LT4673B - Nitrogen containing heteroaromatics as factor xa inhibitors - Google Patents

Abstract

A formula (I) is described in this invention:<IMAGE>in which J is N or NH and D can be C(=NH)NH2, nitrogen heteroaromatic structures and their derivatives as well as their pharmaceutically appropriate saline combinations and their drug forms which can be used as inhibitors of Xa factor.

Description

FIELD OF INVENTION

The present invention relates in particular to nitrogen heteroaromatic compounds which are inhibitors of trypsin-like proteases, especially factor Xa, to pharmaceutical compositions containing them and to their use as anticoagulant agents for the treatment and prophylaxis of thromboembolic disorders.

ORIGIN OF THE INVENTION

WO 95/18111 describes fibrinogen receptor antagonists having basic and acidic ends of the formula;

wherein R ¹ represents a basic end, U is an alkylene or heteroatom bridge, V may be a heterocycle, and the right side of the molecule represents an acidic end. The compounds described in this patent do not have the acid end of the compounds of WO 95/18111.

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

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

Baker et al., U.S. Pat. 5,317,103 discusses 5-HT, agonists which are 5-membered indole-substituted heteroaromatic compounds having the formula:

wherein R ¹ may be pyrrolidine or piperidine and A may be a basic group including amino and amidine groups. However, Baker et al. does not indicate that A may be a ring system similar to that of the heteroaromatic compounds of the present invention.

Baker et al. WO 94/02477 discusses 5-HT 1 agonists which are imidazoles,

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

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

Activated factor Xa, which plays a key role in thrombin generation through limited prothrombin proteolysis, occupies a central position by binding to internal and external activation mechanisms in the final total blood coagulation cascade. The generation of thrombin, the final serine protease that produces the fibrin clot in this cascade, is enhanced by the formation of the prothrombinase complex (factor Xa, factor V, Ca ²⁺ and phospholipid) from its precursor. Because it is estimated that one molecule of factor Xa can generate 138 thrombin molecules (Elodi, S., Varadi, K .: Optimization of conditions for the catalytic effect of factor lxa-factor VIII Complex: A Probable Role in the Complex in Ampification blood coagulation (Thromb. Wed. 1979, 15, 617-629), inhibition of factor Xa may be more effective than inhibition of thrombin if interruption of the blood coagulation system is desired.

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

SUMMARY OF THE INVENTION

Thus, one object of the present invention is to provide novel nitrogen aromatic heterocycles which are useful as factor Xa inhibitors, or pharmaceutically acceptable salts thereof, or prodrug forms thereof.

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

Yet another object of the present invention is to provide a method of treating thromboembolic disorders comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one of the compounds of the invention, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

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

(I) Their pharmaceutically acceptable salts or prodrug forms thereof, wherein A, B, D, E, G, J, M, R ^1a , R ^1b , s and m / z are given below are effective factor Xa inhibitors.

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

stereoisomers thereof or pharmaceutically acceptable salts thereof; in the ring, M has, in addition to J, 0-3 N atoms, provided that when M is 2 N atoms, R ^1b is absent, and if M is 3 N atoms, R ^1a and R ^{1b are not present} ;

J is N or NH;

D is selected from CN, C (= NR ⁸ ) NR ⁷ R ⁹ , NHC (= NR ⁸ ) NR ⁷ R ⁹ , NR ⁸ CH (= NR ⁷ ), C (O) NR ⁷ R ^8, and (CR ⁸ R ⁹ ) _t NR ⁷ R ⁸ with the proviso that in E, D is in the meta or para position with respect to G;

E is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and piperidinyl substituted with 1 R;

otherwise, D-E-G together is pyridyl substituted with 1 R;

R is selected from H, halogen, (CH ₂ ) tOR ³ , C _1-4 alkyl, OCF ₃ and CF ₃ ;

G is absent or selected from NHCH ₂ , OCH ₂ and SCH ₂ , provided that when s is 0, then G is attached to the ring carbon atom of M;

Z is selected from C _1-4 alkylene, (CH ₂ ) _r O (CH ₂ ) _r , (CH ₂ ) _r NR ³ (CH ₂ ) _r , (CH ₂ ) _r C (O) (CH ₂ ) _r , (CH ₂ ) _r C (O) C (CH ₂ ) _r , (CH ₂ ) _r C (O) O (CH ₂ ) _r , (CH ₂ ) _r C (O) NR ³ (CH 2) _r , (CH ₂ ) _r NR ³ C (O) (CH 2) r, (CH 2) r OC (O) O (CH2) r, (CH 2) r OC (O) NR ³ (CH 2) _r, (CH _{2) r} NR ³ C (O) O (CH 2) r, (CH2) RNA ³ C (O) NR ³ (CH 2) _r , (CH ₂ ) _r S (O) _p (CH ₂ ) _r (CH ₂ ) _r SO ₂ NR ³ (CH ₂ ) _r , (CH ₂ ) _r NR ³ SO 2 (CH 2) r and (CH 2) rNA ³ SO ² NR ³ (CH ₂ ) _r , with the proviso that Z does not form a bond to N, NO, NS, NCH ₂ N, NCH ₂ O or NCH ₂ S with ring M or group A;

R ^1a and R ^1b, independently of one another, absent or selected from - (CH 2) rr ¹ NCH2R ^1, OCH 2 R ¹ ", SCH 2 R ^1", N (CH2) 2 (CH2) tR = ¹ ', O (CH 2 ) ₂ (CH ₂ ) _t R ¹ and S (CH ₂ ) ₂ (CH ₂ ) _t R ¹ , or are linked together to form a 5- to 8-membered saturated, partially saturated or unsaturated ring system having 0-2 substituents on R ⁴ and having 0-2 heteroatoms selected from the group consisting of N, O and S;

R ¹ is selected from H, C 1-3 alkyl, halogen, (CF 2) r CF 3, OR ² , NR ² R ^2a , C (O) R ^2c , OC (O) R ² , (CF 2) _r CO ₂ R ^2c , S (O) pR ^2b , NR ² (CH ² ) _r OR ² , NR ² C (O) R ^2b , NR ² C (O) NHR ^2b , NR ² C (O) ² R ^2a , OC (O) NR ^2b , C (O) NR ² R ^2a , SO ² NR ² R ^2a , NR ² SO ² R ^2b , C _3-6 carbocyclic moieties substituted with 0-2 R ⁴ and 510 membered heterocyclic systems of 1-4 heteroatoms selected from a group consisting of N, O and S substituted with 0-2 R ⁴ ;

R ¹ is selected from H, C (O) R ^2b , C (O) NR ² R ^2a , S (O) R ^2b , S (O) ² R ^2b and SO ² NR ² R ^2a ;

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

O and S substituted with 0-2 R ^4b ;

R ^{2a is in} each case selected from H, CF ₃ , Ci. _6- alkyl, benzyl, C ₃ -carbocyclic moieties with 0-2 R ^4b and 5-6 membered heterocyclic rings having 1-4 heteroatoms selected from the group consisting of N,

O and S substituted with 0-2 R ^4t> ;

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

R ^{2c is in} each case selected from CF ₃ , OH, C _1-4 alkoxy, Ci. ₆ alkyl, benzyl, C ₃ .6 carbocyclic residue with 0-2 R ^4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O and S, which contains 0-2 substituents R ^4b ;

otherwise, R ² and R ^2a taken together form a 5- or 6-membered saturated, partially saturated or unsaturated ring, substituted with 0-2 R ⁴ and 0-1 additional heteroatoms selected from the group consisting of N, O and S;

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

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

A is selected from:

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

B is selected from:

Χ-Υ, NR ² R ^2a , C (= NR ² ) NR ² R ^2a , NR ² C (= NR ² ) NR ² R ^2a ,

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

Xyra selected from C _r4 alkylene, -CR ² (CR ² R ^2b) (CH 2) o -C (O) -, - C (= NR) -, -CR ² (NR ¹ R ²⁾ -, -CR ² (OR ² ) -, -CR ² (SR ² ) -, -C (O) CR ² R ^2a -, -CR ² R ^2a C (O) -, -S (O) p -, -S (O) ) PCR ² R ^2a -, -CR ² R ^2a S (O) p-, -S (O) 2NR ² -, -NR ² S (O) 2, -NR ² S (O) ² R ^2a 2CR - , -CR ² R ^2a S (O) ₂ NR ² -, -NR ² S (O) ₂ NR ² -, -C (O) NR ² -, -NR ² C (O) -, -C (O) NR ² CR ² R ^2a -, -NR ² C (O) CR ² R ^2a -, -CR ² R ^2a C (O) NR ² -, -CR ² R ^2a NR ² C (O) -, -NR ² C (O) O-, -OC (O) NR ² -, -NR ² C (O) NR ² -, -NR ² -, -NR ² CR ² C ^2a -, -CR ² C ^2a NR ² -, - O-, -CR ² C ^2a O-, and -OCR ² C ^2a -;

Y is selected from:

(CH ₂ ) _r NR ² R _2a , provided that Χ-Υ does not form an NN, ON or SN bond,

CfMo-carbocyclic residues substituted with 0-2 R ^4a and 5-10 membered heterocyclic systems containing 1-4 heteroatoms selected from the group consisting of N, O and S substituted with 0-2 R ^4a ;

R ^{4 is} at each occurrence selected from = O, (CH ² ) f OR ² , halo, C 1-4 alkyl, CN, NO ₂ , (CH ₂ ) _r NR ² R ^2a , (CH ₂ ) _r C (O) R ^2b , NR ² C (O) R ^2a , C (O) NR ² R ^2a , NR ² C (O) NR ² R ^2a , CH (= NR ² ) NR ² R ^2a , NHC (= NR ² ) NR ² R ^2a , SO 2 NR ² R ^2a, NR ² SO 2 NR ² R ^2a, NR ² SO 2 Ci- ₄ alkyl, NR ² SO 2 R ^5, S (O) PR ^5, (CF 2) r CF 3, NCH2R ^{1 1} OCH2R, SCH2R ^1, N ( CH2) ₂ (CH _{2) t} R ^1, O (CH2) 2 (CH2) tR = ¹ ', and S (CH 2) ₂ (CH _{2) t} R ^1, alternatively one of the R ⁴ is a 5-6 membered aromatic heterocycle containing 1 to 4 heteroatoms selected from the group consisting of N, O and S:

R ^{4a is} at each occurrence selected from = O, (CH ₂ ) _r OR ² , halogen, C 1-4 alkyl, CN, NO ² , (CH ₂ ) _r NR ² R ^2a , (CH ₂ ) _r C (O) R ^2b , NR ² C (O) R ^2b , C (O) NR ² R ^2a , NR ² C (O) NR ² R ^2a , CH (= NR ² ) NR ² R ^2a , NHC (= NR ² ) NR ² R ^2a , SO 2 NR ² R ^2a, NR ² SO 2 NR ² R ^2a, NR ² SO 2 Ci- ₄ alkyl, NR ² SO 2 R ^5, S (O) PR ^5, and (CF _{2) r} CF _3;

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

R ^{4b is in} each case selected from = O, (CH ₂ ) _r OR ³ , halogen, C 1-4 alkyl, CN, NO ₂ , (CH ₂ ) _r NR ³ R ^3a , (CH ₂ ) _r C (O) R ³ , NR ³ C (O) R ^3a, C (O) NR ³ R ^3a, NR ³ C (O) NR ³ R ^3a, CH (= NR ³⁾ NR ³ R ^3a, NHC (= NR ³⁾ NR ³ R ^3a , SO 2 NR ³ R ^3a, NR ³ SO 2 NR ³ R ^3a, NR ³ SO 2 Cl. _4- alkyl, NR ³ SO 2 CF ₃ , NR ³ SO 2 -phenyl, S (O) _p CF ₃ , S (O) _p -C _1-4 alkyl, S (O) _p -phenyl and (CF ₂ ) _r CF ₃ ;

R ^{5 is in} each case selected from CF ₃ , Ci. ₆ alkyl, phenyl substituted with 0-2 R ^6, and benzyl substituted with 0-2 ^R6;

R ^{6 is} at each occurrence selected from H, OH, (CH ² ) r OR ² , halogen, C 1-4 alkyl, CN, NO ₂ , (CH ₂ ) _r NR ² R ^2a , (CH ₂ ) _f C (O) R ^2t. , NR ² C (O) R ^2b, NR ² C (O) NR ² R ^2a, CH (= NH) NH2, NHC (= NH) NH _{2 i} SO ₂ NR ² R ^2a, NR ² SO 2 NR ² R ²⁵ and NR ² SO ² C 1-4 alkyl;

R ^{7 is} at each occurrence selected from H, OH, C 1 -C 6 alkyl, C 1 -C 7. ₆ -alkylcarbonyl, Ci-6-alkoxy, Ci-4 alkoxycarbonyl, (CH _{2) n} -phenyl, C ₆ -io aryloxy-C _io-6 aryloxycarbonyl C6io-arilmetilkarbonilo, C. ₄ alkylcarbonyloxy-C 1-4 alkoxycarbonyl, C ₆ -C ₁₀ -arylcarbonyloxy-C 1-4 alkyl; ₄ alkoxycarbonyl, C 1. _6- alkylalkylcarbonyl, phenylaminocarbonyl and phenylC1-4alkoxycarbonyl;

R ^{8 is} at each occurrence selected from H, Ci. _6- alkyl and (CH ₂ ) _n -phenyl;

alternatively, R ⁷ and R ⁵ together form a 5-6 membered saturated ring containing 0-1 additional heteroatoms selected from the group consisting of N, O, and S;

R ^{9 is in} each case selected from H, C,. _6- alkyl and (CH ₂ ) _n -phenyl; n is in each case selected from 0, 1, 2 and 3: m is in each case selected from 0, 1 and 2; p is in each case selected from 0, 1 and 2; r is in each case selected from 0, 1,2 and 3; s is in each case selected from 0, 1 and 2; and t is in each case selected from 0 and 1; with the proviso that DEG- (CH ₂ ) _S - and -ZAB are not both benzamidines.

[2] In a preferred embodiment, the present invention provides novel compounds of formulas la-lh:

, R ^1b //.

FA v _D

D ^b B la, RN / S ' ^{R 1a} , R ^1b

Ib _R 1a

Ic

N-a

Ν / Ί ^ Κ '·

N /

J Z-AB D · ^ ^E

N /,> N

R1a

J ' _Z -ΑId le

N-N // V

N '

N ^{E X} A ^ ^Z Ig

N-N

V

D '

N

I

-E

Z ^ A \

Ih wherein the D-E- and -Z-A-B groups are attached to neighboring ring atoms;

Z is selected from CH ₂ O, OCH ₂ , CH ₂ NH, NHCH ₂ , C (O), CH ₂ C (O), C (O) CH ₂ ,

NHC (O), C (O) NH, CH ₂ S (O) ₂ , S (O) ₂ (CH ₂ ), SO ₂ NH and NHSO ₂ , provided that Z does not form NN, NO, NCH ₂ N or NCH ₂ O bonds to ring N or group A;

A is selected from one of the following carbocyclic and heterocyclic systems substituted with 0-2 R ⁴ :

phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2 4-oxadiazolyl, 1,2,5-oxadiazolyl,

1.3.4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4- triazolyl, 1,2,5-triazolyl,

1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl and isoindazolyl;

B is selected from: Y, Χ-Y, NR ² R ^2a , C (= NR ² ) NR ² R ^2a, and NR ² C (= NR ² ) NR ² R ^2a ;

X is selected from C _1-4 alkylene, -C (O) -, - C (= NR) -,

-CR ² (NR ² R ^2a ) -, -C (O) CR ² R ^2a -, -CR ² R ^2a C (O) -, -C (O) NR ² -, -NR ² C (O) - ,

-C (O) NR ² CR ² R ^2a -, -NR ² C (O) CR ² R ^2a -, -CR ² R ^2a C (O) NR ² -,

-CR ² R ^2a NR ² C (O) -, -NR ² C (O) NR ² -, -NR ² -, -NR ² CR ² R ^2a -, -CR ² R ^2a NR ² -,

-O-, -CR ² R ^2a O-, and -OCR ² R ^2a -;

Y is NR ² R _2a , provided that Χ-Y does not form an NN or 0-N bond;

otherwise, Y is selected from one of the following carbocyclic and heterocyclic systems substituted with 0-2 R ^4a :

cyclopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, thiazolyl, imidazolyl, imidazolyl 3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,

1.3.4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl and isoindazolyl;

otherwise, Y is selected from the following bicyclic heteroaryl ring systems:

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

[3] In a more preferred embodiment, the following compounds of formulas IIa-IIf:

the invention provides new ones

R ¹ =

N-N

H \\ zD '

N

I .E

A \ lld

D _R 1a

N

I / E llc

D '' N '

Itf 'Z- ^ A \ in which:

Z is selected from C (O), CH ₂ C (O), C (O) CH ₂ , NHC (O), C (O) NH, C (O) N (CH ₃ ), CH ₂ S (O) _2l S (O) ₂ (CH ₂ ), SO ₂ NH and NHSO ₂ , provided that Z does not form NN or NCH ₂ N bonds with ring M or group A.

[4] In a more preferred embodiment, the present invention provides novel compounds of formulas IIa-IIf, wherein:

E is phenyl substituted with R or 2-pyridyl substituted with R;

D is selected from NH ₂ , C (O) NH ₂ , C (= NH) NH ₂ , CH ₂ NH _{2 1} CH ₂ NHCH ₃ ,

CH (CH ₃ ) NH ₂ and C (CH ₃ ) ₂ NH ₂ with the proviso that the ring D in the M ring is in the meta or para position with respect to the E group; and

R is selected from H, OCH ₃ , Cl and F.

[5] In another more preferred embodiment, the present invention provides novel compounds of formulas IIa-IIf, wherein:

DE is selected from 3-aminophenyl, 3-amidinophenyl, 3-aminomethylphenyl, 3aminocarbonylphenyl, 3- (methylaminomethyl) phenyl, 3- (1-aminoethyl) phenyl, 3- (2-amino-2-propyl) phenyl, 4-chloro-. 3-aminophenyl, 4-chloro-3-amidinophenyl, 4-chloro-3-aminomethylphenyl, 4-chloro-3- (methylaminomethyl) phenyl, 4-fluoro-3aminophenyl, 4-fluoro-3-amidinophenyl, 4-fluoro-3 -aminomethylphenio, 4-fluoro-3- (methylaminomethyl) phenyl, 6-aminopyrid-2-yl, 6-amidinopyrid-2-yl, 6-aminomethylpyrid-2-yl, 6-aminocarbonylpyrid-2-yl,

6- (methylaminomethyl) pyrid-2-yl, 6- (1-aminoethyl) pyrid-2-yl and 6- (2-amino-2propyl) pyrid-2-yl.

[6] In another more preferred embodiment, the present invention provides novel compounds of formulas IIa-IIf, wherein:

Z is C (O) and CONH, provided that Z does not form an N-N bond with group A;

A is selected from phenyl, pyridyl and pyrimidyl, and is substituted with 0-2 R ⁴ ; and B is selected from Χ-Υ, phenyl, pyrrolidine, morpholine, 1,2,3-triazolyl and imidazolyl, and is substituted with 0-1 R ^4a ;

R ^{4 is} at each occurrence selected from OH, (CH ₂ ) _r OR ² , halogen, C 1-4 alkyl, (CH ₂ ) _r NR ² R ^2a and (CF ₂ ) _r CF ₃ ;

R ^4a is selected from C 1-4 alkyl, CF 3, S (O) PR ⁵ , SO ² NR ² R ^2a and 1-CF ₃ -tetrazol-2-yl;

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

X is CH ₂ or C (O); and Y is selected from pyrrolidine and morpholine.

[7] In yet another more preferred embodiment, the present invention provides novel compounds of formulas IIa-IIf, wherein:

A is selected from the group consisting of: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2aminophenyl and 2-methoxyphenyl; and

B is selected from the group consisting of: 2-CF ₃ -phenyl, 2- (aminosulfonyl) phenyl, 2- (methylaminosulfonyl) phenyl, 2- (dimethylaminosulfonyl) phenyl, 1-pyrrolidinocarbonyl, 2- (methylsulfonyl) phenyl, 4-morpholine, 2 - (1'-CF ₃ ) -tetrazol-2-yl) phenyl, 4-morpholinocarbonyl, 2-methyl-1-imidazolyl, 5-methyl-1-imidazolyl, 2-methylsulfonyl-1-imidazolyl, 2-methylsulfonyl-1-imidazolyl, and 5 -methyl-1,2,3-triazolyl.

[8] In yet another more preferred embodiment, the present invention provides novel compounds of formulas IIa-IIf, wherein:

E is phenyl substituted with R or 2-pyridyl substituted with R;

D is selected from NH ₂ , C (O) NH ₂ , C (= NH) NH ₂ , CH ₂ NH ₂ , CH ₂ NHCH ₃ ,

CH (CH ₃ ) NH ₂ and C (CH ₃ ) ₂ NH ₂ with the proviso that the ring D in the M ring is in the meta or para position with respect to the E group; and

R is selected from H, OCH ₃ , Cl and F;

Z is C (O) CH ₂ and CONH, provided that Z does not form an NN bond to group A; A is selected from phenyl, pyridyl and pyrimidyl, and is substituted with 0-2 R ⁴ ; and B is selected from Χ-Υ, phenyl, pyrrolidine, morpholine, 1,2,3-triazolyl and imidazolyl, and is substituted with 0-1 R ^4a ;

R ^{4 is} at each occurrence selected from OH, (CH ₂ ) _r OR ² , halogen, C 1-4 alkyl, (CH ₂ ) _r NR ² R ^2a and (CF ₂ ) _r CF ₃ ;

R ^4a is selected from C 1-4 alkyl, CF 3, S (O) PR ⁵ , SO ² NR ² R ^2a and 1-CF ₃ -tetrazol-2-yl;

R ° is in any case selected from CF _3l Ci. _6- alkyl, phenyl and benzyl;

X is CH ₂ or C (O); and Y is selected from pyrrolidine and -morpholine.

