions 33-58 produced 0.15 g of the pure material; p.f. 196.1 ° C, HRMS (M + H) + cale, m / z: 653.165176, obs: 653.166000. 3-Trifluoromethyl-5- (N- (2 '-aminosulfonyl- [1,1'] -bifen-4-yl)) -1- (4-methoxyphenyl) pyrrolo [3,4-d] pyrazole-4,6 - (1H, 5H) dione: The product of the above (0.15 g, 0.25 mmol) was heated to reflux in TFA for 1 hour. The reaction was cooled and evaporated to give 0.14 g of the crude material. The product was isolated using MPLC to elute the raw material from a column of flash silica gel (200 g) with Hexane: EtOAc 2: 1 and collecting 25 ml fractions. Fractions 55-90 were combined and triturated with a small amount of Et20. This process gave 0.06 g of pure material; p.f. 210.7 ° C, HRMS (M + H) + cale, m / z: 543.095002, obs: 543.097942.

EXAMPLE 74 3-Trifluoromethyl-l- (4-methoxyphenyl) -lH-pyrazole-5-carbomethoxy- (N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl)) carboxyamide AND EXAMPLE 74 3 -Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5-hydroxymethyl- (N- (2'-aminosulfonyl- [1,1 * 3-biphen-4-yl)) carboxyamide Preparation of a mixture of 3-trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5-carbomethoxy- (N- (2'-Nt-butylaminosulfonyl- [1,1 '] -bifen-4-yl)) carboxyamide and 3-trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5-hydroxymethyl- (N- (2 '-Nt-butylaminosulfonyl- [1,1'] -bifen-4-yl)) carboxyamide: 3-Trifluoromethyl-5- (N- (2 '-Nt-butylaminosulfonyl- [1,1'] -bifen-4-yl)) -1- (4-methoxyphenyl) pyrrolo [3,4-d] pyrazole-4 , 6- (1H, 5H) -dione (0.37 g, 0.62 mmol) in AcCN (30 mL) was added dropwise to a solution of NaBH4 (0.096 g, 2.48 mmol) in MeOH (20 mL) at 0 ° C . The reaction was finished in less than 1 h. (TLC, 3: 1 Hexane: EtOAc). It was evaporated, dissolved in EtOAc and washed with 1N HCl. The organic cap was dried and evaporated to give a mixture of the title compounds (0.37 g). This mixture was separated by MPLC using a 400 g column of flash silica gel and eluting with Hexane: EtOAc 2: 1; 25 ml fractions of the eluent were collected.

From fractions 50-66, 3-trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5-carbomethoxy- (N- (2'-Nt-butylaminosulfonyl- [1,1 '] -bifen- 4-yl)) carboxyamide (0.15 g); HRMS (M + Na) + cale, m / z: 653.165761, obs: 653.164400.

From fractions 69-100, 3-trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5-carbomethoxy- (N- (2'-Nt-butylaminosulfonyl- [1,1 '] -bifen- 4-yl)) carboxyamide (0.12 g); HRMS (M + Na) + cale, m / z: 625.170847, obs: 625.169900. 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5-carbomethoxy- (N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl)) carboxyamide: The product of the fractions 50-66 (0.15 g) was heated to reflow in TFA for 1 hour. The reaction was cooled and evaporated to give 0.14 g of the crude material. Purification of the final product was by HPLC using gradient elution with a mixture of water: acetonitrile with 0.05% trifluoroacetic acid on an inverted phase C18 column (60 A) gave a pure sample of Example 74; p.f. 233.3 ° C, HRMS (M + H) + cale. m / z: 575.121216, obs: 575.120500. 3-Trifluoromethyl-l- (4-methoxyphenyl) -lH-pyrazole-5-hydroxymethyl- (N- (2-aminosulfonyl- [1,1 '] -bifen-4-yl)) carboxyamide: The product of fractions 69 -100 (0.12 g) was heated to reflow in TFA for 1 hour. The reaction was cooled and evaporated to give 0.11 g of the crude material. Purification of the final product was by HPLC using gradient elution with a mixture of water: acetonitrile with 0.05% trifluoroacetic acid on an inverted phase C18 column (60 A) gave a pure sample of Example 75; p.f. 115.4 ° C, HRMS (M + H) + cale, m / z: 547.126302, obs: 547.124400.

EXAMPLE 76 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N-2-fluoro (4- (N-pyrrolidino) formyl) phenyl) carboxyamide • TFA 3-Fluoro-4-nitrobenzamide: 3-Fluoro-4-nitrobenzoic acid (5.0 g, 27 mmol) and S0C12 (6.42 g, 54 mmol) with a few drops of DMF in benzene (100 mL) was refluxed for 3 hours. hours. The reaction was evaporated to dryness, then evaporated several times with Et20 to purify, yielding 5.56 g.

The acid chloride prepared above was dissolved in EtOAc (50 mL) and added dropwise to a biphasic mixture at 0 ° C of EtOAc (150 mL) and concentrated NH 4 OH (100 mL). After 30 minutes, the layers were separated, the aqueous layer was saturated with NaCl and extracted with EtOAc. The combined organic extracts were dried and evaporated to give 4.85 g of the benzamide; LRMS / ES "(M + H)" m / z = 182.9. 3-Fluoro-4-aminobenzonitrile: To a solution of EtOAc at 0 ° C (150 mL) of 3-fluoro-4-nitrobenzamide (4.85 g, 26.4 mmol) and Et3N (5.34 g, 52.8 mmol) was added dropwise a solution of CH2C12 (50 L) of 1,1,1-trichloroacetyl chloride (5.28 g, 29.04 mmol). The reaction was finished in 2 h (TLC, hexane: EtOAc 1: 1), then washed with 1 N HCl, dried (MgSO 4) and evaporated to give 4.1 g of the corresponding nitrile.

The 4-nitrobenzonitrile derivative prepared above (4.1 g, 24.7 mmol) in EtOH / water (80 mL / 40 mL) was heated to reflux with iron powder (8.3 g, 148 mmol) and NH 4 Cl (0.83 g, 15.3 mmol) for 2 hours. The reaction was filtered and evaporated to dryness. The residue was dissolved in EtOAc, washed with brine and dried (MgSO4) to give 2.68 g of the product; LRMS (M + H) + m / z = 137.0. The product was further purified by MPLC on a 360 g column of flash silica gel and eluting with hexane: EtOAc 3: 1; fractions of 25 mL were collected. From fractions 128-195, 1.32 g of the pure product were obtained. 3-Trifluoromethyl-l- (4-methoxyphenyl) -lH-pyrazole-5- (N-2-fluoro-4-cyano) phenyl) carboxyamide: A 3-trifluoromethyl-5-methyl-1- (4-methoxyphenyl) - lH-pyrazole (EXAMPLE 15, 1.13 g, 3.95 mmol) in CH2C12 (100 mL) at 0 ° C was added oxalyl chloride in CH2C12 (2 M solution, 2.96 mL, 5.93 mmol) followed by a few drops of DMF. The reaction was allowed to warm to room temperature and was stirred at 18 h. The reaction was evaporated and pumped for several hours to remove the last traces of HCl.

The acid chloride was combined with 3-fluoro-4-aminobenzonitrile (0.59 g, 4.35 mmol) and DMAP (1.45 g, 11.85 mmol) in CH2C12 (100 mL) and stirred at room temperature for 18 hours. The reaction was then evaporated divided between 1 N HCl and EtOAc. The EtOAc layer was dried and evaporated to give 0.79 g of the crude product. The additional purification was carried out by MPLC with a 360 g column of flash silica, eluting with Hexane: EtOAc 4: 1 and collecting fractions of 25 mL. The 0.83 g of the desired nitrile was obtained from fractions 91-133; p.f. 160.6, LRMS (M + H) + m / z = 405.0. 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (2-fluoro-4- (O-methyl) formyl) phenyl) carboxyamide • HCl: An anhydrous HCl stream was passed through of a solution of 3-trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4-cyano) phenyl) carboxyamide (0.83 g, 2.05 mmol) in dry MeOAc (50 mL) and dry MeOH (10 L) at 0 ° C until saturation. After the 18 hour review at 10 ° C, the hermetically capped flask was deselled and the solvent was removed by distillation in vacuo. The residue was then repeatedly evaporated with dry Et20, then pumped for several hours to remove the last traces of HCl. 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (2-fluoro-4- (N-pyrrolidino) formyl) phenyl) carboxyamide • TFA: 3-Trifluoromethyl-1- (4 -methoxyphenyl) -lH-pyrazole-5- (N- (2-fluoro-4- (O-methyl) formyl) phenyl) carboxyamide • HCl (2.05 mmol) prepared above was dissolved in dry MeOH (15 mL) and pyrrolidine (0.44 g, 6.15 mmol) was added. This mixture was stirred at room temperature for 18 h, then evaporated to dryness. Purification of the final product was by HPLC using gradient elution with a mixture of water: acetonitrile with 0.05% trifluoroacetic acid on an inverted phase C18 (60 A) column gave a pure sample of the title compound; p.f. 61.8 ° C, HRMS (M + H) + cale, m / z: 476.170963, obs: 476.170693.

EXAMPLE 77 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4- (N-pyrrolidino) formyl-N- ((2-propyl) methylcarbamoyl) imino) enyl) carboxyamide 3- Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4- (N-pyrrolidino) formyl-N- ((2-propyl) methylcarbamoyl) imino) phenyl) carboxyamide: At 3-trifluoromethyl -1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4- (N-pyrrolidino) formyl) phenyl) carboxyamide • TFA (EXAMPLE 72, (0.311 g) was added 1N NaOH (25 mL) a suspension formed which was extracted with CH2C12 (2 x 35 mL) The organic extracts were dried and evaporated to give 0.18 g (0.39 mmol) of the free base.The free base was redissolved in CH2C12 (20 mL) and cooled to 0 ° C, then Et3N (0.08 g, 0.78 mmol) was added. To the cooled solution, 4.4 mL (0.44 mmol) of a 0.1 N solution of isobutylchloroformate (0.01 mol to [1.3 mL] of pure isobutylchloroformate in 100 mL of CH2C12) were added dropwise and stirred at 0 ° C for 2 hours. hours. The reaction was evaporated and partitioned between EtOAc and 1 N HCl. The EtOAc layer was dried and evaporated to give 0.10 g of the crude material. This was further purified by MPLC using a 200 g column of flash silica gel and eluting with hexane: EtOAc 2: 1. Fractions of 25 mL were collected and 0.056 g of the pure product was isolated from fractions 40-80; p.f. 90.1 ° C, HRMS (M + H) + cale. m / z: 558.2345, obs: 558.2334.

EXAMPLE 78 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4- (N-pyrrolidino) formyl-N- (mßtansulfamoyl) imino) phenyl) carboxyamide 3-Trifluoromethyl-l- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4- (N-pyrrolidino) formyl-N- (methanesulfamoyl) imino) phenyl) carboxyamide: At 3-trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4- (N-pyrrolidino) formyl) phenyl) carboxyamide • TFA (EXAMPLE 72, (0.332 g) was added 1N NaOH (25 mL), a suspension The organic extracts were dried and evaporated to give 0.18 g (0.39 mmol) of the free base.The free base was re-dissolved in CH2C12 (25 mL) and cooled At 0 ° C, then DMAP (0.095 g, 0.78 mmol) was added.To the cooled solution was added 4.2 mL (0.042 mmol) of a 0.1 N solution of methanesulfonyl chloride (0.01 mol [0.78 mL] of methanesulfonyl chloride). 100 mL of CH2C12) dropwise and stirred at 0 ° C for 48 hours The reaction was evaporated and partitioned between EtOAc and 1 N HCl. The EtOAc layer was dried and evaporated to give 0.11 g of the material This was further purified by MPLC or Extract a 200 g column of flash silica gel and elute with hexane: EtOAc 2: 1. Fractions of 25 mL were collected and 0.050 g of the pure product was isolated from fractions 81-130; p.f. 117.2 ° C, HRMS (M + Na) + obs. m / z: 558.1381.

EXAMPLE 79 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- ((4-amidino) phenyl) methyl) carboxyamide * TFA α-Amino-4-cyanotoluene: A mixture of 4-cyanobenzyl bromide (3 g, 15.3 mmol) and NaN 3 (1.99 g, 30.6 mmol) in DMF (20 mL) was stirred at room temperature for 18 hours. The reaction was diluted with brine and extracted with EtOAc. The organic extracts were washed with brine (5x), dried (MgSO 4) and evaporated to give 1.87 g of the benzylic azide product.

The benzylic azide (1.87 g, 11.84 mmol) and SnCl2 »H20 (7.25 g, 32.2 mmol) in MeOH (50 mL) was stirred at room temperature for 18 hours. The solution was evaporated to dryness, then the residue was dissolved in 1N NaOH and extracted with EtOAc. The EtOAc layer was washed with brine, dried and evaporated to give 0.83 g of a-amino-4-cyanotoluene. 3-Trifluoromethyl-l- (4-methoxyphenyl) -lH-pyrazole-5- (N- ((4-cyano) phenyl) methyl) carboxyamide: 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 CH2C12 (30 L) at 0 ° C was added isobutylchloroformate (0.21 g, 1.54 mmol). The reaction was stirred for 30 minutes at 0 ° C and 0.203 g of a-amino-4-cyanotoluene (1.54 mmol) in CH2C12 (8 mL) was added. After 18 hours, the reaction was washed with 1 N HCl and NaOH, then dried and evaporated to give 0.54 g of the crude material. The additional purification was carried out by MPLC with a 200 g column of flash silica, eluting with hexane: EtOAc 2: 1 and collecting fractions of 25 mL. The 0.32 g of the desired nitrile was obtained from fractions 61-120; p.f. 197.5, LRMS (M + H) + m / z = 401.0. 3-Trifluoromethyl-l- (4-methoxyphenyl) -lH-pyrazole-5- (N- ((2-fluoro-4- (O-methyl) formimino) phenyl) methyl) carboxyamide • HCl: An anhydrous HCl gas stream was passed through a solution 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- ((4-cyano) phenyl) methyl) carboxyamide (0.32 g, 0.8 mmol) in Dry MeOAc (25 mL) and dry MeOH (5 mL) at 0 ° C until saturation. After standing for 18 h at 10 ° C, the hermetically capped flask was deselled and the solvent was evaporated by distillation in vacuo. The product was then repeatedly evaporated with dry Et20, then pumped for several hours to remove the last traces of HCl. 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- ((4-amidino) phenyl) methyl) carboxyamide • TFA: The amidate (0.4 mmol) prepared above was dissolved in dry MeOH (15%). mL) and (NH) 2C03 (0.192 g, 2.0 mmol) was added. This mixture was stirred at room temperature for 18 h, then evaporated to dryness. Purification of the final product was by HPLC using gradient elution with a mixture of water: acetonitrile with 0.05% trifluoroacetic acid on an inverted phase C18 (60 A) column gave a pure sample of the title compound, m.p. 131.4, HRMS (M + H) + obs. m / z: 418.1478.

EXAMPLE 80 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- ((4- (N-pyrrolidino) formylimino) phenyl) methyl) carboxyamide • TFA 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- ((4- (N-pyrrolidino) formylimino) phenyl) methyl) carboxyamide • TFA: the 3-trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- ((4- (0-methyl) formimino) phenyl) methyl) carboxyamide • HCl (EXAMPLE 79, 0.4 mmol) prepared above was dissolved in dry MeOH (15 mL) and pyrrolidine (0.09 g, 1.2 mmol) was added. This mixture was stirred at room temperature for 18 h, then evaporated to dryness. Purification of the final product was by HPLC using gradient elution with a mixture of water: acetonitrile with 0.05% trifluoroacetic acid on an inverted phase C18 (60 A) column gave a pure sample of the title compound; LRMS (M + H) + m / z: 472.3.

EXAMPLE 81 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- ((1-benzyl) piperidin-4-yl) carboxyamide • TFA 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- ((1-benzyl) piperidin-4-yl) carboxyamide • TFA: A 3-trifluoromethyl-5-methyl-1- (4 -methoxyphenyl) -lH-pyrazole (EXAMPLE 15, 2.86 g, 10 mmol) and N-methyl-morpholine (1.01 g, 10 mmol) in THF (50 mL) at 0 ° C was added isobutylchloroformate (1.36 g, 10 mmol) The reaction was stirred for 30 minutes at 0 ° C and 1.90 g of l-benzyl-4-aminopiperidine (10 mmol) was added.After 18 h, the reaction was evaporated to dryness and dissolved in 1 N NaOH. it was then extracted with EtOAc The EtOAc layer was washed with brine, then dried and evaporated to give 4.36 g of the crude material The recrystallization with n-butylchloride gave 1.16 g of the product, mp 120.8 ° C.

A sample of 0.10 g in Et20 and added TFa was dissolved to form the TFA salt. Trituration with Et20 and n-butylchloride gave 0.015 g of the crude product; p.f. 175.6 ° C, HRMS (M + H) + clack, m / z: 459,200, obs: 459,199.

EXAMPLE 82 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N - ((1- (pyridin-2-yl) methyl) piperidin-4-yl) carboxyamide »TFA 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N-piperidin-4-yl) carboxyamide • HCl: To a solution of 3-trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole -5- (N- ((benzyl) piperidin-4-yl) carboxyamide (EXAMPLE 81, 1.06 g, 2.31 mmol) in CH2C12 (40 mL) was added 1-chloroethylchloroformate (0.5 g, 3.5 mmol). filter for 2 hours, then evaporated to dryness The residue was dissolved in MeOH (50 mL) and refluxed for 1 hour, the reaction was evaporated to give 0.8 g of the product, LRMS (M + H) + m / z: 369.2. 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- ((1- (pyridin-2-yl) methyl) piperidin-4-yl) carboxyamide • TFA: A 3-trifluoromethyl-1 - (4-methoxyphenyl) -lH-pyrazole-5- (N- (piperidin-4-yl) carboxyamide • HCl (0.21 g) and K2CO3 (0.3 g) in AcOH (20 L) was added 2-picolyl chloride ( 0.16 g) The reaction was stirred at room temperature for 18 hours The reaction was diluted with water and extracted with EtOAc (3x) The extracts were dried (MgSO 4) and evaporated to give 0.29 g of the crude product. of the final product was by HPLC using gradient elution with a water mixture: acetonitrile with 0.05% trifluoroacetic acid on an inverted phase C18 column (60 A) gave a pure sample of the title compound; LRMS (M + H) + m / z: 460.3.

EXAMPLE 83 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4- (2-methylimidazo-1-yl)) phenyl) carboxyamide • TFA 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4- (2-methylimidazo-1-yl)) phenyl) carboxyamide • TFA: A mixture of 3-trifluoromethyl-5-methyl -l- (4-methoxyphenyl) -lH-pyrazole (EXAMPLE 15, 0.20 g, 0.7 mmol), BOP (0.44 g, 1 mmol), Et 3 N (0.1 g, 1 mmol) and 1- (4-aminophenyl) -2 -methylimidazole (0.17 g, 1 mmol) in DMF (20 mL) was heated at 50-55 ° C for 1 h, then cooled to room temperature and stirred at 18 h. The reaction was diluted with water and extracted with EtOAc. The EtOAc extracts were washed with water (5x), dried (MgSO4) and evaporated. Purification of the final product was by HPLC using gradient elution with a mixture of water: acetonitrile with 0.05% trifluoroacetic acid on an inverted phase C18 (60 A) column and a pure sample of the title compound; p.f. 103.7 ° C, HRMS (M + H) + m / z: 442.188.

EXAMPLE 84 3-Methyl-1- (4-methoxy) phenyl-1H-pyrazole-5- (N-. {4- (5-methyl-imidazol-1-yl) phenyl) carboxyamide and EXAMPLE 85 3-Methyl-1- (4-methoxy) phenyl-1H-pyrazole-5- (N-. {4- (5-methyl-imidazol-1-yl) phenyl) carboxyamide N- (4-nitrophenyl) -5-methylimidazole: A solution of p-nitrofluorobenzene (2 g, 14 mmol) in DMF (20 mL) was treated with potassium carbonate (8 g, 58 mmol) and 4-methylimidazole (1.2 g, 14 mmol). After refluxing for 18 hours, the reaction mixture was cooled and concentrated under reduced pressure. The residue was treated with water and the mixture was extracted with ethyl acetate and dried over magnesium sulfate. The organic layer was concentrated and the residue was purified by flash chromatography (methanol / methylene chloride, 0.5: 9.5) to give 1.8 g (62%) of p-nitro-4- (5) -methyl-imidazol-1-yl as a 7: 1 mixture of regioisomers.

N- (4-aminophenyl) -5-methylimidazole: Reduction in MeOH: TFA (9.5: 0.5) with 0.1 ec. of Pd / c (10%) at 55 psi at room temperature for 20 h, followed by filtration over Celite of 1.4 g (93%) of p-amino-4- (5) -methyl-imidazol-1-yl.

Preparation of the mixture of 3-methyl- (4-methoxy) phenyl-1H-pyrazole-5- (N-. {4- (5-methyl-imidazol-1-yl) phenyl) carboxyamide and 3-methyl - (4-methoxy) phenyl-lH-pyrazole-5- (N-. {4- (4-methyl-imidazol-1-yl}. Phenyl) carboxyamide: A solution of 3-methyl-1- ( 4-methoxyphenyl) -lH-pyrazolecarboxylic acid (200 mg, 0.8 mmol) in acetonitrile (5 mL) was treated with an excess of thionyl chloride 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- (-aminophenyl) -5-methylimidazole (131 mg, 0.7 mmol) .The reaction mixture was stirred at room temperature for 20 minutes. The residue was treated with water and the mixture was extracted with ethyl acetate and dried over magnesium sulfate.The organic layer was concentrated and the residue was purified by flash chromatography (methanol / methylene chloride, 0.5: 9.5) giving a mixture of 3-methyl- (-methoxy) phenyl-lH-pyrazole-5- (N- (- (5-met il-imidazol-1-il} phenyl) carboxyamide and 3-methyl- (4-methoxy) phenyl-1H-pyrazole-5- (N-. {4- (4-methyl-imidazol-1-yl) phenyl) carboxyamide The final products are purified by normal phase HPLC eluting with solvent A (hexane) and solvent B (ethanol) using 80% A and 20% B and eluting at 7.5 mL / min.

EXAMPLE 84: 3-Methyl- (4-methoxy) phenyl-lH-pyrazole-5- (N-. {4- (5-methyl-imidazol-1-yl}. Phenyl) carboxyamide: NMR A (CDC13) : 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, 1H).

EXAMPLE 85: 3-Methyl- (4-methoxy) phenyl-lH-pyrazole-5- (N-. {4- (4-methyl-imidazol-1-yl}. Phenyl) carboxyamide: NMR A (CDC13) : 2.31 (s, 3H), 2.36 (s, 3H), 3.83 (s, 3H), 6.71 (s, 1H), 6.94 (m, 3H), 7.26 (m, 2H), 7.39 (m, 2H), 7.58 (m, 2H), 7.92 (s, 1H), 8.23 (s, 1H).

EXAMPLE 86 3-Trifluoromethyl- (4-methoxy) phenyl-1H-pyrazole-5- (N-. {4- (5-carbomethoxy-imidazol-1-yl) phenyl)) carboxyamide: Butyl-glyoxyl (4-nitroanilino) imine: A solution of p-nitroaniline (6.3 g, 53.4 mmol) in ethyl alcohol (50 mL) was treated with n-butyl gluoxylate (8 g, 53.8 mmol). After stirring at room temperature for 18 h, the reaction mixture was concentrated under reduced pressure. The residue was treated with water and the mixture was extracted with ethyl acetate and dried over magnesium sulfate. The organic layer was concentrated to give the title compound in almost quantitative yield, which was used without further purification. 4-amino- (5- (carbomethoxy) imidazol-1-yl) benzene: To the solution of butyl-glyoxy (4-nitroanilino) 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 was stirred for 1 hour at room temperature, then the solvent was removed under reduced pressure. The residue was treated with saturated sodium chloride solution and the mixture was extracted with methylene chloride. The organic extract was concentrated and triturated with methyl alcohol. The precipitate was collected and dried to give an intermediate compound of 4-nitro- (5- (carbomethoxy) imidazol-1-yl) benzene (1.5 g, 94%). MS (ES) m / z (rel. Intensity), 249 (M +, 100).

Reduction to 4-amino- (5- (carbomethoxy) imidazol-1-yl) benzene was achieved according to the procedure described in EXAMPLE 84 and 85; MS (ES) m / z (rel. Intensity), 219 (M +, 100). 3-Trifluoromethyl- (4-methoxy) phenyl-1H-pyrazole-5- (N-. {4- (5-carbomethoxy-imidazol-1-yl) enyl) carboxyamide: To a solution of 4-amino- (5- (carbomethoxy) imidazol-1-yl) benzene (152 mg, 0.7 mmol) was coupled with 3-trifluoromethyl- (4-methoxy) phenyl-1H-pyrazole-5-carbonyl chloride (205 mg, 0.7 mmol) according to the procedure, described in EXAMPLES 84 and 85. Purification by flash chromatography (methanol / methylene chloride, 1: 9) gave 3-trifluoromethyl- (4-methoxy) phenyl-1H-pyrazole-5- (N - { 4- (5-carbomethoxy-imidazol-1-yl.}. Phenyl) carboxyamide, (70 mg, 20%); MS (ES) m / z (re. Intensity), 486 (m +, 100) .

EXAMPLE 87 3-Trifluoromethyl- (4-methoxy) phenyl-1H-pyrazol-5- (N-. {4- (5-carboxy-imidazol-1-yl) phenyl) carboxyamide 3-Trifluoromethyl- (4-methoxy) phenyl-lH-pyrazole-5- (N-. {4- (5-carboxy-imidazol-1-yl) phenyl) carboxyamide: 3-Trifluoromethyl- (-methoxy) phenyl -lH-pyrazole-5- (N- (4- (5-carbomethoxy-imidazol-1-yl.) phenyl) carboxyamide (147 mg, 0.3 mmol) was dispersed in a 4: 1 mixture of THF and water and The reaction mixture was stirred for 1 h at room temperature, neutralized with 1 N HCl, extracted with ethyl acetate, dried over MgSO4 and treated with LiOH (37 mg, 0.9 mmol) in 0.5 mL of water. The final product was purified by inverted phase HPLC on a C-18 VydecR column eluting with solvent mixture A (water: TFA, 99.5: 0.5) and solvent mixture B (acetonitrile: water: TFA, 90: 9.5: 0.5) using a gradient starting with A at 100% and changing B to 100% for 60 minutes, MS (ES) m / z (relative intensity), 471.9 (m +, 100).

EXAMPLE 88-90 The crude acid, 3-trifluoromethyl- (4-methoxy) phenyl-1H-pyrazole-5- (N-. {4- (5-carboxy-imidazol-1-yl) phenyl) carboxyamide, was dissolved in acetonitrile , it was treated with excess thionyl chloride and refluxed for a period of 2 hours The solvent was removed under reduced pressure The coupling with the amines specified below was carried out according to the procedure described in EXAMPLES 84 and 85 to give examples 88-90.The final products were purified by inverted phase HPLC on a C18 VidecR column eluting with a mixture of eluents A (water: TFA, 99.5: 0.5) and solvent mixture B (acetonitrile: water : TFA, 90: 9.5: 0.5) using a gradient starting with A at 100% and changing B to 100% for 60 minutes to obtain EXAMPLES 88-90 as the trifluoroacetic acid salts.

EXAMPLE 88: 3-Trifluoromethyl- (4-methoxy) phenyl-1H-pyrazole-5- (N-. {4- (5-N-methylcarbamide-imidazol-1-yl) phenyl) carboxyamide: Prepared using an excess of N-methylamine * HCl; NMR A (CDC13): 2.89 (d, J = 4.7 Hz, 3H), 6.13 (m, 1H), 6.98 (d, J = 9.1 Hz, 3H), 7.15 (d, J = 8.8 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H), 7.48 (m, 3H), 7.59 (s, 1H), 8.79 (s, 1H).

EXAMPLE 89: 3-Trifluoromethyl- (4-methoxy) phenyl-1H-pyrazole-5- (N-. {4- (5-carbamide-imidazol-1-yl) phenyl) carboxyamide: Prepared upon saturation of the solution of CHC12 at 0 ° C of the acid chloride with NH3 gas, MS (ES) m / z (reite intensity), 468.9 (M +, 100) EXAMPLE 90: 3-Trif.uoromethyl- (4-methoxy) phenyl-1H-pyrazole-5- (N-. {4- (5-methylsulfonylcarbamide-1-imidazole.) Phenyl) carboxyamide: Prepared using methansulfonamide as the amine component; MS (ES) m / z (intensity laugh), 546.9 (M +, 100) EXAMPLE 91 1- (4'-Methoxyphenyl) -3-hydroxylmethyl-1H-pyrazol-5-N- (4'-pyrrolidinocarbonyl) phenyl) carboxyamide 1- (4'-methoxyphenyl) -3-hydroxylmethyl-1H-pyrazole-5 -ethylcarboxylate: To a solution of 1- (4'-methoxyphenyl) -3-methyl-1H-pyrazole-5-ethylcarboxylate (1.58 g, 7.1 mmol) in CC14 (250 mL) was added NBS (1.5 g, 8.5 mmol) and benzoyl peroxide (73 mg, 4% in mmol). The mixture was degassed and filled with nitrogen, refluxed for 18 hours under nitrogen, and then cooled to room temperature. The mixture was diluted with CHC12 (100 mL), washed with 10% NaOH (20 mL x 3), water (20 mL x 3), and brine (10 mL x 2), and dried over MgSO 4. Filtration and concentration gave crude 1- (4'-methoxyphenyl) -3-bromomethyl-1H-pyrazole-5-ethylcarboxylate (2.4 g). To a solution of the crude in aqueous DMSO (75%, 40 mL) was added Cu20 (1.5 g, 10.5 mmol), and the mixture was stirred at 60 ° C for 2 hours. The mixture was filtered to remove excess Cu20, and the filtrate was extracted with ethyl ether. The ether layer was washed with brine (10 mL x 5) and dried over MgSO4. Filtration and concentration, followed by purification by column chromatography on silica gel with EtOAc / CH2Cl2 (1 to 1) gave the title compound (1.5 g, 81% yield). ESMS (M + H) + m / z: 277. 1- (4'-Methoxyphenyl) -3-hydroxylmethyl-lH-pyrazol-5-N- (4'-pyrrolidinocarbonyl) phenyl) carboxyamide: To a solution of 4- (pyrrolidinyl-one) aniline (390 mg, 2.05 mmol) in CH2C12 (20 mL) was added AlMe3 (2 M in hexane, 3 mmol) at 0 ° C.

The mixture was stirred at room temperature for 15 minutes and a solution of 1- (4'-methoxyphenyl) -3-hydroxylmethylene-1H-pyrazole-5-ethylcarboxylate (560 mg, 2.05 mmol) in CH2C12 (5 mL) was added. 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 and brine, and dried over MgSO4. Filtration, concentration, and purification by chromatography on silica gel with gradient solvents (CH2Cl2 to EtOAc) gave the title compound (570 mg, 67% yield). ESMS (M + Na) + m / z: 443. HRMS (M + H) + cale, m / z: 420.1798, obs: 420.1771.

EXAMPLE 92 1- (4'-Methoxyphenyl) -3-formaldehyde-1H-pyrazole-5-N- (4 '- (pyrrolidinocarbonyl) phenyl) carboxyamide To a solution of 1- (4-Methoxyphenyl) -3-hydroxymethyl-1H-pyrazole-5-N- ((4'-pyrrolidinocarbonyl) phenyl) carboxyamide 6 (140 mg, 0.33 mmol) in THF (20 mL) was added MnO2 (435 mg, 4.95 mmol), and the resulting mixture was refluxed for 12 hours. The mixture was filtered to remove the excess Mn0, and the filtrate was concentrated to give EXAMPLE 92 (138 mg, 100%) as a white solid. ESMS (M + H) + m / z: 419.

EXAMPLE 93 1- (4'-Methoxyphenyl) -5-N- (4 '- (pyrrolidinocarbonyl) anuide) -lH-pyrazol-3-yl-carboxylic acid 1- (4'-Methoxyphenyl) -5-N- (4 '- (pyrrolidinocarbonyl) -annide) -lH-pyrazol-3-yl-carboxylic acid: To a solution of AgN03 (34 mg, 0.2 mmol) in H20 ( 0.5 mL) was added NaOH (16 mg, 0.4 mmol), and a solution of 1- (4'-methoxyphenyl) -3-formaldehyde-1H-pyrazole-5-N ((4'-pyrrolidinocarbonyl) phenyl) carboxyamide (EXAMPLE 92, 42 mg, 0.1 mmol) in MeOH (0.5 mL) at 0 ° C. After being stirred at room temperature for 30 minutes, the mixture was carefully acidified with concentrated HCl (35 mL) to pH about 2, and concentrated to give a residue, which was purified by silica gel column chromatography with solvent gradients (CH2Cl2 to EtOAc) to give the title compound (25 mg, 58%). ESMS (M + Na) + m / z: • 456.9.

EXAMPLE 94 1- (4'-Methoxyphenyl) -3-methylcarboxylate-1H-pyrazole-5-N- (4'-pyrrolidinocarbonyl) phenyl) carboxyamide 1- (4'-methoxyphenyl) -3-methylcarboxylate-1H-pyrazole-5 -N- (4'-pyrrolidinocarbonyl) phenyl) carboxyamide: To a solution of 1- ('-methoxyphenyl) -3-formaldehyde-1H-pyrazole-5-N- ((4'-pyrrolidinocarbonyl) phenyl) carboxyamide (EXAMPLE 92 , 42 mg, 0.1 mmol) in MeOH (1 mL) was added KCN (7.8 mg, 0.12 mmol), HOAc (7.2 mg, 0.12 mmol) and Mn02 (120 mg, 0.83 mmol), and the resulting mixture was stirred at room temperature. environment for 2 hours. The mixture was diluted with EtOAc (50 mL), washed with water (10 mL x 3) and brine, dried over MgSO4. The solution was filtered, concentrated, and purified by column chromatography on silica gel EtOAc to give the title compound (38 mg, 85% yield). ESMS (M + Na) + m / z: 471.

EXAMPLE 95 1- (4'-Methoxyphenyl) -3-cyanomethyl-1H-pyrazole-5-N- (4'-pyrrolidinocarbonyl) phenyl) carboxyamide 1- (4'-Methoxyphenyl) -3-cyanomethyl-1H-pyrazole-5-N- (4'-pyrrolidinocarbonyl) phenyl) carboxyamide: To a solution of 1- (4'-methoxyphenyl) -3-hydroxymethyl-1H- pyrazole-5-N- (4'-pyrrolidinocarbonyl) phenyl) carboxyamide (120 mg, 0.29 mmol) in CH 2 Cl (15 mL) was added MsCl (48 mg, 0.43 mmol) and Et 3 N (44 mg, 0.43 mmol). After the room temperature was stirred for 2 hours, the resulting mixture was concentrated. A solution of the residue in DMF (3 mL) was treated with NaCN (43 mg, 0.87 mmol) and stirred for 16 hours. To the reaction mixture was added EtOAc (50 L) and water (5 mL), and the EtOAc layer was washed with brine (10 mL x 5), dried over MgSO 4, concentrated, and purified on TLC silica gel eluted with EtOAc to give the title compound (57 mg, 46%). ESMS (M + Na) + m / z: 430.

EXAMPLE 96 2- (1 '- (' '-methoxyphenyl) -5' - (4"-pyrrolidinocarbonyl) anilide-1H-pyrazol-3'-yl) acetic acid 2- (1 '- (' '-Metoxyphenyl) -5' - (4"-pyrrolidinocarbonyl) anilide-1H-pyrazol-3'-yl) acetic acid 1- (4'-methoxyphenyl) -3-cyanomethyl- 1H-pyrazole-5-N- ((4'-pyrrolidinocarbonyl) phenyl) carboxyamide (27 mg, 0.063 mmol) was added 6N HCl (1 mL), and the resulting mixture was stirred at 75 ° C for 16 hours. The mixture was extracted with EtOAc and the organic layer was dried over MgSO4, concentrated and purified on EtOAc plates of silica gel eluted with 20% MeOH in EtOAc to give the title compound (2 mg, 7%). MS (ES-) (M + H) + m / z: 447.

EXAMPLE 97 1- (4'-Methoxyphenyl) -3-bromomethyl-1H-pyrazol-5-N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide 1- (4'-Methoxyphenyl) -3-hydroxymethyl-1H-pyrazol-5-N- (2'-tert-butylaminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide: To a solution of 4- (2'-tert-butylaminosulfonylphenyl) aniline (1.33 g, 4.3 mmol) in CH2C12 (40 mL) was added AlMe3 (2M in hexane, 6.5 mmol) at 0 ° C. After the mixture was stirred at room temperature for 30 minutes, a solution of 1- (4'-methoxyphenyl) -3-hydroxylmethyl-1H-pyrazole-5-ethylcarboxylate (1.09 g, 3.95 mmol) in CH2C12 (5 mL) was added. , and the resulting mixture was refluxed for 6 hours and quenched with water (5 mL). The mixture was filtered through a pad of Celite, and the filtrate was washed with water and with brine, and dried over MgSO4. Filtration, concentration and purification by silica gel column chromatography with gradient solvents (CH2C12 to EtOAc to 10% MeOH / EtOAc) gave the title compound (1.8 g, 85%). ESMS (M + H) + m / z: 535. 1- (4'-Methoxyphenyl) -3-bromomethyl-1H-pyrazol-5-N- (2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide: To a solution of 1- (4 '-methoxyphenyl) -3-hydroxymethyl-1H-pyrazol-5-N- (2'-tert-butylaminosulfonyl- [1,1'] - biphen-4-yl) carboxyamide (880 mg, 2.49 mmol) in CH2C12 (100 mL) PBr3 (675 mg, 2.49 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours and concentrated. The residue was treated with TFA (10 mL), refluxed for 2 hours, and then concentrated. The residue was dissolved in EtOAc (50 mL) and water (5 mL). The EtOAc layer was washed with brine (10 mL), dried over MgSO4, concentrated and purified by column chromatography on silica gel with gradient solvents (hexane to EtOAc) to give the title compound (800 mg, 90 mL). %). ESMS (M + H) + m / z: 541/543.

EXAMPLE 98 1- (4'-Methoxyphenyl) -3-aminomethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide 1- (4'-Methoxyphenyl) -3-aminomethyl-lH-pyrazol-5-N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide: To a solution of 1- (4 '-methoxyphenyl) -3-bromomethyl-1H-pyrazol-5-N- (2'-aminosulfonyl- [1,1'] -bifen-4-yl) carboxyamide (104 mg, 0.259 mmol) in a mixture of solvents ( EtOH / CH3CN / H20 = 10: 5: 1, 20 mL) was added with NaN3 (50.5 mg, 0.776 mmol). After refluxing for 16 hours, the resulting solution was cooled to room temperature. A solution of SnCl2 »2H20 (350 mg, 1.55 mmol) in MeOH (4 mL) was added to the above solution, and the resulting mixture was stirred at room temperature for 2 hours. The mixture was neutralized with 1 N NaOH to pH 8-9, and extracted with EtOAc. The EtOAc layer was concentrated and purified on TLC plates on silica gel eluted with 20% MeOH in CH2C12 to give the title compound (126 mg, approximately 100%). ESMS (M + H) + m / z: 478.1.

EXAMPLE 99 i- (4'-Methoxyphenyl) -3- (N-methylsulfonylamino) methyl-lH-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide 1- (• -methoxyphenyl) -3- (N-methylsulfonylamino) methyl-lH-pyrazol-5-N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide: To a solution of 1- (4'-methoxyphenyl) -3-aminomethyl-1H-pyrazol-5-N- (2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide (15 mg, 0.031 mmol) in CH2C1 (1 mL) was added MsCl (3.6 mg, 0.035 mmol) and Et3N (4.7 mg, 0.047 mmol). After stirring at room temperature for 2 hours, the resulting mixture was concentrated and purified on a TLC plate of silica gel eluted with EtOAc-CH2Cl2 (1: 1) to give the title compound (12 mg, 70% ). HRMS (M + H) + cale, m / z: 556.1324, obs: 556.1320.

EXAMPLE 100 1- (4'-Methoxyphenyl) -3- (imidazol-1-yl) methyl-1H-pyrazol-5-N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide 1- (4'-Methoxyphenyl) -3- (imidazol-1-yl) methyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide: A a solution of 1- (4'-methoxyphenyl) -3-bromomethyl-1H-pyrazol-5-N- (2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide (30 mg, 0.055 mmol ) in CH 2 Cl 2 (2 mL) was added imidazole (12 mg, 0.176 mg), and the resulting mixture was stirred at room temperature for 8 hours. The mixture was concentrated and purified on silica gel TLC plates eluted CH2Cl2 / EtOAc (1: 3) to give the title compound. ESMS (M + H) + m / z: 528.5.

EXAMPLE 101 1- (4'-Methoxyphenyl) -3-hydroxylmethyl-1H-pyrazol-5-N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide EXAMPLE 102 1- (4'-Methoxyphenyl) -3-trifluoroacetylhydroxylmethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide Preparation of a mixture of 1- (4'-methoxyphenyl) -3-hydroxylmethyl-lH-pyrazol-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide and 1- (4'-methoxyphenyl) -3 -trifluoroacetylhydroxylmethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide: A 1- (4'-methoxyphenyl) -3-hydroxylmethyl-1H-pyrazole- 5-N- (2'-tert-butylaminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide (40 mg, 0.075 mmol) was added with 25% TFA in CH2C12 (6 mL), and the mixture was added. stirred at room temperature for 20 hours. The mixture was concentrated and purified by preparative HPLC to give example 101: 1- (4'-methoxyphenyl) -3-hydroxylmethyl-1H-pyrazol-5-N- (2'-aminosulfonyl- [1,1 '] - biphenyl) carboxyamide (8 mg, 22%): ESMS (M + H) + m / z: 479; and EXAMPLE 102: 1- (4'-methoxyphenyl) -3-trifluoroacetylhydroxylmethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide (18 mg, 42 %): ESMS (M + H) + m / z: 575.

EXAMPLE 103 1- (4'-Methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazol-5-N- (2'-methylsulfonyl- [1,1 '] -bifen-4-yl) carboxyamide IN- (4'-Methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-5-methylpyrazole: To a solution of 2-bromo-5-methoxyphenyl-methylcarboxylate (4.9 mg, 20 mmol) in DMF (25 mL), added 3-methyl-5-trifluoromethylimidazole (3.0 g, 20 mmol), CuBr (1 g, 7 mmol), and K2C03 (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, and the filtrate was washed with water and brine (10 mL x 5), and dried over MgSO4. Filtration, concentration and purification by silica gel column chromatography with hexane-CH2Cl2 (1: 1) gave the IN- (4 '-methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole (3.17 g, 51%). %). ESMS (M + H) + m / z: 315.

INN- (4'-methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-carboxylic acid: To a solution of IN- (4'-methoxy-2-methoxycarbonylphenyl) -3-trifluoromethyl-5- methylpyrazole (2.54 g, 8.09 mmol) in CC14 (150 L) was added NBS (2.88 g, 16.18 mmol), benzoyl peroxide (31 mg, 0.12 mmol), and AIBN (123 mg, 0.44 mmol), and the mixture was added to the mixture. degassed and then filled with nitrogen. After refluxing under nitrogen for 24 hours, the mixture was cooled to 0 ° C and filtered. The filtrate was concentrated to give a crude oil. To a solution of crude oil in CH3CN (50 mL) and water (20 mL) was added KMn04 (1.8 g, 11.4 mmol). The mixture was stirred at 95 ° C for 1.5 hours and cooled to room temperature. A solution of Na 2 SO 3 (5 g in 15 mL of water) and NaHCO 3 (5.5 g in 30 mL of water) was added, and the resulting mixture was filtered through a pad of Celite. The filtrate was extracted with ether and the aqueous layer was carefully acidified with concentrated HCl to pH 2 and extracted with EtOAc. The EtOAc layer was washed with brine (10 mL) and dried over MgSO4. Filtration and concentration gave the pure N, 2- (1-methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-lH-pyrazole-5-carboxylic acid (1.2 g, 43.1%). ESMS (M + H) + m / z: 345. 1- (4'-Methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazol-5-N- (2'-methylsulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide: To a solution of IN- (4' -methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-carboxylic acid (344 mg, 1 mmol) in DMF (5 mL) was added PyBrop (559 mg, 1.2 mmol), and the mixture was stirred at room temperature for 30 minutes. Then N, N-diisopropylethylamine (288 mg, 2.5 mmol) was added, the resulting mixture was stirred for 10 minutes, and then a solution of 4- (2'-methylsulfonylphenyl) aniline (265 mg, 1 mmol) was added. The resulting mixture was stirred at 90 ° C for 16 hours, diluted with EtOAc (100 mL), washed with 1 N HCl (20 mL x 2), 10% NaHCO 3 (20 mL x 2), water (10 mL ), and brine (20 mL x 4), dried over MgSO, and concentrated. The residue was dissolved in CH2C12 (20 mL) and treated with DOWAX (1 g) for 30 minutes). The mixture was filtered and the filtrate was purified by column chromatography on silica gel with gradient solvents (CH2C12 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) carboxyamide To a solution of 1- (4'-methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazol-5-N- (2'-methylsulfonyl- [1,1 '] - biphen-4-yl) carboxyamide (290 mg, 0.49 mmol) in MeOH (10 mL) was added aqueous NaOH (0.39 g in 5 mL of water), and the mixture was stirred at room temperature for 16 hours. After extraction with ether, the resulting aqueous solution was carefully acidified with concentrated HCl to pH 2 and extracted with EtOAc. The EtOAc layer was dried over MgSO4, concentrated, and purified by column chromatography on silica gel with EtOAc to give 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'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide To a solution of IN- (4'-methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-carboxylic acid (344 mg, 1 mmol) in DMF (5 mL) was added PyBrop (559 mg, 1.2 mmol), and the mixture was stirred at room temperature for 30 minutes, N, N-diisopropylethylamine (288 mg, 2.5 mmol) was added and the resulting mixture was stirred for 10 minutes, and then a solution of hydrochloride salt was added. of 4- (2'-tert-butylaminosulfonylphenyl) aniline (358 mg, 1 mmol). The resulting mixture was stirred at 90 ° C for 16 hours and quenched with EtOAc (100 mL). The mixture was washed with 1 N HCl (20 mL x 2), 10% NaHCO 3 (20 mL x 2), water (10 mL), and brine (20 mL x 4), dried over MgSO 4, and concentrated. The residue was dissolved in CH2C12 (20 mL) and treated with DOWEX (1 g) for 30 minutes, and filtered. The filtrate was purified by silica gel column chromatography with gradient solvents (CH2C12 to EtOAc) to give 1- (4'-methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2 '-tert-butylaminosulfonyl- [1,1'] -bifen-4-yl) carboxyamide (550 mg, 85%). ESMS (M + H) + m / z: 649.

A 1- (4'-Methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazol-5-N- (2'-tert-butylaminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide ( 200 mg) was added TFA (5 mL), and the resulting solution was refluxed for 2 hours. The mixture was concentrated and purified on silica gel TLC plates eluted with 10% EtOAc in CH2C12 to give the title compound (160 mg, 87 5). ESMS (M + H) + m / z: 593.

EXAMPLE 106 1- (4'-Methoxy-2'-hydroxycarbonyl-phenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide To a solution of 1- (4'-methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'-tert-butylaminosulfonyl- [1,1 '] -bifen-4-yl carboxyamide (350 mg, 0.54 mmol) in MeOH (5 mL) was added aqueous NaOH (90 mg in 5 mL of water), and the mixture was stirred at room temperature for 16 hours. After extraction with ether, the resulting aqueous solution was carefully acidified with concentrated HCl to pH 2 and extracted with EtOAc. The EtOAc layer was dried over MgSO4, concentrated and purified by silica gel column chromatography in EtOAc to give 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-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide 1- (4'-methoxy-2'-hydroxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'-tert-butylaminosulfoni1- [1,1 '] -bifen-4-yl) carboxyamide (210 mg, 0.33 mmol) was added TFA (5 mL), and the resulting solution was refluxed for 1 hour. The mixture was concentrated and purified on silica gel TLC plates eluted 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'-hydroxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide To a solution of 1- (4 '-methoxy-2'-hydroxycarbonyl-phenyl) -3-trifluoromethyl-1H-pyrazo-1-5-N- (2'-aminosulfonyl-phenyl) carboxyamide (210 mg, 0.36 mmol) in THF (5%). mL) at 0 ° C was added N, N-diisopropylethylamine (62 mg, 0.54 mmol) and isopropylchloroformate (freshly distilled, 46 mg, 0. 38 mmol), and the resulting mixture was stirred at room temperature for 1.5 hours. NaBH 4 (30 mg, 0.79 mmol) was added and the mixture was stirred for 1 hour. The reaction was quenched with 1N HCl and stirred for 30 minutes, the mixture was diluted with EtOAc and the organic layer was washed with water and brine, and dried over Na2SO4, and purified on silica gel TLC plates. eluted with EtOAc to give the title compound (75 mg, 37%). ESMS (M + H) + m / z: 586.9.

EXAMPLES 109 TO 115 IN- (4'-Methoxyphenyl) -3-methylpyrazol-5-yl) ethylcarboxylate: To a solution of 4-methoxyphenylhydrazine (8.65 g, 50 mmol) in HOAc (300 mL) at 80 ° C was added oxime (Ethyl 2-N- (methoxy) imino-4-oxopentanoate (see Example 1), 6 g, 32 mmol), and the mixture was refluxed for 18 hours and concentrated. The residue was dissolved in EtOAc (300 mL), washed with 10% NaOH (100 mL), water (100 mL x 2), and brine (20 mL x 2), dried over MgSO4, concentrated and purified by silica gel column chromatography CH2C12 to give the partially purified product, which was recrystallized from hexane to give the title compound (10.5 g, 80%). ESMS (M + H) + m / z: 261.

IN (4'-Methoxyphenyl) -3-methylpyrazol-5-yl) carboxylic acid: A solution of IN (4'-methoxyphenyl) -3-methylpyrazol-5-yl) carboxylic acid (5.9 g, 22.7 mmol) in THF (50 mL) was treated with 1 N NaOH (50 mL) at room temperature for 24 hours. The aqueous layer of the mixture was carefully acidified with concentrated HCl to pH 2 and extracted with EtOAc. The EtOAc layer was concentrated, concentrated, and purified by column chromatography on silica gel with gradient solvents (CH2C12 to EtOAc) to give the title compound (3.7 g, 66.3%). ESMS (M + H) + m / z: 245.

Preparation of examples 109-115 via a library: To a solution of IN (4'-methoxyphenyl) -3-methylpyrazol-5-yl) carboxylic acid (450 mg, 1.94 mmol) in CH2C12 (30 mL) was added S0C12 ( 1.4 g, 11.6 mmol). The resulting mixture was refluxed for 1.5 hours and then concentrated.

A solution of the residue in THF (30 mL) was divided into portions and added to solutions of anilines or amines (0.1 mmol / sample / well) and DMAP (12.4 mg / well) in THF (1 mL / well) on an aluminum plate. 96-well Polifiltronics filter.

The 96-well Polifiltronics filter plate containing the reaction mixtures was stirred at room temperature for 2 days. To each solution / well was added a suspension of DOWEX (0.2 g) in CH2C12 (0.4 mL) and the resulting mixtures were stirred for 1 hour. The mixtures were filtered and the filtrates were carefully collected and dried under vacuum to give the library.

EXAMPLE 109 1- (4'-Methoxyphenyl) -3-methyl-1H-pyrazol-5-N- (4'-sec-butyl) phenyl) carboxyamide: ESMS (M + H) + m / z: 404.

EXAMPLE 110 1- (4'-Methoxyphenyl) -3-methyl-lH-pyrazol-5-N- (4 '- (3"methyl-3" -pyrazoline-5"-one-2" -il ) phenyl) carboxyamide: ESMS (M + H) + m / z: 364.

EXAMPLE 111 1- (4'-Methoxyphenyl) -3-methyl-lH-pyrazol-5-N- (4 '- (6"-methylbenzothiazol-2" -yl) phenyl) carboxyamide: ESMS (M + H) + m / z: 455.

EXAMPLE 112 1- (4'-Methoxyphenyl) -3-methyl-1H-pyrazol-5-N- (3 ', 4'-dibromophenyl) carboxyamide: ESMS (M + H) + m / z: 364.

EXAMPLE 113 1- (4'-Methoxyphenyl) -3-methyl-lH-pyrazol-5-N- (4 '-n-butyl) phenyl) carboxyamide: ESMS (M + H) + m / z: 464.

EXAMPLE 114 1- (4'-Methoxyphenyl) -3-methyl-lH-pyrazol-5-N- (4 '- (4"-methylpiperidino) phenyl) carboxyamide: ESMS (M + H) + m / z: 405 .

EXAMPLE 115 1- (4'-Methoxyphenyl) -3-methyl-lH-pyrazol-5-N- (4 '- (2"-methylimidazol-1" -yl) phenyl) carboxyamide: ESMS (M + H) + m / z EXAMPLE 116 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5-N- (4-carboxy (N-methylimidazo-2-yl) phenyl) carboxyamide: Part A. A 4-nitro-l- (2'-N-methylimidazoyl) benzene (0.58 g, 2.51 mmol), prepared from 4-nitrobenzoyl chloride and 1-methylimidazole by the method of Regel, E. et al. ., Liebigs Ann. Chem. (1977) 145, ethanol (50 mL), trifluoroacetic acid (1 mL) and 10% palladium in carbon (60 mg) were added. The mixture was hydrogenated in the torque at 40 psi for 0.5 hours. The reaction mixture was filtered and concentrated. The recovered aniline salt was dissolved in water and extracted with ether. The aqueous layer was made basic with 1N NaOH, extracted with ethyl acetate and dried (MgSO4) and evaporated to give 0.35 g (70%) of the aniline. MS (AP +) 202.1 (M + H) +.

Part B. 1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-carboxylic acid (0.25 g, 0.87 mmol) in CH2C12 (15 mL) was added oxalyl chloride (0.1 mL, 1.14 mmol) and several drops of DMF. The reaction was stirred for 24 hours, then concentrated. The aniline from part A (0.175 g, 0.87 mmol), DMAP (0.27 g, 2.2 mmol), and fresh CH2C12 (20 ml) were added to acid chloride and the reaction was stirred for 24 hours. The mixture was concentrated and the residue was dissolved in EtOAc (10 mL) and TFA (0.1 mL), concentrated and purified by reverse phase HPLC and lyophilized to give the title compound 60 mg (11%); NMR A (MNSO-d6) d 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) ppm; HRMS (M + H) + C 22 H 19 F 3 N 5 O 3 470.1443.

EXAMPLE 117 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazol-5-N- (4-hydroxymethyl (2- (imidazol-2-yl) phenyl)) carboxyamide AND EXAMPLE 118 3-Trifluoromethyl-1- ( 4-methoxyphenyl) -lH-pyrazole-5-N- (4-hydroxymethyl (2- (l-benzyl-imidazol-2-yl) phenyl)) carboxyamide EXAMPLE 119 1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5- (N- (4- (2-carboxy-imidazol-2-yl) phenyl)) carboxyamide Part A: A 4-nitro-l- (2'-N-benzylimidazoyl) benzene (0.47 g, 1.53 mmol), prepared from 4-nitrobenzoyl chloride and 1-benzylimidazole by the method of Regel, E. et al. ., Liebigs Ann. Chem. (1977) 145, EtOAc was added (15 mL) and stannous chloride (0.86 g, 3.80 mmol). The reaction was heated to reflux for 2 hours then stirred at room temperature for 18 hours. An additional 0.3 g of stannous chloride was added and the reaction was stirred for 3 hours. The reaction cooled to 0 ° C, cooled rapidly with 6 M NaOH, and extracted with EtOAc and dried (Na2SO4) to give 0.4 g (95%) of orange solid. MS (M + H) + 278.2 (AP +).

Part B. The benzyl compound of part A (0.229 g, 0. 4 mmol) is hydrogen in the Parr in EtOH (30 L) and TFA (0.5 mL) with 30 mg of 10% Pd / C at 40 psi for 0.5 hours. The reaction was filtered, concentrated, and purified via inverted phase HPLC to give the title compounds mentioned above, respectively.

EXAMPLE 117: 5.3 mg (2.2%) NMR A (DMS0-d6) d: 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 = 8.40Hz, 2H), 7.05 (d, j = 8.80 Hz, 2H), 6.55 (brd s, 2H), 6.00 (d, j) = 4.0 Hz, 1H), 3.81 (3H, s) ppm. HRMS for (H + H) + C22H19F3N5? 3 458.1437.

EXAMPLE 118: 73 mg (25%) NMR A (DMSO-d6) d: 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 (brd, 1H), 7.10 (dd, j = 2.20, 5.80 Hz, 2H), 7.06 (d, j = 9.20 Hz, 2H), 6.24 (s, 1H), 5.38 (d, j = 3.70 Hz, 2H), 3.81 (s, 3H) ppm; HRMS (M + H) + for C29H25F3N5O3 548.1923, EXAMPLE 119: 15 mg (6.2%) NMR: H (DMSO-d6) d: 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) ppm; HRMS (M + H) + for C22H17F3N503 456.1271.

EXAMPLE 120 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4- (N- (4-methoxy-enyl) amino- (2-thiazolyl) methyl) phenyl)) carboxyamide AND EXAMPLE 121 1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5- (N- (4- (2-carboxy- (4,5-dihydrothiazol-2-yl) phenyl))) carboxyamide Part A: The p-Aminobenzaldehyde (135 mg, 1.11 mmol), and TEA (0.155 mL, 1.11 mmol) were added to 3-trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5-carboxylic acid chloride ( 0.34 g, 1.11 mmol) in CH2C12 (10 mL). The reaction was stirred for 18 hours, then concentrated. Purification by chromatography on silica gel using hexanes / EtOAc 2: 1 as eluent gave 0.16 g (37%) of pale yellow solid. MS (ESI) M-H) + 388.1. 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4- (N- (4-methoxyphenyl) amino- (2-thiazolyl) -methyl) phenyl)) carboxyamide: Part BA thiazole (0.1 mL, 1.43 mmol) in THF (6 mL) cooled to -40 ° C was added n-BuLi (0.6 mL, 1.43 mmol) and stirred for 1.5 hours. To the aldehyde from part A (0.14 g, 0.36 mmol) in benzene (10 mL) and MeOH (5 mL) were added 4A molecular sieves and p-anisidine (44 mg, 0.36 mmol) and the mixture was heated to reflux for 15 minutes. minutes The mixture was filtered and concentrated to give the imine. to the imine in THF (5 mL) at -78 ° C the thiazole anion was added by cannula. The reaction was stirred at 0 ° C for 0.5 h then quenched with KHS0 (0.4 mL). The product was extracted with EtOAc and dried (MgSO4). Purification by silica gel column chromatography, using Hexane / EtOAc, 1: 2 gave 0.113 g (54%) of the title compound; MS (M + H) + 578.1; NMR A (CDC13) d: 7.74 (d, j = 3.30 Hz, 1H), 7.50 (d, j = 15.4 Hz, 2H), 7.41 (broad 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) ppm. 1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5- (N- (4- (2-carboxyl- (4,5-dihydrothiazol-2-yl) phenyl)) carboxyamide: Part C: To the product from part B (98 mg, 0.17 mmol) in acetonitrile (10 mL) at 0 ° C was added ceric ammonium nitrate (0.185 g, 0.34 mmol) in water (10 mL), the reaction was stirred for 10 minutes, then The residue was dissolved in EtOAc and washed with aqueous sodium bisulfite and dried (MgSO.sub.4) The product was purified by silica gel chromatography, reverse phase HPLC, and lyophilized to give the title compound ( 10 mg, 12%) .H-NMR (CDCl 3) d: 8.54 (d, j = 8.80 Hz, 2H), 8.09 (d, j = 2.90 Hz, 1H), 7.73 (d, j = 3.30 Hz, 1H), 7.66 (s, 1H), 7.59 (d, j = 8.80 Hz, 2H), 7.48 (d, j = 8.80 Hz, 2H), 7.19 (s, 1H), 7.05 (d, j = 9.20 Hz, 2H), 3.88 (s, 3H) ppm; MS (M + H) + 473.2 (AP +).

EXAMPLE 122 1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazol-5-N-4- (2- (4 ', 5'-dihydro-1'H-imidazol-2'yl) phenyl) carboxyamide And EXAMPLE 123 1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- (4- (N-2'-aminoethylenecarboxyamide) phenyl) carboxyamide To trimethylaluminum (1.2 mL, 2 M in heptane), cooled to 0 ° C was added ethylene diamine (57 mg, 0.95 mmol) and the mixture was stirred for 15 minutes. A suspension of previously prepared ethyl-3-trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4-carboxyphenyl) carboxyamide (0.2 g, 0.47 mmol) in toluene (10 mL) was added. The reaction was heated at 50 ° C for a total of 9 hours and at room temperature for 18 hours.The reaction was quenched with ice water, filtered and concentrated.The aqueous layer was extracted with CH 2 Cl 2 which was then extracted with HCl The acid layer was basified and extracted with EtOAc and dried (MgSO 4) Purification by inverted phase HPLC and freeze drying gave 56 mg (22%) of the imidazoline (EXAMPLE 122) and 7 mg ( 3%) of the ring-open amide (EXAMPLE 123).

EXAMPLE 122: For imidazoline: NMR A (DMS0-d6) d: 11.10 (s, 1H), 10.40 (s, 1H), 7.91 (d, j = 3.60 Hz, 4H), 7.64 (s, 1H), 7.48 (d, j = 8.80 Hz, 2H), 7.07 (d, j = 9.20 Hz, 2H), 3.99 (s, 4H), 3.82 (s, 3H) ppm; MS (ESI) 430.2 (M + H) +.

EXAMPLE 123: For the imide: NMR A (DMSO-d6) d: 10.88 (s, 1H), 8.59 (t, j = 5.50 Hz, 1H), 7.87 (d, j = 8.80 Hz, 2H), 7.79 (, 2H) 7.75 (d, j = 8.80 Hz, 2H), 7.61 (s, 1H), 7.47 (d, j = 9.2 Hz, 2H), 7.06 (d, j = 8.80 Hz, 2H), 3.82 (s, 3H) ), 3.51 (q, j = 5.50 Hz, 2H), 2.98 (q, j = 5.90 Hz, 2H) ppm; MS (ESI) 448.2 (M + H) +.

EXAMPLE 124 1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazol-5- [4- (1,4,5,6-tetrahydro-pyrimid-2-yl) -phenyl] carboxyamide Ethyl-3-trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4-carboxyphenyl) carboxyamide (0.2 g, 0.48 mmol) and 1,3-diaminopropane (70 mg, 0.95 mmol) was coupled as described above Purification by reverse phase HPLC and freeze drying gave 20 mg (7.5%). NMR A (DMSO-d6) d: 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); HRMS for C22H21F3N5O2 fnd 444.1646.

EXAMPLE 125 1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazol-5- [4- (N-methyl-4,5,6-trihydro-pyrimid-2-yl) -phenyl] carboxyamide Ethyl-3-trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4-carboxyphenyl) carboxyamide (0.2 g, 0.48 mmol) and N-methyl-1,3-propanediamine (0.1 mL, 0.95 mmol) was coupled as described above Purification by inverted phase HPLC and freeze drying gave 58 mg (21%). NMR A (DMSO-d6) d: 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) ppm.

EXAMPLE 126 1- (4-Methoxyphenyl) -3-trifluoromethyl-lH-pyrazol-5-Nl- (2-fluoro-4-imidazolinophenyl] carboxyamide Part A: To 3-fluoro-4-nitrobenzoic acid (2.81 g, 15 mmol ) in CH2C12 (75 mL) oxalyl chloride (1.72 mL, 19.7 mmol) and several drops of DMF were added in. The reaction was stirred at 6 h, purified and ethanol (20 mL) was added after 18 hours. the ethanol was removed and EtOAc (30 mL) and stannous chloride (13.7 g, 61 mmol) were added.The reaction was heated to reflux for 2 hours, cooled and quenched with saturated NaHCO3, extraction with EtOAc and drying ( MgSO4) gave 2.7 g (97%) of the aniline.