[9] In yet another more preferred embodiment, the present invention provides novel compounds of formulas IIa-IIf, wherein:

DE is selected from 3-aminophenyl, 3-amidinophenyl, 3-aminomethylphenyl, 3aminocarbonylphenyl, 3- (methylaminomethyl) phenyl, 3- (1-aminoethyl) phenyl, 3- (2-amino-2-propyl) phenyl, 4-chloro- 3-aminophenyl, 4-chloro-3-amidinophenyl, 4-chloro-3-aminomethylphenyl, 4-chloro-3- (methylaminomethyl) phenyl, 4-fluoro-313 aminophenyl, 4-fluoro-3-amidinophenyl, 4-fluoro- 3-aminomethylphenyl, 4-fluoro-3- (methylaminomethyl) phenyl, 6-aminopyrid-2-yl, 6-amidinopyrid-2-yl, 6-aminomethylpyrid-2-yl, 6-aminocarbonylpyrid-2-yl,

6- (methylaminomethyl) pyrid-2-yl, 6- (1-aminoethyl) pyrid-2-yl, 6- (2-amino-2propyl) pyrid-2-yl;

A is selected from the group consisting of: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2aminophenyl and 2-methoxyphenyl; and

B is selected from the group consisting of: 2-CF ₃ -phenyl, 2- (aminosulfonyl) phenyl, 2- (methylaminosulfonyl) phenyl, 2- (dimethylaminosulfonyl) phenyl, 1-pyrrolidinocarbonyl, 2- (methylsulfonyl) phenyl, 4-morpholine, 2 - (1'-CF ₃ ) -tetrazol-2-yl) phenyl, 4-morpholinocarbonyl, 2-methyl-1-imidazolyl, 5-methyl-1-imidazolyl, 2-methylsulfone 1-1 -imidazolyl and 5-methyl 1-1.2 , 3-triazolyl.

[10] In another more preferred embodiment, the present invention provides a novel compound of formula Ha.

[11] In yet another more preferred embodiment, the present invention provides a novel compound of formula IIb.

[12] In yet another more preferred embodiment, the present invention provides a novel compound of formula IIc.

[13] In a still more preferred embodiment, the present invention provides a novel compound of formula lld. [14] In yet another more preferred embodiment, the present invention provides a novel compound of formula lle.

[15] In yet another more preferred embodiment, the present invention provides a novel compound of formula IIf.

[16] In yet another more preferred embodiment, the present invention provides novel compounds of formulas IIa-IIf, wherein:

D is selected from C (= NR ⁸ ) NR ⁷ R ⁸ , C (O) NR ⁷ R ⁸ , NR ⁷ R ⁸ and CH ₂ NR ⁷ R ⁸ , provided that the ring D in the M group is meta to E. or in a parapet;

E is phenyl substituted with R or pyridyl substituted with R;

R is selected from H, Cl, F, OR ³ , CH ₃ , CH ₂ CH ₃ , OCF ₃ and CF ₃ ;

Z is selected from C (O), CH ₂ C (O), C (O) CH ₂ , NHC (O) and C (O) NH, provided that Z does not form an NN bond to ring M or a group A;

R ^1a and R ^1b , independently of one another, are absent or selected from

- (CH ₂ ) _r -R ¹ ', NCH ₂ R ¹ , OCH 2 R ¹ , SCH 2 R ¹ , N (CH ₂ ) ₂ (CH ₂ ) _t R ¹ , O (CH ₂ ) ₂ (CH ₂ ) _t R ¹ and S (CH ₂ ) ₂ (CH ₂ ) _t R ¹ , or are joined together to form a 5-8 membered saturated, partially saturated or unsaturated ring system having 0-2 substituents on R ⁴ and having 0-2 heteroatoms selected from the group consisting of consisting of N, O and S;

R ^{1 is} at each occurrence selected from H, C 1-3 alkyl, halogen, (CF 2) r CF 3, OR ² , NR ² R ^2a , C (O) R ^2c , (CF 2) _r CO ₂ R ^2c , S (O) ) PR ^2b, NR ² (CH 2) _r OR ^2, NR ² C (O) R ^2b, NR ² C (O) 2 R ^2b, C (O) NR ² R ^2a, SO 2 NR ² R ^2a mRNA ² SO ₂ R ^2b ;

A is selected from one of the following carbocyclic and heterocyclic systems substituted with 0-2 R ⁴ :

phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl and imidazolyl;

B is selected from: Y, Χ-Υ, NR ² R ^2a , C (= NR ² ) NR ² R ^2a, and NR ² C (= NR ² ) NR ² R ^2a ;

X is selected from CH ₂ , -CR ² (CR ² R ^2b ) (CH ₂ ) _r , -C (O) -, -C (= NR) -, -CH (NR ² R ^2a ) -C (O) NR ² -, -NR ² C (O) -, -NR ² C (O) NR ² -, -NR ² -, and -O-;

Y is NR ² R _2a , provided that Χ-Υ does not form an NN or ON bond; otherwise, Y is selected from one of the following carbocyclic and heterocyclic systems substituted with 0-2 R ^4a :

phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazothyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadolazole, 2,4-oxadiazolyl,

1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,

1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl and 1,3,4-triazolyl;

R ^{4 is} at each occurrence selected from = O, OH, Cl, F, C 1-4 alkyl, (CH ² ) _r R ² R ^2a , (CH 2) _r C (O) R ^2b , NR ² C (O) R ^2a , C (O) NR ² R ^2a , CH (= NH) NH ₂ ,

NHC (= NH) NH ₂ , SO ₂ NR ² R ^2a , NR ² SO ₂ -Ci. _4- alkyl, NR ² SO ² R ⁵ , S (O) PR ⁵ and (CF ₂ ) _r CF ₃ ;

R ^{4a is} at each occurrence selected from = O, OH, Cl, F, Ci. _4- alkyl, (CH ₂ ) r NR ² R ^2a , (CH ₂ ) r C (O) R ^2b , NR ² C (O) R ^2b , C (O) NR ² R ^2a , CH (= NH) NH 2, NHC ( = NH) NH ₂ , SO ₂ NR ² R ^2a , NR 4 Os -C 1-4 alkyl, NR ² SO ² R ⁵ , S (O) PR ⁵ (CF ₂ ) _r CF ₃ and 1-CF ₃ -tetrazol-2- pleasure;

R ^{5 is in} each case selected from CF ₃ , Ci. ₆ alkyl, phenyl substituted with 0-2 R ^6, and benzyl substituted with 0-2 ^R6;

R ^{6 is} at each occurrence selected from H, = O, OH, OR ² , Cl, F, CH 3, CN, NO ² , (CH ² ) r NR ² R ^2a , (CH ² ) r C (O) R ^2b , NR ² C ( O) R ^2b , CH (= NH) NH ₂ , NHC (= NH) NH ₂ and SO ₂ NR ² R ^2a ;

R ^{7 is} at each occurrence selected from H, OH, Ci. _6- alkyl, Ci. _6- alkylcarbonyl, Ci. _{A 6-} alkoxy group, a C _1-4 alkoxycarbonyl, benzyl,

C _6-10 -ariloksigrupės C ₆ -io _{aryloxycarbonyl,} C6-io arilmetilkarbonilo, C.

₄ -alkylcarbonyloxy-C _1-4 -alkoxycarbonyl, C ₆ -C ₁₀ -arylcarbonyloxy-C 1-4 alkyl; ₄ alkoxycarbonyl, C 1-6 alkylaminocarbonyl, phenylaminocarbonyl and phenylC 1-4 alkoxycarbonyl;

R ^{8 is} at each occurrence selected from H, Ci. _6- alkyl and benzyl; otherwise R ⁷ and R ⁸ together form a morpholine group; and

R ^{9 is} at each occurrence selected from H, C _1-6 alkyl and benzyl.

[17] In yet another more preferred embodiment, the present invention provides novel compounds of formulas IIa-IIf, wherein:

E is phenyl substituted with R or 2-pyridyl substituted with R;

R is selected from H, Cl, F, OCH ₃ , CH ₃ , OCF ₃ and CF ₃ ;

Z is selected from C (O) CH ₂ and C (O) NH, provided that Z does not form an NN bond to group A;

R ^1a is selected from H, CH3, CH2CH3, Cl, F, CF 3, OCH 3, NR ² R ^2a, S (O) pR ^2b, CH 2 S (O) pR ^2b CH2NR ² S (O) pR ^2b, C (O ) R ^2c , CH ² C (O) R ^2c , C (O) NR ² R ^2a and SO ₂ NR ² R ^2a ;

R ^1b is selected from H, CH3, CH2CH3, Cl, F, CF 3, OCH 3, NR ² R ^2a, S (O) pR ^2b, CH 2 S (O) pR ^2b CH2NR ² S (O) pR ^2b, C (O ) R ^2c , CH ² C (O) R ^2c , C (O) NR ² R ^2a and SO ₂ NR ² R ^2a ;

A is selected from one of the following carbocyclic and heterocyclic systems substituted with 0-2 R ⁴ :

phenyl, pyridyl, pyrimidyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl and imidazolyl;

B is selected from: Y and Χ-Υ;

X is selected from CH ₂ , -CR ² (CR ² R ^2b ) -, -C (O) -, -C (= NR) -, -CH (NR ² R ^2a ) -, -C (O) NR ² -, -NR ² C (O) -, -NR ² C (O) NR ² -, -NR ² -, and -O-;

Y is NR ² R _2a , provided that Χ-Υ does not form an NN or ON bond; otherwise, Y is selected from one of the following carbocyclic and heterocyclic systems substituted with 0-2 R ^4a :

phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, 1-thiazolyl, oxadiazolyl, thiadolazole 2,4-oxadiazolyl,

1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,

1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl and 1,3,4-triazolyl;

R ^{2 is} at each occurrence selected from H, CF ₃ , CH ₃ , benzyl and phenyl;

R ^{2a is} at each occurrence selected from H, CF ₃ , CH ₃ , benzyl and phenyl;

R ^{2b is in} each case selected from CF ₃ , OCH ₃ , CH ₃ , benzyl and phenyl;

R ^{2c is} at each occurrence selected from CF ₃ , OH, OCH ₃ , CH ₃ , benzyl and phenyl;

alternatively, R ² and R ^2a form a 5- or 6-membered saturated, partially unsaturated or unsaturated ring containing 0-1 additional heteroatoms selected from the group consisting of N, O and S;

R ^{3 is} at each occurrence selected from H, CH ₃ , CH ₂ CH ₃ and phenyl;

R ^{3a is} at each occurrence selected from H, CH ₃ , CH ₂ CH ₃ and phenyl;

R ^{4 is} at each occurrence selected from OH, Cl, F, CH 3 CH 2 CH 3, NR ² R ^2a , CH ² NR ² R ^2a , C (O) R ^2b , NR ² C (O) R ^2b , C (O) NR ² R ^{2a is} CF ₃ ;

R ^{4a is in} each case selected from OH, Ci, F, CH ₃ , CH ₂ CH ₃ , NR ² R ^2a ,

CH ₂ NR ² R ^2a , C (O) R ^2b , C (O) NR ² R ^2a , SO ² NR ² R ^2a , S (O) PR ⁵ , CF ₃ and 1-CF ₃ tetrazol-2-yl;

R ^{5 is in} each case selected from CF ₃ , Ci. ₆ alkyl, phenyl substituted with 0-2 R ^6, and benzyl substituted with 0-2 ^R6;

R ^{6 is} at each occurrence selected from H, OH, OCH 3, Cl, F, CH 3 CN, NO 2, NR ² R ^2a , CH ² NR ² R ^2a and SO ₂ NR ² R ^2a ;

R ^{7 is} at each occurrence selected from H, OH, Ci. _3- alkyl, Ci. _3- alkylcarbonyl, Ci. ₃ -alkoxy, Ci- ₄ alkoxycarbonyl, benzyl, phenoxy, phenoxycarbonyl, benzylcarbonyl, C. _4- alkylcarbonyloxy-Cl. ₄ alkoxycarbonyl, phenylcarbonyloxy-C _1-4 alkoxycarbonyl, C ₁ -C ₄ ; ₆ alkylaminocarbonyl, phenylaminocarbonyl and phenyl-C _1-4 alkoxycarbonyl;

R ^{8 is} at each occurrence selected from H, CH ₃ and benzyl; otherwise R ⁷ and R ⁸ together form a morpholine group; and

R ^{9 is} at each occurrence selected from H, CH ₃ and benzyl.

[18] In yet another more preferred embodiment, the present invention provides novel compounds of formulas IIa-IIf, wherein:

R ^1a is absent or is selected from Ή, CH3, CH2CH3, Cl, F, CF3l OCH 3, NR ² R ^2a, S (O) pR ^2b, C (O) NR ² R ^2a, CH 2 S (O) pR ^2b CH2NR ² S (O) pR ^2b, C (O) R ^2c, CH 2 C (O) R ^2c irSO ₂ NR ² R ^2a;

R ^1b is absent or selected from H, CH 3, CH 2 CH 3, Cl, F, CF 3, OCH 3, NR ² R ^2a , S (O) p R ^2b , C (O) NR ² R ^2a , CH 2 S (O) p R ^2b , CH2NR ² S (O) pR ^2b, C (O) R ^2b, CH 2 C (O) R ^2b, NR ₂ irSO ² R ^2b;

A is selected from one of such carbocyclic and heterocyclic systems substituted with 0-2 R ⁴ ;

phenyl, pyridyl and pyrimidyl;

B is selected from: Y and Χ-Υ;

X is selected from -C (O) - and O;

Y is NR ² R _2a , provided that Χ-Υ does not form an ON bond:

otherwise, Y is selected from one of the following carbocyclic and heterocyclic systems substituted with 0-2 R ^4a :

phenyl, piperazinyl, pyridyl, pyrimidyl, morpholinyl, pyrrolidinyl, imidazolyl and 1,2,3-triazolyl;

R ^{2 is} at each occurrence selected from H, CF ₃ , CH ₃ , benzyl and phenyl;

R ^{2a is} at each occurrence selected from H, CF ₃ , CH ₃ , benzyl and phenyl;

R ^{2b is in} each case selected from CF ₃ , OCH ₃ , CH ₃ , benzyl and phenyl;

R ^{2c is} at each occurrence selected from CF ₃ , OH, OCH ₃ , CH ₃ , benzyl and phenyl; alternatively, R ² and R ^2a form a ring selected from pyrrolidinyl, piperazinyl and morpholine;

R ^{4 is} at each occurrence selected from Cl, F, CH 3, NR ² R ^2a and CF 3;

R ^{4a is} at each occurrence selected from Cl, F, CH 3, SO ² NR ² R ^2a , S (O) PR ⁵ and CF 3; R ⁵ at any occurrence, is selected from CF 3, CH _3, [19] Specifically preferred compounds of this invention are selected from the group consisting of:

1- (3-amidinophenyl) -2 - [[(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrrole;

- (3-amidinophenyl) -2 - [[(2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrrole;

1- (3-amidinophenyl) -2 - [[{2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] 4-bromopyrrole;

- (3-amidinophenyl) -2 - [[5- (2'-aminosulfonylphen-1-yl) pyridin-2-yl] aminocarbonyl] pyrrole;

benzyl-3 - [(2'-amino-sulfonyl- [1,1 '] - biphen-4-yl) -aminocarbonyl] -4- (3-amidinophenyl) -pyrrole;

1-benzyl-3 - [(2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -4 (3-amidinophenyl) pyrrole;

1- (3-amidinophenyl) -4 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] imidazole;

1- (3-amidinophenyl) -4 - [(2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4yl) aminocarbonyl] -imidazole;

- (3-amidinophenyl) -2 - [(2'-aminophenyl- [1,1 '] - biphen-4-yl) aminocarbonyl] imidazole;

1- (3-amidinophenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole;

- (3-amidinophenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carbonylamino] pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - [(2 '- (5' -CF ₃ -tetrazol [) - [1,1'] -biphen-4-yl) aminocarbonyl] pyrazole;

- (3-amidinophenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] 4-chloro-3-methylpyrazole;

- (3-amidinophenyl) -5 - ^((2: -t-butilaminosulfonif- [1,1 '] biphen-4-yl) aminocarbonyl] -3-trifluoromethyl-pyrazole;

1- (3-amidinophenyl) -4-methoxy-5 - ((2'-aminosulfonyl- [1,1 '] - biferi'4-yl)' aminocarbonyl] -3-trifluoromethyl-pyrazole;

1- (3-amidinophenyl) -3-methyl-5- (4 '- (imidazol-1-yl) phenyl) aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - [(4 '- (2' -sulfonylmethyl) phenoxyphenyl) aminocarbonyl] pyrazole;

- (3-amidinophenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4yl) methylcarbonylpyrazole;

1- (3-amidinophenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] 1,2,3-triazole;

1- (3-amidinophenyl) -5 - [(2'-trifluoromethyl- [1,1 '] - biphen-4-yl) aminocarbonyl] tetrazole;

1- (3-amidinophenyl) -5 - [(2'-aminosulfonyl-3-chloro- [1,1 '] - biphen-4-yl) methylthio) tetrazole;

1- (3-amidinophenyl) -5 - [(2'-aminosulfonyl-3-chloro- [1,1 '] - biphen-4yl) methylsulfoxide] tetrazole;

1- (3-amidinophenyl) -5 - [(2'-aminosulfonyl-3-chloro- [1,1 '] - biphen-4yl) methylsulfonyl] tetrazole;

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

- (3-amidinophenyl) -3-methyl-2 - [[5- (2'-aminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -3-methyl-2 - [[5- (2'-aminosulfonylphenyl-1-yl) pyrimidin-2-yl] aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - [(2'-aminosulfonyl-2-chloro [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole;

- (3-amidinophenyl) -3-methyl-5 - [(2'-aminosulfonyl-2-fluoro [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole;

- (3-amidinophenyl) -3-methyl-5 - [(2'-aminosulfonyl-4'-fluoro [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole;

- (3-amidinophenyl) -3-methyl-5 - [(2'-trifluoromethyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - [(3-chloro-2'-trifluoromethyl- ^[1,1!] Biphen-4-yl) aminocarbonyl;

1- (3-amidinophenyl) -3-methyl-5 - [(3-fluoro-2'-trifluoromethyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -3-methyl-2 - [[5- (2'-trifluoromethylphenyl-1-yl) pyridin-2-yl] aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - [(2'-fluoro- [1,1 '] -biphen-4-yl) aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - [(3-chloro-2'-fluoro- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole;

- (3-amidinophenyl) -3-methyl-5 - [(2'-methylsulfonyl- [1,1 '] - biphen-4yl) aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) (N'methyl) aminocarbonyl] pyrazole;

- (3-amidinophenyl) -3-n-butyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole;

- (3-amidinophenyl) -3-n-butyl-5 - [((2'-aminosulfonylphenyl-1-yl) pyridin-2-yl) aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -3-n-butyl-5 - [((2'-trifluoromethylphenyl-1-yl) pyridin-2-yl) aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -5 - [(2'-methylsulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-trifluoromethyl-pyrazole;

1- (3-amidinophenyl) -5 - [(2'-trifluoromethyl- [1,1]] -biphen-4-yl) aminocarbonyl] -3-trifluoromethyl-pyrazole;

1- (3-amidinophenyl) -4-methoxy-5 - [(2'-trifluoromethyl- [1,1 T] -biphen-4-yl) aminocarbonyl] -3-trifluoromethyl-pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - [(4-trifluoromethylphenyl] aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -4-methyl-5 - [(2'-aminosulfonyl- [1,1] '] -biphen-4-yl) aminocarbonylimidazole;

1- (3-amidinophenyl) -5 - [((2'-aminosulfonylphenyl-1-yl) pyridin-2-yl) aminocarbonyl] -1,2,3-triazole;

1- (3-amidinophenyl) -5 - [(2'-trifluoromethyl- [1,1 '] - biphen-4-yl) aminocarbonyl] 1,2,3-triazole;

1- (3-amidinophenyl) -5 - [(2'-aminosulfonyl- [1,1 T] -biphen-4-yl) aminocarbonyl] 3-trifluoromethyl-1,2,4-triazole;

3-methyl-1- (3-amidinophenyl) -5- (4 '- ^(4' -chiorfenil) thiazol-2'yl) aminocarbonyl] pyrazole;

1- (3-amidino) phenyl-3-methyl-5 - [(2'-trifluoromethylsulfido [1,1] biphen-4-yl) aminocarbonyl] pyrazole;

1- (3-amidino) phenyl-3-methyl-5 - [(2'-trifluoromethylsulfoxido [1,1] biphen-4-yl) aminocarbonyl] pyrazole;

1- (3-amidino) phenyl-3-methyl-5 - [(2'-trifluoromethylsulfonyl- [1,1] biphen-4-yl) aminocarbonyl] pyrazole;

1- (3-amidino) phenyl-3-methyl-5- [4 '- (carboxymethyl) phenylaminocarbonyl] pyrazole;

1- (3-amidino) phenyl-3-methyl-5- [4 '- (N, N-dimethylaminocarbonyl) phenylaminocarbonyl] pyrazole;

1- (3-amidino) phenyl-3-methyl-5- [4 '- (N, N-dimethylaminosulfonyl) phenylaminocarbonyl] pyrazole;

1- (3-amidino) phenyl-3-methyl-5 - [(4'-tert-butylaminosulfonylphenyl) aminocarbonyl] pyrazole;

1- (3-amidino) phenyl-3-methyl-5 - [(4'-aminosulfonylphenyl) aminocarbonyl] pyrazole;

- (3-amidino) phenyl-3-methyl-5 - [(4'-trifluoromethylphenyl) aminocarbonyl] pyrazole;

1- (3-amidino) phenyl-3-methyl-5 - [(4'-benzylsulfonylpiperidyl) -aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) -N-methylaminocarbonyl] -3-methylpyrazole;

1- (3-amidinophenyl) -5 - [(4'-fluoro- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methylpyrazole;

1- (3-amidinophenyl) -5 - [[5- (2'-aminosulfonylphenyl) pyridin-2-yl] aminocarbonyl] -3-methylpyrazole;

- (3-cyanophenyl) -5 - [[5- (2'-aminosulfonylphenyl) pyridin-2-yl] aminocarbonyl] 3-methylpyrazole, ·

1- (3-amidinophenyl) -5 - [(2'-trifluoromethyl- [1,1 '] - biphen-4-yl) -aminocarbonyl] -3-methyl-pyrazole;

1- (3-aminocarbonylphenyl) -5 - [(2'-aminophenyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methylpyrazole;

1- (3-amidinophenyl) -5 - [(2'-aminosulfonyl) -3-chloro- [1,1 T] -biphen-4-yl) aminocarbonyl] -3-methylpyrazole;

- (3-amidinophenyl) -5 - [(2'-trifluoromethyl-3-chloro- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methyl-pyrazole;

- (3-amidinophenyl) -5 - [(2'-aminosulfonyl) - [1,1 '] - biphen-4-yl) aminocarbonyl] 3-n-bulylpyrazole;

1- (3-amidinophenyl) -5 - [(2'-trifluoromethyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3n-butylpyrazole;

1- (3-amidinophenyl) -5 - [[5- (2'-aminosulfonylphenyl) pyridin-2-yl] aminocarbonyl] -3-n-butylpyrazole;