Part B: 1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazole-5-carboxylic acid (0.21 g, 0.73 mmol) in CH2C12 (15 mL) was added oxalyl chloride (0.08 mL, 0.95 mmol) and several drops of DMF. The reaction was stirred for 24 hours, then concentrated. The acid chloride, DMAP (0.27 g, 2.20 mmol), and the aniline of part A (134 mg, 0.73 mmol) were combined in fresh CH2C12 and stirred at 18 h. The reaction mixture was washed in 1 N HCl, saturated NaHCO 3, brine and dried (MgSO 4). Purification by chromatography on silica gel using hexanes / EtoAc 1: 1 as eluent gave 254 mg (79.6%). NMR A (CDC13) d: 8.44 (t, j = 8.10 Hz, 1H), 7.89 (d, j = 3.30 Hz, 1H), 7.84 (d, j = 9.60Hz, 1H), 7.77 (dd, j = 11.40 , 1.50 Hz, 1H), 7.46 (d, j = 9.10 Hz, 2H), 7.20 (s, 1H), 7.04 (d, j = 8.80 Hz, 2H), 4.39 (q, j = 7.0 Hz, 2H), 3.88 (s, 3H), 1.41 (t, j = 6.90 Hz, 3H) ppm.

Part C: To Trimethylaluminum (0.57 mL, 2 M in heptane), cooled to 0 ° C was added ethylene diamine (27.6 mg, 0.46 mmol) and the mixture was stirred for 15 minutes. A suspension of ethyl-3-trifluoromethyl-1- (4-methoxyphenyl) -1H-pyrazole-5- (N- (4-carboxy-2-fluorophenyl) carboxyamide (0.1 g, 0.23 mmol) in toluene (10 mL) was added. The reaction was heated at 50 ° C for 18 hours and then cooled with ice water, filtered and concentrated.The aqueous layer was extracted with CH2C12 which was then extracted with 1 N HCl. The acid layer was basified and extracted with EtOAc and dried (MgSO4) Purification by reverse phase HPLC and lyophilization gave 26 mg (20%). NMR A (DMSO-d6) d 10.90 (s, 1H), 10.55 (s, 1H ), 8.10 (t, j = 8.06 Hz, 1H), 7.93 (d, j = 11.0, 1.5 Hz, 1H), 7.80 (d, j = 8.79 Hz, 1H), 7.64 (s, 7.47 (d, j = 9.15 Hz, 2H), 7.06 (d, j = 8.80 Hz, 2H), 4.01 (s, 4H), 3.81 (s, 3H) ppm, HRMS for C2? H18F? 2N5 found 488.1393.

EXAMPLE 127 1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazol-5-Nl- (2-fluoro-4-N-methylimidazolinophenyl) carboxyamide N-Methylethyl diamine (52 mg, 0.71 mmol) and ethyl were coupled -3-trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4-carboxy-2-fluorophenyl) carboxyamide (150 mg, 0.35 mmol) by the same procedure as in the previous example. purification by reverse phase HPLC and lyophilization gave 54 mg (27%) NMR A (DMSO-d6) d: 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 Hz, 2H), 7.05 (d, j = 8.80 Hz, 2H), 4.06 (m, 2H), 3.95 (m, 2H), 3.80 (s, 3H), 3.08 (s, 3H) ppm; MS (ESI) 462.3 (M + H) + Analysis calculated for C22Hi9F4N5? 2 (TFA) 1.4 (H20) C: 46.61 H: 3.53 NAO.96, found C: 46.68 H: 3.29 NAO.91.

EXAMPLE 128 1- (4-Methoxyphenyl) -3-trifluoromethyl-lH-pyrazol-5-N- [4- (4,5-dihydro-l-N-methyl-imidazol-2-yl) phenyl) carboxyamide EXAMPLE 129 1- (4-Methoxyphenyl) -3-trifluoromethyl-lH-pyrazol-5-N- [4- carbonylguanidine) phenyl) carboxyamide Part A: To a solution of dichloromethane (50 mL) of acid N-4'-methoxyphenyl-3-trifluoromethyl-pyrazole-5-carboxylic acid (2 g, 6.99 mmol) 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 pale yellow solid and redissolved in dichloromethane (50 mL). This solution was then added methyl-4-amino-benzoate (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) and organics extracted with ethyl acetate (2 x 100 mL), dried (MgSO4) and evaporated to a solid. yellow. Purification of the crude coupled product via flash silica gel chromatography (hexane: ethyl acetate 7: 3) gave the coupled, desired precursor as colorless crystals (1.9 g). LRMS (ESI) m / z 420.0 (100). NMR: H (CDC13): d 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) ppm. 1- (4-Methoxyphenyl) -3-trifluoromethyl-lH-pyrazol-5-N- [4- (4,5-dihydro-lN-methyl-imidazol-2-yl) phenyl) carboxyamide: Part B: The product of Part A (0.2 g, 0.048 mmol) in dichloromethane (50 mL) was subjected to treatment with Nl-methylethylenediamine (0.071 g, 0.099 mmol) followed by trimethylaluminum (1.23 mL, 2.45 mmol). The reaction mixture was stirred at room temperature overnight and then cooled with dilute HCl (5 mL). The product was concentrated in vacuo and purified via preparative HPLC (acetonitrile / water, 10% TFA). Lyophilization gave colorless crystals (0.167 g) of the desired product. LRMS (ESI) m / z 444.2 (100). HRMS: (M + H) + cale. 444.1647, found 444.1644. NMR A (DMSO-d6): d 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) ppm. 1- (4-Methylphenyl) -3-trifluoromethyl-1H-pyrazole-5-N- [4-carbonylguanidine) phenyl] carboxyamide: Part C: The product of part A (150 mg, 0.358 mmol) is subjected to the methodology Weinreb of standard described above with guanidine hydrochloride (103 mg, 1074 mmol) and trimethylaluminum (103 mg, 1432 mmol) in dichloromethane (10 mL) The mixture was stirred at room temperature for 18 hours and then cooled rapidly with hydrochloric acid 1 N (5 mL). The slurry was then basified (pH 9, saturated sodium bicarbonate). The organic products were extracted with dichloromethane (3 x 100 mL) and dried Na2SO4). Evaporation of the solvent followed by purification via preparative reverse phase HPLC and lyophilization then gave the desired acylguanidyl compound as colorless crystals. LRMS (ESI) m / z 447.2 (100); HRMS (M + H) + 447.1392 (cale), 447.1391 (obs); NMR A (DMSO) d: 11.20 (s, 1H); 11.00 (s, 1H); 8.33 (broad, 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) ppm.

EXAMPLE 130 1- (4-methoxyphenyl) -3-trifluoromethyl-lH-pyrazol-5-N- [4- (pyrimidin-2-yl) phenyl) carboxyamide Part A: Standard Suzuki coupling of 4-trifluoromethylphenylboronic acid (0.88 g, 3.77 mmol) and 2-bromopyrimidine (0.5 g, 3.144 mmol) gave the coupled product (0.47 g). LRMS (ESI) m / z 268.1 (100); RMN A (CDC13) d: 8.82 (d, J = 5.1, 2H): 8.52 (d, J = 4.8, 2H): 7.96 (broad, 1H): 7.73 (d, J = 8.8, 2H); 7.23 (t, J = 4.8, 1H) ppm; Hydrolysis of this compound with 1 N NaOH / EtOH (1: 1, 10 mL for 18 hours, followed by purification using flash silica gel chromatography (Hexanes: ethyl acetate / 4: 1) gave the desired anilinopyrimidyl precursor (0.24 g). LRMS (NH3-CI) m / z 172.2 (100); NMR A (CDCl 3) d: 8.73 (d, J = 5.1, 2H); 2.28 (m, 2H); 7.06 (t, J = 5.1, 1H); 6.67 (m, 2H); 3.94 (broad, 2H) ppm. 1- (4-Methoxyphenyl) -3-trifluoromethyl-lH-pyrazol-5-N- [4-pyrimidin-2-yl) phenyl) carboxyamide: Part B: the coupling of normal DMAP (0.23 g, 1.92 mmol) of the compound obtained in part A (0.13 g, 0.77 mmol) with acid chloride of trifluoromethylpyrazole (0.22 g, 0.77 mmol of carboxylic acid) obtained previously gave the desired coupled product which was purified via flash chromatography on silica gel (Hexane / ethyl acetate). ethyl, 1: 1) to give the title compound as colorless crystals (0.14 g). LRMS (ESI) 440.1 (100); HRMS (M + H) + 440.1334 (cale.) 440.1333 (obs); NMR-A (DMSO-D6) d: 10.89 (s, 1H): 8.88 (d, J = 4.8, 2H): 8.39 (d, J = 8.8, 2H): 7.82 (d, J = 8.4, 2H): 7.61 (s, 1H): 7.48 (d, J = 8.8, 2H): 7.43 (t, J = 4.7, 1H): 7.07 (d, J = 9.2, 2H): 3.82 (s, 3H) ppm.

EXAMPLE 131 2- (Carboxyamide) -4- [(4-methoxy) phenyl] -5- [(2'-amino-sulfonyl- [1,1 '] -biphenyl-4-yl) carboxyamide] thiazole 2-Bromo-4- [(4-methoxy) phenyl] -5- (methoxycarbonyl) thiazole. A mixture of copper (II) bromide (11.43 g, 51.2 mmol) and tert-butylnitrile (6.0 g, 58.2 mmol) in 200 mL of acetonitrile was stirred at 80 ° C until the gas emission was stopped (approximately 30 minutes ). To this solution was added 2-amino-4- [(4-methoxy) phenyl] -5- (methoxycarbonyl) thiazole (12.3 g, 46.55 mmol) in 100 mL of acetonitrile. The solution was stirred at 80 ° C until the gas emission was stopped (approximately 1 hour). The mixture was cooled, diluted with saturated aqueous Na 2 CO 3 and then filtered through a pad of celite. The filtrate was diluted with ethyl acetate and the organic layer was washed with saturated aqueous Na2CO3, dried (MsSO4) and concentrated to give 8.95 g (59%) of the title compound, which was used without purification. LRMS (ES +): 328 (M + H) +. 2-Bromo-4- [(methoxy) phenyl] thiazole-5-carboxylic acid. To a solution of 2-Bromo-4- [(4-methoxy) phenyl] -5- (methoxycarbonyl) thiazole (6.24 g, 19.74 mmol) in 20 L. of methanol and 20 L of water was added lithium hydroxide monohydrate (0.91 g, 21.7 mmol). The mixture was stirred at room temperature for 1 hour, after which additional lithium hydroxide monohydrate (0.91 g, 21.7 mmol) was added. After stirring for an additional 1 hour, the volatiles were removed in vacuo and the residue was rapidly cooled with 10% aqueous HCl. The mixture was extracted with ethyl acetate and the organic products were washed with brine, dried (MgSO4) and concentrated. The residue was re-crystallized from chloroform / hexane to give 2.2 g (37%) of the title compound as a white solid. LRMS (ES-): 303 (M-H) J Tert-Butylcarboxyamido-4- [(4-methoxy) phenyl] thiazole-5-carboxylic acid. To a solution of 2-bromo-4- [(4-methoxy) phenyl] thiazole-5-carboxylic acid (2.0 g, 6.36 mmol) in 70 mL of tetrahydrofuran at -78 ° C was added tert-butylithium (12.3 mL of a 1.7 M solution in hexanes, 21.0 mmol) dropwise. The reaction was stirred for 5 minutes and then tert-butyl isocyanate was added dropwise. The cooling bath was removed and the reaction was allowed to stir by warming to room temperature for 18 hours. The reaction was quenched with 10% HCl then diluted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and concentrated to give 0.9 g (43%) of the title compound which was used without purification. LRMS (ES-): 332.9 (M + H) +. 2- (tert-Butylcarboxyamide) -4- [(4-methoxy) phenyl] -5 - [(2 '- (terbutylamino) sulfonyl- [1,1'-] -bifen-4-yl) carboxyamide] thiazole. To a solution of 2-tert-Butylamino) carbonyl-4- [(4-methoxy) phenyl] thiazole-5-carboxylic acid (0.50 g, 1.49 mmol) in 10 mL of methylene chloride was added oxalyl chloride (0.16 mL, 1.86 mmol) and three drops of dimethylformamide. The reaction was allowed to stir at room temperature for 4 hours and then the volatiles were removed in vacuo. The residue was dissolved in 10 mL of methylene chloride and then 4-dimethylaminopyridine (0.36 g, 2.99 mmol) was added. The mixture was stirred at room temperature for 15 minutes and then 2 '- (tert-butylamino) sulfonyl- [1,1'] -bifen-4-ylamine (0.38 g, 1.24 mmol) was added. The reaction was allowed to stir for 24 hours. The reaction mixture was diluted with ethyl acetate, washed sequentially with 10% aqueous HCl, saturated aqueous NaHCO3, and brine, dried (MgSO4) and concentrated to give 0.69 g (75%) of the title compound which it was used without purification. LRMS (ES +): 643.4 (M + Na) +. 2- (tert-Butylcarboxyamide-4- [(4-methoxy) phenyl] -5 - [(2'-amino-sulfonyl- [1,1 '-] biphen-4-yl) carboxyamide] thiazole A solution of 2- ( tert-Butylcarboxyamide-4- [(4-methoxy) phenyl] -5 - [(2 '- (tert-butylamino) sulfonyl- [1,1'] -biphen- -yl) carboxyamide] thiazole (0.69 g, 1.11 mmol ) in 5 mL of trifluoroacetic acid was stirred at 80 ° C for 1 hour and then cooled and concentrated in vacuo.The residue was purified by preparative HPLC (C18 inverted phase column, elution with a gradient of H20 / CH3CN with TFA 0.5%) was lyophilized to give 0.34 g (53%) of the title compound as a white powder, LRMS (ES +): 565.1 (M + H) +. 2- (Carboxyamide) -4- [(4-methoxy) phenyl] -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide] thiazole. A solution of 2- (tert-butylcarboxyamide) -4- [(4-methoxy) phenyl] -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide] thiazole (70 mg , 0.10 mmol) in 20 mL of trifluoroacetic acid was stirred at 80 ° C for 24 hours. The reaction was cooled and concentrated in vacuo. The residue was purified by preparative HPLC (C18 inverted phase column, elution with a gradient of H20 / CH3CN with 0.5% TFA) and lyophilized to give 20 mg (32%) of the title compound as a white powder. LRMS (ES +): 508.8 (M + H) +.

EXAMPLE 132 2- (2-Methoxyethylamino) -4- [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide] thiazole A solution of 2-bromo-4- [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide] thiazole (25 mg, 0. 046 mmol) in 3 mL of acetonitrile was added 2-methoxyethylamine (0.04 mL, 0.46 mmol). The resulting solution was stirred at 60 ° C for 18 hours and then cooled, filtered through a small pad of silica gel and concentrated in vacuo. The residue was purified by preparative HPLC (inverted phase column C18, elution with a gradient of H20 / CH3CN with 0.5 TFA %) and lyophilized to give 10 mg (41%) of the title compound as a white powder. LRMS (ES +): 538.9 (M + H) +.

EXAMPLE 133 2- (3-Hydroxypropylamino) -4- [(4-methoxy) phenyl] -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide] thiazole A solution of 2-bromo-4- [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide] thiazole (50 mg, 0.092 mmol) 3 mL of acetonitrile was added with 3-hydroxypropylamine (0.5 mL, 5.5 mmol). The resulting solution was stirred at 60 ° C for 18 hours and then cooled, filtered through a small pad of silica gel and concentrated in vacuo. The residue was purified by preparative HPLC (C18 inverted phase column, elution with a H20 / CH3CN gradient with 0.5% TFA) and lyophilized to give 19 mg (37%) of the title compound as a white powder. LRMS (ES +): 538.9 (M + H) +.

EXAMPLE 134 2- (2-Cyanoethylamino) -4- [(4-methoxy) phenyl] -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide] thiazole A solution of 2-bromo-4- [(4-methoxy) phenyl] -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide] thiazole (80 mg, 0.15 mmol) 3-aminopropionitrile (0.11 mL, 1.5 mmol) was added in 3 L of acetonitrile. The resulting solution was stirred at 60 ° C for 48 hours and then cooled, filtered through a small pad of silica gel and concentrated in vacuo. The residue was purified by preparative HPLC (C18 inverted phase column, elution with a gradient of H20 / CH3CN with 0.5% TFA) and lyophilized to give 35 mg (41%) of the title compound as a white powder. LRMS (ES +): 534.2 (M + H) +.

EXAMPLE 135 2- (3-Methoxypropylamino) -4- [(4-methoxy) phenyl] -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide] thiazole To a solution of 2-bromo-4- [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide] thiazole (80 mg, 0.15 mmol ) 3-methoxypropylamine (0.15 mL, 1.5 mmol) was added in 3 mL of acetonitrile. The resulting solution was stirred at 60 ° C for 18 hours and then cooled, filtered through a small pad of silica gel and concentrated in vacuo. The residue was purified by preparative HPLC (C18 inverted phase column, elution with a gradient of H20 / CH3CN with 0.5% TFA) and lyophilized to give 25 mg (31%) of the title compound as a white powder. LRMS (ES +): 552.8 (M + H) +.

EXAMPLE 136 2- (N-β-Alinyl) -4- [(4-methoxy) phenyl] -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide] thiazole 2- (2- (methoxycarbonyl) ethylamino) -4- [(-methoxy) phenyl] -5 - [(2'-amino-sulfonyl- [1,1 '] -bipheni-1-yl) carboxyamide] thiazole. To a solution of 2-bromo-4- [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide] thiazole (80 mg, 0.15 mmol ) in 3 mL of acetonitrile was added methyl 3-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 and then cooled, filtered through a small pad of silica gel and concentrated in vacuo. The residue was purified by preparative HPLC (C18 inverted phase column, elution with a gradient of H20 / CH3CN with 0.5% TFA) and lyophilized to give 45 mg (55%) of the title compound as a white powder. LRMS (ES +): 567.2 (M + H) +. 2- (N-β-Alinyl) -4- [(4-methoxy) phenyl] -5 - [(2'-amino-sulfonyl- [1,1 '] - biphen-4-yl) carboxyamide] thiazole. To a solution of 2- (2- (methoxycarbonyl) ethylamino) -4- [(-methoxy) phenyl] -5 - [(2'-amino-sulfonyl- [1,1 '] -bifeni1-4-i1) carboxyamide] thiazole . (38 mg, 0.066 mmol) in 2 mL of tetrahydrofuran and 2 mL of water was added lithium hydroxide monohydrate (5 mg, 0.13 mmol). The resulting solution was stirred at room temperature for 18 hours and then concentrated in vacuo. The residue was purified by preparative HPLC (C18 inverted phase column, elution with a gradient of H20 / CH3CN with 0.5% TFA) and lyophilized to give 32 mg (88%) of the title compound as a white powder. LRMS (ES +): 665.0 (M + H) +.

EXAMPLE 137 2- (Isopropylamino) -4- [(4-methoxy) phenyl] -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide] thiazole To a solution of 2-bromo-4- [(4-methoxy) phenyl) -5 - [(2'-aminosulfonyl- [1,1 '] -biphenyl-4-yl) carboxyamide] thiazole (80 mg, 0.15 mmol ) in 3 mL of acetonitrile was added isopropylamine (0.13 mL, 1.5 mmol). The resulting solution was stirred at 60 ° C for 72 hours and then cooled, filtered through a small pad of silica gel and concentrated in vacuo. The residue was purified by preparative HPLC (C18 inverted phase column, elution with a gradient of H20 / CH3CN with 0.5% TFA) and lyophilized to give 28 mg (37%) of the title compound as a white powder. LRMS (ES +): 523.1 (M + H) +.

EXAMPLE 138 2- (1, 3-Dihydroxy-2-propylamino) -4- [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide ] thiazole To a solution of 2-bromo-4- [(4-methoxy) phenyl) -5 - [(2'-aminosulfonyl- [1,1 '] -biphenyl-4-yl) carboxyamide] thiazole (80 mg, 0.15 mmol 3-dihydroxy-2-aminopropane (0.13 g, 1.5 mmol) was added in 3 mL of acetonitrile. The resulting solution was stirred at 60 ° C for 72 hours and then at 75 ° C for an additional 24 h. The reaction mixture was cooled, and filtered through a small pad of silica gel and concentrated in vacuo. The residue was purified by preparative HPLC (C18 inverted phase column, elution with a gradient of H20 / CH3CN with 0.5% TFA) and lyophilized to give 30 mg (37%) of the title compound as a white powder. LRMS (ES +): 555.1 (M + H) +.

EXAMPLE 139 2- [(Methoxycarbonyl) methylamino] -4- [(4-methoxy) phenyl] -5- [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide] thiazole To a solution of 2-bromo-4- [(4-methoxy) phenyl) -5 - [(2'-aminosulfonyl- [1, 1 '] - biphenyl-4-yl) carboxyamide] thiazole (80 mg, 0.15 mmol ) in 3 mL of acetonitrile was added glycine methyl ester hydrochloride (0.18 g, 1.5 mmol) and N, N-diisopropylethylamine (0.26 mL, 1.5 mmol). The resulting solution was stirred at 60 ° C for 72 hours and then at 75 ° C for an additional 24 h. The reaction mixture was cooled, and filtered through a small pad of silica gel and concentrated in vacuo. The residue was purified by preparative HPLC (C18 inverted phase column, elution with a gradient of H 2 O / CH 3 CN with 0.5% TFA) and lyophilized to give 40 mg (49%) of the title compound as a white powder. LRMS (ES +): 553.0 (M + H) +.

EXAMPLE 140 2- (N-Glycyl) -4- [(4-methoxy) phenyl] -5- [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide] thiazole To a solution of 2- (2-methoxycarbonyl) methylamino) -4- [(4-methoxy) phenyl] -5 - [(2'-amino-sulfonyl- [1,1 '] -biphenyl-4-yl) carboxyamide] thiazole (27 mg, 0.049 mmol) in 2 mL of tetrahydrofuran and 2 mL of water was added lithium hydroxide monohydrate (4 mg, 0.098 mmol). The resulting solution was stirred at room temperature for 18 hours and then concentrated in vacuo. The residue was purified by preparative HPLC (C18 inverted phase column, elution with a gradient of H20 / CH3CN with 0.5% TFA) and lyophilized to give 16 mg (61%) of the title compound as a white powder. LRMS (ES +): 536.8 (M + H) +.

EXAMPLE 141 1- [(4-methoxy) phenyl] -3- (ethoxycarbonyl) -lH-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide 1- [4-methoxy) phenyl] -3,5-dimethylpyrazole. To a solution of 4-methoxyphenylhydrazine hydrochloride (118.7 g, 0.68 mmol) in 300 mL of glacial acetic acid was added 2,4-pentanedione (68.0 g, 0.68 mol). The resulting solution was stirred at 100 ° C for 18 hours and then cooled and concentrated vacuo. The residue was dissolved in ethyl acetate, filtered through a pad of silica gel and concentrated to give 131 g (95%) of the title compound, which was used without purification. LRMS (NH4-CI): 203.3 (M + H) +. 1- [4-methoxy) phenyl] pyrazol-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 to 70 ° C and stirred for 1 hour. The reaction was filtered and the filter cake was washed with hot water. The filtrate was acidified with HCl and then extracted twice with ethyl acetate. The combined organic products were washed with brine, dried (MgSO4) and concentrated. The residue was triturated with chloroform and filtered to give 39.7 g (23%) of the title compound. LRMS (ES-): 260.9 (M-H).

Dimethyl 1- [(4-methoxy) phenyl] pyrazole-3,5-dicarboxylate. A solution of 1- [4-methoxy) phenyl] pyrazole-3,5-dicarboxylic acid (39.7 g, 0.15 mol) in 300 mL of anhydrous methanol was cooled to 0 ° C and then anhydrous HCl was bubbled through the solution for 15 minutes through a gas dispersion tube. The flask was sealed and the reaction was allowed to stir at room temperature for 24 hours. The volatile products were removed in vacuo. The residue was dissolved in ethyl acetate, filtered through a pad of silica gel and concentrated in vacuo to give 32.8 g (74%) of the title compound which was used without purification. LRMS (NH4-CI): 291.2 (M + H) +. 1- [(4-Methoxy) phenyl] -5- (methoxycarbonyl) pyrazole-3-carboxylic acid. To a solution of dimethyl 1- [(4-methoxy) phenyl] pyrazole-3,5-dicarboxylate (32.7 g, 110 mmol) in 50 mL of dioxane and 100 mL of water was added concentrated sulfuric acid (1.50 mL, 28.2 g. mmol). The resulting solution was stirred at 100 ° C for 18 hours and then cooled to room temperature. The reaction was then made basic with potassium carbonate and then extracted with ether to remove the unreacted diester. The aqueous layer was acidified with HCl and extracted twice with ethyl acetate. The combined organic products were washed with brine, dried (MgSO4) and concentrated to give 19.2 g (63%) of the title compound with 5.0 g (15%) of the unreacted starting material. The title compound was used without further purification. LRMS (ES-): 274.9 (M-H). 1- [(4-methoxy) phenyl] -3- (ethoxycarbonyl) -5- (methoxycarbonyl) pyrazole. A solution of l - [(4-methoxy) phenyl] -5- (methoxycarbonyl) pyrazole-3-carboxylic acid (7.50 g, 27.1 mmol) in 50 mL of thionyl chloride was stirred at 80 ° C for 1 hour. The volatile products were then removed and the residue was azeotroped with 20 mL of toluene and dried in vacuo. The residue was dissolved in 100 mL of tetrahydrofuran and then diisopropylethylamine (11.8 mL, 67.9 mmol) and pure ethanol were added. (3.2 mL, 54.3 mmol). The reaction mixture was allowed to stir at room temperature for 24 hours. The volatiles were removed and the residue was dissolved in ethyl acetate. This solution was filtered through a pad of silica gel and concentrated in vacuo to give 3.7 g (45%) of the title compound which was used without purification. LRMS (DCI): 305.1 (M + H) +. 1- [(4-Methoxy) phenyl] -3- (ethoxycarbonyl) pyrazole-5-carboxylic acid. To a solution of 1- [(4-methoxy) phenyl] -3- (ethoxycarbonyl) -5- (methoxycarbonyl) pyrazole (4.0 g, 13.2 mmol) in 40 mL of tetrahydrofuran and 20 L of water was added an aqueous solution of lithium hydroxide monohydrate (0.55 g, 13.2 mmol). The reaction was allowed to stir at room temperature for 1 hour. The tetrahydrofuran was removed in vacuo and the aqueous layer was extracted with ether to remove the unreacted diester. The aqueous layer was acidified with HCl and extracted with ethyl acetate. The organic products were washed with brine, dried (MgSO4) and concentrated to give 3.2 g (84%) of the title compound, which was used without further purification. LRMS (ES-): 289.0 (M + H). " 1- [(4-methoxy) phenyl] -3- (ethoxycarbonyl) -lH-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenylcarboxyamide) A solution of 1- [(4-methoxy) phenyl] -3 acid - (ethoxycarbonyl) pyrazole-5-carboxylic acid (3.2 g, 11.1 mmol) in 20 mL of thionyl chloride was stirred at 80 ° C for 1 hour, the volatiles were then removed and the residue was azeotroped with 20 mL of toluene dried in vacuo The residue was dissolved in 50 mL of methylene chloride and then triethylamine (4.6 mL, 33.3 mmol) and 4- (N-pyrrolidinocarbonyl) aniline (3.2 mL, 54.3 mmol) were added. allowed to stir at room temperature for 4 hours, volatile products were removed and the residue was dissolved in ethyl acetate, washed sequentially with 10% aqueous HCl and brine, dried (MgSO4), filtered through a short pad of silica gel and concentrated to give 2.5 g (50%) of the title compound, A small portion was further purified by HPLC p reparative (inverted phase C18 column, elution with a gradient of H20 / CH3CN with 0.5% TFA) and lyophilized to give the title compound as a white powder. LRMS (ES +): 463.1 (M + H) +.

EXAMPLE 142 1- [(4-Methoxy) phenyl] -3- (carboxyamide) -lH-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide 1- [(4-Methoxy) phenyl] -l-H-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide-3-carboxylic acid. To a solution of 1- [(4-methoxy) phenyl] -3- (ethoxycarbonyl) -1H-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide (2.05 g, 4.43 mmol) in 10 mL of THF and 10 mL of water were added potassium hydroxide (0.32 g, 5.76 mmol). The resulting solution was stirred for 18 hours. The THF was removed in vacuo and the aqueous layer was extracted with ether to remove the unreacted ester. The aqueous layer was acidified with HCl and extracted with ethyl acetate. The organic products were washed with brine, dried (MgSO 4) and concentrated to give 1.1 g (57%) of the title compound, which was used without further purification. LRMS (ES-): 433.0 (M-H) " 1- [(4-Methoxy) phenyl] -3- (carboxyamido) -lH-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide. To a solution of l- [(4-methoxy) phenyl] -lH-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide-3-carboxylic acid (117 mg, 0.27 mmol) in 10 mL of THF / CH3CN 1: 1 triethylamine (0.056 mL, 0.40 mmol) and isobutyl chloroformate (0.038 mL, 0.30 mmol) were added. After stirring at room temperature for 30 minutes, methanolic ammonia solution (1.34 mL of a 2.0 M solution of ammonia in methanol) was added. The reaction was stirred for 1 hour and then the volatiles were removed. The residue was purified by preparative HPLC (C18 inverted phase column, elution with a gradient of H20 / CH3CN with 0.5% TF) was lyophilized to give 50 mg (43%) of the title compound as a white powder. LRMS (ES +): 434.1 (M + H) +.

EXAMPLE 143 1- [(4-Methoxy) phenyl] -3- [(2-hydroxyethyl) carboxyamido] -1H-pyrazole-5- [(4-N-pyrrolidinocarbonyl) phenyl) carboxyamide To a solution of 1- [(-methoxy) phenyl] -lH-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide-3-carboxylic acid (110 mg, 0.25 mmol) in 5 mL of acetonitrile was added. added triethylamine (0.053 mL, 0.38 mmol) and isobutyl chloroformate (0.037 mL, 0.28 mmol). After stirring at room temperature for 30 minutes, ethanolamine (0.06 mL, 1.01 mmol) was added. The reaction was stirred for 1 hour and then volatile products were removed. The residue was purified by preparative HPLC (inverted phase column, C18, elution with a gradient of H20 / CH3CN with 0.5% TFA) and lyophilized to give 80 mg (67%) of the title compound as a white powder. LRMS (ES +): 478.0 (M + H).

EXAMPLE 144 1- [(4-Methoxy) phenyl) -lH-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide-3-hydroxamic acid To a solution of 1- [(4-methoxy) phenyl] -lH-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide-3-carboxylic acid (100 mg, 0.23 mmol) in 5 mL of acetonitrile triethylamine (0.064 mL, 0.46 mmol) and isobutyl chloroformate (0.030 mL, 0.23 mmol) were added. After stirring at room temperature for 30 minutes, hydroxylamine hydrochloride (16 mg, 0.23 mmol) was added. The reaction was stirred for 1 hour and then the volatiles were removed. The residue was purified by preparative HPLC (C18 reversed-phase column, elution with a gradient of H2-O / CH3CN with 0.5% TFA) and lyophilized to give 28 mg (27%) of the title compound as a white powder. LRMS (ES-): 562.1 (M-H + TFA) ".

EXAMPLE 145 1- [(4-Methoxy) phenyl] -3- [phenylcarboxyamido] -1H-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide To a solution of 1- [(4-methoxy) phenyl] -lH-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide-3-carboxylic acid (100 mg, 0.23 mmol) in 5 mL of acetonitrile triethylamine (0.064 mL, 0.46 mmol) and isobutyl chloroformate (0.030 mL, 0.23 mmol) were added. After stirring at room temperature for 30 minutes, aniline (0.02 mL, 0.23 mmol) was added. The reaction was stirred for 1 hour and then volatile products were removed. The residue was purified by preparative HPLC (inverted phase column, C18, elution with a gradient of H20 / CH3CN with 0.5% TFA) was lyophilized to give 22 mg (19%) of the title compound as a white powder. LRMS (ES +): 510. 2 (M + H) +.

EXAMPLE 146 1- [(4-Methoxy) phenyl] -3- [(3-hydroxypropyl) carboxyamido] -1H-pyrazole-5- [(4-N-pyrrolidinocarbonyl) phenyl) carboxyamide To a solution of 1- [(4-methoxy) phenyl] -lH-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide-3-carboxylic acid (100 mg, 0.23 mmol) in 5 mL of acetonitrile triethylamine (0.064 mL, 0.46 mmol) and isobutyl chloroformate (0.030 mL, 0.23 mmol) were added. After stirring at room temperature for 30 minutes, 3-hydroxypropylamine (0.02 mL, 0.23 mmol) was added. The reaction was stirred for 1 hour and then the volatiles were removed. The residue was purified by preparative HPLC (inverted phase column, C18, elution with a gradient of H20 / CH3CN with 0.5% TFA) was lyophilized to give 38 mg (30%) of the title compound as a white powder. LRMS (ES +): 492. 3 (M + H) ".