1- (3-amidinophenyl) -5 - [(2'-trifluoromethyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-trifluoromethyl-4-methoxypyrazole;

1- (3-amidinophenyl) -5 - [(2'-trifluoromethyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-trifluoromethyl-pyrazole;

1- (3-amidinophenyl) -5 - [(2'-sulfonylmethyl- [1,1 T] -biphen-4-yl) aminocarbonyl] -3-trifluoromethylpyrazole;

1- (3-amidinophenyl) -5 - [(2'-aminosulfonyl-3-bromo- [1,1 T] -biphen-4-yl) aminocarbonyl] -3-methylpyrazole;

- (3-aminocarbonylphenyl) -5 - [(2'-aminosulfonyl-3-bromo- [1,1 '] - biphen-4'L) aminocarbonyl] -3-methylpyrazole;

1- (3-amidinophenyl) -3-methyl-5 - [(2'-aminosulfonyl) - [1,1 T] -biphen-4-yl) methylcarbonyl] pyrazole;

1- (3-aminocarbonylphenyl) -5- [5 - [(2'-aminosulfonylphen-1-yl) pyridin-2-yl] aminocarbonyl] -3-methylpyrazole;

1- (3-amidinophenH) -5 - [[5- (2'-t-butylaminosulfonylphenyl) pyrimidin-2-yl] aminocarbonyl] -3-trifluoromethylpyrazole;

1- (3-amidinophenyl) -5 - [[5- (2'-aminosulfonylphenyl) pyrimidin-2-yl] aminocarbonyl] -3-trifluoromethylpyrazole;

1- (3-aminocarbonylphenyl) -5 - [[5- (2'-aminophenylphenyl) pyrimidin-2-yl] aminocarbonyl] -3-trifluoromethylpyrazole;

1- (3-cyanophenyl) -5 - [((4 '- (imidazol-1-yl) phenyl) aminocarbonyl] -3-trifluoromethylpyrazole;

1- (3-amidinophenyl) -5 - [(4 '- (morpholin-1-yl) phenyl) aminocarbonyl] -3-trifluoromethylpyrazole;

1- (3-aminocarbonylphenyl) -5 - [(4 '- (morpholin-1-yl) phenyl) aminocarbonyl] -3-trifluoromethylpyrazole;

- (3-amidinophenyl) -5 - [[5- (2'-aminosulfonylphenyl) pyridin-2-yl] aminocarbonyl] -3-trifluoromethylpyrazole;

1- (3-aminocarbonylphenyl) -5 - [[5- (2'-aminosulfonylphenyl) pyridin-2-yl] aminocarbonyl] -3-trifluoromethylpyrazole;

1- (3-amidinophenyl) -5 - [(4 '- (3-methyltetrazol-1-yl) phenyl) aminocarbonyl] -3-trifluoromethylpyrazole;

1- (3-Amidinophenyl) -5- (2'-naphthylaminosulfonyl) -3-methylpyrazole:

1- (3-amidinophenyl) -5 - [(4-bromophenyl) aminosulfonyl] -3-methylpyrazole;

- (3-aminomethylphenyl) -5 '[(2'-aminosulfonyl) - [1,1'] - biphen-4-yl) aminocarbon [] - 3-methylpyrazole;

1- (3-Aminomethylphenyl) -5 - [(2'-aminosulfonyl) - [1,1 '] - biphen-4-yl) aminocarbonyl] -3-trifluoromethylpyrazole;

1- (3-amidinophenyl) -3-methyl-5 - [((2'-trifluoromethylphenyl) pyrid-2-yl) aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - [((2'-aminosulfonyl-1-yl) pyrimidin-5-yl) aminocarbonyl] pyrazole;

- (3-amidinophenyl) -3-methyl-5 - [(2'-fluoro- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -3-methyl-5- [3-chloro- (2'-fluoro- [1,1] T-biphen-4-yl) aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - [(3-fluoro-2'-fluoro- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole;

- (3-amidinophenyl) -3-methyl-5 - [(3-fluoro-2'-aminosulfonyl- [1,1] -biphen-4-yl) aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -3-methyl-5- [5- (2'-fluorophen-1-yl) pyrid-2-yl] aminocarbonyl] pyrazole;

- (3-amidinophenyl) -3-methyl-5 - [[5- (2'-tetrabutylaminosulfonylphenyl] pyrimid-2ii] aminocarbonyl] pyrazo (o:

1- (3-amidinophenyl) * 3-methyl-5 - [[5- (2'-aminosulfonylphenyl] - _[1> 6] dihydropyrimidine-2-yl] aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - [(4- (pyrid-3'-yl) phen-1-yl) aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - [[2- (2'-pyridyl) ethyl] aminocarbonyl] pyrazole:

1- (3-amidinophenyl) -3-methyl-5 - [(3-phenylpropyl) aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -3-methyl-5- [4- (pyrid-2'-yl) phenyl-1-ylaminocarbonyl] pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - [(4- (isopropyloxy) phenyl) aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - [(5- (2'-trifluoromethylphenyl) pyrimidin-2-yl) aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - [(4- (piperidinosulfonyl) phenyl) aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - [(4- (piperidinocarbonyl) phenyl) aminocarbonyl] pyrazole;

1- (3-amidino-4-fluorophenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole;

- (3-aminocarbonyl-4-f) fluorophenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen4-yl) aminocarbonyl] pyrazole;

1-methyl-3- (3-amidino) phenyl-4 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - [[4- (pyrazol-4'-yl) phen-1-yl] aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - ([5- (2'-methylsulfonylphenyl) pyrid-2-yl] aminocarbonyl) pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - ([5- (2'-methylsulfonylphenyl) pyrimidin-2-yl] aminocarbonyl) pyrazole;

- (3-cyanophenyl) -3-methyl-5 - ([5- (2'-methylsulfonylphenyl) pyrimidin-2-yl] aminocarbonyl) pyrazole;

1- (3-aminocarbonylphenyl) -3-methyl-5 - ([5- (2'-methylsulfonylphenyl) pyrimidin-2-yl] aminocarbonyl] pyrazole;

1- (3- (N-aminoamidino) phenyl) -3-methyl-5 - [(2'-tert-butylaminosulfonyl- [1,1 '] biphen-4-yl) aminocarbonyl] pyrazole;

1- (3- (N-aminoamidino) phenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1 J] -biphen-4-yl) aminocarbonyl] pyrazole;

1- (3- (N-methyl-N-hydroxyamidino) phenyl) -3-methyl-5 - [(4'-t-butylaminosulfonyl [1,1'j] biphen-4-yl) aminocarbonyl] pyrazole;

1- (3- (N-methylamidino) phenyl) -3-methyl-5 - [(2'-tert-butylaminosulfonyl- [1,1 '] biphen-4-yl) aminocarbonyl] pyrazole;

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

1- (3-amidinophenyl) -5 - [(2'-aminosulfonylphenyl) pyridin-2-yl] aminocarbonyl] tetrazole;

1- (3-aminocarbonylphenyl) -5 '{[5- (2'-aminosulfonylphenyl) pyridin-2-yl] aminocarbonyl} tetrazole;

1- (3-amidinophenyl) -5 - {[5- (2'-trifluoromethylferi'1-yl) pyridin-2-yl] aminocarbonyl} tetrazole;

1- (3-amidinophenyl) -5 - [(4'-bromophen-1-H) aminocarbonyl] tetrazole;

1- (3-aminocarbonylphenyl) -5 - {'- 5- (2'-trifluoromethylphen-1-yl) pyridin-2-yl] aminocarbonyl} tetrazole;

5- (3-amidinophenyl) -1 - [(2'-trifluoromethyl- [1,1 '] - biphen-4-yl) methyl] tetrazole:

- [(3-amidinophenyl) methyl] -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole;

1 - [(4-amidinophenyl) methyl] -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -2 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] imidazole;

1- (3-amidinophenyl) -4-methyl-2 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) · aminocarbonyl] imidazole;

1- (3-amidinophenyl) -5-chloro-4-methyl-2 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] imidazole;

5- (3-amidinophenyl) -2-methyl-4 - [(2'-aminosulfonyl- [1,1 T] -biphen-4-yl) aminocarbonyl] imidazole;

1- (3-amidinophenyl) -3-methyl-5 - [(4 '- (benzimidazol-1-yl) phen-1-yl) aminocarbonyl] pyrazole;

1- (3-aminocarbonylphenyl) -3-methyl-5 - [(4'-benzimidazol-1-yl) phen-1-yl) aminocarbonyl] pyrazole;

- (3-amidinophenyl) -3-methyl-5 - [(4 '- (2-methylimidazol-1-yl) phenyl) aminocarbonite] pyrazole;

1- (3-aminocarbonylphenyl) -3'methyl-5 - [(4 '- (2-methylimidazol-1-yl) phenyl) aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - [(4 '- (1,2,3-triazol-2-yl) phenyl) aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - ((4'-cyclohexylphenyl) aminocarbonyl) pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - [[1,1 '] - biphen-4-ylaminocarbonyl] pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - ((4'-molinolinophenyl) aminocarbonyl) pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - [(4 '- ((2-trifluoromethyl) tetrazol-1-yl) phenyl) aminocarbonyl] pyrazole;

1- (3-aminomethylphenyl) -3-methyl-5 - [(4 '- ((2-trifluoromethyl) tetrazol-1-yl) phenyl) aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - [((4 '- (N, N-dimethylamino) carbonylamino) phenyl) aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - [(4 '- (N, N-diethylamino) phenyl) aminocarbonyl] pyrazole;

1- (3-aminocarbonylphenyl) -3-methyl-5 - [((4 '- (N, N-diethylamino) phenyl) aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - [(4 '- (1-tetrazolyl) phenyl) aminocarbonyl] pyrazole;

1- (3-aminocarbonylphenyl) -3-methyl-5 - ((441-tetrazolyl) phenyl) aminocarbonyl) pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - [(4 '- (N-acetylpiperazin-1-yl) phenyl) aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - [(4 '- (N-tert-butyloxycarbonylpiperazin-1 (a) phenyl) aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - ((4'-piperazin-1-yl) phenyl) aminocarbonyl) pyrazole;

1- (3-amidinophenyl) -3-trifluoromethyl-5 - ((4'-cyclohexylphenyl) aminocarbonyl) pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - [(4 '- (N-morpholino) -3'-chlorophenyl) aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -5 - [(2'-aminosulfonyl- [1,1] biphen-4-yl) aminocarbonyl] 3- (methylthio) pyrazole;

1- (3-amidinophenyl) -5 - [(2'-aminosulfonyl- [1,1 '], biphen-4-yl) aminocarbonyl] 3- (methylsulfin [) pyrazole;

1- (3-amidinophenyl) -5 - ^[(2, -aminosulfonil- [1 _{T H} E] -biphen-4-yl) aminocarbonyl] -3- (metilsulfor) II) pyrazole;

1- (3-aminocarbonylphenyl) -5 - [(2'-trifluoromethyl- [1,1 T] -biphen-4-yl) methyl] tetrazole;

1- (3-aminokarbonilfeniJ) -5 - ^{[(2, -aminosulfonil- [1,1 '] - biphen-4-yl) methyl} tetrazole;

1- (3-amidinophenyl) -5 - [(4'-cyclopentyloxyphenyl) aminocarbonyl] -3-methylpyrazole;

1- (3-amidinophenyl) -5 - [(3 - ((pyrid-2-yl) methylamino) phenyl) aminocarbonyl] -3-methylpyrazole;

1- (3-amidinophenyl) -3-methyl-5 - [(4 '- (N-imidazolyl) phenyl) aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -3-trifluoromethyl-5 - [(4 '- (N-morpholino) -3-chlorophenyl) aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - [(4 ^: - (N-pyrrolidinocarbonyl) -3'-chlorophenyl) aminocarbonyl] pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - [(4 '- (N-morpholinocarbonyl) -3-chlorophenyl) aminocarbonyl] pyrazole;

1- (3-cyanophenyl) -5 - [(4 '- (N-imidazolyl) phenyl) aminocarbonyl] -3-trifluoromethylpyrazole;

1- (3-amidinophenyl) -5 - [(4 '- (N-imidazolyl) phenyl) aminocarbonyl] -3-trifluoromethylpyrazole;

1- (3-amidinophenyl) -5 - [(4 '- (N-methyltetrazolon-1-yl) phenyl) aminocarbonyl] -3-trifluoromethyl-pyrazole;

- (3'-aminocarbonylphenyl) -5 - [(2'-aminosulfonylphenyl- [1,1 '] - biphen-4yl) methylcarbonyl] -3-methylpyrazole;

1- (3-amidinophenyl) -5- [4 '- (pyrrolidinomethyl) phenyl) aminocarbonyl] -3-methylpyrazole;

1- (3-aminophenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole;

1- (2'-Aminophenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole;

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

1- (3-amino-4'-fluorophenyl) -3-methyl-5 - [(2'-aminosulfonyl ^[1,1!] Biphen-4-yl) aminocarbonyl;

1- (3-amino-4'-methoxyphenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole;

1- (3-amino-4'-chlorophenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] tetrazole;

1- (3-amino-4'-chlorophenyl) -5 - {[(2'-aminosulfonylphenyl) pyridin-2-yl] aminocarbonyl] -tetrazole;

1- (3-amino-4'-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1 _a 1 '] - biphen-4-yl) aminokarboniljtetrazolo;

1- (3-Aminomethylphenyl) -5 - [(2'-aminosulfonylphenyl) pyrid-2-yl] aminocarbonyl] 3-methylpyrazole;

1- (3-Aminomethyl-4'-methyl-phenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) -aminocarbonyl] -3-methyl-pyrazole;

1- (3-aminomethyl-4'-fluorophenyl) -5 - [(2'-aminosulfonyl- ^[1,1] -biphen-4-yl) aminocarbonyl] -3-methyl-pyrazole;

1- (3-aminomethylphenyl) -5 - [(4 '- (N-pyrrolidinocarbonyl) phenyl) aminocarbonyl] 3-trifluoromethyl-pyrazole;

- (3-etilkarboksiamidinofenil) -5 - [(2'-aminosulfonyl- [1.1 ^1] -biphen-4-yl) aminocarbonyl] -3-methyl-pyrazole;

1- (3- (1'-imino-1 '- (N-morpholino)) methyl) phenyl) -5 - [(2'-tert-butylaminosulfonyl [1,1'] - biphen-4-yl) aminocarbonyl ] -3-methylpyrazole, '

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

1- [3- [N - ((5-methyl-2-oxo-1,3-dioxol-4-yl) methoxycarbonyl) amidino] phenyl] 5 - ((2'-aminosulfonyl- [1,1] biphenyl) -4-yl) aminocarbonyl) -3-methylpyrazole;

1- (pyrid-2-yl) -3-methyl-5 - [(3-fluoro-2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole;

1- (6-Bromopyridin-2-yl) -3-methyl-5 - [(3-fluoro-2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole;

1- (3-amino-4-chlorophenyl) -5 - ^[(2! -Aminosulfonil-3-chloro- [1,1 '] - biphen-4-yl) aminokarboniljtetrazolo;

1- (3-amino-4-chlorophenyl) -5 - [(4 '- (1-pyrrolidinocarbonyl) phenyl) aminocarbonyl] tetrazole;

1- (3-aminomethylphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] tetrazole;

- (3-aminomethylphenyl) -5 - [(2'-aminosulfonyl-3-fluoro- [1,1 '] - biphen-4-yl) aminocarbonyl] tetrazole;

- (3-aminomethylphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] imidazole;

1- (3-aminomethylphenyl) -5 - [(2'-methylsulfonylmethyl- [1,1 '] - biphen-4-yl) aminocarbonyl] imidazole;

1- (3-amidinophenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] imidazole;

1- [3- (methylaminomelyl) phenyl] -5 - [(2'-aminosulfonyl-3-fluoro [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methylpyrazole;

1- [3- (methylaminomethyl) phenyl] -5 - [(2'-methylsulfonyl-3-fluoro [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methylpyrazole;

1- (3-Aminomethylphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -4'methoxy-3-trifluoromethyl-pyrazole;

- (3-aminomethylphenyl) -5 - [(2-fluoro-4- (N-pyrrolidinocarbonyl) phenyl) aminocarbonyl] -3-trifluoromethylpyrazole;

1- (3-aminomethylphenyl) -5 '- [(3-fluoro-4- (N-pyrrolidinocarbonyl) phenyl) aminocarbonyl] -3-trifluoromethylpyrazole;

- (3-aminomethylphenyl) -5 - [(2'-sulfonylmethyl- [1,1 '] - biphen-4-yl) aminocarbonyl] 3-trifluoromethyl-pyrazole;

- (3-aminomethylphenyl) -5 - [(2'-aminosulfonyl-3-fluoro [1,1 '] - biphen-4-yl) aminocarbonyl] -3-trifluoromethyl-pyrazole;

1- (3-aminomethylphenyl) -5 - [(2'-aminosulfonylphenyl- [1,6-dihydro] pyrimidin-2-yl) aminocarbonyl] -3-trifluoromethyl-pyrazole;

1- (3-aminomethylphenyl) -5 - {(5- (2'-aminosulfonylphenyl) pyrimidin-2-yl) aminocarbonyl] -3-trifluoromethyl-pyrazole;

1- [3- (2'-Ethylaminophenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-trifluoromethyl-pyrazole;

1- [3- (1- (N-Morpholino) imino) phenyl) -5 - [(2'-aminosulfonyl-3-fluoro [1,1 '] biphen-4-yl) aminocarbonyl] -3-trifluoromethyl -pyrazole;

1- (3-Aminomethylphenyl) -5- [2- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) -1-hydroxyethyl] -3-trifluoromethyl-pyrazole;

1- (3-Aminomethylphenyl) -5 - [(3-fluoro-2'-methylsulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-trifluoromethyl-pyrazole;

1- (3-aminomethylphenyl) -5 - [(5- (2'-methylsulfonylphenyl) pyrimidin-2-yl) aminocarbonyl] -3-trifluoromethyl-pyrazole;

- (3-amidinophenyl) -5 - [(3-fluoro-2'-methylsulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-trifluoromethyl-pyrazole;

- (3-amidinophenyl) -5 - ^{[(3-fluoro-2,} -aminosulfonil- [1,1 '] biphen-4-yl) aminocarbonyl] -3-trifluoromethyl-pyrazole;

1- (3-aminomethyl) Fenn-5 - [(2'-aminosulfonyl [1,1 ^i] biphen-4-yl) carbonylmethyl] -3-trifluoromethyl-pyrazole;

1- (3-aminomethyl) phenyl-5 - [(2'-aminosulfonyl ^[1,1!] Biphen-4-yl) aminocarbonyl] -3- (metilsulfonilmetil) pyrazole;

1- (3-amidino) phenyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] 3- (methylaminosulfonylmethyl) pyrazole;

1- (3-Aminomethylphenyl) -5 - [(2'-aminosulfonyl-3-fluoro [1.1 '] - biphen-4-yl) aminocarbonyl] -3- (methylaminosulfonylmethyl) pyrazole:

1- (3- (N-carboxymethyl) amidinophenyl) -5 - [(5- (2'-aminosulfonylphenyl) pyrimidin-2-yl) aminocarbonyl] -3-methylpyrazole;

1- (3-aminomethylphenyl) -5 - [(2'-methylsulfonyl- [1,1'J-biphen-4-yl) aminocarbonyl] -3-methylpyrazole;

1- (3-aminomethylphenyl) -5 - [(2'-aminosulfonyl-3-methyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-trifluoromethyl-pyrazole;

1- (3-aminomethylphenyl) -5 - [(3-fluoro-2'-methylsulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -1,2,3-triazole;

1- (3-Aminomethyl-4-methyl) -phenyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methyl-pyrazole:

- (3-aminomethyl-4-fluoro) phenyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methyl-pyrazole;

- (3-aminomethyl-4-chloro) phenyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methylpyrazole;

1- (3-Aminomethyl-4-fluoro) -phenyl-5 - [(2'-aminosulfonyl-3-fluoro [1,1 '] - biphen-4-yl) -aminocarbonyl] -3-trifluoromethyl-pyrazole;

- (3-aminomethyl) phenyl-5 - [(2'-aminosulfonyl-3-fluoro [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methylpyrazole;

1- (3-Aminomethyl) phenyl-5 - [(3-fluoro-2'-methylsulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-trifluoromethyl-pyrazole;

1- (3-amidinophenyl) -3-methyl-5 - [(3-fluoro-4- (N-morphohno) phenyl) aminocarbonyl] pyrazole;

1- (3-Aminomethylphenyl) -3-methyl-5 - [(3-fluoro-4- (N-mololino) phenyl) aminocarbonyl] pyrazole;

1- (3-aminomethylphenyl) -3-trifluoromethyl-5 - ((3-fluoro-4- (2-methylimidazol-1-yl) phenyl) aminocarbonyl) pyrazole;

- (3-cyanophenyl) -3-trifluoromethyl-5 - (([1,1 '] - biphen-4-yl) oxymethyl) pyrazole;

- (3-amidinophenyl) -3-trifluoromethyl-5 - (([1,1 '] - biphen-4-yl) oxymethyl) pyrazole;

1- (3-carboxamidophenyl) -3-trifluoromethyl-5 - (([1,1 '] - biphen-4-yl) oxymethyl) pyrazole;

1- (3-amidinophenyl) -3-trifluoromethyl-5 - ((2-fluoro-4- (N-morpholino) phenyl) aminocarbonyl) pyrazole;

1- (3-Carboxamidophenyl) -3-trifluoromethyl-5 - ((2-fluoro-4- (N-morpholino) phenyl) aminocarbonyl) pyrazole;

1- (3-aminomethylphenyl) -3-trifluoromethyl-5 - ((3-trifluoromethyl-4- (N-morpholino) phenyl) aminocarbonyl) pyrazole;

- (3-aminomethylphenyl) -3-ethyl-5 - [(3-fluoro-2'-tert-butylaminosulfonyl- [1,1 '] biphen-4-yl) aminocarbonyl] pyrazole;

1- (3-aminomethylphenyl) -3-ethyl-5 - ((3-fluoro-2'-methylsulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl) pyrazole;

- (3-aminomethylphenyl) -3-ethyl-5 - [(2-fluoro-4- (2-methylsulfonylimidazol-1-yl) phenyl)] aminocarbonyl) pyrazole;

1 - [(6- (aminomethyl) pyrid-2-yl)] - 3-methyl-5 - [(2'-aminosulfonyl- [1,1 T] -biphen-4-yl) aminocarbonyl] pyrazole;

1 - [(6- (N-hydroxyamidino) pyrid-2-yl)] - 3-methyl-5 - [(2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole;

1- [6-amidinopyrid-2-yl] -3-methyl (-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl) pyrazole;

- [6-amidinopyrid-2-yl] -3-methyl-5- [3-fluoro- (2'-methylsulfonyl- [1,1 '] - biphen-4yl) -aminocarbonyl] pyrazole;

1- (3-aminomethylphenyl) -3-methyl-5 - ((2-methoxy-4- (N-morpholino) phenyl) aminocarbonyl) pyrazole;

1- (3-aminomethylphenyl) -3-methyl-5- [4 '- (3' -methyl-5 '-oxo-3' -pyrazolin-2 '-yl) phenyl) aminocarbonyl] pyrazole;

1- [3- (aminomethyl) phenyl] -5 - [(2'-methylsulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3- (methylthio) pyrazole;

1- (3-Aminomethyl-4-fluorophenyl) -3-trifluoromethyl-5 - [(3-fluoro-2'-methylsulfonyl [1,1] biphen-4-yl) aminocarbonyl] pyrazole;

1- [3- (aminomethyl) phenyl] -5- [3-fluoro-2'-methylsulfonyl- [1,1 '] -biphen-4-yl) aminocarbonyl] pyrazole-3-carboxylic acid ethyl ester;

- [3- (aminomethyl) -phenyl] -5- [3-fluoro-2'-methylsulfonyl- [1,1 '] -biphen-4-yl) aminocarbonyl] pyrazole-3-carboxylic acid;

1- [3- (aminomethyl) phenyl] -3- [aminocarbonyl] -5- [3-fluoro-2'-methylsulfonyl [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole;

1- [3- (aminomethyl) phenyl]. -3-trifluoromethyl-5 - [(3-fluoro-2'-methylsulfonyl- [1,1 '] biphen-4-yl) aminocarbonyl] pyrazole-4- ethyl carboxylic acid ester;

1- [3- (aminomethyl) phenyl] -5 - [(3-fluoro-2'-methylsulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3- (methylthio) pyrazole;

- [3- (aminomethyl) phenyl] -5 - [(3-fluoro-2'-methylsulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3- (methylsulfonyl) pyrazole;

1- [3- (aminomethyl) phenyl] -5 - [(4- (5- (methoxyaminocarbonyl) imidazol-1-yl) phen-14] aminocarbonyl] -3-trifluoromethyl-pyrazole; and

- (3-aminomethylphenyl) -5 - [(4- (5-methyl-1,2,3-triazol-1-yl) phen-1-yl) aminocarbonyl] -3-trifluoromethyl-pyrazole; and pharmaceutically acceptable salts thereof.

In a second embodiment, the present invention provides novel pharmaceutical compositions comprising a pharmaceutically acceptable carrier and an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In a third embodiment, the present invention provides a novel method of treatment or prophylaxis of thromboembolic disorders comprising administering to a patient in need of such treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

DEFINITIONS

The compounds described herein may have asymmetric centers. The compounds of the present invention having an asymmetrically substituted atom may be isolated in optically active or racemic forms. Those skilled in the art will know how to make optically active forms, for example, by resolution of racemic forms or by synthesis from optically active starting materials. The compounds described herein may also contain various olefins, C = N double bonds, and the like. geometric isomers, and the present invention includes all such stable isomers. The geometric eis and trans isomers of the compounds of the present invention are described and may be isolated either as a mixture of isomers or as individual isomeric forms. Unless a particular stereochemistry or isomeric form is specified, all chiral, diastereomeric, racemic forms and all geometric isomeric forms of this structure are meant.

As used herein, the term "substituted" means that one or more hydrogens at the specified atom is substituted with one of the specified groups, provided that the normal atomic valence of the indicated atom is not exceeded and that the substitution produces a stable compound. If the substituent is a keto group (i.e. = 0) then 2 hydrogens are substituted on that atom.

If any variable (eg R ⁶ ) occurs more than once in any part of a compound or formula, its value is in any case independent of its value otherwise. For example, if it is shown that there are 0-2 substituents on R ⁶ in the group, then there may be up to two R ⁶ groups in said group, and R ^{6 is} in any case independently selected from the set of R ⁶ groups. In addition, combinations of substituents and / or variables are permissible only to give stable compounds.

If the substituent bond is shown to cross to connect the two atoms of the ring, then such substituent may be attached to any atom of the ring. If no substituent atom is attached which is attached to the remainder of the compound of the formula given, such substituent may be attached via any substituent atom. Combinations of substituents and / or variables are permissible only to give stable compounds.

As used herein, the term "C 1-6 alkyl" means that branched and unbranched aliphatic hydrocarbon groups having the specified number of carbon atoms 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 understood to include straight or branched chain hydrocarbon chains and one or more unsaturated carbon bonds which may be in any stable position in the chain, such as ethenyl, propenyl, etc.,

As used herein, the terms "Hal" or "halogen" refer to fluorine, chlorine, bromine or iodine; o 'counterion refers to small particles of negative charge, such as chloride, bromide, hydroxide. acetate, sulfate and the like.

As used herein, the term "carbocycle or" carbocyclic residue "refers to any stable 3-7 membered monocyclic or bicyclic, or 7-13 membered bicyclic or tricyclic group, which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl; [3.3.0] bicyclooctane, [4.3.0] bicycllononane, [4.4.0] bicyclooctane (decalin), [2.2.2] bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl or tetrahydronaphthyl (tetralin).

As used herein, the term "heterocycle" or "heterocyclic system" refers to any stable 5-7 membered monocyclic or bicyclic, or 7-10 membered bicyclic heterocyclic ring, saturated, partially unsaturated, or unsaturated (aromatic) and containing carbon atoms and 1-4 heteroatoms independently selected from the group consisting of N, O and S, and includes any bicyclic group in which any of the above heterocyclic rings are fused to a benzene ring. Nitrogen and sulfur heteroatoms may be oxidized if desired. The heterocyclic ring may be attached via its optional group to any heteroatom or carbon atom which gives a stable structure. The heterocyclic rings described herein may be substituted on carbon or nitrogen atoms if the resulting compound is stable. If specifically noted, the nitrogen atom of the heterocycle may be quaternized. Preferably, if the total number of S and O atoms in the heterocycle is greater than 1, these heteroatoms need not be adjacent to one another. Preferably, the total number of S and O atoms in the heterocycle is not greater than 1. As used herein, the term "aromatic heterocyclic system" means any stable 5-7 membered monocyclic or bicyclic, or 7-10 membered bicyclic heterocyclic aromatic ring containing carbon. atoms and 1-4 heteroatoms independently selected from the group consisting of N, O and S. Preferably, the total number of S and O atoms in the aromatic heterocycle is not greater than 1.

Heterocycle moieties include, but are not limited to, 1H-indazole, 2-pyrrolidinyl, 2H, 6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2, 5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiophuranyl, benzothiophenyl, benzothiazolyl, benzthiazolyl, benzisoxazolyl, carbazolazolyl, benzazothiazolyl, carbazolyl, 4a 6H-1,5,2-dithiazinyl, dihydrofuro [2,3b] -tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isochromanyl, iso isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxad. iazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolidinylpyrimidinyl, phenanthridinyl, phenanthrolinyl, phenoxazinyl, oxazolyl, fenarazinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phthalazinyl, piperazinyl, piperidinyl, piperidinyl, piperidinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, pyrrolyl, quinazolinyl, quinolyl, 4H-quinolizinyl, quinoxalinyl, quinucanilyl 2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiazolyl, thiantrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thienophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthate Nile. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl or isatino. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

As used herein, the phrase "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms which, according to the medical description, are suitable for use in contact with human or animal tissues without causing excessive toxicity, irritation, allergic response or other problems and complications. benefit / risk ratio.

As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the compounds of the invention in which the parent compounds are modified to form their salts with acids or bases. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of basic residues, such as amino groups, with mineral or organic acids; alkaline or organic salts of acidic residues such as carboxy groups; and etc. Pharmaceutically acceptable salts include the ordinary non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, with non-toxic inorganic or organic acids. For example, such common non-toxic salts include salts derived from inorganic acids such as hydrochloric, hydrobromic, sulfate, sulfamic, phosphate, nitrate and the like; and salts derived from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamo, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanyl, 2-acetoxybenzoic, fumar, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxal, isethion and the like. of acids.

Pharmaceutically acceptable salts of the compounds of this invention may be synthesized from the parent compound having a basic or acidic residue by conventional chemical means. Typically, such salts may be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the corresponding base or acid in water or an organic solvent, or a mixture of both: typically non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. A list of suitable salts is found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418, which is given here as a source of literature.

"Prodrugs" are intended to encompass any covalently attached carrier which will release the active parent drug of formula (I) of the present invention when administered to a mammal. Prodrugs of a compound of formula (I) of the present invention are prepared by modifying the functional groups present in the compound such that such modifications are cleaved either by conventional manipulation or in vivo to the parent compound. Prodrugs are compounds of the present invention wherein the hydroxyl, amino or sulfhydryl group is attached to a group such that when such a prodrug of a compound of formula (i) is obtained in a mammal, it is cleaved to form a free hydroxyl, amino or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate or benzoate derivatives of alcohol and amino functional groups of compounds of formula (I), and the like. Preferred prodrugs are amidine prodrugs wherein D is C (= NR ⁷ ) NH 2 or their tautomer C (= NH) NHR ⁷ and R ⁷ is selected from OH, Ci. _4- alkoxy, β-ι-aryloxy, C _1-4 -alkoxycarbonyl, C ₆ -io-aryloxycarbonyl, C ₆ -arylmethylcarbonyl, Ci. _4- alkylcarbonyloxy-C ₁ . _4- alkoxycarbonyl and C 6-10 arylcarbonyloxy-C _1-4 alkoxycarbonyl. Particularly suitable prodrugs are those wherein R ⁷ is OH, methoxy, ethoxy, benzyloxycarbonyl, methoxycarbonyl and methylcarbonyloxymethoxycarbonyl.

"Stable compound and" stable structure "is intended to mean a compound which is sufficiently resistant to withstand isolation from the reaction mixture to an appropriate degree of purity and preparation of an effective therapeutic agent composition.

SYNTHESIS

The compounds of the present invention can be prepared by various methods known to those skilled in the art of organic synthesis. The compounds of the present invention may be synthesized using the methods described below, in conjunction with synthetic methods known in the art of organic chemistry, or employing variations known to those skilled in the art. The preferred methods are, but are not limited to, those described below. Reactions are carried out on reagents and materials used, and in a solvent suitable for transformation. It will be clear to those skilled in the art of organic synthesis that the functional group present in the molecule must conform to the proposed transformations. In order to obtain the desired compound of the present invention, it may sometimes be necessary to modify the order of the synthetic steps or to select a particular process scheme. It should also be recognized that another important consideration in planning the synthesis pathway in this field is the intelligent selection of the blocking group used to block the reactive functional groups of the compounds of the present invention. An authoritative review describing various alternatives to an experienced practitioner is Greene and Wuts (Protective Groups in Organic Synthesis, Wiley and Sons, 1991). All references cited herein are hereby incorporated by reference in their entirety.

Compounds of formula I wherein ring M is pyrrole may be prepared according to the procedures described in Schemes 1-9. Scheme 1 illustrates the production of pyrroles in which the QE group is attached to the pyrrole nitrogen, wherein Q is a functional group which can be converted into the formula I group D, R ^e is a functional group which can be converted into the formula I ZAB and R ^f is a functional group which can be converted into R ^{1a of} formula I. Oxidation of furan with bromine in acetic acid can yield 2,5-diacetoxydihydrofuran, which can react with the amine QE-NH ₂ to form pyrrole. Formylation of Vilsmeier-Haack with phosphorus oxychloride and DMF can best acylate the pyrrole ring at the C-2 position. Oxidation of the resulting aldehyde can yield carboxylic acids. The carboxylic acid can then be converted to the amine derivative by either cleavage of the resulting Hofmann primary amide (Huisgen et al. Chem. Ber. 1960, 93, 65) or by rearrangement of the resulting acyl azide Curtius (J. Prakt. Chem. 1909; 42, 477). Derivatives containing a sulfur atom attached to a pyrrole ring may be obtained by direct sulfonation with a pyridine-sulfur dioxide complex to form sulfonic acids, or by treatment with copper (II) thiocyanate (J. Het. Chem. 1988, 25, 431) followed by reduction. intermediate thiocyanate with sodium borohydride to form mercaptan.

scheme

Rf

R ^f

1) Br ₂ , HOAc

2) QE-NH ₂ ”solvent, reflux welding

Q-E

CHO

KMnO ₄

I

Rf

Q-E

1) IBCF, base, followed by NH ₃

2) Vand. KOBr, or

NH 1) SOCl ₂

2) NaN ₃

3) heat; followed by H ₂ O

R ^f

Q-E

R ^f Rf

I I

Q — E Q-E

The scheme illustrates how to produce pyrroles wherein QE is attached at the 2-position where R ^f and R ^{9 are} together hydrogen or a group which can be converted into R ^1a and R ^{1b of} formula I. This synthesis of Hantzch's pyrrole is an interchangeable reaction involving the cyclization of the corresponding β-ketoester with an alpha-halo ketone or aldehyde in the presence of a primary amine (Ber. Dtsch. Chem. Ges. 1890, 23, 1474). β-Ketoesters can be prepared from chloro anhydrides (X = Cl) by coupling a magnesium anion with potassium alkyl malonate followed by decarboxylation (Synthesis 1993, 290). Alternatively, the β-ketoesters can be prepared from the corresponding aldehyde (R = H) by Reformatsky reaction with α-bromoacetate followed by oxidation. Cyclization with an α-halogenoketone or aldehyde in the presence of a primary amine can yield pyrroles. Acid hydrolysis of 3-carboalkoxypyrrole can yield carboxylic acids. Pyrroles containing a 3-amino substituent can be prepared from acids by reacting Curtius with phosphoryl azide and triethylamine to form isocyanates (J. Med. Chem. 1981, 24, 33), which can be hydrolyzed to give 3-aminopyrides. . Pyrroles having a sulfur atom at the C-3 position can be prepared from acids using the Hunsdiecker procedure to obtain the 3-bromo derivatives. Haiogeno-methyl exchange at low temperature with aikilličio reagent can give 3-lithio-derivative, which may be broken in various electrophiles such as S ₈ directly obtaining thiols, or Cu (SCN) ₂ to afford a thiocyanate which can be reducing a sodium borohydride. These thiols can be further oxidized to sulfonic acid derivatives using an oxidizing agent such as KMnO ₄ .

Q-E

(R = Cl, H) Schematic

K ⁺ O ² CCH ² CO ² R ^h MgCl 2, Et ₃ N; HCl (R = Cl) or

1) BrCH ₂ CO ₂ R ^h , Zn

2) oxidation (R = H)

Q-E

CO, R '[Br, Cl]

R ^f RaNH,

t-BuLi, -78 ° C ₃ . or

E-Q t-BuLi, -78 ° C, Cu (SCN) ₂ ; followed by NaBH ₄

The diagram illustrates how to produce the pyrrole in which QE is attached in position 3. This scheme is based on the particularly convenient Knorr pyrolysis method which involves the condensation of α-amino ketones with β-ketoesters. These aminoketones can be prepared from the β-ketoesters (Scheme 2) by nitrosation followed by reduction with zinc / acetic acid. o.-Condensation of aminoketones with the corresponding β-ketoesters can give good yields of the pyrrole. These intermediates are very easily exchangeable and can be converted to pyrroles with a wide variety of substituents by changing the substitution pattern. In cases where R® (precursor of ZAB) is in the 2-position, the C-3 ester can be selectively hydrolyzed by acid hydrolysis. Heating can decarboxylate. Hydrolysis of 2-carboxylic acid can be carried out under basic conditions. Curtius rearrangement of this acid as described above can give amino derivatives. For the preparation of compounds in which the sulfur atom is attached to C-2, basic hydrolysis and decarboxylation can yield C-2 unsubstituted pyrroles. These pyrroles can undergo electrophilic substitution to give thiols (Cu (SCN) ₂ , followed by NaBH ₄ ) and sulfonic acids (pyridine-SO ₃ complex or chlorosulfonic acid). The R ^1a group in formula I can be derived from both the remaining ester, and R ^f . Alternatively, thiol and sulfonic acid derivatives may also be obtained from C-2 acids by manipulating the carboxylic acid group as described previously.

scheme

Q-E

CO ₂ R ^h

1) HNO ₂

CO ₂ R ^h

2) Zn / HOAc

H ₂ SO ₄ heat {-CO ₂

H

H

R'O ₂ C EQ

// \\

N

I

H

H

Mon.SO,

R'O ₂ C EQ

R ^f '^ N ^z ^ SO3H

I

Scheme H shows how to produce pyrroles in which Q-E is attached at the 3-position. Cyclization of α-amino ketones with β-ketoesters, as described above, can yield pyrroles. Hydrolysis under basic conditions allows the selective hydrolysis of the C-2 ester which, upon heating, must undergo decarboxylation to form the 2-unsubstituted pyrrole. The C-3 ester is then hydrolyzed under acidic conditions to give the 3-carboxypyrrole. The rearrangement of Curtius under the conditions described above can yield the 3-aminopyroles. The carboxylic acids can be used to make derivatives of 3-mercapto and 3-sulfonic acids. The Hunsdiecker technique may be used to make the 3-bromopyrroles. Halogen metal exchange with t-BuLi at low temperature followed by cleavage with copper isocyanate should introduce the isocyanate group at C-3. This intermediate can be reduced with sodium borohydride to form 3-mercaptopyrols. Alternatively, the carboxylic acids can be decarboxylated to give pyrroles which can be N-blocked with a high-volume protecting group such as triisopropylsilyl (TIPS). This high volume group directs electrophilic substitution to the C-3 atom of the pyrrole ring. Thus, reaction with copper isocyanate followed by reduction with sodium borohydride and deprotection of TIPS with fluoride can yield 3-mercaptopyroles. The sulfonation of the N-blocked pyrrole with the pyridine-sulfur trioxide complex can again be redirected to the C-3 position of the pyrrole and the TIPS deprotection yields the 3-sulfonic acids.

scheme

LiOH or NaOH, heat (-CO,)

H

Another general method for the synthesis of pyrrole that can be used to prepare the compounds of the present invention. is shown in Scheme 5. This strategy (Cushman et al., J. Org. Chem. 1996, 61, 4999) utilizes N-blocked α-amino aldehydes readily obtained from α-amino acids by first preparing N-methoxy-N-methylamides followed by the addition of Grignard reagent. (ketones are obtained) or by reduction with a hydride reducing agent such as lithium aluminum hydride or diisobutylaluminium hydride. Such aldehydes and ketones can be reacted with enolates of other ketones to give intermediate aldol linkages which cyclize under acidic conditions to the formation of pyrroles. The reacting partners in this strategy can be very diverse and can be selected so that an experienced specialist in the field will be able to produce various pyrols.

scheme

1) Base ^

2) HCl

PGHN. .CO-, Η 1) (Me0) NHMe

And copying agent PGHN

R '

R ¹ 2) H'or RMgX (PG = blocking group)

Another very common method for the synthesis of pyrrole suitable for the preparation of the compounds of the present invention is the Paal-Knor reaction shown in Scheme 6. In this reaction, 1,4-diketones or 1,4-ketoaldehydes are reacted with primary amines to yield pyrroles. The starting 1,4-diketones and 1,4-ketoaldehydes can be prepared using standard enolate chemistry or other techniques known to those skilled in the art of organic synthesis. The reaction is very wide-ranging and the starting materials can be selected to produce a wide variety of pyrroles.

scheme

O

R

R '

R '

O

f I

Q-E

R®

Scheme R ^f (J = NH, NEQ, NR ^S ) illustrates how compounds of Schemes 1-6 wherein R ^e is a carboxyester group can be converted to compounds having a ZAB moiety. In the case of an amide bond (Formula I, Z = -CONH-), where R @ 4 = carboalkoxy, as described above, it may be hydrolyzed to the acid, either basic or acidic, depending on the substituent structure. Preparation of the chloro anhydride by treatment with thionyl chloride followed by addition of the corresponding amine H ₂ NAB affords compounds with an amide linkage. Alternatively, the acid may be coupled to the amine H ₂ NAB in the presence of a suitable peptide copolymer such as ΒΟΡ-Cl, HBTU or DCC. Alternatively, the ester may be directly coupled to an aluminum reagent prepared by attaching trimethylaluminum to the amino H ₂ NAB.

The acid can be reduced to the alcohol to obtain the compounds of formula I with an ethereal or thioetheric (Z = CH ₂ O-, -CH ₂ S-) linkage. The preferred methods for this transformation are boron-THF reduction or mixed anhydride reduction with sodium borohydride (IBCF = isobutyl chloroformate and NMM = N-methylmorpholine). Compounds of formula I with an ether or thioether linkage may be readily prepared by the Mitsunobu procedure with the appropriate phenol, thiophenol or hydroxy or mercaptoheterocycle ikl-Α-Β (X = O, S) (Formula I, A = aryl or heteroaryl). Other ethers or thioethers (X = O, S) may be prepared after the initial conversion of the alcoholic group to a suitable leaving group such as tosylate. At X = S, the thioethers can be further oxidized to give the sulfones (Formula I, Z = -CH ₂ SO ₂ -).

To obtain compounds of formula I with an amino linkage (Z = -CH ₂ NH-), the alcohol may be oxidized to the aldehyde by a variety of methods; the two most suitable methods are Swern oxidation and pyridine chlorochromate (PCC) oxidation. Alternatively, in some cases, the aldehyde may be prepared by direct formylation of the pyrrole ring according to the Vilsmeier-Haak procedure, as shown in the previous schemes. Reductive amination of the aldehyde with the corresponding amine H ₂ NAB and sodium cyanoborohydride can then yield the amino-linking compounds.