EXAMPLE 147 1- [(4-Methoxyphenyl) phenyl] -3- [methylcarboxyamide] -lH-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide To a solution of 1- [(4-methoxy) phenyl] -lH-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide-3-carboxylic acid (100 mg, 0.23 mmol) in 5 mL of acetonitrile triethylamine (0.096 mL, 0.69 mmol) and isobutyl chloroformate (0.033 mL, 0.25 mmol) were added. After stirring at room temperature for 30 minutes, methylamine hydrochloride (23 mg, 0.35 mmol) was added. The reaction was stirred for 1 hour and then volatile products were removed. The residue was purified by preparative HPLC (C18 inverted phase column, elution with a gradient of H20 / CH3CN with 0.5% TFA) and lyophilized to give 15 mg (15%) of the title compound as a white powder LRMS (ES + ): 448.2 (M + H) +.

EXAMPLE 148 1- [(4-Methoxy) phenyl] -3- [(benzyl) carboxyamide] -lH-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide To a solution of 1- [(4-methoxy) phenyl] -lH-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide-3-carboxylic acid (100 mg, 0.23 mmol) in 5 mL of acetonitrile triethylamine (0.096 mL, 0.69 mmol) and isobutyl chloroformate (0.033 mL, 0.25 mmol) were added. After stirring at room temperature for 30 minutes, benzylamine hydrochloride (49 mg, 0.35 mmol) was added. The reaction was stirred for 1 h and then the volatile products were removed. The residue was purified by preparative HPLC (inverted phase column, C18, elution with a gradient of H0 / CH3CN with 0.5% TFA) was lyophilized to give 19 mg (16%) of the title compound as a white powder. LRMS (ES +): 524.2 (M + H) + EXAMPLE 149 1- [(4-Methoxy) phenyl] -3- (dimethyl) carboxyamido] -1H-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide To a solution of 1- [(4-methoxy) phenyl] -lH-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide-3-carboxylic acid (100 mg, 0.23 mmol) in 5 mL of acetonitrile triethylamine (0.096 mL, 0.69 mmol) and isobutyl chloroformate (0.033 L, 0.25 mmol) were added. After stirring at room temperature for 30 minutes, aqueous dimethylamine (0.040 mL of a 40% aqueous solution, 0.80 mmol) was added. The reaction was stirred for 1 hour and then volatile products were removed. The residue was purified by preparative HPLC (reversed phase C18 column, elution with a gradient of H20 / CH3CN with 0.5% TFA) and lyophilized to give 20 mg (19%) of the title compound as a white powder. LRMS (ES +): 462.2 (M + H).

EXAMPLE 150 1- [(4-Methoxy) phenyl] -3- [(phenylethyl) carboxyamid] -lH-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide To a solution of 1- [(4-methoxy) phenyl] -lH-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide-3-carboxylic acid (100 mg, 0.23 mmol) in 5 mL of acetonitrile added triethylamine (0.096 mL, 0.69 mmol) and isobutyl chloroformate (0.033 mL, 0.25 mmol). After stirring at room temperature for 30 minutes, fentanylamine (0.043 mL, 0.80 mmol) was added. The reaction was stirred for 1 hour and then volatile products were removed. The residue was purified by preparative HPLC (C18 inverted phase column, elution with a gradient of H20 / CH3CN with 0.5% TFA) and lyophilized to give 15 mg (12%) of the title compound as a white powder. LRMS (ES +): 538.2 (M + H) +.

EXAMPLE 151 1- [(4-Methoxy) phenyl] -3- [(2-hydroxyphenyl) carboxyamido] -1H-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide To a solution of 1- [(4-methoxy) phenyl] -lH-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide-3-carboxylic acid (100 mg, 0.23 mmol) in 5 mL of acetonitrile triethylamine (0.096 mL, 0.69 mmol) and isobutyl chloroformate (0.033 mL, 0.25 mmol) were added. After stirring at room temperature for 30 minutes, 2-hydroxyaniline (75 mg, 0.69 mmol) was added. The reaction was stirred for 1 hour and then the volatiles were removed. The residue was purified by preparative HPLC (C18 inverted phase column, elution with a gradient of H20 / CH3CN with 0.5% TFA) was lyophilized to give 10 mg (8%) of the title compound as a white powder. LRMS (ES +): 526.1 (M + H) + EXAMPLE 152 1- [(4-Methoxy) phenyl] -3- [(3-hydroxyphenyl) carboxyamido] -1H-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide To a solution of 1- [(4-methoxy) phenyl] -lH-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamido-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 minutes, 3-hydroxyaniline (75 mg, 0.69 mmol) was added. The reaction was stirred for 1 hour and then the volatiles were removed. The residue was purified by preparative HPLC (C18 inverted phase column, elution with a gradient of H20 / CH3CN with 0.5% TFA) and lyophilized to give 12 mg (10%) of the title compound as a white powder. LRMS (ES +): 526.2 (M + H) + EXAMPLE 153 1- [(4-Methoxy) phenyl] -3- [(4-hydroxyphenyl) carboxyamid] -1H-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide To a solution of 1- [(4-methoxy) phenyl] -lH-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide-3-carboxylic acid (100 mg, 0.23 mmol) in 5 mL of acetonitrile triethylamine (0.096 mL, 0.69 mmol) and isobutyl chloroformate (0.033 mL, 0.25 mmol) were added. After stirring at room temperature for 30 minutes, 4-hydroxyaniline (75 mg, 0.69 mmol) was added. The reaction was stirred for 1 hour and then the volatiles were removed. The residue was purified by preparative HPLC (C18 inverted phase column, elution with a gradient of H 2 O / CH 3 CN with 0.5% TFA) was lyophilized to give 12 mg (10%) of the title compound as a white powder. LRMS (ES +): 548.1 (M + Na) + EXAMPLE 154 1- [(4-Methoxy) phenyl] -3- [methoxycarbonyl] amine] -lH-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide 1- [(4-Methoxy) phenyl] -3- [(methoxycarbonyl) amine] -5- (methoxycarbonyl) pyrazole. To a solution of l - [(4-methoxy) phenyl] -5- (methoxycarbonyl) pyrazole-3-carboxylic acid (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 resultant was stirred for 30 minutes after which an aqueous solution of sodium azide (2.82 g, 43.4 mmol) was added. The reaction was stirred at 0 ° C for 1 hour. The reaction was then diluted with ethyl acetate and washed with brine. The organic products were dried (MgSO4) and concentrated in vacuo. The residue was dissolved in 50 mL of toluene and stirred at 100 ° C for 1 hour. The volatiles were removed in vacuo and the residue was dissolved in methanolic sodium methoxide (5 mL of a 25% solution of sodium methoxide in methanol, in 21 mmol) was stirred at room temperature for 2 hours. The reaction was diluted with ethyl acetate, diluted with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (elution with hexane / ethyl acetate 1: 1) to give 1.1 g (33%) of the title compound as a solid. LRMS (DCI): 306.3 (M + H) +. 1- [(4-Methoxy) phenyl] -3- [(methoxycarbonyl) amine] -lH-pyrazole-5- [(2'-tert-butylaminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide. To a solution of (2'-tert-butylaminosulfonyl- [1, 1 '] -bifen-4-yl) amine (0.90 g, 2.95 mmol) in 20 mL of methylene chloride at room temperature was added trimethylaluminum (8.85 mL of a 2.0 M solution in toluene, 17.68 mmol) dropwise. The resulting solution was allowed to stir until no more gas emission was observed (approximately 15 minutes). To this solution was added 1- [(4-methoxy) phenyl] -3- (methoxycarbonylamine) -5- (methoxycarbonyl) pyrazole (0.90 g, 2.95 mmol) in 10 mL of methylene chloride. The resulting solution was stirred at 40 ° C for 16 hours and then cooled to room temperature and quenched by the addition of aqueous, saturated NH 4 Cl. After dilution with ethyl acetate, the organic layer was washed with aqueous HCl, 10%, saturated aqueous NaHCO3, and brine, dried (MgSO4), filtered through a pad of silica and concentrated in vacuo. . The solid residue was recrystallized from hexane / ethyl acetate to give 1.4 g (82%) of the title compound. LRMS (ES +): 577.9 (M + H) +. 1- [(4-Methoxy) phenyl] -3- [(methoxycarbonyl) amine] 1-lH-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide. A solution of 1- [(4-methoxy) phenyl] -3- [(methoxycarbonyl) amine] -lH-? Irazol-5- [(2'-tert-butylaminosulfonyl- [1,1 '] -bifen-4- il) carboxyamide. (0.40 g, 0.69 mmol) in 5 mL of trifluoroacetic acid was stirred at reflux for 20 minutes and then cooled to room temperature and concentrated in vacuo. The residue was purified by preparative HPLC (C18 inverted phase column, elution with a gradient of H20 / CH3CN with 0.5% TFA) and lyophilized to give 200 mg (56%) of the title compound as a white powder. LRMS (ES +): 521.8 (M + H) +.

EXAMPLE 155 1- [(4-Methoxy) phenyl] -3-amine-lH-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide To a solution of 1- [(4-methoxy) phenyl] -3- [(methoxycarbonyl) amine] -lH-pyrazole-5- [(21-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide (0.22 g, 0.42 mmol) in 10 mL of water / methanol 1: 1 was added potassium hydroxide (2.0 g, 35 mmol). The resulting mixture was stirred at 70 ° C for 4 h and then cooled to room temperature and acidified with aqueous HCl. The reaction mixture was diluted with ethyl acetate and the organic products were washed with brine, dried (MgSO) and concentrated in vacuo. The residue was purified by preparative HPLC (C18 inverted phase column, elution with a gradient of H20 / CH3CN with 0.5% TFA) and lyophilized to give 75 mg (38%) of the title compound as a white powder. LRMS (ES +): 463.8 (M + H) +.

EXAMPLE 156 1- [(4-Methoxy) phenyl] -3- [(methoxycarbonyl) methylamine] -1H-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide To a solution of 1- [(4-methoxy) phenyl] -3-amine-lH-pyrazole-5- [(2'-tert-butylaminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide (1.0 g, 1.92 mmol) in 10 mL of DMF was added sodium bicarbonate (0.24 g, 2.88 mmol) and methyl bromoacetate (0.22 mL, 2.30 mmol). The resulting mixture was stirred at 85 ° C for 16 hours. The reaction was not finished so that additional portions of sodium bicarbonate were added (0.48 g, 5.76 mmol) and methyl bromoacetate (0.22 mL, 2.30 mmol) and the reaction was stirred at 95 ° C for a further 6 hours. The reaction was cooled to room temperature diluted with ethyl acetate. The organic products were washed with brine, dried (MgSO 4) and concentrated in vacuo. The residue was dissolved in 5 mL of trifluoroacetic acid and stirred at reflux for 20 minutes and then cooled to room temperature and concentrated in vacuo. The residue was purified by preparative HPLC (C18 inverted phase column, elution with a gradient of H20 / CH3CN with 0.5% TFA) and lyophilized to give 450 mg (44%) of the title compound as a white powder. LRMS (ES +): 536.0 (M + H) +.

EXAMPLE 157 1- [(4-Methoxy) phenyl] -3 - [(2-hydroxy) ethylamine] -lH-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide 1- [(4-Methoxy) phenyl] -3- [N-glycy] -lH-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide. To a solution of 1- [(4-methoxy) phenyl] -3- [(methoxycarbonyl) methylamine] -lH-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide (0.40 g, 0.75 mmol) in 10 mL of methanol / water 1: 1 was added lithium hydroxide monohydrate (0.13 g, 2.98 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction was acidified with aqueous HCl and diluted with ethyl acetate. The organic products were washed with brine, dried (MgSO 4) and concentrated in vacuo. The residue was purified by preparative HPLC (C18 inverted phase column, elution with a gradient of H20 / CH3CN with 0.5% TFA) and lyophilized to give 200 mg (51%) of the title compound as a white powder. LRMS (ES +): 522.0 (M + H) +. 1- [(4-Methoxy) phenyl] -3 - [(2-hydroxy) ethylamine] -lH-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide. To a solution of 1- [(4-methoxy) phenyl] -3- [N-glycy] -lH-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide (0.14 g, 0.27 mmol) in tetrahydrofuran at -20 ° C was added triethylamine (0.038 mL, 0.27 mmol) and ethyl chloroformate (0.026 mL, 0.27 mmol). This mixture was stirred for 30 minutes and then sodium borohydride (20 mg, 0. 54 mmol) in a minimum amount of water. The reaction mixture was stirred under slow heating at room temperature for 1 hour and then quenched with 10% aqueous HCl. After dilution with ethyl acetate, the organic products were washed with brine, dried (MgSO 4) and concentrated in vacuo. The residue was purified by preparative HPLC (C18 inverted phase column, elution with a gradient of H20 / CH3CN with 0.5% TFA) and lyophilized to give 35 mg (26%) of the title compound as a white powder. LRMS (ES +): 507.9 (M + H) +.

EXAMPLE 158 1- [(4-Methoxy) phenyl] -3- [E-2- (methoxycarbonyl) ethenyl] 3-H-pyrazole-5- [(2'-amino-sulfonyl- [1,1 '] -biphen-4 -il) carboxyamide 1- [(4-Methoxy) phenyl] -3- (hydroxymethyl) -lH-pyrazole-5- (methoxycarbonyl) irazole. To a solution of l - [(4-methoxy) phenyl] -lH-pyrazole-5- (methoxycarbonyl) 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 minutes and then sodium borohydride (0.66 g, 17.4 mmol) was added in a minimum amount of water. The reaction mixture was stirred under slow heating at room temperature for 1 hour and then quenched with 10% aqueous HCl. After dilution with ethyl acetate, the organic products were washed with brine, dried (MgSO 4) and concentrated in vacuo. The residue was purified by flash chromatography (elution with ethyl acetate / hexane 3: 2) to give 1.4 g (61%) of the title compound. LRMS (DCI): 263.3 (M + H). 1- [(4-Methoxy) phenyl] -3- (hydroxymethyl) -lH-pyrazole-5- [(2-tert-butylaminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide. To a solution of (2'-tert-butylaminosulfonyl- [1, 1 '] -bifen-4-yl) amine (1.44 g, 4.73 mmol) in 40 mL of methylene chloride at room temperature was added trimethylaluminum (14.2 mL of a 2.0 M solution in toluene, 28.4 mmol) dropwise. The resulting solution was allowed to stir until no more gas emission was observed (approximately 15 minutes). To this solution was added 1- [(4-methoxy) phenyl] -3- (hydroxymethyl) -5- (methoxycarbonyl) pyrazole (1.24 g, 4.73 mmol) in 10 mL of methylene chloride. The resulting solution was stirred at 40 ° C for 16 hours and then cooled to room temperature and quenched by the addition of saturated aqueous NH 4 Cl. After dilution with ethyl acetate, the organic layer was washed with. 10% aqueous HCl, saturated aqueous NaHCO3, and brine were dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo. The solid residue was recrystallized from hexane / ethyl acetate to give 1.7 g (68%) of the title compound. LRMS (ES +): 557.1 (M + Na) +. 1- [(4-Methoxy) phenyl] -3- (carboxaldehyde) -lH-pyrazole-5- [(2'-tert-butylaminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide. To a solution of oxalyl chloride (0.33 mL, 3.81 mmol) in 20 mL of methylene chloride at -78 ° C was added dimethyl sulfoxide (0.54 mL, 7.63 mmol). This mixture was stirred for 15 minutes and then 1- [(4-methoxy) phenyl] -3- (hydroxymethyl) -lH-pyrazole-5- [(2'-tert-butylaminosulfonyl- [1, 1 '] - bifen-4-yl) carboxyamide (1.70 g, 3.18 mmol) was added 10 mL of methylene chloride. The reaction was allowed to stir while heating slowly to room temperature for 2 hours. Triethylamine (2.21 mL, 15.90 mmol) was added and the reaction was stirred at room temperature for 30 minutes. The reaction was diluted with ethyl acetate and the organic layer was washed with 10% HCl, saturated aqueous NaHCO3, and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo. to give 1.3 g (76%) of the title compound that was sufficiently pure to be used without purification. LRMS (ES +): 533.2 (M + H) +. 1- [(4-Methoxy) phenyl] -3- [E-2- (methoxycarbonyl) tenyl] -1H-pyrazole-5- [(2'-tert-butylaminosulfonyl- [1,1 '] -bifen-4- il) carboxyamide. To a solution of 1- [(4-methoxy) phenyl] -3- (carboxaldehyde) -lH-pyrazole-5- [(2'-tert-butylaminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide (1.30 g, 2.44 mmol) in 30 mL of methylene chloride was added (triphenylphosphoranylidene) methyl acetate (0.98 g, 2.92 mmol). The mixture was allowed to stir at room temperature for 18 hours. The volatiles were removed in vacuo and the residue was purified by flash chromatography (elution with ethyl acetate / hexane 1: 1) to give 1.2 g (83%) of the title compound. LRMS (ES +): 589.1 (M + H) ". 1- [(4-Methoxy) phenyl] -3- [E-2- (methoxycarbonyl) ethenyl] -1H-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide. To a solution of 1- [(4-methoxy) phenyl] -3- [E-2- (methoxycarbonyl) ethenyl] -lH-pyrazole-5- [(2'-tert-butylaminosulfonyl- [1, 1 '] - bifen-4-yl) carboxyamide (1.2 g, 2.04 mmol) in 10 mL of trifluoroacetic acid was stirred at reflux for 20 minutes and then cooled to room temperature and concentrated in vacuo. The residue was purified by preparative HPLC (C18 inverted phase column, elution with a gradient of H20 / CH3CN with 0.5% TFA) and lyophilized to give 1.0 g (90%) of the title compound as a white powder. LRMS (ES +): 533.0 (M + H) J EXAMPLE 159 1- [(4-Methoxy) phenyl] -3- [2- (methoxycarbonyl) tyl] -lH-pyrazol-5- [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide To a solution of 1- [(4-methoxy) phenyl] -3- [E-2- (methoxycarbonyl) ethenyl] -lH-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] -bifen- 4-yl) carboxyamide (35 mg, 0.065 mmol) in 20 mL of pure ethanol at room temperature was added 10% palladium catalyst in carbon (3.5 mg). This mixture was stirred under an atmosphere of hydrogen gas for 3 hours and then filtered through a pad of celite and concentrated in vacuo. The residue was purified by preparative HPLC (C18 inverted phase column, elution with a gradient of H20 / CH3CN with 0.5% TFA) and lyophilized to give 15 mg (42%) of the title compound as a white powder. LRMS (ES +): 534.9 (M + H) +.

EXAMPLE 160 1- [(4-Methoxy) phenyl] -3- [E-2- (carboxy) ethenyl] -lH-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] -bifen-4- il) carboxyamide To a solution of 1- [(4-methoxy) phenyl] -3- [E-2- (methoxycarbonyl) ethenyl] -lH-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] -bifen- 4-yl) carboxyamide (1.2 g, 2.25 mmol) in 20 mL of methanol / water 1: 1 at room temperature was added lithium hydroxide monohydrate (0.19 g, 4.5 mmol). This mixture was stirred for 3 hours and then acidified with aqueous HCl and diluted with ethyl acetate. The organic products were washed with brine, dried (MgSO 4) and concentrated in vacuo. The residue was purified by preparative HPLC (C18 inverted phase column, elution with a gradient of H20 / CH3CN with 0.5% TFA) and lyophilized to give 1.0 g (83%) of the title compound as a white powder. LRMS (ES +): 516.8 (M + H) ".

EXAMPLE 161 1- [(4-Methoxy) phenylj -3- [2- (carboxy) ethyl] -lH-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide To a solution of 1- [(4-methoxy) phenyl] -3- [E-2- (carboxy) ethenyl] -lH-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] - biphen- 4-yl) carboxyamide (40 mg, 0.077 mmol) in 20 mL of pure ethanol at room temperature was added catalyst and 10% palladium on carbon (20 mg). This mixture was stirred under an atmosphere of hydrogen gas for 3 hours and then filtered through a pad of celite and concentrated in vacuo. The residue was purified by preparative HPLC (C18 inverted phase column, elution with a gradient of H20 / CH3CN with 0.5% TFA) and lyophilized to give 10 mg (25%) of the title compound as a white powder. LRMS (ES +): 520.9 (M + H) +.

EXAMPLE 162 1 [(4-Methoxy) phenyl] -3- [E-2- (carboxyamide) ethenyl] -1-H-pyrazol-5- [2'-aminosulfonyl- [1,1 '] -bifen-4- il-carboxyamide.

To a solution of 1- [(4-Methoxy) phenyl] -3- [E-2- (carboxyl) ethenyl] -lH-pyrazol-5- [2'-aminosulfonyl- [1,1 '] - biphen-4 Carboxyamide (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 minutes, methanolic ammonia solution (0.27 mL of a 2.0 M solution of ammonia in methanol, 0.54 mmol) was added. The reaction was stirred for 16 h and then the volatiles were removed. The residue was purified by preparative HPLC (C18 inverted phase column, elution with a gradient of H20 / CH3CN with 0.5% TFA) was lyophilized to give 35 mg (25%) of the title compound as a white powder. LRMS (ES +): 517.9 (M + H) +.

EXAMPLE 163 1- [4 (-Metoxy) phenyl] -3- [E-2- (hydroxymethyl) ethenyl] -1H-pyrazole-5- [2'-aminosulfonyl- [1,1 '] -bifen-4- il-carboxyamide.

To a solution of 1- [4 (-Metoxy) phenyl] -3- [E-2- (carboxyl) ethenyl] -lH-pyrazole-5- [2'-aminosulfonyl- [1,1 '] - biphen-4 -carboxyamide (1.0 g, 1.93 mmol) in 20 mL of tetrahydrofuran at minus 20 ° C triethylamine was added (0.27 mL, 1.93 mmol) and isobutyl chloroformate (0.25 mL, 1.93 mmol). This mixture was stirred for 30 minutes and then sodium borohydride (0.22 g, 5.78 mmol) was added in a minimum amount of water. The reaction mixture was stirred under slow heating at room temperature for one hour and then quenched with 10% aqueous HCl. After dilution with ethyl acetate, the organic products were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by preparative HPLC (inverted phase C-18 column, elution with gradient H2 / CH3CN with 0.5% TFA) and lyophilized to give 0.5 g (52%) of the title compound as a white powder. LRMS (ES +): 504.9 (M + H) +.

EXAMPLE 164 1- [(4-Methoxy) phenyl] 3- (3-hydroxypropyl) -lH-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl-carboxyamide.

And EXAMPLE 165 1- [(4-Methoxy) phenyl] -3-propyl) -lH-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl-carboxyamide.

To a solution of 1- [4 (-Metoxy) phenyl] -3- [E-2-hydroxymethyl]) ethenyl] -lH-pyrazole-5- [2'-aminosulfonyl- [1,1 '] -bifen-4 -carboxyamide (40 mg, 0.08 mmol) in 20 L of methanol at room temperature, 10% palladium catalyst in carbon (4 mg) was added. This mixture was stirred under an atmosphere of hydrogen gas for three hours and then filtered through a pad of celite and concentrated in vacuo. The residue was purified by preparative HPLC (inverted phase C-18 column, elution with a gradient of H20 / CH3CN with 0.5% TFA) and lyophilized to give 15 mg (38%) of EXAMPLE 164 as a white powder. LRMS (ES +): 506.9 (M + H). 8 mg (20%) of Example 165 was obtained as a white powder. LRMS (ES +): 490.9 (M + H) +.

EXAMPLE 166 1- [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4-cyano-lH-pyrazole-5- [(2'-methylsulfonyl-3-fluoro- [1,1 '] -bifen-4- il) carboxamide. 1- [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4-cyano-lH-pyrazol-5- (2'-furyl) pyrazole. To a solution of 2-furoylacetonitrile (0.91 g, 6.73 mmol) in 20 mL of pure ethanol was added sodium ethoxide (2.5 mL of a 21% by weight solution in ethanol, 6.73 mmol) followed by 2, 2, 2, -trifluoroacetoyl bromide-N- (4-methoxyphenyl) hydrazone (2.0 g, 6.73 mmol). This mixture was stirred at room temperature for 4 hours. The volatiles were removed in vacuo and the residue was dissolved in ethyl acetate, washed with water and brine, dried (MgSO 4) and concentrated. The residue was purified by recrystallization from hexane / ethyl acetate to give 1.1 g (49% of the title compound. 1- [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4-cyano-pyrazole-5 acid. carboxylic To a solution of l - [(4-methoxy) phenyl] -3- (trifluoromethyl) -4-cyano-5- (2-furyl) pyrazole (0.68 g, 2.04 mmol) in carbon tetrachloride / actonitrile / water 4: 4: 6 sodium periodate (1.96 g, 9.2 mmol) and ruthenium (III) chloride monohydrate (42 mg, 0.20 mmol) were added. The resulting biphasic region was stirred vigorously at room temperature for 24 hours. The reaction was quenched with 10% aqueous HCl and diluted with ethyl acetate. The organic products were washed with brine, dried (MgSO 4), filtered through a pad of celite and concentrated. The residue was dissolved in hexane / ethyl acetate 1: 1 and extracted with saturated, aqueous Na 2 CO 3 (2 times). The combined aqueous extracts were acidified and extracted with ethyl acetate. The ethyl acetate extracts were washed with brine, dried (MgSO4) and concentrated to give 0.42 g (67%) of the title compound as a solid LRMS (ES-): 310.0 (M-H). 1 [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4-cyano-lH-pyrazole-5- [(2'-methylsulfonyl-3-fluoro- [1,1 '] -bifen-4-yl) carboxyamide .

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 was added oxalyl chloride (0.17 mL, 1.98 mmol) and 2 drops of dimethylformamide. The reaction was stirred at room temperature for 6 hours and then the volatiles were removed in vacuo. The residue was dissolved in 20 mL of methylene chloride and then 4-dimethylaminopyridine (0.48 g, 3.96 mmol) was added. The reaction was stirred for 10 minutes and then (2 '-methylsulfonyl-3-fluoro- [1,1'] -bifen-4-yl) amine hydrochloride (0.47 g, 1.45 mmol) was added. The resulting mixture was allowed to stir at room temperature for 16 hours. The reaction was dissolved with ethyl acetate and the organic products were washed with 10% aqueous HCl, saturated aqueous NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated to give 0.6 g (81%) of the title compound as a solid LRMS (ES +): 581.3 (M + Na) +.

EXAMPLE 167 1- [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4- (amidino) -1H-pyrazole-5- [(2'-methylsulfonyl-3-f) luoro- [1, 1 '] - bifen-4-yl) carboxyamide.

EXAMPLE 168 1- [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4- (N-hydroxyamidino) -lH-pyrazole-5- [(2'-methylsulfonyl-3-fluoro- [1,1 '] -bifen-4-yl) carboxyamide.

To a solution of 1- [(4-methoxy) phenyl] -3- (trifluoromethyl) -4-cyano-lH-pyrazole-5- [2 ('-methylsulfonyl-3-fluoro- [1,1'] - bifen -4-yl) carboxyamide (100 mg, 0.18 mmol) in 5 mL of pure ethanol was added hydroxylamine hydrochloride (38 mg, 0.54 mmol) and sodium carbonate (29 mg, 0.27 mmol). This mixture was stirred at 80 ° C. for 16 hours. The reaction was diluted with water and ethyl acetate. The organic products were washed with brine, dried (MgSO 4) and concentrated to a solid. The residue was dissolved in 10 L of pure ethanol and then cyclohexene (1 mL) 20% palladium hydroxide in carbon (50 mg) and acetic acid (0.02 mL, 0.36 mmol) was added. The resulting mixture was stirred at 80 ° C for 6 hours. The reaction was allowed to cool and filtered through a pad of celite and concentrated in vacuo. The residue was purified by preparative HPLC (inverted phase C column, 18 elution with a H20 / CH3CN gradient with 0.5% TFA) and lyophilized to give 20 mg (16%) of EXAMPLE 167 as a white powder LRMS (ES +) : 576.2 (M + H) +. 15 mg (12%) of Example 168 was also obtained as a white powder. LRMS (ES +): 592.2 (M + H) +.

EXAMPLE 169 1- [(4-Methoxy) phenyl] -3- (tri-luomomethyl) -4- (ethoxycarbonyl) -lH-pyrazole-5- [(2'-methylsulfonyl-3-fluoro- [1,1 '] -bifen 4-yl) carboxyamide. 1- [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4- (ethoxycarbonyl) -5-2-furyl) -pyrazol. To a solution of ethyl 3- (2-furyl) -3-ketopropionate (2.45 g, 13.4 mmol) in 20 mL of pure ethanol was added sodium ethoxide (4.6 mL of a 21% by weight solution in ethanol, 12.2 mmol) 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 hours. The volatiles were removed in vacuo and the residue was dissolved in ethyl acetate, washed with water and brine, dried (gS?) And concentrated. The residue was purified by recrystallization from hexane / ethyl acetate to give 1.4 g (61%) of the title compound LRMS (ES +): 381. 2 (M + H)? 1- [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4- (ethoxycarbonyl) -pyrazol-5-carboxylic acid. To a solution of 1- [(4-methoxy) phenyl] -3- (trifluoromethyl) -4- (ethoxycarbonyl) -5- (2-furyl) pyrazole. (1.0 g, 2.63 mmol) in carbon tetrachloride / acetonitrile / water 4: 4: 6 was added sodium periodate (2.5 g, 11.8 mmol) and ruthenium chloride (III) monohydrate (11 mg, 0.05 mmol). The resulting biphasic reaction was stirred vigorously at room temperature for 24 hours. The reaction was quenched with 10% aqueous HCl and diluted with ethyl acetate. The organic products were washed with brine, dried (MgSO4), filtered through a pad of celite and concentrated. The residue was dissolved in hexanes / ethyl acetate 1: 1 and extracted with a2C03 (2 times). The combined aqueous extracts were acidified and extracted with ethyl acetate. The ethyl acetate extracts were washed with brine, dried (MgSO4), and concentrated to give 0.5 g (53%) of the title compound as a solid LRMS (ES-): 357.0 (M-H) ". 1- [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4- (ethoxycarbonyl) -lH-pyrazole-5- [(2'-methylsulfonyl-3-fluoro- [1,1 '] -bifen-4- il) carboxyamide. To a solution of l - [(4-methoxy) phenyl] -3- (trifluoromethyl) -4- (ethoxycarbonyl) -pyrazol-5-carboxylic acid (0.5 g, 1.4 mmol) in 10 mL of methylene chloride was added chloride of oxalyl (0.18 mL, 2.1 mmol) and 2 drops of dimethylformamide. The reaction was stirred at room temperature for 6 hours and then the volatiles were removed in vacuo. The residue was dissolved in 20 mL of methylene chloride and then 4-dimethylaminopyridine (0.51 g, 4.2 mmol) was added. The reaction was stirred for 10 minutes and then (2'-methylsulfonyl-3-fluoro-) hydrochloride was added. , 1 '] -bifen-4-yl) amine (0.42 g, 1.4 mmol). The resulting mixture was allowed to stir at room temperature for 16 hours. The reaction was diluted with ethyl acetate and the organic products were washed with 10% aqueous HCl, saturated aqueous NaHC03 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated to give 0.6 (70%) of the compound of EXAMPLE 169 as a solid. A portion was purified by preparative HPLC (inverted phase C-18 column, elution with a gradient of H20 / CH3CN with 0.5% TFA) and lyophilized to give the title compound as a white powder. LRMS (ES +): 628.1 (M + Na) +.

EXAMPLE 170. 1- [(4-Methoxy) phenyl] -3- (trifluoromethyl) -lH-pyrazole-5- [(2'-methylsulfonyl-3-fluoro- [1,1 '] -bifen-4-yl) acid. carboxyamido-4-carboxylic acid.

To a solution of 1- [(4-methoxy) phenyl] -3- (trifluoromethyl) -4- (ethoxycarbonyl) -lH-pyrazole-5- [(2'-methylsulfonyl-3-fluoro- [1, 1 '] - bifen-4-yl) carboxamide (0.30 g, 0.49 mmol) in 10 mL of methanol / water 1: 1 was added potassium hydroxide (55 mg, 0.98 mmol). The reaction was stirred at 60 ° C for 2 hours and then cooled to room temperature and acidified with 10% HCl. The mixture was diluted with ethyl acetate, washed with brine, dried (MgSO4) and concentrated. The residue was purified by preparative HPLC (inverted phase C-18 column, elution with a gradient of H20 / CH3CN with 0.5% TFA) was lyophilized to give 150 mg (53%) of the title compound as a white powder. LRMS (ES-): 576.2 (M + -) ".