The aldehyde may also be used to prepare compounds of formula I having a ketone bond (Z = -COCH ₂ -). Alcohol can be obtained by exposure to organometallic substances. It is best to make organometallic materials (where M = magnesium or zinc) from the corresponding halide by treatment with metallic magnesium or zinc. Such reagents should readily react with aldehydes to form alcohols. Oxidation of alcohol by a variety of procedures, such as Swern oxidation or PCC oxidation, can yield compounds having a ketone bond.

scheme

oxidation

Q-E

H

N _x

A-B

oxidation

Other compounds of formula I wherein the M / Z linking group has a nitrogen atom attached to ring M may be prepared according to the procedures outlined in Scheme 8. The amines can be converted to sulfonamides (Formula I, M / Z-NHSO ₂ ) by treatment with the corresponding sulfonyl chloride BA-SO _{2 in the} presence of a base such as triethylamine. The amines can be converted into amides (Formula I, Z = -NHCO-) by treatment with the appropriate chloro-anhydride CI-CO-AB in the presence of a base or treatment with the corresponding carboxylic acid HO-CO-AB in the presence of a suitable peptide copolymer such as DCC, HBTU or BOP. The amines can also be converted to compounds having an amino bond (Formula I, Z = -NHCH ₂ -) by reductive amination using the corresponding aldehyde OHC-AB.

scheme

Other compounds of formula I wherein the linking group Z contains a sulfur atom attached to ring M may be prepared according to the procedures described in Scheme 9. Treatment of sulfonic acids with phosphorus pentachloride followed by treatment with the corresponding amine H ₂ NAB affords sulfonamidine-linking compounds (Formula I, Z = -SO ₂ NH-). The thiols may be alkylated with a suitable alkylation reagent in the presence of a base to give thioethers (Formula I, Z = -SCH ₂ -). These compounds can be further oxidized with various reagents to give sulfonic linkages (Formula I, Z = -SO ₂ CH ₂ -).

scheme

Compounds of formula I wherein ring M is imidazole may be prepared using the procedures described in Schemes 10-16. The N-substituted imidazole derivatives may be prepared according to the general procedure shown in Scheme 10 wherein V 'is either V or (CH ₂ ) _n V precursor, V is nitro, amino, thio, hydroxyl, sulfonic acid, sulfonester, sulfonyl chloride, ester, an acid or a halide, n is 0 and 1, and PG is either hydrogen or a protecting group. The substitution can be accomplished by copying the imidazole with the halogen-containing moiety QEG-Hal in the presence of a catalyst such as a base, Cu / CuBr / base or Pd / base, and then converting V 'j (CH ₂ ) _n V. D and eventually V can be converted to j -ZAB according to the methodologies shown in Schemes 7-9. Alternatively, V may be converted to ZAB and deprotected N, This product may be copied according to the procedure described above to give the desired imidazole.

scheme

One way to prepare amidine-phenyl-imidazole derivatives is shown in Scheme 11. The 4-lmidazolecarboxylic acid can be treated with thionyl chloride and then copolymerized with H ₂ NAB in the base and then heated with 3-fluorobenzonitrile in the base. The Pinner reaction known to those skilled in the art using standard procedures may be used to obtain the amidine group.

scheme

The 1,2-disubstituted and 1,5-disubstituted imidazole derivatives may be prepared according to the general procedures described in Scheme 12, wherein R ^1b is either hydrogen or alkyl and U is an aldehyde, ester, acid amide, amino group, thiol, hydroxyl, sulfonic acid, sulfonester, sulfonyl chloride or methylene halide. Step a is carried out in the presence of a catalyst such as base, Cu / CuBr / base or Pd / base. If R ^1b is hydrogen, it can be deprotonated with a lithium base and bound to formate, formamide, carbon dioxide, sulfonyl chloride (sulfur dioxide followed by chlorine) or isocyanate to form 1,2-disubstituted imidazoles (path b1). In addition, on the b1 pathway, when R ^{1b is} CH ₃ , it can be oxidized with SeO ₂ , MnO ₂ , NalO ₄ / catalyst by RhCl ₃ or NBS to form U. If R ^1b is hydrogen, stepwise deprotonation and cleavage with lithium base and trim'ethylsilyl chloride followed by a second deprotonation with lithium base and cleavage with formate, formamide, carbon dioxide, sulfonyl chloride (sulfur dioxide followed by chlorine) or isocyanate can yield 1.5-substituted imidazoles (path b2). If R ^1b is not hydrogen, then the b2 pathway procedure can again be used to obtain 1,5-disubstituted imidazoles (path b3).

R ^1a

A more preferred method of preparing the 1,2-disubstituted and 1,5-disubstituted imidazole derivatives is shown in Scheme 13. Imidazole can be heated with 3-fluorobenzonitrile in the presence of a base. The copolished product can then be treated with an alkyl base and cleaved with CICO ₂ Me to give the 1,2-substituted compound. Further treatment with a solution of H ₂ NAB and trimethylaluminium can give the amide which can be further modified by the Pinner reaction to give the desired product. The 1,5-disubstituted compounds can be prepared by the same procedure except that the starting anion is blocked and a second anion is obtained, which is then cleaved as described above. Further modifications can be made using the same procedures as for 1,2-substituted compounds.

CN

F

Another method for the preparation of 1,2-disubstituted imidazole derivatives is described in Scheme 14. Treatment of the N-substituted imidazole with cyanate affords the amide. This amide can then be copolymerized with Group B as will be described later.

R ⁴

Another method for preparing the 1.5-disubstituted imidazole derivatives is described in Scheme 15. Alkylation with 2-bromoethyl acetate followed by reaction with a Gold reagent in the presence of a base such as NaOMe or LDA can yield imidazoles with ester substituents which can be further modified as described above.

scheme

The general procedure for the preparation of 2,4,5-tri-substituted or 4,5-disubstituted imidazole derivatives is shown in Scheme 16. After the metal-halogen exchange of the QEG moiety, it is possible to act on the amide shown, brominate in NBS, cyclize in the presence of excess NH ₃ and R ^1a CO ₂ H to obtain the imidazole. This imidazole can be modified as described above.

scheme

O

OEt

The general procedure for the preparation of 4,5-disubstituted triazole derivatives is described in Scheme 17. The ethylpropiolate can be substituted in the presence of Cul / Pd, then treated with NaN _{3 to} form the triazole. This triazole can be modified as described above.

scheme

The tetrazole derivatives of the present invention wherein Z is -CONH- may be prepared according to the example shown in Scheme 18. The corresponding amine may be acylated with ethyl oxalyl chloride. The resulting amide can be converted to tetrazole either according to the procedures described by Duncia (J. Org. Chem. 1991, 2395-2400) or by Thomas (Synthesis 1993, 767-768). This amide can then be first converted to imirthoyl chloride and treated with NaN ₃ to form 5-carboethoxytetrazole (J. Org. Chem. 1993, 58, 32-35 and Bioorg. & Med. Chem. Lett. 1996, 6, 1015-1020 ). The 5-carboethoxytetrazole can then be further modified as described in Scheme 7.

The tetrazole compounds of the present invention wherein Z is -CO- may also be prepared via iminoyl chloride (Chem. Ber. 1961, 94, 1116 and J. Org. Chem. 1976, 41, 1073) using acyl chloride as appropriate starting material. . The ketone bond may be reduced to compounds wherein Z is alkyl.

scheme

QE-NH

The methods described in the Scheme for CO ₂ Et may also be used to synthesize compounds wherein EQ is attached to a carbon atom of tetrazole, as shown in Scheme 19. The 5-substituted tetrazole can then be alkylated or acylated to give the desired products.

scheme

EQ

Method A: Method b: Ph ₃ P / DEAD Tf ₂ O / NaN ₃ TMSN-,

T

N = N

EQ

Ph ₃ P

CCI ₄

EQ

The tetrazole derivatives of the present invention wherein Z is -SO2NH-, -S-, -S (O) - can be prepared from thiols as shown in Scheme 20. The thioisocyanate, with appropriate substituents, can be treated with sodium azide to form 5-thiotetrazole (J. Org. Chem. 1967, 32, 3580-3592). This thio compound can be modified as shown in Scheme 9.

The tetrazole compounds of the present invention wherein Z is -O- can be prepared in the same manner as described in Scheme 20 using starting material isocyanate with appropriate substituents. This hydroxy compound can be modified in a manner similar to the thiols described in Scheme 9.

scheme

NCS NaN ₃ NN eq chci ₃ / h _! o '·

I

EQ

The compounds of the present invention wherein Z is -NH-, -NHCO-, -NHSO ₂ - can be prepared from 5-aminotetrazole, which can be prepared by Smiles rearrangement as shown in Scheme 21, and the thio compound produced by Scheme 20, can be alkylated with 2-chloroacetamide. The resulting compound can then be refluxed in ethanolic sodium hydroxide to give the corresponding 5-aminotetrazole {Chem. Pharm. Bull. 1991, 39, 3331-3334). The resulting 5-aminotetrazole can then be alkylated or acylated to give the desired products.

scheme

l

EQ

I EQ

N-N

NH ₂ NaOH / EtOH W

V

I

EQ

NH ₂

The pyrazoles of formula I (such as those depicted in Scheme 22) can be prepared by condensation of the appropriately substituted hydrazine with various diketoesters. This type of condensation usually yields a mixture of pyrazole regioisomers which can be successfully resolved by chromatography over a silica gel column. These esters can be converted to Z-A-B as described previously.

Alternatively, if the starting ketone is CH 3 instead of CO ₂ Et, the resulting methyl pyrazole may be resolved and oxidized according to Scheme 12 b1 to give the pyrazolecarboxylic acid.

Rla ^ CO ₂ Et

Oh the scheme

If ketoididates are used for condensation with hydrazines, the corresponding pyrazole amino esters are obtained (Scheme 23). These intermediates can then be converted into the final compounds of formula I by blocking the amino group with a suitable protecting group or by preparing derivatives (e.g., sulfamide) followed by modification of the ester as described above.

scheme ^HN <^ / \ / ^C0 2 ^Et NHNH OMe O ^{+ EQ}

NH,

Me ₂ SO ₂ CI pi ridid h ₂ n

N

EQ

V CO ₂ Et

+

NHSO ₂ Me

MeO ₂ SHN,

Ί \\

N

I

EQ

CO ₂ Et

As shown in Scheme 24, the pyrazoles which are substituted at the 4-position can be prepared by bromination (bromine or NBS or dichloromethane or acetic acid) of the starting pyrazole. 4-Bromopyrazole can be converted to 4-carboxypyrazole by various methods known in the art of organic synthesis. Further manipulations described above may yield the pyrazoles of the present invention.

QE

CO ₂ Et

NHNH,

J 1b

Pd °, CO, t-BuOH followed by TFA scheme QE

N. J N i

R1b

QE Br

K

N

I

R1b

EQ

The pyrazoles can also be prepared by the method described in Scheme 25. Brompyrazoles are formed in the same manner as in Scheme 24. This can be followed by QE copulation using palladium-catalyzed Suzuki cross-copying methodology. Other modifications may be made by the methods described above.

_R 1a r ^c ° ^2Et + o

nhnh ₂

Boc scheme

The 5-substituted phenylpyrazoles can be prepared according to the method shown in Scheme 26. Conversion of 5-hydroxypyrazole to its triflate (triflo anhydride, lutidine in dichloromethane) or bromide (POBr ₃ ) followed by palladium-catalyzed Suzuki cross-coupling with appropriately substituted phenylboronic acid should yield the 5-substituted pyrazoles. Conversion of this intermediate to the 4-bromo derivative followed by carbonylation according to Scheme 24 should yield the corresponding ester which can be further converted to the compounds of formula I. 26 Scheme _R 1a

1a

CO ₂ Et

NHNH ₂ | --►

Boc

Νχ> N

Boc

1) POBr ₃ or Tf ₂ O, iutidine

2) QE-B (OH) ₂ , _v Pd (PPh ₃ ) ₄ , 2N Na ₂ CO ₃

The 1-substituted-1,2,3-triazoles of the present invention can be prepared by reacting the correspondingly substituted azide with various dipolar aryls (Tetrahedron 1971, 27, 845 and

J. Amer. Chem. Soc. 1951, 73, 1207) as shown in Scheme 27. Usually a mixture of regioisomers is obtained which can be readily resolved and converted into triazole carboxylic acids. Further transformations according to the procedures described above may yield the compounds of the present invention.

scheme

R

EQ EQ

R = CH ₃ , KMnO ₄ R = CH (OMe) ₂ 1) Hydrolysis

T 2) Ag, 0

EQ EQ

N //

N.

EQ

N

I

EQ

COOH

The 1,2,4-triazoles of the present invention can be obtained according to Huisgen et al. (Liebigs Ann. Chem. 1962, 653, 105) using a cyclic coupling reaction of nitrile derivatives (obtained from the interaction of triethylamine with chlorhydrazone) and the corresponding nitrile dipolar diaphragm (Scheme 28). According to this methodology, a variety of 1,2,4-triazoles can be obtained with various substituents at positions 1,3 and 5.

scheme

+ R ^1b CN

Et ₃ N, benzene

R ^1b = ester group, alkyl, aryl

R ^1a = phenyl or ester group

1,2,4-Triazoles can be prepared according to Zeschi et al. (Synthesis 1986, 9, 772) using 'Vittig' aza-condensation (Scheme 29).

Scheme (Ph) ₃ P,

EtO ₂ C

N CO, Me + /

I ² R1a Cl .NH

R ^1a = alkyl or aryl

1,2,4-Triazoles wherein the -E-D (Q) substituent is in the 5-position of the triazole ring can be obtained as shown in Scheme 30.

scheme

CO (lmid) ₂ copol. with amine

EQ

O

N — AB H

The 1,3,4-triazoles of the present invention can be obtained according to Moderhack et al. (J. Prakt. Chem. 1996, 338, 169). As shown in Scheme 31, this reaction involves the condensation of a carbazide with an appropriately substituted commercially available thioisocyanate to form a cyclic thiourea derivative. The alkylation or nucleophilic substitution of the thio-urea intermediate can then yield thio-alkyl or -aryl intermediates which can be hydrolyzed, oxidized, and decarboxylated to give the 5-H 2 -thiothriazole intermediate and can be converted into compounds of the present invention. Alternatively, the thiono-urea intermediate may be oxidized directly to the 2-H triazole which can then be converted to the ester and modified as described above. The thionocarbamide intermediate can be oxidized to the sulfonyl chloride according to the procedures described above.

scheme

The imidazole structure shown in Scheme EQ can be prepared by condensing 3-cyanoaniline with n-butylglyoxylate to give an imine which can then be reacted with TosylMIC in basic methanol to give the desired imidazole compound. Subsequently, the ester copolymerization under standard conditions yields various analogues which, by further manipulation, may yield, for example, benzylamines or benzamidines.

scheme

Compounds of the present invention wherein AB is a biphenylamine or similar amine can be prepared as shown in Scheme 33. 4-Bromanyline can be blocked as a Boc derivative and copolished with phenylboronic acid under Suzuki conditions (Bioorgan. Med. Chem. Lett. 1994, 189). Deprotection with TFA yields the aminobiphenyl compound. Other similar amines wherein A and / or B are heterocycles may be prepared in the same manner using the corresponding boronic acids and aryl bromide. Bromaniline can be first coupled to the ring structure as described above, followed by Suzuki reaction to give the desired product.

scheme

Compounds of the present invention wherein A-B is Α-Χ-Υ can be prepared in a manner similar to the piperazine derivatives shown in Scheme 34.

scheme

BocN

PhSO, CI

-> CH, CUEt, N

BocN

the diagram shows how a cyclic group in which X = NH, O or S can be copied.

NO ₂

R ⁴

Hal scheme

If B is defined as Χ-Y, the following description applies. Groups A and B are obtained either from commercially available literature sources or readily synthesized using standard techniques known to those skilled in the art of organic synthesis. The required reactive functional group attached to analogs A and B is also obtained either from commercially available literature sources or readily synthesized using standard techniques known to those skilled in the art of organic synthesis. The following tables show the chemical reactions required to bind A to B.

Table A: Formation of the amide, ester, urea, sulfonamide and sulfamide bonds between A and B

Reac. No. if A is: this reactive Y substitution is: the following product Α-Χ-Υ is obtained: 1 A-NHR ² as a substituent CIC (O) -Y A-NR ² -C (O) -Y 2 secondary NH as part of the ring or chain CIC (O) -Y A-C (O) -Y 3 A-OH as a substitute CIC (O) -Y A-O-C (O) -Y 4 A-NHR ² as a substituent CIC (O) -CR ² R ^2a -Y A-NR ² -C (O) -CR ² R ^2a -Y 5 secondary NH as part of the ring or chain CIC (O) -CR ² R ^2a -Y AC (O) -CR ² R ^2a -Y 6th A-OH as a substitute CIC (O) -CR ² R ^2a -Y AOC (O) -CR ² R ^2a -Y 7th A-NHR ² as a substituent CIC (O) -NR ² -Y A-NR ² -C (O) NR ² -Y 8th secondary NH as part of the ring or chain CIC (O) -NR ² -Y AC (O) NR ² -Y 9th A-OH as a substitute CIC (O) -NR ² -Y AOC (O) NR ² -Y 10th A-NHR ² as a substituent CISO2-Y a-nr ² -so ₂ -y 11th secondary NH as part of the ring or chain CISO ₂ -Y a-so ₂ -y 12th A-NHR ² as a substituent CISO ₂ -CR ² R ^2a -Y A-NR ² -SO ₂ -CR ² R ^2a -Y 13th secondary NH as part of the ring or chain CISO ₂ -CR ² R ^2a -Y A-SO ₂ -CR ² R ^2a -Y 14th A-NHR ² as a substituent ciso ₂ -nr ² -y A-NR ² -SO ₂ -NR ² -Y 15th secondary NH as part of the ring or chain ciso ₂ -nr ² -y a-so ₂ -nr ² -y 16th A-C (O) Cl HO-Y as a replacement A-C (O) -O-Y 17th A-C (O) Cl NHR ² -Y as a substitute AC (O) -NR ² -Y 18th A-C (O) Cl secondary NH as part of the ring or chain A-C (O) -Y 19th A-CR ² R ^2a C (O) CI HO-Y as a replacement A-CR ² R ^2a C (O) -OY 20th A-CR ² R ^2a C (O) CI NHR ² -Y as A-CR ² R ^game C (O) -NR ² -Y

replacement 21st A-CR ² R ^2a C (O) CI secondary NH as part of the ring or chain A-CR ² R ^2a C (O) -Y 22nd A-SO ₂ CI NHR ² -Y as a substitute A-SO ₂ -NR ² -Y 23rd A-SO ₂ CI secondary NH as part of the ring or chain a-so ₂ -y 24th A-CR ² R ^2a SO ₂ Ci NHR ² -Y as a substitute A-CR ² R ^2a SO ₂ -NR ² -Y 25th A-CR ² R ^2a SO ₂ CI secondary NH as part of the ring or chain A-CR ² R ^2a SO ₂ -Y

The chemical reactions of Table A can be carried out in aprotic solvents such as carbon tetrachloride, pyridine, benzene or toluene, from -20 ° C to the boiling point of the solvent, in the presence or absence of a trialkylamine base.

Table B: Formation of a ketone linkage between A and B

Reac. No. if A is: this reactive Y substitution is: the following product Α-Χ-Υ is obtained: 1 A-C (O) Cl BrMg-Y A-C (O) -Y 2 A-CR ² R ^2a C (O) CI BrMg-Y A-CR ² R ^2a C (O) -Y 3 A-C (O) Cl BrMgCR ² R ^2a -Y AC (O) CR ² R ^2a -Y 4 A-CR ² R ^2a C (O) Ci BrMgCR ² R ^2a -Y A-CR ² R ^2a C (O) -CR ² R ^2a -Y

The copying reactions of Table B can be performed by a variety of methods. The Grignard reagent required to obtain Y is prepared from the halogen analog of Y in dry ether, dimethoxyethane or tetrahydrofuran from 0 ° C to the boiling point of the solvent. This Grignard reagent can be directly applied under very controlled conditions, i.e., at low temperatures (-20 ° C or below) and in large amounts of chloro-anhydride or catalytic or stoichiometric amounts of the copper bromide-dimethylsulfide complex using dimethylsulfide as solvent or variants thereof. Other available methods include the conversion of Grignard reagent to cadmium reagent and copulation according to the procedure of Carson and Prout (Org. Syn. Col. Vol.3 (1955) 601) or copulation mediated by Fe (acac) ₃ according to Fiandanese et al. (Tetrahedron Lett. (1984))

4805), or copolymer-mediated manganese (II) catalyst (Cahiez and Lab o u e, Tetrahedron Lett. 33 (31), (1992) 4437),

Table C: Formation of etheric and thioetheric bonds between A and B.

Reac. No. if A is: this reactive Y substitution is: the following product Α-Χ-Υ is obtained: 1 A-OH Br-Y A-O-Y 2 A-CR ² R ^2a -OH Br-Y A-CR ² R ^2a OY 3 A-OH Br-CR ² R ^2a -Y A-OCR ² R ^2a -Y 4 A-SH Br-Y A-S-Y 5 A-CR ² R ^2a -SH Br-Y A-CR ² R ^2a SY 6th A-SH Br-CR ² R ^2a -Y A-SCR ² R ^2a -Y

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

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

Reac. No. provided that the starting material is: and it is oxidized AI2O3 (wet) / oxone (Greenhalgh, Synlett, (1992) 253), the product is: and it is oxidized with michloroperbenzoic acid (Satoh et al., Chem. Lett. (1992) 381), the product is 1 A-S-Y A-S (O) -Y a-so ₂ -y 2 A-CR ² R ^2a SY A-CR ² R ^2a S (O) -Y A-CR ² R ^2a SO ₂ -Y 3 A-SCR ² R ^2a -Y AS (O) CR ² R ^2a -Y A-SO ₂ CR ² R ^2a -Y

The thioethers of Table C are a convenient starting material for the preparation of the sulfoxide and sulfonic analogs of Table D. The combination of wet alumina and oxone can be a reliable reagent for the oxidation of a thioether to a sulfoxide, while oxidation with m-chloroperbenzoic acid will yield the sultan.

Table E: Methods of obtaining Group E

Re- acc. Q. D must be present; then the transformation can be used: 1 -CN -C (= NH) NH ₂ E CN ^{i) HClMe} ° ^H -E < ^NH2 ii) NH, OAc, MeOH ' ⁴ NH 2 -CN -ch ₂ nh ₂ EC 1 -N- _{E E} -CH ₂ -NH ₂ Et ₂ O ^{2 2} 3 -CO ₂ H -ch ₂ nh ₂ i) iBuOC (O) Cl 0 NMM.THFpoto EC ^ E ch ₂ -nh ₂ iijMsCl, Et ₃ N, CH ₂ Cl ₂ iii) NaN ₃ , DMF iv) SnCl ₂ . MeOH 4 -co ₂ h -NH ₂ i) iBuOC (O) Cl 0 NMM.THFpoto NaN ₃ and heating E-C --- * - E-NH ₂ ii) t-BuOH, boiling iii) HCl, Et ₂ O

Table E shows some methods for converting functional group Q into group D. Since not all possible functional groups Q and D are listed, and the proposed synthesis pathways are not exhaustive, Table E is intended to illustrate the strategies and transformations that an organic synthesis practitioner can use to obtain compounds of formula I. Reaction 1 of Table E shows the method of converting nitrile to amidine according to Pinner; Reaction 2 illustrates the direct reduction of a nitrile with a hydride reducing agent to methylenamine. Reaction 3 shows the use of a carboxylic acid, which can be readily obtained from its ester or nitrile, if necessary, to obtain methylenamine. This pathway of synthesis is exceptionally flexible as several stable intermediates are produced on the way to the final product. As noted, the formation of an activated analogue, such as mixed anhydride, makes it possible to gently reduce the acid to methylene alcohol; this compound may in turn be transformed into the leaving group by sulfonation or halogenation, or may be subsequently transformed, as required in the synthesis, by the appropriate protecting group. Once methylene alcohol is thus activated, substitution with an efficient nitrogenous nucleophile such as an azide anion may again yield a suitable stable analogue, methylene azide, which can be used as a blocked form of methyleneamine or directly transformed into a methyleneamine group by reduction. Reaction 4 addresses the problem of the direct attachment of an amino group to an E group of formula 1. Again, carboxylic acid is one of the convenient options for Group D. The well-known rearrangement of Curtius is illustrated here; the activated acid analogue can be used to produce the acyl azide, which is regrouped to the corresponding isocyanate by thermal cleavage. This intermediate isocyanate can then be converted to the stable carbamate by addition of the corresponding alcohol and further heating. This carbamate can be used as a stable amine protecting group or directly cleaved to give the desired D. Alternatively, it may be convenient to cleave the intermediate isocyanate with water to obtain the amine directly.

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

EXAMPLES

Intermediate fluoromethylsulfones

4-Amino-3-fluoro-2'-methylsulfonyl- [1,1 '] - biphenyl hydrochloride

Part A: Preparation of 4-Bromo-N-t-butoxycarbonyl-2-fluoranine

To a solution of 4-bromo-2-fluoroaniline (5.01 g, 26 mmol) at 0 ° C in dry DMF (75 mL) was added sodium hydride (1.16 g, 60%, 29 mmol). The ice bath is removed and the reaction mixture is stirred at room temperature for 1 hour. Di-i-butyl dicarbonate (6.33 g, 29 mmol) was added and the reaction mixture was heated at 65 ° C for 17 h. The reaction was quenched by dropwise addition of H ₂ O, after which the mixture was extracted 4 times with H ₂ O. The first two aqueous extracts were mixed and extracted twice with EtOAc. The organic extracts are combined, dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was dissolved in a mixture of CH ₂ Cl ₂ , CHCl 3 and EtOAc and filtered to remove a bright red impurity, then concentrated and chromatographed on silica gel (30% CH ₂ Cl ₂ / hexanes); Obtained as an orange solid (4.76 g, 62%). ¹ H NMR (DMSO) δ: 9.07 (m.s, 1H), 7.57 (td, 1H, J = 8.7, J '= 2.2 Hz), 7.49 (dd, 1H, J = 10.2, J '= 2.2 Hz), 7.30 (dt, 1H, J = 8.8, J' = 1.1 Hz), 1.42 (s, 9H) md

Part B: Preparation of 4- (t-Butoxycarbonylamino) -3-fluoro-2'-methylthio-? 1,1 '1-biphenyl

From a flask containing 4-bromo-Nf-butoxycarbonyl-2-fluoroaniline (6.44 g, 22 mmol), 2- (methylthio) phenylboronic acid (6.00 g, 36 mmol), aqueous sodium carbonate (2.0 M, 36 mL, 72 mmol), tetrabutylammonium bromide (360 mg, 1.1 mmol), and bis (triphenylphosphine) palladium (II) chloride in benzene (180 mL) are evacuated by evacuating under high vacuum for two short periods, argon and refrigerator for 5 hours. After cooling to room temperature, the layers were separated and the aqueous layer was extracted with EtOAc. The organic extracts were combined, dried over Na ₂ SO ₄ , filtered and evaporated. The crude product is chromatographed on silica gel (0-30% EtOAc / hexanes) to give the desired product (6.50 g, 88%). ¹ H NMR (CHCl ₃ ) δ: 8.14 (m.p., 1H, J = 8.1 Hz), 7.30 (m, 2H), 7.17 (m, 4H), 6.75 (m.p. s, 1H), 2.37 (s, 3H), 1.54 (s, 9H) md

Part C: Preparation of 4- (t-Butoxycarbonylamino) -3-fluoro-2'-methylsulfonyl-f,1,1'l-biphenyl

4- (t-Butoxycarbonylarnino) -3-fluoro-2'-methylthio- [1,1 '] - biphenyl (6.50 g, 19.5 mmol) was dissolved in CH ₂ Cl ₂ (150 mL) and cooled to 0 ° C. . MCPBA (14.8 g, 57-86%) was added and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was extracted with saturated sodium sulfite and the aqueous layer was extracted with CH ₂ Cl ₂ . The organic extracts were combined, dried over Na ₂ SO ₄ , filtered and evaporated. The crude product is chromatographed on silica gel (20-30% EtOAc / hexanes) to give the desired product (6.92 g, 97%). ¹ H NMR (CHCl ₃ ) δ: 8.22 (dd, 2H, J = 7.7, J '= 1.5 Hz), 7.64 (td, 1H, J = 7.3, J = 1, 5 Hz), 7.56 (td, 1H, J = 7.7, J '= 1.5 Hz), 7.35 (dd, 1H, J = 7.3, J' = 1.5 Hz) , 7.30 (dd, J = 11.7, J '=

2.2 Hz), 7.17 (d, 1H, J = 8.8 Hz), 6.82 (ss, 1H), 2.69 (s, 3H), 1.55 (s, 9H) md

Part D: Preparation of 4-Amino-3-fluoro-2'-methylsulfonyl-1,1'-biphenyl hydrochloride

4- (t-Butoxycarbonylamino) -3-fluoro-2'-methylsulfonyl- [1,1 '] -biphenyl (1.04 g, 2.8 mmol) was dissolved in HCl / dioxane (4.0 M, 10 mL) and stir for 19 hours. The solid was triturated with Et ₂ O and filtered to give a solid (813 mg, 95%). ¹ H NMR (DMSO) δ: 8.03 (dd, 1H, J = 8.0, J '= 1.4 Hz), 7.69 (td, 1H), J = 7.7, J' = 1 , 1 Hz), 7.59 (t, 1H, J = 7.4 Hz), 7.36 (d. 1H, J = 7.3 Hz), 7.12 (d, 1H, J = 12.4 Hz), 6.94 (m, 2H), 2.78 (s, 3H) md, and 2 examples

1- (3-Amidinophenyl) -2 - [[(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrrole trifluoroacetic acid salt (Example 1) and 1- (3amidinophenyl) -2- [i (2'-tert-Butylaminosulfonyl- [1, T] -biphen-4-yl) aminocarbonyl] pyrrole trifluoroacetic acid salt (Example 2)

Part A: Preparation of 1- (3-cyanophenyl) pyrrole

3-Aminobenzonitrile (47.45 g, 0.401 mol) and 58.4 g (0.441 mol, 59.5 ml) in 2.5 dimethoxytetrahydrofuran are dissolved in 200 ml of acetic acid and refluxed overnight. The solution was allowed to cool to room temperature, diluted with 250 mL of ethyl acetate and washed three times with saturated NaCl solution (200 mL) followed by saturated aqueous sodium carbonate solution (200 mL). The organics were dried over magnesium sulfate and filtered through a pad of silica gel. The volatiles were removed in vacuo and the residue was recrystallized from methanol to give the title compound as a brownish solid (62.82 g, 93%) MS _(H2O-CI) 169 (M + H) ^+.

Part B: Preparation of 1- (3-cyanophenyl) pyrrole-2-carboxaldehyde from dimethylformamide (14.02 g, 191.84 mmol, 14.1 mL) at 0 ° C over 15 min. phosphorus oxychloride is added. The mixture was warmed to room temperature and stirred for 15 min; the solution was again cooled to 0 ° C, followed by the addition of 100 ml of 1,2-dichloroethane. A solution of 1- (3-cyanophenyl) pyrrole (29.33 g, 191.84 mmol) in 250 mL of 1,2-dichloroethane is slowly added dropwise via a dropping funnel and the mixture is refluxed for 15 min. The solution is cooled to room temperature, 86.55 g (1.05 mol) of sodium acetate are added and the solution is refluxed for 15 min. The solution was diluted with 250 mL of ethyl acetate and the organic phase was washed with a saturated NaCl solution followed by a saturated aqueous sodium carbonate solution (250 mL). The organic phase is dried over magnesium sulfate, filtered through a pad of silica gel and the volatiles evaporated in vacuo. Recrystallization of the product from ethyl acetate gives 28.4 g (83%) of the title compound. MS (NH ₃ -Cl) 214 (M + NH ₄ ) ⁺ .

Part C: Preparation of 1- (3-cyanophenyl) pyrrole-2-carboxylic acid

To a cooled (0 ° C) solution of 1- (3-cyanophenyl) pyrrole-2-carboxaldehyde (5.14 g, 26.20 mmol) in 300 mL of 1: 1 acetone / water over 15 min. potassium permanganate (12.42 g, 78.60 mmol) was added and the reaction mixture was allowed to warm to room temperature. When the starting material is consumed, 10.90 g (104.8 mmol) of acidic sodium sulfite are added and the solution is acidified with 10% HCl. The solution is filtered through a pad of celite, diluted with ethyl acetate and washed with 200 mL of saturated NaCl solution. The organic phase is dried over magnesium sulfate, filtered and dried in vacuo. The organic material is recrystallized from methanol to give the title compound (4.11 g, 74%) as an off-white solid. MS (ESI) 211.2 (M-H) -.

Part D: Preparation of 1- (3-cyanophenyl) -2-rf (2'-tert-butylaminosulfonyl-1,1'-biphen-4-yl) aminocarbonylpyrrole to 1- (3-cyanophenyl) pyrrole-2-carboxylic acid ( To a solution of 2.77 g, 13.05 mol) in 50 ml of anhydrous DMF was added triethylamine (1.98 ml, 19.58 mmol), benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (8.66 g, 19.58 g). mmol) and (2'-N-frei-butylaminosulfonyl- [1,1 '] - biphen-4-yl) amino (6.03 g, 19.84 mmol) and heated at 50 ° C overnight. The solution was diluted with ethyl acetate and washed several times with saturated NaCl solution. The organic layer was dried over magnesium sulfate and the volatiles removed in vacuo. The residue was purified by flash chromatography using 3: 2 hexane / ethyl acetate and evaporation of the volatiles in vacuo to afford 1.9 g (29%) of the title compound. MS (NH ₃ -Cl) 516 (M + NH ₄ ) ⁺ .

Part E: 1- (3-Amidinophenyl) -2-r (2'-aminosulfonyl-1R, 1'-biphen-4-yl) aminocarbonylpyrrole trifluoroacetic acid salt (Example 1) and 1- (3amidinophenyl) -2-rf ^(2, Tref-butylaminosulfonyl-f1 Tl biphen-4-yl) -aminokarbonil1pirolo trifluoroacetic acid salt (example 2) obtaining

To 60 ml of a solution of anhydrous methifacetate and anhydrous methanol is added 1- (3-cyanophenyl) -2 - [[2'-tert-butylaminosulfonyl- [1,1'-biphen-4-yl) aminocarbonylpyrrole (0.37 g, 0, 74 mmol) and cooled in an ice bath. 15 mins HCl gas was added, the solution was capped and stirred overnight at room temperature. Volatiles are evaporated in vacuo. The residue is dried under a gentle vacuum for 1 hour. The residue is then dissolved in 100 ml of anhydrous methanol, mixed with 0.43 g (4.45 mmol) of ammonium carbonate and stirred overnight at room temperature. The volatiles were removed in vacuo and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a H 2 O / CH ₃ CN with 0.5% TFA) to afford 1- (3-amidinophenyl) -2 - [[(2'-aminosulfonyl - [1,1 '] - Biphen-4-yl) aminocarbonyl] pyrrole trifluoroacetic acid salt (Example 1), which after lyophilization is a white solid: MS (ESI) 460.3 (M + H) ⁺ ; and further isolating the trifluoroacetic acid salt of 1- (3-amidinophenyl) -2 - [[(2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrrole (Example 2); MS (ESI)

516.4 (M + H) ⁺ .

example

1- (3-Amidinophenyl) -2 - [[(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -4-bromopyrrole trifluoroacetic acid salt

Part A: Preparation of 1- (3-cyanophenyl) -2-formyl-4-bromopyrrole Example 1- (3-Cyanophenyl) pyrrole-2-carboxaldehyde (6.06 g, 30.89 mmol) in Part B is mixed with 6.60 g (37.06 mmol) of N-bromosuccinimide in 150 mL of anhydrous THF and stirred at room temperature overnight. The residue was heated to CCI ₄ and filtered. The residue was dissolved in CHCl ₃ / EtOH, filtered through a silica cover film and the volatiles were evaporated. Recrystallization of the residue from ethyl acetate gives the title compound as a brownish solid (4.49 g, 53%). MS (NH ₃ -Cl) 292 (M + NH ₄ ) ⁺ .

Part B: Preparation of the trifluoroacetic acid salt of 1- (3-amidinophenyl) -2- [f] (2'-aminosulfonyl-1,1,1'-biphen-4-iDaminocarbonine-4-bromopyrrole

According to the procedures described in Example 1 CE, parts 1- (3-cyanophenyl) -2-formyl-4-bromopyrrole are converted to the desired compound which, after purification by HPLC, is a white powder. MS (ESI) 538.2 (M + H) &lt; + &gt;.

example

1- (3-Amidinophenyl) -2 - [[5- (2'-aminosulfonylphenyl) -1-yl) pyridin-2-yl] aminocarbonyl] pyrrole trifluoroacetic acid salt

Part A: 1- (3-cyanophenyl) -2-fr5- ^(2--fref butilaminosulfonilfenil) -1-yl) pyridin-receiving 2illaminokarboninpirolo

At room temperature, 50 ml of anhydrous CH ₂ Cl ₂ are mixed with 1- (3-cyanophenyl) pyrrole-2-carboxylic acid (1.00 g, 4.7 mmol), oxalyl chloride (0.61 mL, 7.06 mmol) in Part C of Example 1. ) and 3 drops of DMF and stir 4 or. The volatiles are evaporated in vacuo and the residue is dried under deep vacuum for 1 hour. This residue is then dissolved in 50 mL of CH ₂ Cl ₂ and ₄ -dimethylaminopyridine (1.15 g, 9.4 mmol) is added and the solution is stirred at room temperature for 5 min, [5- (2'-aminosulfonylphenyl) -1-yl) pyridine is added -2-yl) amino (1.44 g, 4.7 mmol) and stirred at room temperature overnight. This solution was filtered through a pad of silica gel and the volatiles evaporated. The residue was purified by flash chromatography (1: 2 hexane / EtOAc) to give 0.84 g (36%) of the title compound as a tan solid. MS (ESI) 500.3 (M + H) &lt; + &gt;.

Part B: Preparation of 1- (3-amidinophenyl) -2-trans-5- (2'-aminosulfonylphenyl) -1-yl) pyridin-2-ylaminocarbonyl salt of trifluoroacetic acid

According to the procedures described in Example 1 Part E, 1- (3-cyanophenyl) -2 - [[5 (2'-tert-butylaminosulfonylphenyl) -1-yl) pyridin-2-yl] aminocarbonyl] pyrrole is converted to the desired compound, which HPLC purification is a white powder MS (ESI) 461.3 (M + H) ⁺ .

and 6 examples

1-Benzyl-3 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -4- (3amidinophenyl) pyrrole trifluoroacetic acid salt (Example 5) and 1-benzyl3 - [(2') tert-Butylaminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -4- (3amidinophenyl) pyrrole trifluoroacetic acid salt (Example 6)

Part A: Preparation of ethyl 3- (3-cyanophenyl) propiolate in a solution of ethyl propiolate (25.0 g, 0.25 mol) in 750 ml of tetrahydrofuran at -78 ° C is treated dropwise with n-butyl lithium (102 ml of 2.5 M solution in hexane, 0 , 25 mol). After stirring at the same temperature for 1 h, zinc chloride (104.2 g, 0.76 mol) was added to 900 mL of tetrahydrofuran. Allow the mixture to gradually warm to room temperature and keep for 1 hour. To this solution was added 3-iodobenzonitrile (29.2 g, 0.13 mol) and bistriphenylphosphine palladium (II) chloride (4.56 g, 6.5 mmol) and the resulting mixture was stirred at 50 ° C overnight. 150 ml of water and 150 ml of ether are added to this mixture and the mixture is filtered through a pad of celite. The filtrate is extracted 3 times with ether, the combined extracts are washed with saturated NaCl solution, dried (MgSO ₄ ) and filtered through a thick pad of silica. The solvents were evaporated in vacuo and the residue was recrystallized from a mixture of hexane and ethyl acetate to give 8.8 g (35%) of the title compound as a tan solid. ¹ H NMR (CDCl ₃ ) δ: 7.85 (s, 1H), 7.8 (d, 1H), 7.72 (d, 1H), 7.52 (t, 1H), 4.30 (s) 2H), 1.37 (t, 3H).

Part B: Preparation of 1-Benzyl-3-carbethoxy-4- (3-cyanophenyl) -? ^3- pyrroline in a solution of N-benzyl-N- (trimethylsilylmethyl) -aminomethyl methyl ether (12.25 g, 51.2 mmol) in 400 of methylene chloride at 0 ° C was added ethyl 3 (3-cyanophenyl) propiolate (6.79 g, 34.1 mmol) followed by trifluoroacetic acid (0.20 mL, 2.6 mmol). The mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was washed with a saturated aqueous solution of NaHCO ₃ and a saturated NaCl solution, dried over fGCCty, filtered through a large pad of silica gel, and concentrated in vacuo. The residue was purified by flash chromatography (5: 1 hexanes / ethyl acetate) to give 3.2 g (28%) of the title compound. MS (ESI) 333.4 (M + H) &lt; + &gt;.

Part C: Preparation of 1-Benzyl-3-F (2'-tert-butylaminosulfonyl-1'-biphen-4-yl) aminocarbonyl-4- (3-cyanophenyl) -A ³ -pyroline a solution of butylaminosulfonyl- [1,1 '] - biphen-4-yl) amino (1.10 g, 3.6 mmol) in 50 mL of methylene chloride was added dropwise at room temperature with trimethylaluminium (6.6 mL of a 2.0 M solution in toluene, 13, 2 mmol). The solution was stirred (30 min.) Until gas evolution ceased, followed by the addition of 1-benzyl-3-carbethoxy-4- (3-cyanophenyl) -Δ ³ -pyroline (1.0 g, 3.0 mmol) in 5 mL of methylene chloride. . The resulting solution was stirred at 40 ° C for 2 h, cooled to room temperature and quenched with saturated aqueous NH ₄ Cl. The mixture was diluted with ethyl acetate, washed with water and brine, dried (MgSO ₄₎ and concentrated in vacuo. The residue was purified by flash chromatography (eluting with 4: 1 hexane / ethyl acetate) to give 0.58 g (34%) of the title compound. MS (ESI) 591.5 (M + H) &lt; + &gt;.

Part D: Preparation of 1-Benzyl-3 - ['(2'-tert-butylaminosulfonyl-1,1,1'-biphen-4-yl) aminocarbonyl-4- (3-cyanophenyl) pyrrole

To 1-Benzyl-3 - [(2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -4 (3-cyanophenyl) -Δ ³ -pyrroline (0.47 g, 0 , 8 mmol) was added 2,3-dichloro-5,6-dicano-1,4-benzoquinone (DDQ) (0.27 g, 1.2 mmol) in 20 mL of benzene and the resulting mixture was stirred at 70 ° C for 16 h. or. The mixture is cooled, filtered and concentrated in vacuo. The residue was purified by flash chromatography (5: 1 hexane / ethyl acetate) to give 0.25 g (53%) of the title compound. MS (ESI) 589.6 (M + H) &lt; + &gt;.

Part E: 1-Benzyl-3-r (2'-aminosulfonyl-n, T1-biphen-4-yl) -aminocarbonin-4 (3-amidinophenyl) pyrrole trifluoroacetic acid salt (Example 5) and 1-benzyl-3r ( Preparation of 2'-tert-butylaminosulfonyl-1'1-biphen-4-yl) aminocarbonyl-4- (3-amidinophenyl) pyrrole trifluoroacetic acid salt (Example 6)

A solution of -Benzyl-3 - [(2'-tert-butylaminosulfonyl- [1,1 '] -biphen-4-yl) -aminocarbonyl] -4 (3-cyanophenyl) pyrrole (0.25 g, 0.42 mmol) 50 ml of anhydrous methanol are cooled to 0 ° C. bubble with dry gaseous HCl (until the solution is saturated). Stopper the flask and leave to stand for 16 hours. At 0 ° C. The reaction mixture is concentrated in vacuo. The resulting solid was dissolved in 20 mL of anhydrous methanol, ammonium carbonate (0.20 g, 2.1 mmol) was added and the mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (C18 reverse phase column, eluting with H2O / CH3CN with 0.5% TFA gradient) to afford 120 mg (40%) of 1-benzyl-3 - [(2'-aminosulfonyl- [ 1,1 '] - Biphen-4-yl) aminocarbonyl] -4- (3amidinophenyl) pyrrole trifluoroacetic acid salt (Example 5), which after lyophilization is a white powder. MS (ESI) 550.3 (M + H) &lt; + &gt;. There is also obtained 40 mg (13%) of 1-benzyl-3 - [(2'-tert-butylaminosulfonyl- [1,1'] -biphen-4-yl) aminocarbonyl] -4- (3-amidinophenyl) pyrrole trifluoroacetate acid salts (Example 6) which, after lyophilization, are a white powder. MS (ESI) 606.5 (M + H) &lt; + &gt;.

and 8 examples

1- (3-amidinophenyl) -4 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] imidazole (Example 7) and 1- (3-amidinophenyl) -4- [ (2'-tert-Butylaminosulfonyl- [1, T] -biphen-4-yl) aminocarbonyl] imidazole (Example 8)

Part A: 4-f (2'-tert-butylaminosulfonyl-f1, T1 biphen-4-yl) aminokarbonil1imidazolo aavimas imidazolkarboksirūgšties-4 (168 mg, 1.5 mmol) in CH ₃ CN (30 mL) was added thionyl chloride (714 mg, 6 mmol) and the resulting mixture was heated at 80 ° C for 2 h. After removal of the volatiles, the yellow residue was treated with 4 [(o-SO ₂ -f-Bu) -phenyl] aniline (304 mg, 1 mmol) in pyridine (10 mL) at room temperature for 24 h. After evaporation of the pyridine, the resulting residue was dissolved in EtOAc, washed with water, brine and dried over MgSO ₄ . Concentration and purification of the crude material by column chromatography afforded the title compound (378 mg, 95% yield). ¹ H NMR (CD ₃ OD) δ: 8.10 (dd, J = 7.7 Hz, 1.1 Hz, 1H), 7.79 (d, J = 3.7 Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H), 7.58 (td, J = 7.7 Hz, J = 1.5 Hz, 1H), 7.49 (dd, J = 8.1 Hz, J) = 1.5 Hz, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.34 (dd, J = 7.7 Hz, J = 1.5 Hz, 1H), 1, 06 (s, 9H); MSGMS: 399.3 (M + H) &lt; + &gt;.