Ex. R, E M R1S A-B 1 - Core-A CH3 2 '-H2NS02-bifen-4-il 2 2-CH30 Core-A CH3 2 '-H2NS02-bifen-4-il 3 3-CH3O Core-A CH3 2 '-H2NS02-bifen-4-il 4 4-CH3O Core-A CH3 2 '-H2NS02-bifen-4-il 2-HO Core-A CH3 2 '-H NS02-bifen-4-il 6 3-HO Core-A CH3 2 '-H2NS02-bifen-4-yl 4-HO Core-A CH3 2' -H2NS02-bifen-4-yl 4-CH30 Core-A CH3 2 '-H2NS02-3-F -bifen-4-yl 4-CH3O Core-A CH3 2 '-H2NS02-3-Br-bifen-4-yl 4-CH3O Core-A CH3 2' -H2NS02-3-I-bifen-4-yl 4- CH3O Core-A CH3 2'H2NS02-3-methylbifen-4-yl 4-CH3O Core-A CH3 4- (CH3) 2NC (0) 6H4 4-CH3O Core-A CH3 4- (N- pyrrolidinocarbonyl) C6H 4 -CH3O Core-A CH3 4- (N-pyrrolidinomethyl) C6H4 4-CH3O Core-A CF3 2'-H2NS02-bifen-4-yl 4-CH3O Core-A CF3 4- (N-pyrrolidinocarbonyl) C6H4 4-CH3O Core -A CF3 5- (2'-CH3S02-C6H4) pyrid-2-yl 4-CH3O Core-A CF3 5- (N-pyrrolidinocarbonyl) pyrid-2-yl 4-CH3O Core- CH3 5- (N-pyrrolidino¬ Ach3 carbonyl) pyrid 2-yl 4-CH3O Core-A CH3 5- (2'-H2NS02-C6H4) pyrid-2-yl 4-CH3O Core-F CH3 4- (3'-HO-N- pyrrolidinocarbonyl) C6H4 4 -CH3O Core-F NH2 2 '-H2NS02-bifen-4-yl 4-CH3O Core-F Br 2' -H2NS02-bifen-4-yl 4-CH3O Core-F Cl 2 '-H2NS02-bifen-4-yl 4-HO Core-F Cl 2 '-H2NS02-bifen-4-yl 4-CH30 Core-F CH30 2' -H2NS02-bifen-4-yl 4-CH3O Core-F CH3S 2 '-H2NS02-bifen-4- il 4-CH3O Core-F CH3S (0) 2 '-H2NS02-bifen-4-yl 4-CH3O Core-F CH3SO2 2' -H2NS02-bifen-4-yl 4-CH3O Core-F -CN 2 '-H2NS02 -bifen-4-yl 4-CH3O Core-F (CH3) 2N 2'H2NS02-bif en-4-yl 4-CH3O Core-F ppiirrrrooll-1-yl 2 '-H2NS02-bif en-4-yl 4 -CH3O Core-F CH2C02H 5- (2-H2NS02-C6H4) pyrid-2-yl 4-CH3O Core-E CH2C02H 5- (2-H2NS02-C6H) pyrid-2-yl 4-CH3O Core-E (a) 5- (2 '-H2NS02-C6H4) pyrid-2-yl 4-CH3O Core-E (b) 5- (2-H2NS02-C6H4) pyrid-2-yl 4-CH3O Core-D-2 '-H2NS02-bifen-4-yl 4 -CH3O Core-A CH3 2'H2NS02-bif en-4-yl 4-Cl 4-CF3O Core-A CH3 2' -H2NS02- bif en-4-yl 3-Br Core-A CH3 2 '-H2NS02-bifen-4-yl 3-1 Core-A CH3 2' -H2NS02-bifen-4-yl 3,4- Core-A CH3 2 ' -H2NS02 -bifen-4-yl OCH20 4-CH3O Core-A CH2OH 4- (N-pyrrolidinocarbonyl) CeH4 4-CH3O Core-A CHO 4- (N-pyrrolidinocarbonyl) C6H4 4-CH3O Core-A C02H 4- (N -pyrrolidinocarbonyl) C6H4 4-CH30 Core-A C02CH3 4- (N-pyrrolidinocarbonyl) 4-Cl Core-A CH3 2'-H2NS02-bifen-4-yl 4-Cl Core-A CH3 2 '- (2' -H2NS02 -C6H4) pyrid-2-i 3,4- Core-A CH3 2 '-H2NS02-bifen-4-yl diCl 3-Cl Core-A CH3 2' -H2NS02-bifen-4-yl-Core-F NH2 2 '-H2NS02-bifen-4- il-Core-F Cl 2 '-H2NS02-bifen-4-yl 3-Br Core-F NH2 2' -H2NS02-bifen-4-yl 4-F 4-F Core-F NH2 2 '-H2NS02-bifen- 4-yl 3-Br Core-F NH2 2 '-H2NS02-bifen-4-yl 3-Br Core-F Cl 2'-H2NS02-bifen-4-yl 4-CH30 Core-A-CH3 2'-H2NS02- bifen-4-yl 4-CH3O Core-A CH3 5- (2 '-CH3C02-C6H4) pyrimid-2-yl 4-CH3O Core-A CH3S02 2-H2NS02-bifen-4-yl 4-CH3O Core-A CH3s 4- (N-pyrrolidinocarbonyl) C6H4 4-CH3O Core-A CH3s 2 '-CH3S02-bifen-4-yl 4-CH3O Core-A CH3S02 4- (N-pyrrolidinocarbonyl) C6H4 4-CH3O Core-A CH3OCH2 2-H2NS02 -bifen-4-il 4-CH3O Core-A CH3OC (0) 2'-H2NS02-bifen-4-yl 4-CH30 Core-A CH3S02CH2 2 '-H2NS02-bifen-4-yl 4-CH30 Core-A CF ^ 5- (2'-CH3S? 2-C6H4) pyrimid-2-yl '4-CH30 Core-A CH, 4- (2'-CH3S02- pyrrolidinocarbonyl) C6H4 4-CH3O Core-A CH, 4- (3'-H2N2-pyrrolidinocarbonyl) C6H4 4-CH3O Core-A CH, 4- (3'-CH30- pyrrolidinocarbonyl) C6H4 4-CH3O Core-A CF3 5- (2 ' -H2NS02-C6H4) pyrid-2-yl 4-CH3O Core-A CF3 4-amidinofenil 4-CH3O Core-A CF3 4- (N-pyrrolidino-C (= NH)) C6H4 4-CH3O-CF3 2'- H2NS02-bifen-4-yl 4-CH3O Core-B 3-CF3 2 '-H2NS02-bifen-4-yl 5 -COCH3 4-CH3O Core-B 3-CF3 5- 2'-H2NS02-bifen-4-yl (CH2) 20H 4-CH3O Core-A CF3 4- (N-pyrrolidino-C (= NH)) C6H4 4-CH3O Core-A CF3 4- (N-pyrrolidino-C (= NC2-i-butyl)) C6H4 4-CH3O Core-A CF3 4- (N-pyrrolidino-C (= N) S02CH3) C6H4 4-CH3O Core-A CF3 4-amidinophenylmethyl 4-CH3O Core-A CF3 4- (N-pyrrolidino-C (= NH2 )) C6H4-CH2- 81 4-CH30 Core-A CF3 N-benzyl-piperidin-4-yl 82 4-CH30 Core-A CF3 N-pyrid-2-limethyl) piperidin-4-yl 83 4-CH3O Core-A CF3 4- (2'-methylimidazolyl) C6H4 84 4-CH3O Core-A CH3 4- (5 '-methylimidazolyl) C6H4 85 4-CH3O Core-A CH3 4- (4 '-methylimidazolyl) C6H 86 4-CH3O Core-A CF3 4- (5 '-CH3C (O) -imidazolyl) CeH4 87 4-CH3O Core-A CF3 4- (5' -carboximidazolyl) C6H 88 4-CH3O Core-A CF3 4- (5'CH3NHC (O) -imidazolyl) C6H4 89 4-CH3O Core-A CF3 4- (5'H2NC (Oo) -imidazolyl) CgH 90 4-CH3O Core-A CF3 4- (5 '-CH3NHC (O) -imidazolyl C6H4 91 4-CH3O Core-A CH2OH 4- (N-pyrrolidinocarbonyl) C6H 92 4-CH3O Core-A CHO 4- (N-pyrrolidinocarbonyl) C6H4 93 4-CH3O Core-A C02H 4- (N-pyrrolidinocarbonyl) C6H4 94 4-CH3O Core-A C02 2C ^ Hp3 4- (N-pyrrolidinocarbonyl) C6H4 95 4-CH3O Core-A CH2CN 4- (N-pyrrolidinocarbonyl) C6H4 92 4-CH30 Core-A CH2C02H 4- (N-pyrrolidinocarbonyl) C6H4 97 4-CH30 Core-A CH2Br 2'-H2NS02-bifen-4-il 98 4-CH3O Core-A CH2NH2 2'-H2NS02-bifen-4-il 99 4-CH3O Core-A CH2NH2-SO2CH3 2 '-H2NS02-bifen-4-il 100 4-CH3O Core-A CH2-imidazole 2 '-H2NS02-bif en-4-il 101 4-CH3O Core-A CH20H 2'-H2NS02-bifen-4-il 102 4-CH3O Core-A CH2-OC (O) CF3 2 '-H2NS02-bifen-4-il 103 4-CH3O Core-A CF3 2'-CH3S02-bifen-4-yl 2-C02Me 104 4-CH3O Core-A CF, 2'-CH3S02-bifen-4-yl 2-C02H 105 4-CH3O Core-A CF3 2 '-H2NS02-bifen-4-yl 2- CO2CH3 106 4-CH3O Core-A CF3 2'-t-Bu-HNS02-bifen-4-yl 2-C02H 107 4-CH3O Core-A CF3 2'-H2NS02-bifen-4-yl 2-C02H 108 4-CH3O Core-A CF3 2 '-H2NS02-bifen-4-yl 2 -CH2OH 109 4-CH3O Core -A CH3 4-sec-butyl-f-enyl 110 4-CH3O Core-A CH3 4- (3 '-met i 1-3' -pyrazoline-5'-on-2'-yl) C6H4 111 4-CH30 Core -A CH 3 4- (6'-methylbenzothiazol-2'-yl) C 6 H 4 112 4-CH 30 Core-A CH 3 3,4-dibromophenyl 113 4-CH 3 O Core-A CH 3 4-butylphenyl 114 4-CH 3 O Core-A CH 3 4 - (4-methylpiperidinyl) CÉH4 115 4-CH3O Core-A CH3 4- (2 '-methylimidazolyl) C6H4 116 4-CH3O Core-A CF3 4- (N-Methylimidazol-2-yl-carbonyl) CeH4 117 4-CH3O Core-A CF3 4- (imidazol-2-yl-hydroxymethyl) C6H4 118 4-CH3O Core-A CF3 4- (N-benzylimidazol-2-yl-hydroxymethyl) CdH4 119 4-CH3O Core-A CF3 4- (imidazol-2-yl-carbonyl) C6H4 120 4-CH3O Core-A CF3 [(thiazol-2-yl) (4'-CH3OC6H4-NH) CH2] C6H4 121 4-CH3O Core-A CF3 4- (2'-thiazolin-2-Al-carbonyl) C6H4 122 4-CH3O Core-A CF3 4- (2'-imidazolin-2 ' il) C6H4 123 4-CH3O Core-A CF3 4- (H2N (CH2) 2NHC (0) C6H4 124 4-CH3O Core-A CF3 4- (l '.4' .5 ', 6-tetradhydropyrimid-2-yl) CeH 125 4-CH3O Core-A CF3 4- (N-methyl-1 '., 4' .5 ', 6'-tetrahydropyrimid-2-yl) CdH 126 4-CH3O Core-A CF3 4- (1 ', 4', 5 ', .6'- tetrahydropyrimid-2-yl) C6H4 127 4-CH30 Core-A CF3 4- (N-CH3-4'-imidazolin-2-yl) -2F-C6H4 128 4-CH30 Core-A CF3 4- (N-CH3-4 '-imidazolin-2' - il) C6H4 127 4-CH3O Core-A CF3 4- (N-CH3-4'-imidazolin-2'-yl) -2-F C6H4 128 4-CH3O Core-A CF3 4- (N-CH3-4 'imidazolin-2' ID-2-FC C6H4 129 4-CH3O Core-A CF3 4- (guanidino-carbonyl) CeH4 130 4-CH3O Core-A CF3 4- (pyrimid-2-yl-phenyl) 130 4-CH3O Core-A CF3 4- (pyrimid-2-yl) phenyl 131 4-CH3O Core-F CF3 2 '-H2NS02-bifen-4-yl 132 4-CH3O Core-F NH (CH2) 2- 2 '-H2NS02-bifen-4-yl OCH3 133 4-CH3O Core-F NH (CH2) 3-OH 2'-H2NS02-bifen-4-yl 134 4-CH3O Core-F NH (CH2) 2-CN 2' -H2NS02-bifen-4-yl 135 4-CH3O Core-F NH (CH2) 3- 2'-H2NS02-bifen-4-yl OCH3 136 4-CH3O Core-F NC (CH2) 2- 2 '-H2NS02- bifen-4-yl C02H 137 4-CH3O Core-F NH-i-Pr 2 '-H2NS02-bifen-4-yl 138 4-CH3O Core-F NHCH (CH2OH) 2 2' -H2NS02-bif en-4- 14 139 4-CH3O Core-F NHCH2C02CH3 2'-H2NS02-bifen-4-yl 140 4-CH3O Core-F NHCH2C02H 2'-H2NS02-bifen-4-yl 141 4-CH30 Core-A C02C2H; 4- (N-pyrrolidinocarbonyl) CdH4 142 4-CH30 Core-A CONH 4- (N-pyrrolidinocarbonyl) C6H4 143 4-CH3O Core-A C (0) NH- 4- (N- (CH2) 2OH pyrrolidinocarbonyl) C6H 144 4-CH3O Core-A CONO 4- (N-pyrrolidinocarbonyl) C6H 145 4-CH3O Core-A CONHC6HE 4- (N-pyrrolidinocarbonyl) C6H4 146 4-CH3O Core-A CONH (CH2) 3OH 4- (N-pyrrolidinocarbonyl) C6H4 147 4-CH3O Core-A CONHCH3 4- (N-pyrrolidinocarbonyl) C6H4 148 4-CH3O Core-A CONHCH2C6H5 4- (N-pyrrolidinocarbonyl) CeH4 149 4-CH3O Core-A CON (CH3) 2 4- (N-pyrrolidinocarbonyl) CßH4 150 4-CH3O Core-A CONH (CH2) 2- 4- (N- C6H5 pyrrolidinocarbonyl) C6H4 151 4-CH3O Core-A CON-2-OH- 4- (N- CeH4 pyrrolidinocarbonyl) C6H4 152 4-CH3O Core-A CONH-4-OH- 4- (N- C6H4 pyrrolidinocarbonyl) C6H4 153 4-CH3O Core-A CONH-4-OH- 4- (N- C6H4 pyrrolidinocarbonyl) C6H4 154 4- -CH30 Core-A NHCO2CH3- 2'-H2NS02-bifen-4-il 155 4--CH30 Core-A NH2 2'-H2NS02-bifen-4-il 156 4- -CH3O Core-A NHCH2C02CH3 2 '-H2NS02_bif en-4-il 157 4- -CH3O Core-A NH (CH2) 2OH 2'-H2NS02.bifen-4-il 158 4- CH3O Core-A CH = CHC02CH3 2'-H2NS02_bifen-4-il 159 4- -CH3O Core-A CH2CH2C02CH3 2 '-H2NS02-bifen-4-il 160 4- CH3O Core-A CH = CHC02H 2'-H2NS02-bifen-4-il 161 4- -CH3O Core-A CH2CH2C02H 2 '-H2NS02-bifen-4-il 162 4- CH3O Core-A CH = CHCONH2 2'-H2NS02-bifen-4-il 163 4- CH3O Core-A CH = CHCH2OH 2'-H2NS02-bifen-4-yl. 164 4- -CH3O Core-A (CH2) 3OH 2 '-H2NS02-bifen-4-il 165 4- -CH3O Core-A (CH2) 2CH3 2 '-H2NS02-bifen-4-il 166 4- -CH3O Core-C 3-CF3,4-CN 2 '-CH3S02-3-F-bifen-4-il 167 4- -CH3O Core-C 3-CF3,4- 2 '-CH3S02-3-F-bifen-4-yl amidino 168 4-CH3O Core-C 3-CF3,4- 2' -CH3S02-3-F -bifen-4-yl amidino-OH 169 4-CH3O Core-C 3-CF3,4- 2 '-CH3S02-3-F-bifen-4-yl C02C2H5 170 4-CH3O Core-C 3-CF3, 4- C02H 2 '-CH3S02-3-F-bifen-4-il (a) -CH2C (O) NHCH2CO2CH3 (b) - (1, 2,4-triazol-1-yl) CH: (C) The following tables contain representative examples of the present invention. Each entry in each table is desired to be arranged with each formula at the beginning of the table. For example, example 1 in table 2 is desired to be arranged with each of the formulas a? ~ F9. ai Rla = CH3 b: Rla = CH3 ci Rla = CH3 Rla = CF3 b2 Rla = CF3 c2 Rla = CF3 a3 Rla = SCH3 b3 Rla = SCH3 c3 Rla = SCH3 a4 Rla = SOCH3 b4 Rla = SOCH3 c4 Rla = SOCH3 a5 Rla = S02CH3 b5 Rla = S02CH3 c5 Rla = S02CH3 Rla = CI b6 Rla = CI c6 Rla = CI a7 Rla = Br b7 Rla = Br c7 Rla = Br di Rla = CH3 ei Rla = CH3 fi Rla = CH3 d2 Rla = CF3 e2 Rla = CF3 f2 Rla = CF3 d3 Rla = SCH3 e3 Rla = SCH3 f3 Rla = SCH3 d4 Rla = SOCH3 e4 Rla = SOCH3 f4 Rla = SOCH3 d5 Rla = S02CH3 e5 Rla = S02CH3 f5 Rla = S02CH3 d6 Rla = CI e6 Rla = CI faith Rla = CI d8 Rla = C02CH3 e8 R, 1xa = C02CH3 fe Rla = C02CH3 d9 Rla = CH2OCH3, 1a e9 R? A = CH2OCH3 f9 Rla = CH2OCH3 Ex. • # A 1 phenyl 2- (aminosulfonyl) phenyl 2 phenyl 2- (methylaminosulfonyl) phenyl phenyl 1-pyrrolidinocarbonyl phenyl 2- (methylsulfonyl) phenyl phenyl 4-morpholino phenyl 2- (1 * -CF3-tetrazol-2-yl ) phenyl phenyl 4-morpholinocarboni 1 2-pyridyl 2- (aminosulfonyl) phenyl 9 2-pyridyl 2- (methylaminosulfonyl) phenyl 2-pyridyl-1-pyrrolidinocarbonyl-11-pyridyl-2- (ethylsulfonyl) phenyl-12-pyridyl-4-morpholino-13-pyridyl-2- (1'-CF3-tetrazol-2-yl) -phenyl ester 14 2-pyridyl 4-morpholinocarbonyl-15-pyridyl 2- (aminosulfonyl) phenyl-16-pyridyl 2- (methylaminosulfonyl) phenyl 17 3-pyridyl-1-pyrrolidinocarbonyl-18-pyridyl 2- (methylsulfonyl) phenyl-19-pyridyl-4-morpholino-3-pyridyl 2- (1'-CF3-tetrazol-2-yl) phenyl 21 3-pyridyl 4-morpholinocarbonyl 22 2-pyrimidyl 2- (aminosulfonyl) phenyl-2-pyrimidyl 2- (methylaminosulfonyl) phenyl 24 2-pyrimidyl 1-pyrrolidinocarbonyl 2-pyrimidyl 2- (methylsulfonyl) phenyl 26 2-pyrimidyl 4-morpholino 27 2-pyrimidyl 2- (1'-CF 3 -tetrazol-2-yl) phenyl 28 2 pyrimidyl 4-morpholinocarbonyl 29 5-pyrimidyl 2- (aminosulfonyl) phenyl 30 5-pyrimidyl 2- (methylsulfonyl) phenyl 31 5-pyrimidyl 1-pyrrolidinocarbonyl 32 5-pyrimidyl 2- (methylsulfonyl) phenyl 33 5-pyrimidyl 4-morpholino 34 5-pyrimidyl 2- (1-CF 3 -tetrazol-2-yl) phenyl 35-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-2-Cl-phenyl-4-morpholino-41-Cl-phenyl-2- (1-CF3-tetrazol-2-yl) phenyl 42 2-Cl-phenyl-morpholinecarbonyl 43 2-F-phenyl-2- (aminosulfonyl) phenyl 44 2-F-phenyl-2- (methylaminosulfonyl) phenyl-2-F-phenyl-1-pyrrolidinocarbonyl 4 6 2-F-phenyl 2 - (methylsulfonyl) phenyl 47 2-F-phenyl 4-morpholino 48 2-F-phenyl 2- (1-CF 3 -tetrazol-2-yl) phenyl 49 2-F-phenyl 4-morpholinocarbonyl 2, 5-diF 2-phenyl 2- (aminosulfonyl) phenyl 51 2, 5-diF-phenyl-2- (methylaminosulfonyl) phenyl 52,5,5-diF-phenyl-1-pyrrolidinocarbonyl-53,2,5-diF-phenyl-2- (methylsulfonyl) phenyl l 54 2, 5-di F-phenyl 4-morpholino 55 2, 5-di F-phenyl 2- (l * -CF3-tetrazol-2-yl) phenyl 56 2,5-diF-phenyl 4-morpholinocarbonyl 57 phenyl 2- (N-pyrrolidinyl-methyl) phenyl 58 phenyl 2- (N-piperidinyl-methyl) phenyl-59-phenyl-2- (N-morpholino-methyl) phenyl-60-phenyl-2- (NN'-methylmorpholinium-methyl) phenyl-phenyl-2- (N-pyridinium-methyl) phenyl. phenyl 2- (N-4- (N, N '-dimethylamino) -pyridinium-methyl) phenyl 63 phenyl 2- (N-azatanyl-methyl) phenyl-64-phenyl-2- (N-acetidinyl-methyl) 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 69 phenyl 2- (N-pyridonyl-methyl) phenyl 70 phenyl 2- (N- (N ', N' -dimethylhydrazinylmethyl) phenyl 71 phenyl 2- (amidinyl) phenyl 72 phenyl 2- (N-guanidinyl ) phenyl 73 phenyl 2- (imidazolyl) phenyl 74 phenyl 2- (imidazolidinyl) phenyl 75 phenyl 2- (2-imidazolidinyl-sulfonyl) phenyl 76 phenyl 2- (2-pyrrolidinyl) phenyl77 phenyl 2- (2-piperidinyl) phenyl 78 phenyl 2- (amidinyl-methyl) phenyl-79-phenyl-2- (2-imidazolidinyl-methyl) phenyl 80 phenyl 2- (N- (2-aminoimidazolyl) -methyl) phenyl-phenyl-2- (dimethylaminoimidazol-1-yl-phenyl-2- (3-aminophenyl) -83-phenyl-2- (3-? -rolidolidylcarbonyl) 84-phenyl-2-glycine 85 phenyl 2- (imidazol-1-ylacetyl) 86 2-pyridyl 2- (N-pyrrolidinyl-methyl) enyl 87 2-pyridyl 2- (N-piperidinyl-methyl) phenyl 2-pyridyl 2- (N-morpholino-methyl) ) phenyl 89 2-pyridyl 2- (N, N '-methylmorpholinium methyl) phenyl 90 2-pyridyl 2- (N-pyridinium-methyl) phenyl 91 2-pyridyl 2- (N-4- (N, N * - dimethylamino) -pyridinium-methyl) phenyl 92 2-pyridyl 2- (N-azatanyl-methyl) phenyl 93 2-pyridyl 2- (N-acetidinyl-methyl) phenyl 94 2-pyridyl 2- (N-piperazinyl-methyl) phenyl 95 2-pyridyl 2 (N, N'-BOC-piperazin-1-methyl) phenyl-2-pyridyl 2- (N-imidazolyl-methyl) phenyl-2-pyridyl 2- (N-methoxy-N-methylamino-methyl) phenyl 98 2-pyridyl 2- (pyridonyl-methyl) phenyl 99 2-pyridyl 2- (N- (N 1, N'-dimethylhydrazinylmethyl) phenyl 100 2-pyridyl 2- (amidinyl) phenyl 101 2-pyridyl 2- (N -guanidinyl) phenyl 102 2-pyridyl 2- (imidazolyl) phenyl 103 2-pyr idyl 2- (imidazolidinyl) phenyl 104 2-pyridyl 2- (2-imidazolidinyl-sulfonyl) phenyl 105 2-pyridyl 2- (2-pyrrolidinyl-sulfonyl) phenyl 106 2-pyridyl 2- (2-piperidinyl) phenyl 107 2- pyridyl 2- (amidinyl-methyl) phenyl 108 2-pyridyl 2- (2-imidazolidinyl-methyl) phenyl 109 2-pyridyl 2- (N- (2-aminoidimidazolyl) -methyl) phenyl-2-pyridyl-2-dimethylaminoimidazole-1 -l, l, 2-pyridyl, 2- (3-aminophenyl) 112, 2-pyridyl, 2- (3-pyrrolidinylcarbonyl) 113, 2-pyridyl, 2-glycine, 114, 2-pyridyl, 2- (imidazol-1-ylacetyl), 115-pyridyl, 2- (N-pyrrolidinyl-methyl) phenyl 116 3-pyridyl 2- (N-piperidinyl-methyl) phenyl-117-pyridyl 2- (N-morpholino-methyl) phenyl-3-pyridyl 2- (N, N '-methylmorpholinium-methyl) phenyl 119 3-pyridyl 2- (N-pyridinium-methyl) phenyl 120 3-pyridyl 2- (N-4- (N, N' -dimethylamino) pyridinium-methyl) phenyl 121 3- pyridyl 2- (N-azatanyl-methyl) phenyl 122 3-pyridyl 2- (N-acetidinyl-methyl) phenyl 123 3-pyridyl 2- (N-piperazinyl-methyl) phenyl 124 3-pyridyl 2 (N, '-BOC -piperazinyl-methyl) phenyl-125-pyridyl 2- (N-imidazolyl-methyl) phenyl-126-pyridyl 2- (N-methoxy-N-methylamino-methyl) phenyl-127-pyridyl-2- (pyridonyl-methyl) phenyl 128 3-pyridyl 2- (N- (N'N'-dimethylhydrazinylmethyl) phenyl 129 3-pyridyl 2- (amidinyl) phenyl 130 3-pyridyl 2- (N-guanidinyl) phenyl 131 3-pyridyl 2- (imidazolyl ) phenyl 132 3-pyridyl 2- (imidazolidinyl) phenyl 133 3-pyridyl 2- (2-imidazolidinyl-sulfonyl) phenyl-134-pyridyl 2- (2-pyrrolidinyl-sulfonyl) phenyl-135-pyridyl 2- (2-piperidinyl) ) phenyl 136 3-pyridyl 2- (amidinyl-methyl) phenyl 137 3-pyridyl 2- (2-imidazolidinyl-methyl) phenyl 138 3-pyridyl 2- (N- (2-aminoidimidazolyl) -methyl) phenyl 139 3-pyridyl 2-dimethylaminoimid azole-1-yl 140 3-? iridyl 2- (3-aminophenyl) 141 3-pyridyl 2- (3-pyrrolidinylcarbonyl) 142 3-pyridyl 2-glycine-143-3-pyridyl 2- (imidazol-1-ylacetyl) 144 2-pyrimidyl 2- (N-pyrrolidinyl-methyl) phenyl 145 2-pyrimidyl 2- (N-piperidinyl-methyl) phenyl 146 2-pyrimidyl 2- (N-morpholino-methyl) phenyl 147 2-pyrimidyl 2- (N, N '-methylmorpholinomethyl) phenyl 148 2-pyrimidyl 2- (N-pyridinium-methyl) phenyl 149 2-pyrimidyl 2- (N-4- (N, N'-dimethylamino) pyridinium-methyl) phenyl 150 2-pyrimidyl 2- (N-azatanyl-methyl) phenyl 151 2-pyrimidyl 2- (N-acetidinyl-methyl) phenyl 152 2-pyrimidyl 2- (N-piperazinyl-methyl) phenyl 153 2-pyrimidyl 2- (N-N'-BOC-piperazinyl-methyl) phenyl 154 2-pyrimidyl 2- (N-imidazolyl-methyl) phenyl 155 2-pyrimidyl 2- (N-methoxy-N-methylamino-methyl) phenyl 156 2-pyrimidyl 2- (pyridonyl-methyl) phenyl 157 2-pyrimidyl 2- (N- (N'N * -dimethylhydrazinylmethyl) phenyl 158 2-pyrimidyl 2- (amidinyl) phenyl 159 2-pyrimidyl 2- (N-guanidinyl) phenyl 160 2-pyridyl 2- (imidazolyl ) phenyl 161 2-pyrimidyl 2- (imidazolidinyl) phenyl 162 2-pyrimidyl 2- (2-imidazolidinyl-sulfonyl) phenyl 163 2-pyrimidyl 2- (2-pyrrolidinyl-sulfonyl) phenyl 164 2-pyrimidyl 2- (2-piperidinyl) phenyl 165 2-pyrimidyl 2- (amidinyl-methyl) phenyl 166 2-pyrimidyl 2- (2-imidazolidinyl-methyl) phenyl 167 2-pyrimidyl 2- (N- (2-aminoidimidazolyl) -methyl) phenyl 168 2-pyrimidyl 2-dimethylaminoimidazol-l-yl 169 2-pyrimidyl 2- (3-aminophenyl) 170 2-pyrimidyl 2- (3-pyrrolidinylcarbonyl ) 171 2-pyrimidyl 2-glycinyl 172 2-pyrimidyl 2- (imidazol-1-ylacetyl) 173 2-Cl-phenyl 2- (N-pyrrolidinyl-methyl) phenyl 174 2-Cl-phenyl 2- (N-piperidinyl-methyl) phenyl 175 2-Cl-phenyl 2- (N-morpholino-methyl) phenyl 176 2-Cl-phenyl 2- (N, N '-methylmorpholinium-methyl) phenyl 177 2-Cl-phenyl 2- (N-pyridinium-methyl) phenyl 178 2-Cl-phenyl 2- (N-4- (N, N '-dimethylamino) pyridinium-methyl) phenyl 179 2-Cl-phenyl 2 - (N-azatanyl-methyl) phenyl 180 2-Cl-phenyl 2- (N-acetidinyl-methyl) phenyl 181 2-Cl-phenyl 2- (N-piperazinyl-methyl) phenyl 182 2-Cl-phenyl 2- ( NN '-BOC-piperazinyl-methyl) phenyl 183 2-Cl-phenyl 2- (N-imidazolyl-methyl) phenyl 184 2-Cl-phenyl 2- (N-methoxy-N-methylamino-methyl) phenyl 185 2-Cl phenyl 2- (pyridonyl-methyl) phenyl 186 2-Cl-phenyl 2- (N- (N ', N "-dimethylhydrazinylmethyl) phenyl 187 2-C1- phenyl 2- (to idinyl) phenyl 188 2-C1 - phenyl 2- (N-guanidinyl) phenyl 189 2-C1- phenyl 2- (imidazolyl) phenyl 190 2-C1- phenyl 2- (imidazolidinyl) phenyl 191 2-C1- phenyl 2- (2-imidazolidinyl-sulfonyl) ) phenyl 192 2-C1- • phenyl 2- (2-pyrrolidinyl-sulfonyl) phenyl 193 2-C1- phenyl 2- (2-piperidinyl) phenyl 194 2-C1- phenyl 2- (amidin il-methyl) phenyl 195 2-C1- • phenyl 2- (2-imidazolidinyl-methyl) phenyl 196 2-C1- phenyl 2- (N- (2-aminoidimidazolyl) -methyl) phenyl 197 2-Cl-phenyl 2- dimethylaminoimidazol-1-yl 198 2-Cl-phenyl 2- (3-aminophenyl) 199 2-Cl-phenyl 2- (3-pyrrolidinylcarbonyl) 200 2-Cl-phenyl 2-glycinel 201 2-Cl-phenyl 2- (imidazole 1-ylacetyl) 202 2-F-phenyl 2- (N-pyrrolidinyl-methyl) phenyl 203 2-F-phenyl 2- (N-piperidinyl-methyl) phenyl 204 2-F-phenyl 2- (N-morpholino- methyl) phenyl 205 2-F-phenyl 2- (N, N '-methylmorpholinium methyl) phenyl 206 2-F-phenyl 2- (N-pyridinium-methyl) phenyl 207 2-F-phenyl 2- (N-4 - (N, N'-dimethylamino) pyridinium-methyl) phenyl 208 2-F-phenyl 2- (N-azatanyl-methyl) phenyl 209 2-F-phenyl 2- (N-acetidinyl-methyl) phenyl 210 2-F phenyl 2- (N-piperazinyl-methyl) phenyl 211 2-F-phenyl-2- (NN '-BOC-piperazinyl-methyl) phenyl-212 2-F-phenyl 2- (N-imidazolyl-methyl) phenyl-213 2- F-phenyl 2- (N-methoxy-N-methylaminomethyl) phenyl 214 2-F-phenyl 2- (pyridonyl-methyl) phenyl 215 2-F-phenyl 2- (N- (N ', N'-dimethylhydrazinyl - methyl ) phenyl 216 2-F-phenyl 2- (amidinyl) phenyl 217 2-F-phenyl 2- (N-guanidinyl) phenyl 218 2-F-phenyl 2- (imidazolyl) phenyl 219 2-F-phenyl 2- (imidazolidinyl) ) phenyl 220 2-F-phenyl 2- (2-imidazolidinyl-sulfonyl) phenyl 221 2-F-phenyl 2- (2-pyrrolidinyl-sulfonyl) phenyl 222 2-F-phenyl 2- (2-piperidinyl) phenyl 223 2 -F-phenyl 2- (amidinyl-methyl) phenyl 224 2-F-phenyl 2- (2-imidazolidinyl-methyl) phenyl 225 2-F-phenyl 2- (N- (2-aminoidimidazolyl) -methyl) phenyl 226 2-F-phenyl-2-dimethylaminoimidazol-1-yl 227 2-F-phenyl 2- (3-aminophenyl) 228 2-F-phenyl 2- (3-pyrrolidinylcarbonyl) 229 2-F-phenyl 2-glycine 230 2-F-phenyl 2- (imidazol-1-ylacetyl) 231 2, 5-diF-phenyl 2- (N-pyrrolidinyl-methyl) phenyl 232 2, 5-diF-phenyl 2- (N-piperidinyl-methyl) phenyl 233 2,5-diF-phenyl 2- (N-morpholino-methyl) phenyl 234 2,5-diF-phenyl 2- (N, N '-methylmorpholinylmethyl) phenyl 235 2, 5-diF-phenyl 2- (N-pyridinium-methyl) phenyl 236 2, 5-diF-phenyl 2- (N-4- (N, N '-dimethylamino) pyridinium-methyl) phenyl 237 2,5-diF-phenyl 2- (N-azatanyl-methyl) phenyl 238 2.5 -diF-phenyl 2- (N-acetidinyl-methyl) 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-methylaminomethyl) phenyl 2,43 2,5-diF-phenyl-2- (pyridonyl-methyl) phenyl-2,4- 2, 5-diF-phenyl-2- (N - (*, N '-dimethylhydrazinylmethyl) phenyl 2,45 2,5-diF-phenyl-2- (amidinyl) phenyl 246 2,5-diF-phenyl 2- (N-guanidinyl) phenyl 247 2,5-diF-phenyl 2- (imidazolyl) phenyl 2,48 2,5-diF-phenyl-2- (imidazolidinyl) phenyl 2,49 2,5-diF-phenyl 2- (2-imidazolidinyl-sulfonyl) phenyl 250 2, 5-diF-phenyl 2- (2-pyrrolidinyl-sulfonyl) 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-imidazolidinyl-methyl) phenyl 254 2, 5-diF-phenyl 2- (N- (2-aminoidimidazolyl) -methyl) phenyl 255 2, 5-diF-phenyl-2-dimethylaminoimidazol-1-yl 2, 2, 5-diF-phenyl 2- (3- aminophenyl) 257 2, 5-diF-phenyl 2- (3-pyrrolidinylcarbonyl) 258 2, 5-diF-phenyl 2-glycine 259 2,5-diF-phenyl 2- (imidazol-1-ylacetyl) Ex # A B 1 Phenyl 2- (aminosulfonyl) phenyl 2 phenyl 2- (methylaminosulfonyl) phenyl 3-phenyl-1-pyrrolidinocarbonyl-4-phenyl-2- (methylsulfonyl) phenyl phenyl 4-morpholino 6 phenyl 2- (1 CF 3 -tetrazol-2-yl-phenyl) 7 phenyl 4-morpholinocarbonyl 8 2-pyridyl 2- (aminosulfonyl) phenyl 9 2-pyridyl 2- (methylaminosulfonyl) phenyl 2-pyridyl-1-pyrrolidinocarbonyl-11-pyridyl-2- (methylsulfonyl) phenyl-12-pyridyl-4-morpholino-13-pyridyl-2- (1'-CF3-tetrazol-2-yl-phenyl) 14 2-pyridyl 4-morpholinocarbonyl-15-pyridyl 2- (aminosulfonyl) phenyl-16-pyridyl 2- (methylaminosulfonyl) phenyl 17 3-pyridyl-1-pyrrolidinocarbonyl-18-pyridyl-2- (methylsulfonyl) phenyl-19-pyridyl-4-morpholino-3-pyridyl-2- (1'-CF3-tetrazol-2-yl-phenyl) 21 3-pyridyl 4-morpholinocarbonyl 22 2-pyrimidyl 2- (aminosulfonyl) phenyl-2-pyrimidyl 2- (methylaminosulfonyl) phenyl 24 2-pyrimidyl 1-pyrrolidinocarbonyl 25 2-pyrimidyl 2- (methylsulfonyl) phenyl 26 2-pyrimidyl 4-morpholino 27 2-pyrimidyl 2- (1 * -CF 3 -tetrazol-2-yl-phenyl) 28 2-pyrimidyl 4-morpholinocarbonyl 29 5-pyrimidyl 2- (aminosulfonyl) phenyl 30-pyrimidyl 2- (methylaminosulfonyl) phenyl 31 5-pyrimidyl 1-pyrrolidinocarbonyl 32 5-pyrimidyl 2- (methylsulfonyl) phenyl 33 5-pyrimidyl 4-morpholino-34-pyrimidyl 2- (1-CF 3 -tetrazol-2-yl-phenyl) -5-pyrimidyl 4-morpholinecarbonyl 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-morpholino 41 2-Cl-phenyl 2- (1'-CF3-tetrazol-2-yl-phenyl) 2-Cl-phenyl-morpholinocarbonyl 43 2-F-phenyl 2- (aminosulfonyl) phenyl 44 2-F- phenyl 2- (methylaminosulfonyl) phenyl 45 2-F-phenyl 1-pyrrolidinocarbonyl 46 2-F-phenyl 2- (methylsulfonyl) phenyl 47 2-F-phenyl 4-morpholino 48 2-F-phenyl 2- (1'-CF3 -tetrazol-2-yl-phenyl 49 2-F-phenyl 4-morpholinocarbonyl 50 2, 5-diF-phenyl-2- (aminosulfonyl) phenyl 51 2, 5-diF-phenyl 2- (methylaminosulfonyl) phenyl 52 2.5- diF-phenyl-1-pyrrolidinocarbonyl-53,2,5-diF-phenyl-2- (methylsulfonyl) phenyl-54-di-phenyl-4-morpholino-2,5-di-phenyl-2- (1'-CF3-tetrazol-2) -yl-phenyl-56 2,5-diF-phenyl-4-morpholinecarbon l 57 phenyl 2- (N-pyrrolidinyl-methyl) -phenyl-phenyl-2- (N-piperidinyl-methyl) phenyl-59-phenyl-2- (N-morpholino-methyl) -phenyl-phenyl-2- (N, N'-methylmorpholinium- methyl) phenyl 61 phenyl 2- (N-pyridinium-methyl) phenyl 62 phenyl 2- (N-4- (N, N'-dimethylamino) pyridinium-methyl) phenyl 63 phenyl 2- (N-azatanyl-methyl) phenyl 64 phenyl 2- (N-Acetyidinyl-methyl) phenyl-65-phenyl-2- (N-piperazinyl-methyl) phenyl-phenyl-2- (N, N'-BOC-piperazinyl. -methyl) phenyl 67 phenyl 2- (N-imidazolyl-methyl) phenyl-68-phenyl-2- (N-methoxy-N-methylamino-methyl) phenyl 69 phenyl 2- (N-pyridonyl-methyl) phenyl-phenyl-2- (N- (N *, N '-dimethylhydrazinyl-methyl) phenyl-71-phenyl-2- (amidinyl) phenyl-72-phenyl-2- (N-guanidinyl) phenyl) phenyl 2- (imidazolyl) phenyl-74-phenyl-2- (imidazolidinyl) phenyl-75-phenyl-2- (2-imidazolidinyl-sulfonyl) phenyl Phenyl 2- (2-pyrrolidinyl) phenyl-77-phenyl-2- (2-piperidinyl) phenyl-phenyl-2- (amidinyl-methyl) -phenyl-phenyl-2- (2-imidazolidinyl-methyl) -phenyl-phenyl-2- (N- ( 2-Aminoimidazolyl-methyl) phenyl-phenyl-2-dimethylaminoimidazol-l-yl-phenyl-2- (3-aminophenyl) -83-phenyl-2- (3-pyrrolidinyl-carbonyl-84-phenyl-2-glycine-85-phenyl-2- (imidazol-1-ylacetyl) 2-pyridyl 2- (N-pyrrolidinyl-methyl) -phenyl 87 2-pyridyl 2- (N-piperidinyl-methyl) phenyl 88 2-pyridyl 2- (N-morpholino-methyl) phenyl 89 2-pyridyl 2- (N, N '-methylmorpholinium-methyl) phenyl 90 2-pyridyl 2 - (N-pyridinium-methyl) phenyl 91 2-pyridyl 2- (N-4- (N, N '-dimethylamino) pyridinium-ethyl) phenyl 92 2-pyridyl 2- (N-azatanyl-methyl) phenyl 93 2- pyridyl 2- (N-acetidinyl-methyl) phenyl 94 2-pyridyl 2- (N-piperazinyl-methyl) phenyl 95 2-pyridyl 2- (N, N '-BOC-piperazinyl. -methyl) phenyl 96 2-? iridyl 2- (N-imidazolyl-methyl) phenyl 97 2-pyridyl 2- (N-methoxy-N-methylamino-methyl) phenyl 98 2-pyridyl 2- (N-pyridonyl-methyl) phenyl 99 2-pyridyl 2- (N - (N ', N' -dimethylhydrazinylmethyl) phenyl 100 2-pyridyl 2- (amidinyl) phenyl 101 2-pyridyl 2- (N-guanidinyl) phenyl 102 2-pyridyl 2- (imidazolyl) phenyl 103 2-pyridyl 2 - (imidazolidinyl) phenyl 104 2-pyridyl 2 - ((2-imidazolidin-1-sulfonyl) phenyl 105 2-pyridyl 2 - ((2-pyrrolidinyl) phenyl 106 2-pyridyl 2 - ((2-piperidinyl) phenyl 107 2-pyridyl 2 - ((amidinyl-methyl) phenyl 108 2-pyridyl 2 - ((2-imidazolidinyl) -methyl) phenyl 109 2-pyridyl 2 - ((N- (2-aminoimidazolyl-methyl) phenyl) 110 2-pyridyl 2-dimethylaminoimidazol-1-yl 111 2-pyridyl 2 - ((3-aminophenyl) 112 2-pyridyl 2 - ((3-pyrrolidinyl carbonyl 113 2-pyridyl 2-g icinoyl 114 2-pyridyl 2- ( (imidazol-1-ylacetyl 115 3-pyridyl 2 - ((N-pyrrolidinyl-methyl) phenyl 116 3-pyridyl 2 - ((N-piperidinyl-methyl) phenyl-117-pyridyl 2 - ((N-morpholino-methyl) phenyl 118 3-pyridyl 2 - ((N, N '-methylmorpholinium-methyl) phenyl 119 3-pyridyl 2 - ((N-pyridinium-methyl) phenyl 120 3-pyridyl 2 - ((N-4- (N, N '-dimethylamino) pyridinium-methydiphenyl 121 3-pyridyl 2- ((N-azatanyl- methyl) phenyl 122 3-pyridyl 2 - ((N-acetidinyl-methyl) phenyl 123 3-pyridyl 2 - ((N-piperazinyl-methyl) phenyl 124 3-pyridyl 2 - ((N, N '-BOC-piperazinyl- methyl) phenyl 125 3-pyridyl 2 - ((N-imidazolyl-methyl) phenyl 126 3-pyridyl 2 - ((N-methoxy-N-methylamino-methyl) phenyl 127 3-pyridyl 2 - ((N-pyridonyl-methyl) phenyl-128-3-pyridyl 2- (N- (N ', N'-dimethylhydrazinyl-methyl) phenyl-129-3-pyridyl-2-amidinyl) phenyl-3-pyridyl 2 - N-guanidinyl) phenyl-131-3-pyridyl-2-imidazolyl) phenyl-132-3-pyridyl-2-imidazolidinyl) phenyl-133-pyridyl-2- (2-imidazolidinyl-sulfonyl) phenyl-134-pyridyl-2- pyrrolidinyl) phenyl 135 3 -pyridyl 2- 2-piperidinyl) phenyl-136-3-pyridyl-2-amidinyl-methyl) -phenyl-137-3-pyridyl-2- (2-imidazolidinyl-methyl) -phenyl-3-pyridyl-2- (2-aminoimidazolyl-methyl) phenyl} 3-Pyridyl-2-dimethylaminoimidazol-1-yl-140-3-pyridyl-2-aminophenyl-141-3-pyridyl-2- pyrrolidinyl-carbonyl-142-3-pyridyl-2-glycine-143-3-pyridyl-2- (imidazol-1-ylacetyl-144 -pyrimidyl 2- (N-pyrrolidinyl-methyl) -phenyl 145 2-pyrimidyl 2- (N-piperidinyl-methyl) phenyl-146-pyrimidyl 2- (N-morpholino-methyl) phenyl-2-pyrimidyl 2- (N, N '-methylmorpholinium-methyl) phenyl 148 2-pyrimidyl 2- (N-pyridinium-methyl) phenyl 149 2-pyrimidyl 2- (N-4- (N, N' -dimethylamino) pyridinium-methyl) phen 150 150 2-pyrimidyl 2- (N-azatanyl-methyl) phenyl 151 2-pyrimidyl 2 - ((N-acetidinyl-methyl) phenyl 152 2-pyrimidyl 2- ((N-piperazinyl-methyl) phenyl) 2-pyrimidyl 2 - ((N, N '-BOC-piperazinyl. -methyl) phenyl 154 2-pyrimidyl 2- ((N-imidazolyl-methyl) phenyl 155 2-pyrimidyl 2- ((N-methoxy-N-methylamino-methyl) phenyl) 156 2-pyrimidyl 2- ((N-pyridonyl-methyl) phenyl 157 2-pyrimidyl 2- ((N- (N 1, N'-dimethylhydrazinylmethyl) phenyl 158 2-pyrimidyl 2 - ((amidinyl) phenyl 159 2- pyrimidyl 2 - ((N-guanidinyl) phenyl 160 2-pyrimidyl 2 - ((imidazolyl) phenyl 161 2-pyrimidyl 2 - ((imidazolidinyl) phenyl 162 2-pyrimidyl 2 - ((2-imidazolidin-1-sulfonyl) phenyl 163 2-pyrimidyl 2 - ((2-pyrrolidinyl) phenyl 164 2-pyrimidyl 2 - ((2-piperidinyl) phenyl 165 2-pyrimidyl 2 - ((amidinyl-methyl) phenyl 166 2-pyrimidyl 2 - ((2-imidazolidinyl -methyl) phenyl 167 2-pyrimidyl 2 - ((N- (2-aminoimidazolyl-methyl) phenyl) 168 2-pyrimidyl 2-dimethylaminoimidazol-1-yl 169 2-pyrimidyl 2 - ((3-aminophenyl) 170 2-pyrimidyl 2 - ((3-pyrrolidinyl carbonyl 171 2-pyrimidyl 2-glycinel 172 2-pyrimidyl 2- (( imidazol-1-ylacetyl 173 2-Cl-phenyl 2 - ((N-pyrrolidinyl-methyl) -phenyl) 174 2-Cl-phenyl 2 - ((N-piperidinyl-methyl) phenyl 175 2-Cl-phenyl 2- (N -morpholino-methyl) phenyl 176 2-Cl-phenyl 2- (N, N'-methylmorpholinium-methyl) phenyl 177 2-Cl-phenyl 2- (N-pyridinium-methyl) phenyl 178 2-Cl-phenyl 2- ( N-4- (N, N '-dimethylamino) pyridinium-methyl) phenyl 179 2-Cl-phenyl 2- (N-azatanyl-methyl) phenyl 180 2-Cl-phenyl 2- (N-acetidinyl-methyl) phenyl 181 2-Cl-phenyl 2- (N-piperazinyl-methyl) phenyl 182 2-Cl-phenyl-2 (N, N'-BOC-piperazinyl. -methyl) phenyl 183 2-Cl-phenyl 2- (N-imidazolyl-methyl) ) phenyl 184 2-Cl-phenyl 2- (N-methoxy-N-methylamino-methyl) phenyl 185 2-Cl-phenyl 2- (N-pyridonyl-methyl) phenyl 186 2-Cl-phenyl 2- (N- ( N ', N "-dimethylhydrazinylmethyl) phenyl 187 2-C1- phenyl 2- (amidinyl) phenyl 188 2-C1- phenyl 2- (N-guanidinyl) phenyl 189 2-C1- phenyl 2- (imide zolyl) phenyl 190 2-C1- phenyl 2- (imidazolidinyl) phenyl 191 2-C1- phenyl 2- (2-imidazolidinyl-sulfonyl) phenyl 192 2-C1- phenyl 2- (2-pyrrolidinyl) phenyl 193 2-C1- phenyl 2- (2-piperidinyl) phenyl 194 2-C1- phenyl 2- (amidinyl-methyl) phenyl 195 2-C1- phenyl 2- (2-imidazolidinyl-methyl) phenyl 196 2-C1- 'phenyl 2- (N - (2-aminoimidazolyl-methyl) phenyl 197 2-C1-phenyl-2-dimethylaminoimidazol-1-yl 198 2-Cl-phenyl-2- (3-aminophenyl) 199 2-Cl-phenyl-2- (3-pyrrolidinylcarbonyl) 200 2-Cl-phenyl 2-glycine-201 2-Cl-phenyl-2- (imidazol-1-ylacetyl 202 2-F-phenyl-2- (N-pyrrolidinyl-methyl) -phenyl-203 2-F-phenyl 2- (N-piperidinyl-methyl) phenyl 204 2-F-phenyl 2- (N-morpholino-methyl) phenyl 205 2-F-phenyl 2- (N, N '-methylmorpholinium-methyl) phenyl 206 2-F-phenyl 2 (N-pyridinium-methyl) phenyl 207 2-F-phenyl 2- (N-4- (N, N '-dimethylamino) pyridinium-ethyl) phenyl 208 2-F-phenyl 2 - (N-azatanyl-methyl) phenyl 209 2-F-phenyl 2- (N-acetidinyl-methyl) phenyl 210 2-F-phenyl 2- (N-piperazinyl-methyl) phenyl 211 2-F-phenyl 2 (N , N'-BOC-piperazini-1-methyl) phenyl 212 2-F-phenyl-2- (N-imidazolyl-methyl) phenyl-213 2-F-phenyl-2- (N-methoxy-N-methylamino-methyl) phenyl 214 2- F-phenyl 2- (N-pyridonyl-methyl) phenyl 215 2-F-phenyl 2- (N- (N *, N '-dimethylhydrazinylmethyl) phenyl 216 2-F-phenyl 2- (amidinyl) phenyl 217 2 -F-phenyl 2- (N-guanidinyl) phenyl 218 2-F-phenyl 2- (imidazolyl) phenyl 219 2-F-phenyl 2- (imidazolidinyl) phenyl 220 2-F-phenyl 2- (2-imidazolidinyl-sulfonyl) ) phenyl 221 2-F-phenyl 2- (2-pyrrolidinyl) phenyl 222 2-F-phenyl 2- (2-piperidinyl) phenyl 223 2-F-phenyl 2- (amidinyl-methyl) phenyl 224 2-F-phenyl 2- (2-imidazolidinyl-methyl) phenyl 225 2-F-phenyl 2- (N- (2-aminoimidazolyl-methyl) phenyl 226 2-F-phenyl-2-dimethylaminoimidazol-l-yl 227 2-F-phenyl 2- (3-aminophenyl) 228 2-F-phenyl-2- (3-pyrrolidinyl carbonyl 229 2-F-phenyl-2-glycine 230 2 -F-phenyl 2- (imidazol-1-ylacetyl 231 2,5-diF-phenyl 2- (N-pyrrolidinyl-methyl) -phenyl-2,3,5,5-diF-phenyl 2- (N-piperidinyl-methyl) phenyl 233 2, 5-diF-phenyl 2- (N-morpholino-methyl) phenyl-234 2,5-diF-phenyl-2- (N, N '-methylmorpholinium-methyl) phenyl 235 2,5-diF-phenyl 2- (N-pyridinium-methyl) phenyl 236 2,5-diF-phenyl 2- (N-4- (N, '-dimethylamino) -pyridinium-methyl) phenyl 237 2, 5 -diF-phenyl 2- (N-azatanyl-methyl) phenyl 238 2,5-diF-phenyl 2- (N-acetidinyl-methyl) 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' -dimethylhydrazinylmethyl) phenyl 245 2,5-diF- phenyl 2- (amidinyl) phenyl 246 2,5-diF-phenyl 2- (N-guanidinyl) phenyl 2,47 2,5-diF-phenyl 2- (imidazolyl) phenyl 248 2,5-diF-phenyl 2- (imidazolidinyl) phenyl 249 2, 5-diF-phenyl 2- (2-imidazolidinyl-sulfonyl) phenyl 250 2,5-diF-phenyl-2- (2-pyrrolidinyl) phenyl 251 2, 5-diF-phenyl-2- (2-piperidinyl) phenyl-2,52,2,5-diF-phenyl-2- (amidinyl-methyl) phenyl-253 2 , 5-diF-phenyl-2- (2-imidazolidinyl-methyl) 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-glycine 259 2, 5-diF-phenyl 2- (imidazol-1-ylacetyl) Table 4 a2 R = CF3 b2 Rla = CF3 c2 Rla = CF3 a3 Rla = SCH3 b3 Rla = SCH3 c3 Rla = SCH3 a4 Rla = SOCH3 b4 Rla = SOCH3 c4 Rla = SOCH3 a5 Rla = S02CH3 b5 Rla = S02CH3 c5 Rla = S02CH3 a6 Rla = CI b6 Rla = CI c6 Rla = CI > a8 Rid = C02CH3 b8 Rla = C02CH3 c8 R, 11a = C02CH3 , 1a a9 R = CH2OCH3 b9 R, 1a = C02CH3, 1a c9 Ria = CH2OCH3 d2 Rla = CF3 e2 Rla = CF3 f2 Rla = CF3 d3 Rla = SCH3 e3 Rla = SCH3 f3 Rla = SCH3 d4 Rla = SOCH3 e4 Rla = SOCH3 f4 Rla = SOCH3 d5 Rla = S02CH3 e5 Rl a = S02CH3 J- 5? = -5U2L.rl3 d6 Rla = CI e6 Rla = CI f e Rla = CI d7 Rla = Br e7 Rla = Br f Rla = Br d8 Rla = C02CH3 e8 Rla = C02CH3 f8 Rla = C02CH3 Ex. # AB 1 phenyl 2- ((Me) 2 N -methyl) phenyl 2 phenyl 2- ((Me) NH-methyl) phenyl 3 phenyl 2-H2N-methyl) phenyl 4 phenyl 2-HOCH 2-phenyl 5 2-F phenyl 2- ((Me) 2N-methyl) phenyl 6 2-F-phenyl 2- ((Me) NH-methyl) phenyl 7 2-F-phenyl 2-H2N-methyl) phenyl 8 2-F-phenyl 2 -HOCH2-phenyl-9-phenyl-2-methylimidazol-1-yl-phenyl-2-ethylimidazol-1-yl-11-phenyl-2- ((Me) 2N-methyl) imidazol-1-yl 12 phenyl 2-CH 3 SO 2 -imide zol-1-yl 13 phenyl 2-CH 3 OCH 2 -imide zol-1-yl 14 2-F-phenyl 2 -methyl imide zol-1-yl 2-F-phenyl-2-methyl imide zol - 1-il 16 2-F-phenyl 2- ((Me) 2N-methyl) imide zol-1-il 17 2-F-phenyl 2-CH 3 SO 2 -imidazol-1-yl 2-F-phenyl 2-CH 3 OCH 2 -imidazol-1-yl 19 2-Cl-phenyl 2-methylimidazol-l-yl 2-Cl-phenyl 2 -ethylimidazol-1-yl 21 2-Cl-phenyl 2- ((Me) 2N-methyl) imidazol-1-yl 22 2-Cl-phenyl 2-CH 3 S02-imidazol-l-yl 23 2-Cl-phenyl 2- CH30CH2-imidazol-l-il-2- (Me) 2N-phenyl-2-methylimidazol-1-yl-2- (Me) 2N-phenyl-2-ethylimidazol-l-yl} 2- (Me) 2-N-phenyl 2- ((Me) 2N-methyl) imidazol-1-yl 27 2- (Me) 2N-phenyl 2-CH 3 SO 2 -imidazol-1-yl 28 2- (Me) 2 N -phenyl 2-CH 3 OCH 2 -imidazol-l-yl-phenyl-N-methyl-imidazol-2-yl-phenyl-4-methylimidazole -5-i1 31 phenyl 5-CF 3 -pyrazol-1-yl 32 2-F-phenyl N-methylimidazol-2-yl 2-F-phenyl 4-methylimidazol-5-yl 2-F-phenyl 5-CF 3 -pyrazol-1-yl-35-phenyl-guanidino-36-phenyl-2-thiazolin-2-ylamine-37-phenyl-N-methyl-2-imidazolin-2-yl 38 phenyl N-methyl-1,4,5,6-tetrahydropyrimid-2-yl-phenyl-N-methylimidazol-2-ylthio-phenyl-t-butoxycarbonylamine-41-phenyl (N-pyrrolidino) formylimino-42-phenyl (N-pyrrolidino) -formyl- N-methanesulfamoyl) imino 43 2-F-phenyl Guanidino 44 2-F-phenyl-2-thiazolin-2-ylamine 45 2-F-phenyl N-methyl-2-imidazolin-2-yl 46 2-F-phenyl N-methyl-1,4,5,6-tetrahydropyrimid-2-yl 47 2-F-phenyl N-methylimidazol-2-ilthio 48 2-F-phenyl t-butoxycarbonylamine 49 2-F-phenyl (N-pyrrolidino) formylimino 50 2-F-phenyl (N-pyrrolidino) formyl-N-methanesulfamoyl) imino 51 2-CH30-phenyl (N-pyrrolidino) formylimino 52 2-CH30-phenyl (N-pyrrolidino) formyl-N- (methanesulfamoyl) imino Table 5 Ex. # A B 1 phenyl 2- (Me) 2 N -methyl) phenyl 2 phenyl 2- (Me) NH-methyl) phenyl 3 phenyl 2- (H2N-methyl) phenyl 4 phenyl 2-H0CH2-phenyl 5 2-F-phenyl 2- (Me) 2 N -methyl) phenyl 6 2-F-phenyl 2- (Me) H-methyl) phenyl 7 2-F-phenyl-2- (H2N-methyl) phenyl 8 2-F-phenyl-2-HOCH2-phenyl-9-phenyl-2-methylimido zol-1-yl-10-phenyl-2-yl-1-imide zol-1-yl 11 phenyl 2 ((Me) N-methyl) imidazol-1-yl 12 phenyl 2-CH3S02-imidazol-l-yl 13 phenyl 2-CH3OCH2-imidazol-l-yl 14 2-F-phenyl-2-methylimidazol-1-yl-2-F-phenyl-2-ethylimidazol-l-yl 16 2-F-phenyl-2 ((Me) 2N-methyl) imidazol-1-yl 17 2-F-phenyl 2-CH 3 S0 2 -imidazol-1-yl 2-F-phenyl 2-CH 3 OCH 2 -imidazol-1-yl 19 2-Cl-phenyl-2-methylimidazol-l-yl 2-Cl-phenyl-2-ethylimidazol-1-yl 21 2-Cl-phenyl-2 ((Me) 2N-methyl) imidazol-1-yl 22 2-Cl-phenyl 2-CH 3 S0 2 -imidazol-1-yl 23 2-Cl-phenyl 2-CH 3 OCH 2 -imidazol-1-yl 24 2- (Me) 2N-phenyl-2-methylimidazol-1-yl 2- (Me) 2 N -phenyl-2-ethylimidazol-1-yl 26 2- (Me) 2 N -phenyl 2 ((Me) 2 N -methyl) imidazol-1-il 27 2- (Me) 2N-phenyl 2-CH 3 SO 2 -imidazol-1-yl 28 2- (Me) 2 N -phenyl 2-CH 3 OCH 2 -imidazol-1-yl 29 phenyl N-methylimidazole 2-yl-phenyl-4-methylimidazol-5-yl-31-phenyl-5-CF3-pyrazol-1-yl 32 2-F-phenyl-N-methylimidazol-2-yl 2-F-phenyl-4-methylimidazole -5-il 34 2-F-phenyl 5-CF3-pyrazol-1-yl-phenyl-guanidino-36-phenyl-2-thiazolin-2-ylamine-37-phenyl-N-methyl-2-imidazolin-2-yl 38 Phenyl N-methyl-1,4,5,6-tetrahydropyrimid-2-yl 39 Phenyl N-methylimidazol-2-ylthio 40 phenyl t-butoxycarbonylamine 41 phenyl (N-pyrrolidino) formylimino 42 phenyl (N-pyrrolidino) formyl-N-methanesulfamoyl) imino 43 2-F-phenyl Guanidino 44 2-F-phenyl-2-thiazolin-2-ylamine 45 2-F-phenyl N-methyl-2-imidazolin-2-yl 46 2-F-phenyl N-methyl-1,4,5,6-tetrahydropyrimid-2-yl 47 2-F-phenyl N-methylimidazol-2-ylthio 48 2-F-phenyl t-butoxycarbonylamine 49 2-F-phenyl (N-pyrrolidino) formylimino 50 2-F-phenyl (N-pyrrolidino) formyl-N-methanesulfamoyl) imino 51 2-CH30-phenyl (N-pyrrolidino) formylimino 52 2-CH30-phenyl (N-pyrrolidino) formyl-N- (methanesulfamoyl) imino Table 6 Ci R4 = OCH3 di R = OCH3 and R4 = OCH3 fi R4 = OCH, c2 R4 = C02CH3 d2 R4 = C02CH3 e2 R4 = C02CH3 f2 R4 = C02CH3 c3 R4 = CH2OCH3 d3 R4 = CH2OCH3 e3 R4 = CH2OCH3 f3 R = CH2OCH3 C4 R - CH3 d4 R4 = CH3 e4 R4 = CH3 f4 R = CH, c5 R = CF, d5 R4 = CF3 e5 R4 = CF, f5 R4 = CF3 c6 R = CI d6 R4 = CI e6 R4 = CI faith R4 = CI c7 R «= F d7 R = F e7 R4 = F f7 R4 = F gx R4 = OCH3 hi R4 = OCH3 il R4 = OCH3 ji R4 = OCH3 g2 R4 = C02CH3 h2 R4 = C02CH3 i2 R4 = C02CH3 j 2 R4 = C02CH3 g3 R4 = CH-2OCH3 h3 R4 = CH2OCH3 i3 R4 = CH2OCH3 j 3 R = CH2OCH3 g4 R4 = CH3 h4 RACH3 i4 R4 = CH3 j 4 R = CH3 g5 R4 = CF3 h5 R4 = CF3 i5 R = CF3 js R4 = CF3 ge R4 = I h6 RAcí ie R4 = CI je R4 = CI g7 R4 = F 7 R4 = F i, R = FJ 7 R4 = F Ex. # A B 1 phenyl 2- (aminosulfonyl) phenyl 2 phenyl 2- (methylaminosulfonyl) phenyl 3-phenyl-1-pyrrolidinocarbonyl-4-phenyl-2- (methylsulfonyl) phenyl-5-phenyl-4-morpholino-6-phenyl-2 (1'-CF3-tetrazol-2-yl) phenyl 7 phenyl 4-morpholinocarbonyl 8 2-pyridyl 2- (aminosulfonyl) phenyl 9 2-pyridyl 2- (methylaminosulfonyl) phenyl-2-pyridyl-1-pyrrolidinocarbonyl-11-pyridyl-2- (methylsulfonyl) phenyl-12-pyridyl-4-morpholine 13 2-pyridyl 2- (1-CF 3 -tetrazol-2-yl) phenyl 14 2-pyridyl 4-morpholinocarbonyl-3-pyridyl 2- (aminosulfonyl) phenyl-16-pyridyl 2- (methylaminosulfonyl) phenyl-17-pyridyl-1 pyrrolidinocarbonyl 18 3-pyridyl 2- (methylsulfonyl) phenyl 19 3-pyridyl 4-morpholino-3-pyridyl 2- (1'-CF 3 -tetrazol-2-yl) phenyl-21-pyridyl 4-morpholinocarbonyl-2-pyrimidyl 2 - (aminosulfonyl) phenyl 23 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 24 2-pyrimidyl-1-pyrrolidinocarbonyl-2-pyrimidyl 2- (methylsulfonyl) phenyl-2-pyrimidyl-4-morpholino-27-pyrimidyl 2- (1-pyrimidyl) tetrazol-2-yl) phenyl 28 2-pyrimidyl 4-morpholinocarbonyl 29 5-pyrimidyl 2- (aminosulfonyl) phenyl 30-pyrimidyl 2- (methylaminosulfonyl) phenyl-31-pyrimidyl-1-pyrrolidinocarbonyl-32-pyrimidyl 2- (methylsulfonyl) phenyl 33 5-pyrimidyl 4-morpholino 34 5-pyrimidyl 2- (1-CF 3 -tetrazol-2-yl) phenyl 35-pyrimidyl 4-morpholinocarbonyl 36 2-Cl-phenyl 2- (aminosulfonyl) phenyl 37 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 38 2-Cl-phenyl-1-pyrrolidinocarbonyl-2-Cl-phenyl-2- (methylsulfonyl) phenyl-2-Cl-phenyl-4-morpholino-2-Cl-phenyl-2- (1'-CF3-tetrazol-2-yl) 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 46 2-F-phenyl-2- (methylsulfonyl) phenyl-47 2-F-phenyl-4-morpholino-48 2-F-phenyl-2 (1'-CF3-tetrazol-2-yl) phenyl 49 2-F-phenyl 4-morpholinocarbonyl 50 2, 5-diF-phenyl-2- (aminosulfonyl) phenyl-51,2,5-diF-phenyl-2- (ethylaminosulfonyl) phenyl 52 2, 5-diF-phenyl-1-pyrrolidinocarbonyl-53 2,5-diF-phenyl-2- (methylsulfonyl) phenyl-54,2,5-diF-phenyl-4-morpholino-2,5-di-phenyl-2- (1'-) CF3-tetrazol-2-yl) phenyl 56 2, 5-diF-phenyl 4-morpholinecarbonyl Table 7 Ci R4 = OCH3 di R4 = OCH3 and R4 = OCH3 fi R4 = OCH3 c2 R4 = C02CH3 d2 R4 = C02CH3 e2 R4 = C02CH3 f2 R4 = C02CH3 c3 R4 = CH2OCH3 d3 R4 = CH2OCH3 e3 R4 = CH2OCH3 f3 R4 = CH2OCH3 c4 R = CH3 d4 R4 = CH3 e4 R "= CH3 f4 R4 = CH3 c6 R * - = CI d6 R4 = CI e6 R4 = CI f6 R4 = CI c7 RAF d7 R4 = F e7 R« = F f7 R4 = F g2 R4 = C02CH3 h2 R4 = C02CH3 i2 R4 = C02CH3 j2 R4 = C02CH3 g3 R4 = CH2OCH3 h3 R4 = CH20CH3 i3 R4 = CH2OCH3 j3 R4 = CH20CH3 g4 R4 = CH3 h4 R = CH3 i4 R4 = CH3 j4 R = CH3 g5 R4 = CF3 h5 Rq = CF3 is R "= CF3 js R4 = CF3 g7 R4 = FR" = F i7 R4 = F j7 R4 = F Ex. # AB 1 phenyl 2- (Me) 2 N -methyl) phenyl 2 phenyl 2- (Me) NH-methyl) phenyl 3 phenyl 2 (H 2 N -ethyl) phenyl 4 phenyl 2-HOCH 2 -phenyl 5 2-F-phenyl 2 (Me) 2N-methyl) phenyl 6 2-F-phenyl 2- (Me) NH-methyl) phenyl 7 2-F-phenyl 2 (H2N-methyl) phenyl 8 2-F-phenyl 2-HOCH 2 -phenyl 9 phenyl 2-methylimidazol-l-yl-10-phenyl-2-ethylimidazol-l-yl-11-phenyl-2- (Me) 2N-methyl) imidazol-1-yl 12 phenyl 2-CH3S02-imidazol-l-yl 13 phenyl 2-CH3OCH2-imidazol-l-yl 14 2-F-phenyl-2-methylimidazol-l-yl 2-F-phenyl-2-ethylimidazol-l-yl 16 2-F-phenyl-2- (Me) 2N-methyl) imidazol-1-yl 17 2-F-phenyl 2-CH 3 S0 2 -imidazol-1-yl 2-F-phenyl 2-CH 30 CH 2 -imidazol-1-yl 19 2-Cl-phenyl-2-methylimidazol-l-yl 2-Cl-phenyl-2-ethylimidazol-l-yl 21 2-Cl-phenyl-2- (Me) 2N-methyl) imidazol-1-yl 22 2-Cl-phenyl 2-CH 3 S0 2 -imidazol-1-yl 23 2-Cl-phenyl 2-CH 3 OCH 2 -imidazol-1-yl 24 2- (Me) 2N-phenyl-2-methylimidazol-1-yl 2- (Me) 2N-phenyl-2-ethylimidazol-1-yl 26 2- (Me) 2 N -phenyl 2- (Me) 2 N -methyl) imidazol-1-il 27 2- (Me) 2N-phenyl 2.-CH3S02-imidazol-1-yl 28 2- (Me) 2N-phenyl 2-CH30CH2-imidazol-1-yl 29 phenyl N-methylimidazol-2-yl 30 phenyl 4-methylimidazole-5-yl 31 phenyl 5-CF3-pyrazol-l-yl 32 2-F-phenyl N-methylimidazol-2-yl 33 2-F-phenyl 4- methylimidazol-5-yl 34 2-F-phenyl 5-CF3-pyrazol-1-yl-phenyl-guanidino-36-phenyl-2-thiazolin-2-ylamine-37-phenyl-N-methyl-2-imidazolin-2-yl 38 Phenyl N-methyl-1, 4,5,6-tetrahydropyrimid-2-yl 39 Phenyl N-methylimidazol-2-ylthio 40 phenyl t-butoxycarbonylamine 41 phenyl (N-pyrrolidino) formylimino 42 phenyl (N-pyrrolidino) formyl-N- metanosulfamoil) imino 43 2-F-phenyl Guanidino 44 2-F-phenyl 2-thiazolin-2-ylamine 45 2-F-phenyl N-methyl-2-imidazolin-2- il 46 2-F-phenyl N-methyl-1,4,5,6-tetrahydropyrimid-2-yl 47 2-F-phenyl N-methylimidazol-2-ylthio 48 2-F-phenyl t-butoxycarbonylamine 49 2-F-phenyl (N-pyrrolidino) formylimino 50 2-F-phenyl (N-pyrrolidino) formyl-N-methanesulfamoyl) imino 51 2-CH 3 O- phenyl (N-pyrrolidino) formylimino 52 2-CH30-phenyl (N-pyrrolidino) formyl-N- metanosulfamoil) imino 34 2-F-phenyl 5-CF3-pyrazol-l-yl 35 phenyl guanidino 36 phenyl 2-thiazolin-2-ylamine 37 phenyl N-methyl -2-imidazolin-2-i1 38 Phenyl N-methyl-1,4,5,6-tetrahydropyrimid-2-yl 39 Phenyl N-methylimidazol-2-ylthio 40 phenyl t-butoxycarbonylamine 41 phenyl (N-pyrrolidino) formylimino 42 phenyl (N-pyrrolidino) formyl-N- metanosulfamoil) imino 43 2-F-phenyl Guanidino 44 2-F-phenyl 2-thiazolin-2-ylamine 45 2-F-phenyl N-methyl-2-imidazolin-2- il 46 2-F-phenyl N-methyl-1,4,5,6-tetrahydropyrimid-2-yl 47 2-F-phenyl N-methylimidazol-2-ylthio 48 2-F-phenyl t-butoxycarbonylamine 49 2-F-phenyl (N-pyrrolidino) formylimino 50 2-F-phenyl (N-pyrrolidino) formyl-N-methanesulfamoyl) imino 51 2-CH 3 O- phenyl (N-pyrrolidino) formylimino 52 2-CH30-phenyl (N-pyrrolidino) formyl-N-methanesulfamoyl) imino UTILITY The compounds of the invention are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals. The term "thromboembolic disorders" as used herein includes cardiovascular thromboembolic or cerebrovascular arterial or venous disorders including, for example, unstable angina, myocardial infarction first or recurrent, sudden death esquémica, esquémico transient attack, attack, artherosclerosis , venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, cerebral embolism, kidney embolism and pulmonary embolism. The anticoagulant effect of the compounds of the present invention is believed to be due to the inhibition of factor Xa or thrombin. The effectiveness of the compounds of the present invention as inhibitors of factor Xa was determined using factor Xa purified human synthetic substrate. The hydrolysis rate of factor Xa of the chromogenic substrate S2222 (Kabi Pharmacia, Franklin, OH) was measured both in the absence and in the presence of the compounds of the present invention. Hydrolysis of the substrate resulted in the release of pNA, which was monitored spectrophotometrically by measuring the increase in 405 nM observance. A decrease in the rate of change of observance at 405 nm in the presence of the inhibitor is indicative of enzyme inhibition. The results of this test are expressed as the KJ inhibitory constant. Factor Xa determinations were made in 0.10 M sodium phosphate buffer, pH 7.5, containing 0.20 M NaCl, and 0.5% PEG 8000. The Michealis constant, Km for hydrolysis of the substrate was determined at 25 ° using the method of Lineweaver and Burk. Ki values were determined by allowing human factor Xa at 0.2-0.5 nM (Enzyme Research Laboratories, South Bend, IN) to react with the substrate (0.20 mM-1-mM) in the presence of the inhibitor. The reactions were allowed to proceed for 30 minutes and the velocities were measured (rate of change of observance against time) in the time frame of 25-30 minutes. The following relationship was used to calculate the Kx values (v0-vs) / vs = I / Kj. (1 + S / Km)) where: v0 is the speed of the control in the absence of the inhibitor; vs is the speed in the presence of the inhibitor; I is the concentration of the inhibitor; Ki is the constant dissociation of the enzyme complex: inhibitor; S is the concentration of the substrate; Km is the constant of Michaelis. Using the methodology described above, a number of compounds of the present invention exhibiting a Ki of < 15 μM, thereby configuring the compounds of the present invention as effective Xa inhibitors. The antithrombotic effect of the compounds of the present invention can be shown in a model of rabbit arterio-venous shunt thrombosis (AV). In this model rabbits weighing 2-3 kg were used. anesthetized with a mixture of xylazine (10 mg / kg i.m.) and ketamine (50 mg / kg i.m.). An AV shunt device filled with saline was connected between the femoral artery and the femoral venous cannula. The AV shunt device consists of a 6 cm piece of tygon tubing containing a piece of silk thread. Blood will flow from the femoral artery via the AV shunt to the femoral vein. The exposure of blood flowing to a silk thread will induce the formation of a significant thrombus. After 40 minutes, the shunt is disconnected and the silk thread covered with thrombi is weighed. The test agents or test vehicles will be given (i.v., i.p., s.c., or orally) before the AV bypass opening. The percentage of inhibition of thrombus formation is determined for each treatment group. ID50 values (doses that produce 50% inhibition of thrombus formation) are estimated by linear regression. The compounds of the formula (I) may also be useful as inhibitors of serine proteases, notably human thrombin, plasma kallikrein and plasmin. Due to their inhibitory action, these compounds are indicated for use in the prevention or treatment of physiological reactions, blood coagulation and inflammation catalyzed by the aforementioned class of enzymes. Specifically, the compounds have utility as drugs for the treatment of diseases arising from elevated thrombin activity such as myocardial infarction and as reagents used as anticoagulants in blood to plasma processing for diagnostic and other commercial purposes. Some compounds of the present invention are shown to be inhibitors of serine protease direct action, thrombin, by their ability to inhibit cleavage of small molecule substrates by thrombin in a purified system. In vitro inhibition constants were determined by the method described by Kettner et al. in J. Biol. Che. 265, 18289-18297 (1990), incorporated herein by reference. In these assays, thrombin-mediated hydrolysis of the chromogenic substrate S2238 (helena Laboratories, Beaumont, TX) was monitored spectrophotometrically. The addition of an inhibitor to the test mixture resulted in decreased compliance and is indicative of thrombin inhibition. Human thrombin (Enzyme Research Laboratories, Ind., South Bend, IN) at a concentration of 0.2 in nM in 0.10 M sodium phosphate buffer, pH 7.5 0.20 M NaCl and 0.5% PEG 6000, was incubated with various concentrations of substrate ranging from 0.20 to 0.02 mM. After 25 to 30 minutes of incubation, thrombin activity was assessed by monitoring the rate of increase in compliance at 405 n. which appears due to substrate hydrolysis. Inhibition constants were derived from reciprocal plots of the reaction rate as a function of substrate concentration using the standard Line eaver and Burk methodology. Using the methodology described above, some compounds of this invention were evaluated and found to exhibit a Kx of less than 15 um, thereby confirming the usefulness of the compounds of the present invention as effective Xa inhibitors.

The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents. These include other coagulation inhibitory or anti-coagulant agents, platelet or antiplatelet inhibitory agents, thrombin inhibitors, or thrombolytic or fibrinolytic agents. Compounds are administered to a mammal in a therapeutically effective amount by "therapeutically effective amount", that means an amount of compound of formula I that, when administered alone 0 in combination with an additional therapeutic agent to a mammal, is effective to prevent or ameliorate the condition of thromboembolic disease or the progression of the disease. By "administered in combination" or "combination therapy" is meant that the compound of the formula 1 one or more therapeutic agents are administered concurrently to the mammal being treated. When administered in combination, each component can be administered at the same time or sequentially in any order at different points in time. In this way each component can be administered separately, but in a manner sufficiently close in time to provide the desired therapeutic effect. Other anticoagulant agents (or coagulation inhibiting agents) that can be used in combination with the compounds of this invention include warfarin or heparin, as well as other factor Xa inhibitors such as those described in the publications identified above under the background of the invention. The term anti-platelet agent (or platelet inhibiting agents) as used herein denotes agents that inhibit platelet function such as by inhibiting the aggregation, addition or granular secretion of platelets. These agents include, but are not limited to, the various known non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin and ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxican, diclofenac, sulfinpyrazone, and piroxicam, including pharmaceutically acceptable salts or pro drugs of the same. Of the NSAIDS, aspirin (acetylsalicylic acid or ASA), and piroxicam are preferred. Other suitable anti-platelet agents include ticlopidine, including pharmaceutically acceptable salts or prodrugs thereof. Ticlopidine is also a preferred compound since it is known to be mild in use in the gastrointestinal tract. Still other suitable platelet inhibiting agents include Ilb / IIIa antagonists, thromboxane-A2-receptor antagonists and thromboxane-A2-synthetase inhibitors, as well as pharmaceutically acceptable salts or prodrugs thereof. The term thrombin inhibitors (or anti-thrombin agents), as used herein, denotes inhibitors of serine protease, thrombin. By inhibiting thrombin, several processes mediated by thrombin, such as thrombin-mediated platelet activation (which is, for example, platelet aggregation and / or granular secretion of plasminogen activator inhibitor 1 and / or serotonin ) and / or fibrin formation is destabilized. A number of thrombin inhibitors are known to one skilled in the art and these inhibitors are contemplated to be used in combination with the present compounds. These inhibitors include, but are not limited to, boroarguinine derivatives, boropeptides, heparins, hirudin and argatroban, including pharmaceutically acceptable salts and prodrugs thereof. The boroarguinine and boropeptide derivatives include peptide and N-acetyl boronic acid derivatives, such as C-terminal α-aminoboronic acid derivatives of lysine, ornithine, argininin, homoarguinin and the corresponding isothiouronium analogs thereof. The term "hirudin", as used herein, includes suitable derivatives or analogs of hirudin, referred to herein as "hirus", such as disulfatohirudina. The boropeptide thrombin inhibitors include the compounds described in Kettner et al., U.S. Patent No. 5,187,157 and in European Patent Application Publication No. 293 881 A2, the descriptions of which are incorporated in this way in the present by reference. Other suitable boroarguinine derivatives and inhibitors of boropeptide thrombin include those described in PCT application publication number 92/07869 and European patent application publication number 471, 651 A2, the descriptions of which are incorporated herein. this mode by reference. The term thrombolytic (or fibrinolytic) (or thrombolytic or fibrinolytic) agents as used herein, denotes agents that use blood clots (thrombi). These agents include the tissue plasminogen activator, anistreplase, urokinase or streptokinase, including pharmaceutically acceptable salts or prodrugs thereof. The term "anistreplase", as used herein, refers to the complex of the streptokinase activator, of the anisoylated plasminogen as described, for example, in European Patent Application No. 028,489, the description of which is incorporated in this way to the present by reference. The term urokinase, as used herein, is proposed to denote both dual and individual chain urokinase, the latter also referred to herein as pro-urokinase. The administration of the compound of the formula I of the invention in combination with this additional therapeutic agent, can give an effective advantage over the single agent compounds, and can do so, while allowing the use of lower doses of each. A lower dose minimizes the potential of side effects, thereby providing an increased margin of safety. The compounds of the present invention are also useful as normal or reference compounds, for example as a quality or control standard, in tests or assays comprising the inhibition of factor Xa. These compounds can be provided in commercial equipment, for example, for use in pharmaceutical research comprising factor Xa. For example, a compound of the present invention can be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This would assure the experimenter that the assay was performed properly and will provide a basis for comparison, especially if the test compound was a derivative of the reference compound. When new assays or protocols are developed, the compounds according to the present invention could be used to test their effectiveness. The compounds of the present invention can also be used in diagnostic assays comprising factor Xa. For example, the presence of factor Xa in an unknown sample could be determined by the addition of the chromogenic substrate S2222 to a series of solutions containing the test sample and optionally one of the compounds of the present invention. If the production of pNA is observed in the solutions containing the test sample, but not the compound of the present invention, then it will be concluded that factor Xa was present.