Part B: Preparation of 1- (3-cyanophenyl) -4-f (2'-tert-butylaminosulfonyl-1,1,1'-biphen-4-yl) aminocarbonylimidazole

4 - [(2'-Ifef-Butylaminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] imidazole was heated with 3-fluorobenzonitrile (121 mg, 1 mmol) in K ₂ CO ₃ , DMF 100 At 8 ° C for 8 hours. and yields the desired compound in almost quantitative yield. 1 H NMR (acetone-d ₆ ) δ: 9.47 (s, 1H), 8.39 (d, J = 1.5 Hz, 1H), 8.34 (d, J = 1.5 Hz, 1H), 8.25 (d, J = 1.5 Hz, 1H), 8.15-8.10 (m, 1H), 8.02 (d, J =

8.4 Hz, 2H), 7.88-7.79 (m, 2H), 7.65 (td, J = 7.3 Hz, J = 1.5 Hz, 1H), 7.56 (dd, J = 7.7 Hz, J = 1.5 Hz, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.38 (dd, J = 7.7 Hz, J = 1 , 5 Hz, 1H), 2.80 (s, 1H), 1.03 (s, 9H); MSGMS: 500.1 (M + H) ⁺ .

Part C: 1- (3-Amidinophenyl) -4-i (2'-aminosulfonyl-1'-biphen-4-yl) aminocarbonylimidazole (Example 7) and 1- (3-amidinophenyl) -4-r (2 ' Preparation of -Tefbutylaminosulfonyl-H, 1'-1-biphen-4-yl) aminocarbonyl-1-imidazole (Example 8)

Further, the Pinner reaction of 1- (3-cyanophenyl) -4 - [(2'-tert-butylaminosulfonyl- [1, T] -biphen-4-yl) aminocarbonylimidazole according to standard procedures gave 7 (309 mg, 62%). % yield) and Example 8 (67 mg, 12% yield).

Example compound: ¹ H NMR (CD ₃ OD) δ: 8.32 (d, J = 1.4 Hz, 2H),

8.12 (s, 1H), 8.10 (d, J = 8.1 Hz, 1H), 8.08 (dd, J = 7.7 Hz, J = 1.4 Hz, 1H),

7.88-7.81 (m, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.61 (td, J = 7.7 Hz, J = 1.5 Hz,

1 H), 7.52 (td, J = 7.7 Hz, J = 1.5 Hz, 1H). 7.44 (d, J = 8.4 Hz, 2H), 7.35 (dd,

J = 7.3 Hz, J = 1.1 Hz, 1H): ¹³ C NMR (CD ₃ OD) δ: 167.59, 162.59, 143.08, 141.63, 139.32, 138.97 , 138.68, 137.58, 137.33, 133.72, 132.94, 132.44, 131.62, 131.28, 128.72, 128.66, 128.49, 127.66, 122 , 94, 122.12, 121.00; ESMS: 461.3 (M + H) ⁺ ; DSGMS: 461.1387 (found), 461.1396 (calculated).

Example compound: ¹ H NMR (CD ₃ OD) δ: 8.33 (s, 2H), 8.12 (s, 1H),

8.10 (dd, J = 8.4 Hz, J = 1.5 Hz, 1H), 8.05 (dd, J = 8.1 Hz, J = 2.2 Hz, 1H),

7.88-7.80 (m, 3H), 7.79 (d, J = 8.4 Hz, 2H), 7.61 (td, J = 7.7 Hz, J = 1.5 Hz,

1H), 7.53 (td, J = 7.7 Hz, J = 1.2 Hz, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.35 (dd,

J = 7.3 Hz, J = 1.5 Hz, 1H); 1.02 (s, 9H); ¹³ C NMR (CD 3 OD) δ: 167.58, 162.57, 143.51, 141.65, 139.02, 138.68, 137.30, 137.33, 133.89, 133.05, 132, 44, 131.64, 131.52, 128.72, 129.53, 128.77, 128.50, 127.65, 122.96, 122.12, 120.99, 55.06, 30.11; ESMS: 517.4 (M + H) ⁺ ; DSGMS: 517.2025 (found), 517.2022 (calculated); Analysis: (C ₂₇ H ₂₈ N ₆ O ₃ Si + 1.35 TFA + 0.17 HCl + 0.6 H ₂ O) C, H, N, S, F, Cl.

example

1- (3-amidinophenyl) -2 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] imidazole

Part A: Preparation of 1- (3-cyanophenyl) imidazole

3-Fluorobenzonitrile (4.84 g, 40 mmol) was heated with imidazole (2.72 g, mmol) in K ₂ CO ₃ , DMF at 100 ° C for 8 h to give the desired compound as a white solid in quantitative yield. ¹ H NMR (CDCl ₃ ) δ; 7.89 (s, 1H), 7.70 (d, J = 0.8 Hz, 1H), 7.68-7.58 (m, 3H), 7.30 (d, J = 1.0 Hz) , 1H), 7.26 (s, 1H); MSGMS: 170 (M + H) &lt; + &gt;.

Part B:

Preparation of methyl 1- (3-cyanophenyl) imidazol-2-ylcarboxylate

1- (3-Cyanophenyl) imidazole (1.52 g, 9 mmol) was slowly treated with n-BuLi (1.6 M, 6.3 mL) in THF (60 mL) at -78 ° C for 40 h, then slowly decompose at the same temperature with chloromethyl formate (942 mg, 10 mmol). The resulting mixture was stirred at -78 ° C for 2 hours. warm to room temperature, then pour into a mixture of water and ethyl acetate. The organic layer was separated and washed with water, brine, and dried over MgSO ₄ . After evaporation of ethyl acetate, the residue was purified by column chromatography eluting with ethyl acetate and methylene chloride (1: 1); yielding the title compound (1.33 g, 65%) as a white solid. ¹ H NMR (CDCl 3) δ: 7.80-7.77 (m, 1H), 7.65-7.61 (m, 3H), 7.33 (s, 1H), 7.20 (s,

1H); MSGMS: 228 (M + H) &lt; + &gt;.

Part C: Preparation of 1- (3-cyanophenyl) -2- (2'-tert-butylaminosulfonyl-1,1''-biphen-4-yl) aminocarbonylimidazole

To a stirred solution of 4 - [(o-SO ₂ tBu) -phenyl] aniline (304 mg, 1 mmol) in CH ₂ Cl ₂ (20 mL) at 0 ° C was slowly added trimethylaluminum (2M in hexane, 1 mL), and min the resulting mixture is warmed to room temperature.

After addition of a solution of methyl 1- (3-cyanophenyl) imidazol-2-yl) carboxylate in CH ₂ Cl ₂ (5 mL), the resulting mixture was refluxed for 2 hours. The mixture was quenched with water, diluted with ethyl acetate and filtered through celite. The organic layer was separated, washed with water, brine, and dried over MgSO ₄ . After evaporation of ethyl acetate, the residue was purified by column chromatography eluting with ethyl acetate and methylene chloride (1: 1); yielding the title compound (260 mg, 52%) as a white solid. ¹ H NMR (CDCl ₃ ) δ: '

9.41 (s, 1H), 8.15 (dd, J = 7.7 Hz, J = 1.5 Hz, 1H), 7.78 (dd, J = 7.3 Hz, J =

1.1 Hz, 1H), 7.74-7.57 (m, 6H), 7.55 (td, J = 7.7 Hz, J = 1.1 Hz, 1H), 7.49 (dd,

J = 8.8 Hz, J = 1.8 Hz, 2H), 7.29 (dd, J = 8.1 Hz, J = 1.5 Hz, 1H), 7.28 (d, J = 0, 8 Hz, 1H), 7.22 (d, J = 0.8 Hz, 1H), 3.64 (s, 1H), 0.99 (s, 9H); MSGMS:

500.1 (M + H) ⁺ .

Part D: Preparation of 1- (3-Amidinophenyl) -2- (2'-aminosulfonyl-H, 1'-1-biphen-4-yl) aminocarbonylimidazole

Further, a Pinner reaction with 1- (3-cyanophenyl) -2 - [(2'-tert-butylaminosulfonyl- [1,1'] -biphen-4-yl) aminocarbonylimidazole] gave the title compound (120 mg, 50%). ¹ H NMR (CD ₃ OD) δ: 8.08 (dd, J = 7.7 Hz, J = 1.1 Hz, 1H), 7.91-7.88 (m, 2H), 7.83 (dd, J = 8.4 Hz, J = 1.5 Hz, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H ), 7.58 (dd, J = 7.3 Hz, J = 1.1 Hz, 1H), 7.50 (s, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.32 (s, 1H), 7.30 (dd, J = 7.3 Hz, J =

1.1 Hz, 1H); ESMS: 461 (M + H) &lt; + &gt;.

example

1- (3-Amidinophenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 T] -biphen-4-yl) aminocarbonyl] pyrazole trifluoroacetic acid salt

Part A: Preparation of Ethyl 1- (3-Bromophenyl) -3-methyl-pyrazol-5-ylcarboxylate and Ethyl 1- (3-Bromophenyl) -5-methyl-pyrazol-5-ylcarboxylate in Ethanolic 3-Methoxy-trichloroacetylcrotonate (Fischer et al. Synthesis) 1991, 83) 2-Bromophenylhydrazine hydrochloride (6.5 g, 0.029 mol) was added portionwise. The reaction mixture was refluxed for 48 hours, cooled and concentrated. The residue was dissolved in ethyl acetate (100 mL) and washed with HCl (1N, 50 mL), brine (50 mL) and dried (magnesium sulfate). Evaporation gives an oil which is chromatographed on a silica gel column (hexane: ethyl acetate, 6: 1) and. to give ethyl 1- (3-bromophenyl) -5-methyl-pyrazol-5-ylcarboxylate (3.73 g) and ethyl 1- (3-bromophenyl) -3-methyl-pyrazol-5-ylcarboxylate (3.65 g), which are pure compounds. The pyrazole carboxylate thus obtained is directly used in Part B.

Part B: Preparation of ethyl 1- (3-cyanophenyl) -3-methyl-pyrazol-5-ylcarboxylate

Ethyl 1- (3-bromophenyl) -3-methylpyrazol-5-ylcarboxylate (2.3 g) was dissolved in N-methylpyrrolidinone (4 mL) and CuCN (1 g) was added. The reaction mixture was refluxed for 2 hours, then stirred at room temperature overnight. The mixture was quenched with water (100 mL), and the organic material was extracted with ethyl acetate (2 x 100 mL) and dried (magnesium sulfate). Chromatography on a silica gel column (hexane: ethyl acetate, 3: 1) gives the title compound (0.59 g). ¹ H NMR (CDCl 3) δ: 7.76 (t, 1H), 7.70 (dd, 1H), 7.58 (t, 1H), 6.68 (s, 1H), 4.3 (s). 2H), 2.36 (s, 3H), 1.31 (t, 3H) md; IR (neat): 2230, 1728, 1586, 1540, 1494, 1438, 1298, 1242, 1106, 1046, 760, 682 cm ^-1 ; mass spectrum for chemical ionization at m / z (relative intensity) 256 (M + H, 100).

Part C: Preparation of 1- (3-cyanophenyl) -3-methyl-pyrazol-5-ylcarboxylic acid

Ethyl 1- (3-cyanophenyl) -3-methyl-pyrazol-5-ylcarboxylate (0.55 g) was dissolved in THF (20 mL) and LiOH (0.5 M, 5.6 mL) was added to the solution. The reaction mixture was stirred at room temperature for 18 hours, then quenched with water (50 mL). The unreacted organic material is extracted with ethyl acetate (2 x 50 mL). The aqueous layer was acidified, extracted with ethyl acetate (2 x 50 mL), dried (magnesium sulfate) and evaporated to give the pure acid. ¹ H NMR (DMSO-d 6) δ: 8.02 (t, 1H), 7.91 (d, 1H), 7.82 (dd, 1H), 7.09 (t, 1H), 6.89 ( s, 1H), 2.27 (s, 3H) md; IR (PEC) 2930, 2232, 1724, 1710, 1540, 1496, 1458, 1276, 1230, 1186, 1146, 1112, 900, 768, 754, 690 cm ^-1 ; mass spectrum for chemical ionization m / z (rel intensity) 228 (M + H, 100).

Part D: Preparation of 1- (3-Cyanophenyl) -3-methyl-5 - [(2'-tert-butylaminosulfonyl-H, T1-biphen4-yl) aminocarboninpyrazole

To a solution of 1- (3-cyanophenyl) -3-methyl-pyrazol-5-ylcarboxylic acid (0.2 g) in dichloromethane (20 mL) was added oxalyl chloride (0.11 mL). The reaction mixture is stirred at room temperature for 2 hours and then added to this solution

2-tert-butylsulfonamide-1-biphenylanilium (0.27 g) and triethylamine (0.5 mL). The reaction mixture was stirred at room temperature for 24 h, then quenched with water (50 mL), extracted with ethyl acetate (2 x 50 mL), washed with brine (50 mL) and dried (magnesium sulfate). Evaporation gives an oil which is chromatographed on a silica gel column (dichloromethane: MeOH 9: 1) to give the title compound (0.45 g). ¹ H NMR (CDCl ₃ ) δ: 8.16 (d, 1H), 8.05 (s,

H), 7.8 (d, 1H), 7.76 (d, 1H), 7.68 (d, 3H), 7.58 (m, 2H), 7.50 (md, 3H), 7, 30 (d, 1H), 6.76 (s, 1H), 3.64 (s, 1H), 2.42 (s, 3H), 1.03 (s, 9H) md; IR (PEC) 3320, 2976, 2232, 1682, 1592, 1540, 1522, 1488, 1464, 1438, 1368, 1320, 1242, 1152, 1128, 758, 682, 608 cm ^-1 : mass spectrum of chemical ionization m / z (relative intensity) 458 (MH, 100).

Part E: Preparation of the trifluoroacetic acid salt of 1- (3-Amidinophenyl) -3-methyl-5 - [(2'-aminosulfonyl-11,1'1-biphen-4-yl) aminocarbonyl] pyrazole

1- (3-Cyanophenyl) -3-methyl-5 - [(2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole was dissolved in saturated HCl anhydrous MeOH (20 mL). The reaction mixture was stirred at room temperature for 24 h before the MeOH was evaporated. The residue was redissolved in MeOH (20 mL) and excess ammonium carbonate was added. The reaction mixture was stirred at room temperature for 18 hours. The MeOH was evaporated and the residue was purified by HPLC to give the title compound as the TFA salt (0.15 g). ¹ H NMR (DMSO-d ₆ ) δ: 10.66 (s, 1H), 9.44 (s, 1.5H), 9.09 (s, 1.5H), 8.03 (d, 1H) , 7.97 (s, 1H), 7.83 (t, 1H), 7.75 (d, 1H), 7.70 (d, 2H), 7.62 (m, 2H), 7.37 ( d, 2H), 7.32 (d, 1H), 7.27 (s, 2H), 7.03 (s, 1H), 2.50 (s, 3H) md; IR (PEC) 3288, 1704, 1660, 1592, 1526, 1484, 1438, 1322, 1206, 1160, 762, 724 cm ^-1 ; high resolution mass spectrum: calcd. for C24H22N6O3S 475.155236, found 475.153767.

example

1- (3-Amidinophenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carbonylamino] pyrazole trifluoroacetic acid salt

Part A: Preparation of 5-Amino-1- (3'-cyanophenyl) -3-methylpyrazole

3-Aminocrotonitrile (1 g, 12.2 mmol) was mixed with 3-cyanophenylhydarzine hydrochloride (2 g, 11.8 mmol) and 1: 1 ethanol / acetic acid (20 mL) was refluxed for 4 hours. The reaction mixture was concentrated, the residue was basified with dilute NaOH and extracted with ethyl acetate. The crude product was purified by silica gel flash chromatography eluting with hexanes / ethyl acetate (4: 1) to give 1.2 g of crude amine. This amine is dissolved in dilute HCl and the solution is extracted with ethyl acetate. The aqueous layer was basified with NaOH, extracted with ethyl acetate and dried (MgSO ₄ ) to give 0.66 g (28%) of amino: Ή NMR (CDCl ₃ ) δ: 7.97 (s, 1H), 7.92 (m, 1H). , 7.57 (s + d, 2H), 5.51 (s, 1H), 3.75 (s, 2H), 2.23 (s, 3H); MS (H ₂ O / GC) m / z 199 (M + H) ^+.

Part B: Preparation of 1- (3'-cyanophenyl) -3-methyl-5 - ((4'-bromophenyl) carbonylamino) pyrazole in a solution of the product from Part A (0.66 g, 3.3 mmol) in methylene chloride (20 mL) ) A solution of 2M trimethylaluminium (8.3 mL, 16.7 mmol) in heptane was added at 0 ° C. Stir the mixture for 15 min. and methyl 4-bromobenzoate (0.72 g, 3.3 mmol) was added. The reaction mixture was stirred overnight. The reaction was quenched with 1N HCl, extracted with methylene chloride and dried (Na ₂ SO ₄ ). Recrystallization from methylene chloride / hexanes gave 0.48 g (45%) of the title compound; ¹ H NMR (CDCl ₃ ) δ; 7.86 (s, 1H), 7.78 (d, J = 7.69 Hz, 1H), 7.67 (d, J = 7.69 Hz, 1H), 7.63 (m, 4H), 7, 60 (m, 1H), 6.52 (s, 1H), 2.36 (s, 3H); MS (ESI) m / z 381.1-383.1 (M + H) ⁺ .

Part C: Preparation of 1- (3-cyanophenyl) -3-methyl-5-i (2'-aminosulfonyl-f,1,1'-biphen-4-yl) carbonylamino] pyrazole

The above part B amide (0.4 g, 1 mmol), 2- (fbutylsulfonamide) phenylboronic acid (0.38 g, 1.5 mmol), 2M Na ₂ CO ₃ (1.3 mL), toluene (10 mL) ) and ethanol (10 ml) are degassed with nitrogen and then tetrakistriphenylphosphine palladium (10 ml) is added. The reaction mixture was refluxed overnight, cooled, filtered and concentrated. The residue was diluted with water, extracted with ethyl acetate and dried (MgSO ₄ ). The crude product was purified by silica gel flash chromatography eluting with hexanes / ethyl acetate (2: 1) to give 0.46 g (86%) of a foam; ¹ H NMR (CDCl ₃ ) δ: 7.94 (m, 5H), 7.63 (m, 7H), 7.32 (d, J = 7.7

Hz, 1H), 6.55 (s, 1H), 4.13 (s, 1H), 2.39 (s, 3H), 0.99 (s, 9H); MS m / z 514.3 (M + H ⁺ ).

Part D; 1- (3-amidinophenyl) -3-methyl-5-f (2'-aminosulfonyl-ri, ^1, 1-biphen-4-yl) karbonilaminolpirazolo trifluoroacetic acid salt The

The product of Part D is then subjected to a standard Pinner amidine reaction sequence to give the desired benzamidine, which, after preparative HPLC (acetonitrile / water with 0.05% TFA), is colorless crystals (44% yield). H NMR (DMSO-d _s) δ: 10.57 (s, 1H), 9.43 (s, 1.5H), 9.14 (s, 1.5H), 8.07 (s, 1H) , 8.05 (m, 1H), 7.94 (d, J = 6.96 Hz, 1H), 7.89 (d, J = 8.42 Hz, 2H), 7.76 (m, 2H) , 7.65 (m, 2H), 7.53 (d, J = 8.42 Hz, 2H), 7.39 (s, 2H), 7.35 (m, 1H), 2.29 (s, 3H); MS (ESI) m / z 475.2 (M + H) ⁺ ; Analysis: calculated for C24H22N6O3S1 (TFA) 1.4 (H ₂ O) 1: C, 49.36; H, 3.93; N, 12.89; Found: C, 49.69; H, 3.71; N, 12.77.

example

1- (3-amidinophenyl) -3-methyl-5- (2 '- (5' -CF ₃ -tetrazolyl) - [1,1 '] - biphen-4-yl) aminocarbonyl) pyrazole

Part A: Preparation of 2- (5'-CF ₃ ) -tetrazolyl) biphenylaniline

To a cold (0 ° C) solution of 2'-trifluoroacetanilide-1-nitrobiphenyl (0.15 g, 0.48 mmol) in CCl ₄ (3 mL) was added triphenylphosphine (0.24 g, 0.97 mmol), cold reaction mixture After stirring for 0.15 min, allow to warm to room temperature and then slowly reflux overnight. Evaporation of the solvent gives a residue which is treated with hexane (20 ml) and filtered to give crude chlorimine which is dissolved in acetonitrile (10 ml). To this solution was added sodium azide (0.038 g, 0.58 mmol) and the reaction mixture was stirred at room temperature overnight. Evaporation of the solvent and purification by flash chromatography on silica gel (hexane / ethyl acetate 4: 1) afforded the desired nitrobiphenyltetrazole precursor (0.12 g) as a yellowish solid. ¹ H NMR (CDCl ₃ ) δ: 8.2 (d, 2H), 7.80 (t, 1H), 7.70 (t, 1H), 7.61 (d, 1H), 7.50 (d , 1H), 7.3 (d, 2H) md;

ammonia Cl mass spectrum, m / z (rel intensity) 353.0 (M + NH ₄ ⁺ , 100).

The above nitro-biphenyl is then hydrogenated in ethanol (20 mL) with 10% Pd / C for 6 hours to give the title compound (0.11 g). ¹ H NMR (CDCl 3) δ: 7.70 (t, 1H), 7.59 (d, 1H), 7.50 (d, 1H), 7.40 (d, 2H), 6.8 (d , 2H), 6.55 (d, 2H), 3.75 (pi.d, 2H) md; mass spectrum of ammonia Cl, m / z (relative intensity) 323 (M + NH ₄ ⁺ , 100).