Dosage and Formulation The compounds of this invention can be administered in oral dosage forms such as tablets, capsules (each of which includes sustained release or programmed release formulations), pills, powders, granules, elixirs, pigments, suspensions, syrups and emulsions. They can also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those skilled in the pharmaceutical art. They can be administered alone, but in general will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and normal pharmaceutical practice. The dosage regimen for the compounds of the present invention will, of course, vary, depending on known factors, such as the pharmacodynamic characteristics of the particular people and their mode and route of administration; the species, age, sex, health, medical condition and weight of the recipient; the nature and degree of the symptoms; the class of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient and the desired effect. A physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counteract, or arrest the progress of thromboembolic disorder. As a general guide, the daily oral dose of each active ingredient, when used for the indicated effects, will vary between about 0.001 to 1000 mg / kg of body weight, preferably between 0.01 to 100 mg / kg of body weight per day, and more preferably between about 1.0 to 20 mg / kg / day. Intravenously, the most preferred dose will vary from about 1 to about 10 mg / kg / minute during a constant rate infusion. The compounds of this invention can be administered in a daily, individual dose, or the total daily dose can be administered in divided doses in two, three, or four times a day. The compounds of this invention can be administered in intranasal form via the utopic use of suitable intranasal vehicles, or via routes, using transdermal skin patches. When a transdermal delivery system is administered in one form, dose administration will of course be continuous rather than intermittent throughout the dose regimen. The compounds are typically administered. in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "pharmaceutical carriers") selected in an appropriate manner with respect to the proposed form of administration, ie, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices. For example, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an inert, non-toxic pharmaceutically acceptable carrier, such as lactose, starch, sucrose, glucose, methyl cellulose, stearate magnesium, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any inert, pharmaceutically acceptable, non-toxic, oral carrier such as ethanol, glycerol, water, and the like. In addition, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture when desired or necessary. Suitable binding agents include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, synthetic and natural gums such as gum arabic, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. The compounds of the present invention can also be administered in the form of liposome systems and distribution, such as small unilamellar vehicles, large unilamellar vesicles, and multilamellar vesicles. The liposome can be formed from a variety of phospholipedes such as cholesterol, stearylamine, or phosphatidylcholines.

The compounds of the present invention can also be coupled with soluble polymers as carriers of searchable drugs. These polymers may include polyvinylpyrrolidone, pyran copolymer, polydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Additionally, the compounds of the present invention can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid polylactic and polyglycolic acid copolymers, polyepsilon-caprolactone, polyhydroxy acid -butyric, polyorthoesters, polyacetals, polyhydropyrans, polyanoacylates, and cross-linked or antipathetic block polymers of hydrogels. Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams of the active ingredient per unit dose. In those pharmaceutical compositions, the active ingredient will ordinarily be present in an amount of about 0.5-95% 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 can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide continuous release of the drug over a period of hours. Compressed tablets can be reduced with sugar or reduced with film to mask any unpleasant taste and to protect the tablet from the atmosphere, or enterically coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration may contain coloration and flavors to increase patient acceptance. In general, water, a suitable oil, saline solution, aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycol are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffering substances. Antioxidant agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, are suitable stabilizing agents. Also used are citric acid and its sodium EDTA salts. In addition, parenteral solutions may contain preservatives, such as benzalkonium chloride, methyl-o-propyl-paraben, and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Scienes, Mack Publishing Company, a standard reference text in this field. Useful, representative pharmaceutical dosage forms for the administration of the compounds of this invention can be illustrated as follows: Capsules A large number of unit capsules can be prepared by filling hard gelatin capsules, two normal pieces, each with 100 milligrams of active ingredient in powder, 150 milligrams of lactose, 50 milligrams of cellulose and 6 milligrams of magnesium stearate.

Soft gelatin capsules A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil, olive oil can be prepared and injected by means of a gelatin positive displacement pump to form soft gelatine capsules containing 100 milligrams of the active ingredient. The capsules should be washed and dried.

Tablets Tablets can be prepared by conventional procedures so that the dosage unit is 100 milligrams of the active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch, and 98.9 milligrams. of lactose. Appropriate coatings may be applied to increase the good taste or delay absorption.

Injectable A parenteral composition suitable for administration by injection can be prepared by stirring 1.5% by weight of the active ingredient in 10% by volume of propylene glycol and water. The solution should be made isotonic with sodium chloride and sterilized.

Suspension An aqueous suspension can be prepared for oral administration so that each 5 mL contains 100 mg of the finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution. U.S.P. and 0.025 mL vanillin. Where the compounds of this invention are combined with other anticoagulant agents, for example, a daily dose may be about 0.1 to A00 milligrams of the compound of the formula I and about 1 to 7.5 milligrams of the second anticoagulant per kilogram of the patient's body weight. For a tablet dosage form, the compounds of this invention may be presented in general in an amount of about 5 to 10 milligrams per unit dose, and the second anticoagulant in an amount of about 1 to 5 milligrams per unit dose. Where the compounds of the formula I are administered in combination with an anti-platelet agent, by means of the general guidance, typically a daily dose may be from about 0.01 to 25 milligrams of the compound of the formula I and about 50 to 150 milligrams of the anti-platelet agent, preferably about 0.1 to 1 milligrams of the compound of the formula I and about 1 to 3 milligrams of the antiplatelet agents, per kilogram of the patient's body weight. Where the compounds of the formula I are administered in combination with the anti-thrombolytic agent, typically a daily dose may be from about 0.1 to 1 milligrams of the compound of the formula I, per kilogram of the patient's body weight, and in the case of the thrombolytic agents, the usual dose of thrombolytic agent when administered alone can be reduced by about 70-80% when administered with a compound of formula I. Where two or more of the above second therapeutic agents are administered with the compound of the formula I, in general the amount of each component in a typical daily dose and the typical dosage form can be reduced relative to the usual dose of the agent when administered alone, in view of the additive synergistic effect of the therapeutic agents when they administer in combination. In particular, when they are provided as an individual dose unit, the potential exists for a chemical interaction between the active ingredients, combined. For this reason, when the compound of the formula I and a second therapeutic agent are combined in a single dose unit, they are formulated such that although the active ingredients are combined in a single dose unit, physical contact between the active ingredients is minimized. (that is, reduce). For example, an active ingredient can be enteric coated. By enterically coating one of the active ingredients it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the gastrointestinal tract. the stomach but rather it is released in the intestines. One of the active ingredients can be coated with a material that effects sustained release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Additionally, the sustained released component can be additionally coated in an enteric form such that the release of its component occurs only in the intestine. Still another approach will comprise the formulation of a combination product in which the component is coated with an enteric and / or sustained release polymer, and the other component is also coated with a polymer such as a low viscosity grade of hydroxypropyl Dspecific ( HPMC) or other suitable materials as is known in the art, in order to specifically separate the active components. The coating of the polymer serves to form an additional barrier to the specific one with the other component. These as well as other ways to minimize contact between the components of the combination products of the present invention, whether administered in a single dose or administered in separate forms, but at the same time in the same manner, will be readily apparent to those experts in the art, once armed with the present description. Obviously, numerous modifications and variations of the present invention are possible in view of the above teachings. Therefore, it is to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.

Claims (10)

1 . A compue sto of the I formula or stereoisomers or pharmaceutically acceptable salts thereof, characterized in that: ring D is phenyl or pyridyl; E is selected from F, Cl, Br, I, OH, C? -3 alkoxy, SH, C? -3 alkyl-S, S (0) R3, S (0) 2R3a, S (O) 2NR Ra, and OCF3 R is selected from H, F, Cl, Br, I, OR3, SR3, C02R3, N02 and CH2OR ' alternatively, E and R combine to form methylenedioxy or ethylenedioxy; M is selected from the group ss J is O Ja is NH or NRla; Z is selected from a bond, alkylene of 1-4 carbon atoms, (CH2) rO (CH2) r, (CH2) rNR3 (CH2) r, (CH2) rC (0) (CH2) r, (CH2) ) rC (0) 0 (CH2) r, (CH2) rOC (O) (CH2) r, (CH2) rC (0) NR3 (CH2) r, CH2) rNRA (O) (CH2) r, (CH2) r0C (0) 0 (CH2) r, (CH2) rOC (O) NR (CH2 (CH2) rNR3C (0) 0 (CH2) r, (CH; rNR3C (O) NR3 CH2) (CH2) rS (0) p (CH2) r, (CH2) rS02NRACH2) r, (CH2) rNR3S02 (CH2) r, and (CH2), rNR3S02NR3 (CH2) r, with the proviso that Z does not form an NN, NO, NS, NCH20, or NCH2S bond with the M ring or the A group; R la R, 1Jb are independently absent are selected from - (CH2) rR1 ', -CH = CH-R1', NCH2R1", OCH2R1", SCHzR1", NH (CH2) 2 (CH2) tR1 ', 0 (CH2) 2 (CH2) tR1', and S (CH2) ) 2 (CH2) tRX ', * alternatively Rla and Rlb when joined to the adjacent carbon atoms, together with the atoms to which they are attached, form a partially saturated, 5- to 8-membered ring substituted with 0-2 R4 and containing 0-2 heteroatoms selected from a group consisting of N, O, and S; alternatively, when Z is C (O) NH and Rla is attached to a ring carbon adjacent to Z, then Rla is a C (O) that replaces the hydrogen of the Z-measure to form a cyclic imide; R1 'is selected from H-alkyl of 1 to 3 carbon atoms, F, Cl, Br, I, -CN, -CHO (CF2) rCF3,' (CH2) rOR2, NR2R2a, C (0) R c , 0C (0) R2 CF2) rCO R 'S (O) pR' NR "(CH2) rOR ', (CH = NR 2" AC. NR'R, 2a R'C (O) R: b NRA (O) NHR 2b NR C (0) 2R2a, OC (0) NR2 R2b C (0) NR'R "a, C (O) NRACH2) rOR2, NRA? 2R, 2b carboxylic residues of 6 'to 3 carbon atoms substituted with 0-2 R4, and a heterocyclic system of 5-10 members which they contain from 1-4 heteroatoms selected from a group consisting of N, 0. and S, substituted with 0-2 R4; PJ "is selected from H, CH (CH20R2) 2, C (0) R2c, C (0) NR'R-β, S (0) R, 2b, S (0) 2R 2b, and S02NR, 2AD2-aaa; R2, in each occurrence is selected from H, CF3, alkyl of 1 to 6 carbon atoms, benzyl, carbocyclic residue of 3 to 6 carbon atoms substituted with 0-2 R4b and heterocyclic system of 5-6 members containing of 1-4 heteroatoms selected from the group consisting of N, O and S substituted with 0-2 R 4b R "a, in each occurrence is selected from H, 10 CF3, alkyl of 1 to 6 carbon atoms alkyl, benzoyl, phenethyl, carbocyclic residue of 3 to 6 carbon atoms substituted with 0-2 R4b, and heterocyclic system of 5-6 members containing from 1-4 heteroatoms selected from from the group that ic, consists of N, O, and S substituted with 0-2 R4b; R2b, in each occurrence is selected from CF3, alkoxy of 1-4 carbon atoms, alkyl of 1 to 6 carbon atoms, benzyl, carboxylic residue of 20 to 6 carbon atoms substituted with 0-2 R4b and 5-6 membered heterocyclic system containing from 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4t; R 2c, in each occurrence is selected from CF 3, OH, alkoxy of 1-4 carbon atoms, alkyl of 1 to 6 carbon atoms, benzyl, carboxylic residue of 3 to 6 carbon atoms substituted with 0-2 R 4b and 5-6 membered heterocyclic system containing from 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b; alternatively R2 and R2a, together with the atom to which they are attached, combine to form a partially unsaturated, saturated, 5- or 6-membered ring substituted with 0-2 R4b and containing 0-1 additional heteroatoms selected from from the group consisting of N, O, and S; R, in each occurrence is selected from H, alkyl of 1 to 4 carbon atoms, and phenyl; R3a in each occurrence is selected from H, alkyl of 1 to 4 carbon atoms and phenyl; pA in each occurrence is selected from H, alkyl of 1 to 4 carbon atoms, and phenyl; R, 3c in each occurrence is selected from H, alkyl of 1 to 4 carbon atoms, and phenyl; A is selected from: carbocyclic residue of 3 to 10 carbon atoms substituted with 0-2 R * and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S is substituted with 0-2 R4; B is selected from: H, Y, and X-Y; X is selected from alkylene 1-4 carbon atoms -CP: (CR2R2b) (CH2) t-, -C (O) -C (^ NR1") -, -CR2 (NR: A2) -, -CR2 (OR2) -, CRASR2), -C (O) CR2R2a-, CR2R2aC (0), S (0) p-, -S (0) pCR2R2a-, -CR2R2aS (0) P-, -S (0) 2NR2-, -NR2S (0) 2-, -NR: S (O) 2CR2R a-, CR2R: aS (O): NR2-, -NR2S (O) 2NR2-, C (0) NR: -, -NR2C (0) -, -C (O) NR: CR: R a-, -NR2C (O) CR2R2a-, -CR2R2aC (O) NR2-, -CR2R2aNR2C (O) - , -NR2C (0) 0-, OC (0) NR2-, -NR2C (O) NR2-, -NR2-, -NR2CR2R2a-, -CR2R2aNR-, O, -CR2R2aO-, and OCR: R a-; And it is selected from (CH) rNR, 2Rr, 2 Ja with the proviso that X-Y does not form a bond N-N, O-N, or S-N, carbocyclic residue of 3 to 10 carbon atoms substituted with 0-2 R4a, and 5-10 member heterocyclic system containing 1-4 heteroatoms selected from the group consisting of N, O, and S and is substituted with 0-2 R4a R4, in each occurrence, is selected from H, = 0, (CH2), rOR2, F, Cl, Br, I, C? - «alkyl, -CN, N02 (CH :) rNR R a, (CH2) rC (0) R2c, NR2C (0) R2b, C (0) NR2R2a, NR-C (O) NR, 2'Rn 2'a CH (= NR *) NR'R 'CH (= NS (0) 2RD) R 2¿R "' 2a NHC (= NR ") NRA 2a C (0) NHC (= NR2) NR2R2a, S02NR2R2a, NR2SO: NR2R to NR2S02-C? -4 alkyl, NR2S02R5, S (0) pR5, (CF2) rCF3, NCH2R1", OCH2R:" SCH2R "", N (CH2) 2 (CH2) tR1 ', O (CH) : (CH2) tR1 ', and S (CH:) r (CH:) tR1', alternatively, an R4 is a 5-6 membered aromatic heterocycle containing 1-4 heteroatoms from the group consisting of K , O and S; R4a, in each occurrence, is selected from H, = 0, (CH2) rOR2, (CH2) rF, (CH2) r-Br, (CH2) r-Cl, I, d-4 alkyl, -CN, N02, (CH2) rNR2R2a, (CH2) rNR2R2b, (CH2) rC (0) R2c, NR C (0) R2b, C (0) NR2R2a, C (O) NH (CH2) 2NR2R2a, NR2C (O) NR2R2a, CH (= NR2) NR2R2a, NHC (= NR2) NR R2a, S02NR2R2a, NR2S02NR2R2a, NR S02-C? -4 alkyl, C (O) NHS02-C? -4 alkyl, NR2S02R5, S (0) pR5, and (CF2) rCF3; alternatively, an R4a is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from a group consisting of N, 0, and S and substituted with 0-1 R5; R4b, in each occurrence, is selected from H, = 0, (CH :) r0R3, F, Cl, Br, I, C? -4 alkyl, -CN, N02, (CH2) rNR3R3a, (CH :) rC (0) R3, (CH2) rC (O) OR3c, NR3C (0) R a, C (0) NR3R3a, NR3C (O) NR3R3a, CH (= NR3) NR3R3a, NH3C (= NR3) NR3R3a, S02NR3R3a, NR3S02NR3R3a, NR3S02-C? -4 alkyl, NR3S0: CF3, NR3S0; - f eni 1, S (0) pCF3, S (0) p-C: -4 alkyl, S (0) p-f eni lo, and (CF2) rCF3; R5, in each occurrence, is selected from CF3, alkyl of 1 to 6 carbon atoms, substituted by 0-2 R6, and benzyl substituted by 0-2 PÁ R < in each occurrence we select from H, OH, (CH2) rOR 'F, Cl Br, 1-4 alkyl, CN, N02, (CH2) rNRA 2n2a, (CH2) rC (0) R 2"b, NR2C (0) R2b, NR2C (O) NR2R2a, CH (= NH) NH2, NHC (= NH) NH2, S02NR2R2a, NR2S02NR2R2a, and NR2S02C? -4 alkyl; n is selected from 0, 1, 2, and 3; m is selected from 0, 1, and 2; p is selected from 0, 1, and 2; r is selected from 0, 1, 2, and 3; s is selected from 0, 1, and 2; and, t is selected from 0 and 1.

2. A compound according to claim 1, characterized in that M is selected from the group consisting of: Z is selected from CH2) rC (0) (CH2) r, (CH2) rC (0) 0 (CH2) r, (CH2) rC (0) NR3 (CH2) r, (CH2) rS (0) p (CH2) r , Y (CH :) rS02NR3 (CH2) r; and, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R a; phenyl, piperidinyl, piperzinilo, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, tiazoliio, isothiazolyl, pyrazolyl, ITIDA olyl, 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-tria zol, 1,2,4-triazole, l, 2,5-triazole, 1,3, 4-triazole, benzofuran, benzothiofuran, indole, benzimidazole, benzoxazole, bencitiazol, indazole, benzisoxazole, benzisothiazole, and isoindazole; And it can also be selected from the following heterocyclic ring systems, bicyclic: K is selected from O, S, NH, and N.

3. A compound according to claim 2, characterized in that the compound is of the formula: M Id Ib where; ring D is phenyl or pyridyl: E is selected from F, Cl, Br, and alkoxy of 1 to 3 carbon atoms; R is selected from H, F, Cl, Br, OR3, and CH2OR3; M is selected from the group: Z is selected from (CH2) rC (0; (CH;) ry (CH2) rC (0) NR3 (CH2) r; Y, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a; phenyl, piperidinyl, piperzinilo, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazole, thiadiazole, triazole, 1,2,3- oxadiazole, 1, 2,4-oxadiazole, 1, 2, 5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1, 3, 4-thiadiazole, 1, 2, 3-triazole, 1,2,4-triazole, 1, 2, 5-triazole, 1, 3, 4, -t riazol, benzofuran, benzothiofuran, indole, benzimidazole, benzoxazole, benzthiazole, indazole, benzisoxazole, benzisothiazole, and isoindazole;

4. A compound according to claim 3, characterized in that ring D is phenyl; E is selected from F, Cl, Br, and OCH3; R is selected from H, F, Cl, and Br; M is selected from the group: A is selected from: carbocyclic residue of 5 to 6 carbon atoms substituted with 0-2 R4, and heterocyclic system of 5-6 members containing 1-4 heteroatoms selected from the group consisting of N, O, and S replaced with 0-2 R4; Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, benzimidazolyl, oxadiazole, thiadiazole, triazole, 1, 2, zol 3-oxadia 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-triazole, 1, 2, 5-t ria zol, and 1,3,4-triazole; R2, in each occurrence, is selected from H, CF3, alkyl of 1 to 6 carbon atoms, benzyl, carbocyclic residue of 5 to 6 carbon atoms, substituted with 0-2 R4b 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 b; R2a, at each occurrence, heterocyclic system 5 is selected from H, CF3, alkyl of 1 to 6 carbon atoms, benzyl, phenethyl, carbocyclic residue 5-6 carbon atoms substituted with 0-2 R4T), and -6 members containing from 1-4 heteroatoms selected from a group consisting of N, O, and S substituted with 0-2 R4b, R b, at each occurrence, is selected from CF3, alkoxy from 1 to 4 carbon atoms, alkyl of 1 to 6 carbon atoms, benzyl, carbocyclic residue of 5-6 carbon atoms substituted with 0-2 R4, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from a group consisting of N, O, and S substituted with 0-2 R4b, R2c, at any occurrence, is selected from CF3 , OH, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 6 carbon atoms benzyl, carbocyclic residue of 5 to 6 carbon atoms substituted with 0-2 R4b 'and heterocyclic system of 5-6 members containing 1 -4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 Rb; Alternatively, R2 and R2a, together with. the atom to which they bind, combine to form a ring selected from imidazolyl, morpholino, piperazinyl, pyridyl, and pyrrolidinyl, substituted with 0-2 R 4b, -R, in each occurrence, is selected from H, = 0, OR2, CH2OR2, F, Cl, CX-4 alkyl, NR2R2a, CH2NR2R2a, C (0) R2c, CH2C (0) R2c, C (0) NR2R a, CH (= NR2) NR2R2a, CH (= NS (O) 2R5) NR2R2a, S02NR2R2a, NR2S02-C? -4 alkyl, S (0) 2R5, and CF3 with the proviso that if B is H, then R4 is different from tetrazole, C (0) -alkoxy, and C (0) NR2R2a; i 4a in each occurrence is selected from H, = 0, (CH2) rOR, F, Cl, C? -4 alkyl, NR2R2a, CH2NR R2a, NR2R2b, CH2NR2R2b, (CH2) rC (O) R2c, NR2C (0 ) R2b, C (O NR2R2a, C (O) NH (CH2) 2NR2R2a, NR2C (O NR2R2a S02NR2R2a, S (0) 2R5, and CF3; and R, 4b, in each occurrence is selected from H, = 0, (CH2) rOR3, F, Cl, C? -4 alkyl, NR3R3a, CH2NR3R3a, C (0) R3, CH2C (0) R3, C (0) 0R3c, C (0) NR, 3AD3Ja%, S02NR 3JrR3a, NRJS02-C! _4 alkyl, NR3S02CF3, NR3S02-phenyl, S (0) 2CF3, S (0) 2-C? -4 alkyl, S (0) 2-phenyl , and CF3.

5. A compound according to claim 1, characterized in that the compound is selected from: 3-Methyl-1-phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide; 3-Methyl-l- (2-methoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide; 3 - . 3 - . 3 - . 3 - . 3 -Meti1-1- (3-methoxy) phenyl-1H-pyrazole-5 (N- (2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide; 3-Methyl-1- (4-methoxy) phenyl-1H-pyrazole-5 (N- (2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide; 3-Methyl-1- (2-hydroxy) phenyl-1H-pyrazole-5- (N- (2'-aminosul-fonyl- [1, 1 '] -bifen-4-yl) carboxyamide; 3-Methyl-1- (3-hydroxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide; 3-Methyl-l (4-hydroxy) phenyl-1H-pyrazole-5- (N- (2'-α-inosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide; 3-Methyl-1- (4-methoxy phenyl) -lH-pyrazole-5- (N- (3-fluoro- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 3-Methyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (3-bromo-4- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 3-Methyl-1- (4-methoxy phenyl) -lH-pyrazole-5- (N- (3-iodo- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 3-Methyl-1- (4-methoxy phenyl) -lH-pyrazole-5- (N- (3-methyl- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 3-Methyl-1- (4-methoxy phenyl) -lH-pyrazole-5- (N- (4-N-carboxyldimethylamine) phenyl) carboxyamide; 3 -Methyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4-N-pyrrolidinocarbonyl) phenyl) carboxyamide; 3-Methyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4-a-meth i 1-N-pyrrolidine) phenyl) carboxyamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (2'-amino-sulfonyl- [1,1 '] -bifen) -4-yl) carboxyamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4-N-pyrrolidinocarbonyl) phenyl) carboxyamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (5- (2-methanesulfonyl) phenyl) pyridin-2-yl) carboxyamide; 3-Trifluoromet il-1- (4-methoxy-phenyl) -lH-pyrazole-5- (N- (5- (N-pyrrolidinocarbonyl) pyridin-2-yl) carboxyamide; 3-Methyl-1- (4-methoxy phenyl) -lH-pyrazole-5- (N- (5-N-pyrrolidinocarbonyl) pyridin-2-yl) carboxyamide; 3-Methyl-1- (4-methoxy phenyl) -lH-pyrazole-5- (N- (5- (2-sulfonamide) phenyl) pyridin-2-yl) carboxyamide; 3-Methyl-1- (4-methoxy phenyl) -lH-pyrazole-5-N- (4- (N-carboxyl-3-hydroxypyrrolidine) phenyl) carboxyamide; 2 - . 2 - . 2-amino-4 - (4-methoxyphenyl) -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] thiazole; 2-Bromo-4- (4-methoxyphenyl) -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] thiazole; 2-Chloro-4- (4-methoxyphenyl) -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] thiazole; 2-Chloro-4- (4-phenoxy) -5 - [(2 * -aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] thiazole; 2-Methoxy-4- (4-methoxy phenyl) -5 - [(2'-aminosulfonyl 1- [1,1 '] -bifen-4-yl) aminocarbonyl] thiazole; 2-Thiomethyl-4- (4-methoxy phenyl) -5- [2'-aminosulfonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] thiazole; 2-Methylsulfoxida-4- (4-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) aminocarbonyl] thiazole; 2-Methyl sulfon-4- (4-methoxyphenyl) -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] thiazole; 2-Cyano-4- (4-methoxy phenyl) -5 - [(2'-amino-fonyl- [1, 1 '] -bifen-4-yl) aminocarbonyl] thiazole; 2-N, N-Dimethylamino-4- (4-methoxyphenyl) -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] thiazole; 2- (1-Pyrrole) -4- (4-methoxyphenyl) -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] thiazole; 3- (4-Methoxyphenyl) -5- [5- (2'-amino-sulfonyl-phenyl-1-yl) -pyridin-2-yl] -aminocarbonyl-5-carbomethoxymethyl-isoxazoline; 3- (4-Methoxyphenyl) -5- [5- (2'-amino-sulfonyl-phenyl-1-yl) -pyridin-2-yl] -aminocarbonyl-5-carboxymethyl-isoxazoline; 3- (4-Methoxy phenyl) -5- [5- (2'-amino-sulfonyl-1-phenyl-1-yl) -pyridin-2-yl] -aminocarbonyl-5- (N-carbomethoxymethyl) carboxamidomethyl-isoxazoline; 3- (4-Methoxy phenyl) -5- [5- (2'-aminosulphonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl-5- (1, 2,4-triazol-1-yl) methyl -isoxazoline 1- (4-Methoxyphenyl) -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] tetrazole; 3-Methyl-1- (4-methoxy-3-chloro) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide;. 3-Methyl-1- (4-trifluoromethoxy) phenyl-1H-pyrazole-5- (N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 1- (3-Bromophenyl) -3-methyl-1H-pyrazole-5 - [(2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide; 1- (3-Iodophenyl) -3-methyl-1H-pyrazole-5- [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 1- (3, 4-Methylenedioxanophenyl)) -3-methyl-1H-pyrazole-5- [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 1- (4-Methoxy phenyl) -3-hydroxylmethylene-1H-pyrazole-5- (4'-pyrrolidinocarbonyl) anuide; 1- (4-Methoxyphenyl) -3-formaldehyde-1H-pyrazole-5- (4'-pyrrolidinocarbonyl) anuide; 1- (4-Methoxyphenyl) -5- (4'-pyrrolidinocarbonyl) anilide-3-pyrazolecarboxylic acid; 1- (4-Methoxy phenyl) -3-methylcarboxylate-1H-pyrazole-5- (4'-pyrrolidinocarbonyl) anuide; 1- (4'-Chlorophenyl) -3-met yl-lH-pyrazol-5- [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 1- (4'-Chlorophenyl) -3-methyl-1H-pyrazol-5- [(2'-aminosulfonyl- [1-pyridyl-1'-phenyl] -4-yl) carboxyamide; l- (3 ', 4'-Dichlorophenyl) -3-met yl-lH-pyrazole-5- [(2'-aminosulfonyl- [1, 1'] -bifen-4-yl) carboxyamide; 1- (3'-Chlorophenyl) -3-met yl-lH-pyrazol-5- [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 2-Amino-4-phenyl-5- [(2'-aminosulfonyl- [1, 1 *] - biphen-4-yl) aminocarbonyl] thiazole; N- (2'-Aminosulfonyl- [1,1 '] - biphen-4-yl) -1- (4-methoxy phenyl) -3- (methylsulfonyl) -lH-pyrazole-5-carboxyamide; N- (4-Benzoylpyrrolidine) -1- (4-methoxy phenyl) -3- (methylthio) -lH-pyrazole-5-carboxyamide; l- (4-Methoxyphenyl) -N- (5- (2'-methylsulfonylphenyl) pyrimid-2-yl) -3- (methylthio) -lH-pyrazole-5-carboxyamide; N- (4-Benzoylpyrrolidine) -1- (4-methoxy phenyl) -3- (methylsulphyl) -lH-pyrazole-5-carboxyamide; N- (2'-Aminosulfonyl- [1, 1 '] - biphen-4-yl) -l- (4-methoxyphenyl) -3- (methoxymethyl) -lH-pyrazole-5-carboxyamide; N- (2'-Aminosulfonyl- [1, 1 '] - biphen-4-yl) -l- (4-methoxyphenyl) -3-carbomethoxy-1H-pyrazole-5-carboxyamide; N- (2'-Aminosulfonyl- [1, 1 '] - biphen-4-yl) -l- (4-methoxy phenyl) -3- (methylsulfonylmethyl) -lH-pyrazole-5-carboxyamide; 3 - . 3 - . 3 - . 3 - . 3-Trifluoromet il-1- (4-methoxy phenyl) -lH-pyrazole-5- (N- (5- (2-methanesulfonyl) phenyl) pyrimidin-2-yl) carboxyamide; 3-Methyl-l- (4-methoxy phenyl) -lH-? Irazol-5-N- (4- (N-carboxyl-2-carbomethoxypyrrolidine) phenyl) carboxyamide; 3-Methyl-l- (-methoxyphenyl) -lH-pyrazole-5-N- (4- (N-carboxyl-3-aminopyrrolidine) phenyl) carboxyamide; 3-Methyl-1- (4-methoxy phenyl) -lH-pyrazole-5-N- (4- (N-carboxyl-3-methoxypyrrolidine) phenyl) carboxyamide; 3-Tri fluoromethyl-1- (4-methoxy phenyl) -lH-pyrazole-5- (N- (5- (2-aminosulfonyl) phenyl) pyridin-2-yl) carboxyamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4-amidine) phenyl) carboxyamide; 3-Tri-fluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4- (N-pyrrolidine) formylimine) phenylcarboxyamide; 3 -Tri fluoromethyl- 5- (N- (2'-amino-sulfonyl- [1,1 '] - biphen-4-yl)) -1- (-methoxymethyl) pyrrolo [3,4-d] pyrazole-4, 6- (1H, 5H) -dione; 3-Trifluoromethyl-1- (methoxyphenyl) -lH-pyrazole-5-carbomethoxy- (N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl)) carboxyamide; 3-Trifluoromethyl-l- (4-methoxyphenyl) -lH-pyrazole-5-hydroxymethyl- (N- (2'-aminosulfonyl- [1, 1 '] -bifen-4-yl)) carboxyamide; 3-Trifluoromet il-1- (4-methoxy phenyl) -lH-pyrazole-5- (N-2-fluoro (4- (N-pyrrolidine) formylimine) phenyl) carboxyamide; 3-Tri? Uoromethyl-1- (4-methoxy phenyl) -lH-pyrazole-5- (N- (4- (N-pyrrolidine) formyl-N- (2-propyl) methylcarbamoyl) imino) phenyl) carboxyamide; 3-Tri fluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4- (N-pyrrolidine) formyl-N- (methanesul famoyl) imino) phenyl) carboxyamide; 3 - . 3 - . 3 - . 3-Trifluoromethyl 1-1- (4-methoxyphenyl) -lH-pyrazole-5- (N - ((4-amidine) phenyl) methyl) carboxyamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- ((4- (N-pyrrolidine) formylimine) phenyl) methyl) carboxyamide; 3-Trifluoromet-il-1- (-methoxy-phenyl) -lH-pyrazole-5- (N- ((1-benzyl) piperidin-4-yl)) carboxyamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (. N - ((1- (pyridin-2-yl) methyl) piperidin-4-yl)) carboxyamide; 3-Trifluoromethyl-l- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4- (2-methylimidazo-l-yl) phenyl) carboxyamide; 3-Methyl- (4-methoxy) phenyl-1H-pyrazole-5- (N-. {- (5-methyl-imide zol-1-yl) phenyl) carboxyamide; 3-Methyl- (4-methoxy) phenyl-1H-pyrazole-5- (N-. {4- (4-methyl-imide zol-1-yl}. Phenyl) carboxyamide; 3-Trifluoromethyl- (4-methoxy) phenyl-1H-pyrazole-5- (N-. {4- (5-carbomethoxy-imidazol-1-yl) phenyl) carboxyamide; 3-Trifluoromet i 1- (4-methoxy) phenyl-1H-pyrazole-5- (N-. {4 (5-carboxy-imidazol-1-yl) phenyl) carboxyamide; 1- (4'-Methoxyphenyl) -3-hydroxy-1-yl-lH-pyrazol-5-N- (4'-pyrrolidinocarbonyl) phenyl) carboxyamide; 1- (4'-Methoxyphenyl) -3-formaldehyde-1H-pyrazol-5-N- (4 '- (pyrrolidinocarbonyl) phenyl) carboxyamide; 1- (4'-Methoxyphenyl) -5-N- (4 ') acid (pyrrolidinocarbonyl) anuide) -lH-pyrazol-3-yl-carboxylic acid; 1- (4'-Methoxyphenyl) -3-methylcarboxylate-1H-pyrazole-5-N- (4'-pyrrolidinocarbonyl) phenyl) carboxyamide; 1- (4'-Methoxyphenyl) -3-cyanomethyl-1H-pyrazole-5-N- (4'-pyrrolidinocarbonyl) phenyl) carboxyamide; 2- (1 '- (4"-Metoxyphenyl) -5' - (4" -pyrrolidinyl-one) anilide-1H-pyrazol-3'-yl) acetic acid; 1- (4'-Methoxyphenyl) -3-brornomethyl i 1- lH-pyrazol-5-N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 1- (4'-Methoxyphenyl) -3-aminomethyl-1H-pyrazol-5-N- (2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide; 1- (4'-Methoxyphenyl) -3- (N-methylsulfonylamino) met il-lH-pyrazol-5-N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 1- (4'-Methoxyphenyl) -3- (imide zol-1-yl) methyl-1H-pyrazol-5-N- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carboxyamide; 1- (4'-Methoxyphenyl) -3-hydroxylmethyl-1H-pyrazol-5-N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 1- (4'-Methoxy phenyl) -3-trifluoroacetylhydroxylmethyl-1H-pyrazol-5-N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 1- ('-Metoxy-2'-methoxycarbonyl-phenyl) -3-trifluoromethyl-1H-pyrazol-5-N- (2'-methylsulfonyl- [1, 1'] -bifen-4-yl) carboxyamide; 1- (4'-Methoxy-2'-hydroxycarbonyl-phenyl) -3-trifluoromethyl-1H-pyrazol-5-N- (2'-methylsulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 1- (4'-Methoxy-2'-methoxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazol-5-N- (2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 1- (4'-Methoxy-2'-hydroxycarbonylphenyl) -3-trifluoromethyl-1H-pyrazol-5-N- (2'-tert-butylaminosulfonyl) - [1,1 '] -biphenyl) carboxyamide; 1- (4'-Methoxy-2'-hydroxycarbonylphenyl) -3-t-rifluoromet-1H-pyrazole-5-N- (2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 1- (4'-Methoxyphenyl) -3-methyl-lH-pyrazol-5-N- (4 '- (3"-met i 1-3" -pyrazolin-5"-one-2" -yl) phenyl) carboxyamide; 1- (4'-Methoxyphenyl) -3-methyl-1H-pyrazol-5-N- (4 '- (6"-methylbenzothiazol-2" -yl) phenyl) carboxyamide; 1- (4'-Methoxyphenyl) -3-methyl-1H-pyrazol-5-N- (4 '- (4"-methylpiperidine) phenyl) carboxyamide; 1- (4'-Methoxyphenyl) -3-methyl-1-pyrazol-5-N- (4 '- (2"-methylimidazol-1" -yl) phenyl) carboxyamide; 3-Trifluoromet-il-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4-carboxy (N-methylimidazo-2-yl) phenyl) carboxyamide; 3-Trifluoromethyl-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4-hydroxymethyl (2- (imidazol-2-yl) phenyl))) carboxyamide; 3-Trifluoromet il-1- (4-methoxyphenyl) -lH-pyrazole-5- (N- (4-yl) phenyl))) carboxyamide; 1- (4-Methoxyphenyl) -3-tri fluoromethyl-1H-pyrazole-5- (N- (4- (2-carboxy (imidazol-2-yl) phenyl))) carboxyamide; 3-Trifluoromethyl-l- (-methoxyphenyl) -lH-pyrazole-5- (N- (4- (N- (4-methoxyphenyl) amino- (2- (thiazolyl) methyl) phenyl))) carboxyamide; 1- (4-Methoxyphenyl) -3-trifluoromethyl-lH-pyrazole-5- (N- (4- (2-carboxyl- (4,5-dihirothiazol-2-yl) phenyl))) carboxyamide; 1- (4-Methoxy phenyl) -3-tri fluorometyl-1H-pyrazol-5-N-4 (2- (4 ', 5'-dihydro-1'H-imide zol-2'-yl) phenyl) carboxyamide; l- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazol-5- [4 - (1, 4, 5, 6-tetrahydro-pyrimid-2-yl) -phenyl] carboxyamide; 1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazol-5- [4- (N-methyl-4,5,6,6-trihydro-pyrimid-2-yl) -phenyl] -carboxyamide; 1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazol-5-N- 1- (2-fluoro-4-imadazolinophenyl) carboxyamide; 1- (4-Methoxyphenyl) -3-trifluoromethyl-1H-pyrazol-5-N-l (2-fluoro-4-N-methylimidazolinophenyl) carboxyamide; 1- (4-Methoxyphenyl) -3-tri-fluoromethyl-1H-pyrazol-5-N- [4- (4, 5-dihydro-1-N-methyl-imidazo-2-yl) phenyl] carboxyamide; 1- (4-Methoxyphenyl) -3-t rifluoromet il-lH-pyrazol-5-N- [4- (pyrimidine-2-yl) phenyl] carboxyamide; 2- (Carboxyamide) -4- [(4-methoxy) phenyl] -5 - [(2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide] thiazole; 2- (2-Methoxyethylamino) -4- [(4-methoxy) phenyl] -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide] thiazole; 2- (3-Hydroxypropylamino) -4- [(4-methoxy) phenyl] -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide] thiazole; 2- (2-Cyanoethylamino) -4 - [(4-methoxy) phenyl] -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide] thiazip; 2- (3-Methoxypropylamino) -4- [(4-methoxy) phenyl] -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide) thiazole; 2- (N-b-Alanyl) -4- [(4-methoxy) phenyl] -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide] thiazole; 2- (Isopropylamino) -4- [(-methoxy) phenyl] -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide] thiazole; 2- (1, 3-Dihydroxy-2-propylamino) -4- [(4-methoxy) phenyl] 5- [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide] thiazole; 2- [(Methoxycarbonyl) methylamino] -4- [(4-methoxy) phenyl] -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide] thiazole; 2- (N-Glycyl) -4- [(4-methoxy) phenyl] -5 - [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide] thiazole; 1- [(4-Methoxy) phenyl] -3- (ethoxycarbonyl) -lH-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- (carboxyamido) -lH-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1- [(4-Methoxy) phenyl] -3 - [(2-hydroxyethyl) carboxyamid] -1H-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1- [(4-Methoxy) phenyl] -lH-pyrazol-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide-3-hydroxamic acid; 1- [(4-Methoxy) phenyl] -3- [phenylcarboxyamide] -1H-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1- [(4-Methoxy) phenyl] -3 - [(3-hydroxypropyl) carboxyamido] -lH-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- [methylcarboxyamide] -1H-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- [(benzyl) carboxyamide] -1H-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- [(dimethyl) carboxyamido] -1H-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- [(phenylethyl) carboxyamido] -1H-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- [(hydroxyphenyl) carboxyamid] -lH-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- [(3-hydroxyphenyl) carboxyamido] -lH-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- [(4-hydroxyphenyl) carboxyamido] -lH-pyrazole-5- [(4- (N-pyrrolidinocarbonyl) phenyl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- [(methoxycarbonyl) amino] -1H-pyrazole-5- [(2'-aminosulfonyl- [1,1 *] - biphen-4-yl) carboxyamide; 1- [(4-Methoxy) phenyl] -3-amino-1H-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 1- [(-Metoxy) phenyl] -3- [methoxycarbonyl) methylamino] lH-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; l- [(4-Methoxy) phenyl] -3 - [(2-hydroxy) ethylamino] -1H-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- [E-2- (methoxycarbonyl) ethenyl] -lH-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl. carboxyamide; 1- [(4-Methoxy) phenyl] -3- [2- (methoxycarbonyl) ethyl] -lH-pyrazole-5- [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- [E-2- (carboxy) ethenyl] -1H-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- [2- (carboxy) ethyl] -lH-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- [E-2- (carboxyamide) ethenyl] -1H-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- [E-2- (hydroxymethyl) ethenyl] -1H-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- [3-hydroxypropyl] -lH-pyrazole-5- [(2'-aminosulfonyl- [1,1 '] -bifen-4-yl) carboxyamide; 1- [(4-Methoxy) phenyl] -3-propyl-1H-pyrazole-5 - [(2'-aminosulfonyl- [1, 1 '] -bifen-4-yl) carboxyamide; l - [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4-cyano-lH-pyrazole-5- [(2'-methyl-sulfonyl-3-fluoro- [1,1 '] -bifen-4-yl] carboxyamide; 1- [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4- (amidine) -lH-pyrazole-5 - [(2'-methylsulfonyl-3-fluoro- [1,1 '] - bi phenyl-4-yl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4- (N-hydroxyamidino) -lH-pyrazole-5- [(2'-methylsulfonyl-3-fluoro- [1, 1]] - bifen-4-yl) carboxyamide; 1- [(4-Methoxy) phenyl] -3- (trifluoromethyl) -4- (ethoxycarbonyl) -lH-pyrazole-5 - [(2'-methylsulfonyl-3-fluoro- [1, 1 '] -bifen-4 -yl) carboxyamide; Y, l- [(4-Methoxy) phenyl] -3- (trifluoromethyl) -lH-pyrazol-5- [(2'-methyl-sulfonyl-3-fluoro- [1,1 '] -bifen-4-yl) carboxyamide- 4 -carboxylic; and pharmaceutically acceptable salts thereof

6. A compound of the formula or stereoisomers or pharmaceutically acceptable salts thereof, characterized in that: M is selected from the group: Z is selected from C (0) CH2 and C (O) NR3; R1 'is selected from H, alkyl of 1 to 3 carbon atoms, F, Cl, Br, CH (CH202) 2, (CF2) rCF3, (CH2) rOR2, NR2R2a, S (0) pR b, NR2 (CH2) rOR2 NR2C (0) R2b, C (0) NR R2a, C (O) NR2 (CH2) rOR2, and S02NR2R2a; R2, in each occurrence, is selected from H, CF3, alkyl of 1 to 6 carbon atoms, benzyl, carbocyclic residue of 3 to 6 carbon atoms substituted with 0-2 R4, and heterocyclic system of 5-6 members containing 1-4 heteroatoms selected from a group consisting of N, 0, and S substituted with 0-2 R4; R2a, in each occurrence is selected from H, CF3, alkyl of 1 to 6 carbon atoms, benzyl, carbocyclic residue of 3 to 6 carbon atoms substituted with 0-2 R4, and heterocyclic system of 5-6 members which contains 1-4 heteroatoms selected from a group consisting of 'N, 0, and S substituted with 0-2 R4; R2b, in each occurrence, is selected from CF3, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 6 carbon atoms, carbocyclic residue of 3 to 6 carbon atoms substituted with 0-2 R4, and heterocyclic system 5-6 members containing from 1-4 heteroatoms selected from a group consisting of N, O, and S, substituted with 0-2 R4; alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a saturated or unsaturated, saturated, 5-6 membered ring substituted with 0-2 R4 containing 0-1 selected additional heteroatoms from a group consisting of N, O, and S; R, in each occurrence is selected from H, alkyl of 1 to 4 carbon atoms, and phenyl; A is selected from phenyl, pyridyl, and pyrimidyl, and A is substituted with 0-2 R4; B is selected from: H and Y; Y is selected from phenyl, pyridyl, tetrazolyl, and morpholino, and Y is substituted with 0-2 R4a; R4, in each occurrence is selected from F, Cl, Br, I, C (0) NR2R a, and (CF2) rCF3; R, 4a, in each occurrence, is selected from F, Cl, Br, I, alkyl of 1 to 4 carbon atoms, C (0) NR2R2a, S02NR2S02-C: -4 alkyl, S (0) pR5, and (CF2) rCF3; R5, in each occurrence, is selected from CF3, alkyl of 1 to 6 carbon atoms, phenyl, and benzyl; p is selected from 0, 1, and 2; and r is selected from 0, 1, 2 and 3.

7. A compound according to claim 6, characterized in that the compound is selected from: 3-Methyl-1-phenyl-H-pyrazol-5- (N- (2-aminosulfonyl- [1, 1] -bifen) -4-yl) carboxyamide; 2-Amino-4-f-enyl-5- [2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] thiazole; and, 2-Chloro-4-phenyl-5- [(2'-amino-sulfonyl- [1,1 '] -bifen-4-yl) aminocarbonyl] thiazole; and pharmaceutically acceptable salts thereof.

8. A pharmaceutical composition, characterized in that it comprises: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to any of claims 1-7 or a pharmaceutically acceptable salt thereof.

9. A compound according to any of claims 1-7 or a pharmaceutically acceptable salt thereof for use in therapy.

10. The use of a compound according to any of claims 1-7 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a thromboembolic disorder.