Part B: Preparation of 1- (3-Cyanophenyl) -3-methyl-5- (2 '- (5' -CF 3 -tetrazolyl) - [1,1'] -biphen-4-ylaminocarbonylpyrazole

The 5- (5'-CF ₃ -tetrazolyl) - [1,1 '] -biphenylaniline is then coupled with 1- (3-cyanophenyl) -3-methyl-pyrazole-5-carboxylic acid (0.09 g, 0.39 mmol). using the chloro-anhydride methodology described above to give the title compound (0.12 g) which, after chromatography on a silica gel column (dichloromethane: methanol, 9.6: 0.4), is a colorless solid; ¹ H NMR (CDCl ₃ ) δ: 7.82 (s, 1H), 7.70 (m, 4H), 7.61 (m, 2H), 7.45 (m, 3H), 7.05 (d) , 2H), 6.65 (s, 1H), 3.50 (d, 1H), 2.40 (s, 3H) md; ammonia Cl mass spectrum, m / z (rel intensity) 522.0 (M + NH ₄ ⁺ , 100).

Part C: Preparation of 1- (3-Amidinophenyl) -3-methyl-5- (2 '- (5' -CF ₃ -tetrazolyl) - [1,1'-biphen-4yl) aminocarbonyl) pyrazole

The product of Part B is then subjected to the standard Pinner's amidine reaction sequence described above to give the title compound which, after preparative HPLC (acetonitrile / water with 0.05% TFA), is colorless crystals; ¹ H NMR (DMSO-d ₆ ) δ: 10.61 (s, 1H), 9.42 (s, 2H), 9.12 (s, 2H), 7.94 (s, 1H), 7.89 (d, 1H), 7.82 (t, 2H), 7.75 (m, 4H), 7.62 (d, 2H), 7.02 (s, 2H), 6.98 (s, 1H) , 2.32 (s, 3H) md; ESI mass spectrum, m / z (relative intensity)

532.4 (M + H, 100); high resolution mass spectrum: calcd. for CHNFO 532.182116, found 532.18271.

example

1- (3-Amidinophenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -4-chloro-3-methylpyrazole trifluoroacetic acid salt

Part A: 4-Chloro-1- ^(3, -cianofenii) -3-methyl-5 - ((2'-F-f1,1'1bifen butylaminosulfonyl-4-yl) aminocarbonyl) pyrazole

Chlorination of methyl 1- (3'-cyanophenyl) -3-methyl-5-pyrazolecarboxylate (255 mg, 1 mmol) with NCS (139 mg, 1.05 mmol) under reflux in acetonitrile (10 mL) for 3 h affords the desired 4-chloropyrazole carboxylate in quantitative yield. Ή NMR (CDCl ₃₎ δ: 7.72 to 7.70 (m, 2H), 7.65 to 7.54 (m, 2H), 4.31 (q. J = 7.0 Hz, 2H); 2.23 (s, 3H), 1.28 (t, J = 7.0 Hz, 3H); MSGMS: 290 (M + H) @ +. A solution of this ester in dichloromethane (5 mL) at 0 ° C was added to a pre-treated solution of 2'-i-butylsulfonamid-biphenylaniline in dichloromethane (20 mL) and trimethylaluminum (2M in hexane, 1 mL) and the resulting mixture was stirred for 15 min. Warm to room temperature, then reflux for 3 hours. The mixture was quenched with water, extracted with CH 2 Cl 2 (200 mL) and filtered through celite. The organic layer was separated, washed with water, brine, and dried over MgSO ₄ . Evaporation of the CH ₂ Cl _2i residue gave a residue which was chromatographed on a silica gel column eluting with ethyl acetate: methylene chloride (1: 1) to give the title compound (330 mg, 60.3%) as a white solid. ¹ H NMR (CDCl 3) δ: 8.38 (s, 1H), 8.17 (dd, J = 8.7, J = 1.5 Hz, 1H), 7.78 (d, J = 1.5) Hz, 1H), 7.73-7.69 (m, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 7.7 Hz, 1H), 7.55 (dd, J = 7.7 Hz, J = 1.5 Hz, 1H), 7.52 (d, J = 8.7 Hz, 2H), 7.51-7.48 (m, 1H ), 7.29 (dd, J = 7.3 Hz, J = 1.5 Hz, 1H), 3.62 (s, 1H), 2.40 (s, 3H), 1.03 (s, 9H) ); MSGMS: 548 (M + H) @ +.

Part B: Preparation of the trifluoroacetic acid salt of 1- (3-Amidinophenyl) -5-i (2'-aminosulfonyl-n, 1'1-biphen-4-yl) aminocarbonyl] -4-chloro-3-methylpyrazole

Thereafter, the product of Part A of the standard Pinner'io amidine reaction sequence and after purification by preparative HPLC using CH3CNH ₂ O-TFA the title compound (350 mg). ¹ H NMR (CD ₃ OD) δ: 8.09 (dd, J = 8.1 Hz, J = 1.4 Hz, 1H), 8.00 (t, J = 1.8 Hz, 1H), δ , 81 (td, J = 7.7 Hz, J = 1.9 Hz, 2H), 7.71 (d, J = 8.1 Hz, 1H), 7.64 (d, J = 8.4 Hz) , 2H), 7.59 (dd, J = 7.3 Hz, J = 1.4 Hz, 1H), 7.52 (td, J = 7.7 Hz, J = 1.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.32 (dd, J = 8.4 Hz, J = 1.4 Hz, 1H), 2.36 (s, 3H); ESMS: 509.1 (M + H) ⁺ .

example

1- (3-amidinofeniI) -5 - ((2'-t-butylaminosulfonyl- [1, T] -bi ^ien - ⁴ - ^{i |)} aminocarbonyl) -3-trifIuormetilpirazolas

Part A; Preparation of 1- (3-cyanophenyl) -5-methyl-3-trifluoromethylpyrazole

1,1,1-Trifluoro-2,4-pentandione (1.35 mL, 11.2 mmol) was mixed with 3-bromophenylhydrazine hydrochloride (3 g, 13.4 mmol) in glacial acetic acid (20 mL) and 2-methoxyethanol (10 mL). ml) and refluxed for 2 hours. The solvents were evaporated in vacuo and the residue was dissolved in ethyl acetate. This ethyl acetate solution was washed successively with dilute HCl, saturated NaHCO ₃ , saturated NaCl and dried (MgSO ₄ ). The crude material was purified by flash chromatography on silica gel eluting with hexanes / ethyl acetate (8: 1). The product is a mixture of two isomers 88/12 in which the desired 5-methylpyrazole isomer predominates. This mixture was mixed with 1-methylpyrrolidine (7 mL) and copper cyanide (1.3 g, 14.5 mmol) and refluxed overnight. The reaction mixture was cooled, diluted with ethyl acetate and filtered. The filtrate was washed with water, brine and dried (MgSO ₄ ). Purification by silica gel flash chromatography afforded the desired 5-methylpyrazole isomer (0.66 g, 24%); ¹ H NMR (CDCl 3) δ: 7.81 (d, J = 1.8 Hz, 1H), 7.77 (m, 2H), 7.67 (t, J = 8.06 Hz, 1H), 6.52 (s, 1H), 2.42 (s, 3H); MS (NH 3) m / z 252.1 (M + H ⁺ ), 269.2 (M + NH 4 ⁺ ).

Part B: Preparation of 1- (3-cyanophenyl) -5-hydroxymethyl-3-trifluoromethylpyrazole To the compound obtained in Part A (0.65 g, 2.59 mmol) was added N -bromosuccinimide (0.48 g, 2.7 mmol) and benzoyl. peroxide (20 mg) in carbon tetrachloride (20 mL) and the reaction mixture was refluxed for 6 h. The mixture was cooled, filtered and the filtrate concentrated to give crude bromide. This bromide was mixed with a 1: 1 mixture of dioxane / water (20 mL) and calcium carbonate (0.46 g, 4.6 mmol) and heated on a steam bath for 6 hours. The reaction mixture was cooled, filtered and the filtrate concentrated. The aqueous residue was extracted with ethyl acetate and dried (MgSO ₄ ). The crude product was purified by silica gel flash chromatography eluting with hexanes / ethyl acetate (1: 1) to give a yellow solid (0.31 g, 44%); 1 H NMR (CDCl ₃ ) δ: 8.07 (s, 1H), 8.01 (dd, J = 2.2, 8.0 Hz, 1H), 7.77 (d, J = 7.7 Hz) , 1H), 7.68 (t, J = 8.05 Hz, 1H), 6.76 (s, 1H), 4.72 (d, J = 5.85 Hz, 2H), 2.02 (t , J = 5.86 Hz, 1H); MS (NH ₃ ) m / z 268.1 (M + H ⁺ ), 285 (M + NH ₄ ⁺ ).

Part C: Preparation of 1- (3-cyanophenyl) -3-trifluoromethylpyrazole-5-carboxylic acid

To the alcohol described above (0.18 g, 0.67 mmol) was added acetonitrile (5 mL), sodium periodate (0.3 g, 1.4 mmol) in water (5 mL) and one crystal of ruthenium (III) chloride hydrate. The reaction mixture was stirred for 18 hours. at room temperature. The reaction mixture was filtered and concentrated. The aqueous residue was extracted with ethyl acetate, dried (MgSO ₄ ) to give 0.17 g (89.9%) of the acid. ¹ H NMR (CDCl ₃ + DMSO-d ₆ ) δ: 7.82 (d, J = 1.47 Hz), 7.78 (dd, J = 8.0, 1.47 Hz, 1H), 7, 63 (t, J = 7.3, 8.42 Hz, 1H), 7.29 (s, 1H); MS (ESI-) m / z 280.2 (MH).

Part D: Preparation of 1- (3-cyanophenyl) -5 - ((2'-t-butylaminosulfonyl-1,1''-biphen-4-yl) aminocarbonyl) -3-trifluoromethylpyrazole (0.35 g, m.p. Oxalyl chloride (0.15 mL, 1.7 mmol) and 2 drops of DMF were added in 1.2 mmol of methylene chloride. The reaction mixture was stirred for 2 hours. at room temperature, then concentrated in vacuo. This chloro-anhydride was mixed with 2'-t-butylsulfonamide-biphenylaniline (0.38 g, 1.25 mmol), methylene chloride (10 mL) and N, N-dimethylaminopyridine (0.38 g, 3.1 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was washed with dilute HCl, saturated NaHCO ₃ , saturated NaCl, and dried (MgSO ₄ ). The crude product was purified by silica gel flash chromatography eluting with hexanes / ethyl acetate (1: 1) to give 0.41 g (58%) of a yellow foam. ¹ H NMR (CDCl ₃ + DMSO-d ₆ ) δ: 9.88 (s, 1H), 8.18 (dd, J = 7.69, 1.47 Hz, 1H), 7.87 (d, J = 1.83 Hz, 1H), 7.79 (m, 4H), 7.64 (m, 3H), 7.50 (m, 3H), 7.30 (d, J = 7.3 Hz, 1H) ), 3.67 (s, 1H), 1.02 (s, 9H): MS (ESI) m / z 590.14 (M + Na).

Part E: Preparation of 1- (3-Amidinophenyl) -5 - ((2'-t-butylaminosulfonyl-1,1''-biphen-4-yl) aminocarbonyl-D-3-trifluoromethylpyrazole

The product of Part D is then subjected to a standard Pinner amidine reaction sequence to give the title compound which, after purification by preparative HPLC (acetonitrile / water with 0.05% TFA), is colorless crystals (46% yield). Ή NMR (DMSO-d ₆₎ δ: 10.85 (s, 1H), 9.47 (s, 1.5H), 9.20 (s, 1.5H), 8.05 (s, 1H) 8.04 (dd, J = 7.69, 1.84 Hz, 1H), 7.96 (m, 2H), 7.82 (d, J = 7.69 Hz, 1H), 7.75 (s) , 1H), 7.68 (d, J = 8.79 Hz, 2H), 7.62 (m, 2H), 7.39 (d, J = 8.43 Hz, 2H), 7.32 (s) + m, 3H); MS (ESI) m / z 529.03 (M + H ⁺ ); Analysis: Calculated for C ₂₄ H ₁₉ F ₃ N ₆ O ₃ Si (TFA) 1.2 (H ₂ O) 1: C 46.40; H, 3.27; N, 12.30; Found: C, 46.11; H, 3.06; N, 12.05.

example

1- (3-amidinophenyl) -4-methoxy-5 - ((2'-aminosulfonyl- [1,1 T] -biphen-4-yl) aminocarbonyl) -3-trifluoromethylpyrazole

Part A: Preparation of 1- (3-Bromophenyl) -4-methoxy-5-methyl-3-trifluoromethylpyrazole

3-Bromophenylhydrazine (9.4 g, 50.5 mmol) and trifluoroacetaldehyde hydrate (8.7 g, 75 mmol) were heated at 100 ° C for 1 h. The reaction mixture was cooled, diluted with methylene chloride, washed with brine and dried (MgSO ₄ ). To this crude hydrazone was added 40% aqueous pyruvate aldehyde (22.6 g, 126 mmol), MgSO ₄ (13 g), butyl acetate (150 mL) and a few drops of acetic acid, and the reaction mixture was refluxed overnight. The reaction mixture was filtered and concentrated. The residue was dissolved in 1N NaOH and extracted with diethyl ether. The aqueous layer was acidified with HCl, extracted with ethyl acetate and dried (MgSO ₄ ). Collect the crude orange solid (11.3 g, 70%). To this solid was added acetone (50 mL), K ₂ CO ₃ (7.3 g, 53 mmol) and iodomethane (8.8 mL, 140 mmol), and the mixture was refluxed for 2 hours. The reaction mixture was filtered, concentrated and the crude product was purified by flash chromatography on silica gel eluting with hexanes / ethyl acetate (4: 1); 6.9 g (60%) of a yellow oil are obtained. ¹ H NMR (CDCl ₃ ) δ: 7.65 (d, J = 1.83 Hz, 1H), 7.58 (dd, J = 2.2, 6.96 Hz, 1H), 7.39 (s + m, 2H), 3.85 (s, 3H), 2.31 (s, 3H); MS (H ₂ O / GC) m / z 335-337 (M + H ^+).

Part B: Preparation of 1- (3-cyanophenyl) -4-methoxy-5-methyl-3-trifluoromethylpyrazole

1- (3-Bromophenyl) -4-methoxy-5-methyl-3-trifluoromethylpyrazole (6.9 g, 20.6 mmol) and CuCN (2.8 g, 30.9 mmol) are mixed in N-methylpyrrolidinone (12 mL) ) and refluxed for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were washed with water, brine, and dried (MgSO ₄ ). The product was purified by flash chromatography on silica gel eluting with hexanes / ethyl acetate (4: 1); 4.2 g (72%) of a yellow solid are obtained. Δ NMR (CDCl ₃ ) δ: 7.79 (s, 1H), 7.74 (m, 2H), 7.66 (d, J = 7.3 Hz, 1H), 3.86 (s, 3H). , 2.35 (s, 3H); MS (H ₂ O / GC) m / z 282 (M + H ^+); IR (KBr) 2232, 1588, 1320, 1170, 1120, 804 cm ^-1 ; Analysis: calculated for Ci Hi _{0 3} F ₃ N ₃ Oi: C, 55.52; H, 3.58; N, 14.94; Found: C, 55.44; H, 3.76; N, 14.95.

Part C: Preparation of 5-Bromomethyl-1- (3-cyanophenyl) -4-methoxy-3-trifluoromethylpyrazole

To the product from Part B (2.65 g, 9.40 mmol) was added N-bromosuccinimide (1.76 g, 9.90 mmol), CCl ₄ (15 mL) and benzoyl peroxide (10 mg). The reaction mixture was refluxed for 4 hours, then cooled and filtered. The crude bromide was dissolved in 1: 1 dioxane / water (20 mL) and CaCO ₃ (1.7 g, 16.9 mmol) was added. The reaction mixture was stirred at room temperature overnight. The product was purified by silica gel flash chromatography eluting with hexanes / ethyl acetate (2: 1) to give 2.2 g (79%) of a solid. The sample is recrystallized from methylene chloride / hexanes. ¹ H NMR (CDCl ₃ ) δ: 8.10 (m, 1H), 8.05 (dd, J = 8, 1.46 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H ), 7.66 (t, J = 7.69 Hz, 1H), 4.67 (d, J = 5.13 Hz, 2H), 3.95 (s, 3H), 2.17 (t, J = 5.13 Hz, 1H); MS (ESI) m / z 288.2 (M + H ⁺ ); Analysis: Calculated for C 13 H 10 F 3 N 3 O 2: C, 52.53; H, 3.39; N, 14.14; Found: C, 52.35; H, 3.21; N, 14.13.

Part D: Preparation of 1- (3-cyanophenyl) -4-methoxy-3-trifluoromethylpyrazole-5-carboxylic acid

To the product of Part C (0.64 g, 2.2 mmol) in CH ₃ CN (5 mL) was added sodium periodate (0.98 g, 4.5 mmol) in water (5 mL) at 0 ° C, followed by one crystal of ruthenium (III) chloride. The reaction mixture was stirred for 30 min under reflux followed by 30 min. at room temperature. The reaction mixture was concentrated and partitioned between ethyl acetate and dilute NaOH. The ethyl acetate layer was dried (MgSO ₄ ), filtered and concentrated to give the aldehyde (0.42 g, 66%). The alkaline layer was acidified, extracted with ethyl acetate, dried (MgSO ₄ ) to give the carboxylic acid (0.16 g, 23%). Ethanol (50 mL), silver nitrate (0.48 g, 2.8 mmol) and 0.5 N NaOH (12 mL) were added to the aldehyde (0.42 g, 1.40 mmol). The reaction mixture was stirred for 3 hours, then filtered through celite and concentrated. The aqueous layer was extracted with ethyl acetate, dried (MgSO ₄ ) to give the title compound (0.4 g, 91%). ¹ H NMR (CDCl 3 + DMSO-d 6) δ: 7.80 (m, 3H), 7.61 (m, 1H), 4.01 (s, 3H).

Part E: Preparation of 1- (3-cyanophenyl) -4-methoxy-5 - ((2'- ^t -butylaminosulfonyl-1,1'-biphen4-yl) aminocarbonyl) -3-trifluoromethylpyrazole-5-carboxylic acid acid (0.44 g, 1.4 mmol) was added methylene chloride (15 mL), oxalyl chloride (0.17 mL, 1.9 mmol) and 2 drops of DMF. The reaction mixture was stirred for 3 hours and then concentrated. To this crude chloro anhydride was added 2'-t-butylsulfonamide-biphenylaniline (0.43 g, 1.4 mmol), methylene chloride (15 mL) and triethylamine (0.8 mL, 5.6 mmol). The reaction mixture was stirred for 18 h, then diluted with methylene chloride and washed with dilute HCl, saturated NaHCO ₃ , brine, dried (MgSO ₄ ) to give 0.6 g (52%) of a foam. ¹ H NMR (CDCl ₃ ) δ: 9.3 (s, 1H), 8.18 (m, 1H), 7.80 (s, 1H), 7.78 (m, 2H), 7.66 ( d, J = 8.79 Hz, 2H), 7.65 (m, 1H), 7.56 (m, 2H), 7.52 (d, J = 8.79 Hz, 2H), 7.27 (m, 1H), 4.19 (s, 3H), 1.03 (s, 9H); MS (ESI) m / z 598.4 (M + H ⁺ ).

Part F: Preparation of 1- (3-Amidinophenyl) -4-methoxy-5 - ((2'-aminosulfonyl-1,1''-biphen-4yl) aminocarbonyl) -3-trifluoromethylpyrazole

The product of Part D is then subjected to the standard Pinner amidine reaction sequence to give the desired benzamidine which, after purification by preparative HPLC (acetonitrile / water with 0.05% TFA), is colorless crystals (46% yield). ¹ H NMR (DMSO-d 6) δ: 11.05 (s, 1H), 9.49 (s, 1.5H), 9.22 (s, 1.5H), 8.03 (m, 2H), 7.89 (m, 3H), 7.65 (m + d, J = 8.05 Hz, 4H), 7.39 (m + d, J = 8.40 Hz, 5H), 3.96 (s , 3H); MS (ESI) m / z 559.4 (M + H ⁺ ); Analysis: calculated for C25H ₂ iF3N6O ₄ S (TFA): C, 48.22; H, 3.31; N, 12.50; Found: C, 47.86; H, 3.34; N, 12.24.

example

1- (3-amidinophenyl) -3-methyl-5- (4 '- (imidazol-1-yl-phenyl) aminocarbonyl) pyrazole

Part A: Preparation of 1- (4-Aminophenyl) imidazole

1- (4-Nitrophenyl) imidazole (5.0 g) and 200 mL methanol are stirred at room temperature to make a solution. After adding a catalytic amount of 10% palladium on carbon, the solution turns into a 'slurry. After the reaction mixture is placed under hydrogen atmosphere, reduction is started. The reaction was carried out overnight (15 hours) at room temperature. Filtration through a pad of celite separates the catalyst. Concentration of the filtrate under reduced pressure affords the desired product as a yellowish solid (3.99 g). ¹ H NMR (DMSO-d 6) δ: 7.95 (s, 1H), 7.45 (s, 1H), 7.18 (d, 2H), 6.99 (s, 1H), 6.60 ( d, 2H), 5.25 (s, 2H) md MSGMS (GC / MS) m / z 160 (M + H, 100).

Part B: Preparation of N- (3-cyanophenyl) -3-methyl-5-f ((4'-imidazol-1-yl) phenyl) aminocarbonyl) pyrazole, 0.203 g of N- (3-cyanophenyl) -3-methylpyrazole- 5-Carboxylic acid and 10 ml of dichloromethane are added oxalyl chloride and 2 drops of DMF. The reaction is carried out overnight. Concentration of the reaction mixture and maintaining under deep vacuum affords the crude chlorohydride, which is then coupled with the product of Part A under standard conditions and, after purification according to standard procedures, the title compound (0.118 g). ¹ H NMR (DMSO-d _s) δ: 10.73 (s, 1H), 9.35 (s, 1H), 8.13 (s, 1H), 7.95 (s, 1H), 7 , 90-7.60 (complex, 8H), 7.00 (s, 1H), 2.30 (s, 3H) md MSGMS (ESI) m / z 369.2 (M + H, 100). DSGMS (NH ₃ -Cl) calculated 369.146384, found 369.145884.

Part C: Preparation of N- (3-amidinophenyl) -3-methyl-5-i ((4'-imidazol-1-yl) phenyl) aminocarbonylpyrazole

The standard transformation of the benzonitrile from Part B into benzamidine via ethylimidate converts 0.113 g of benzonitrile to 0.070 g of HPLC-purified benzamidine bis-TFA salt. ¹ H NMR (DMSO-d ₆ ) δ: 10.65 (s, 1H), 9.40 (s, 2H), 9.00 (s, 2H), 8.19 (s, 1H), 7.90 (s, 1H), 7.80-7.55 (complex, 8H), 7.06 (s, 1H), 7.00 (s, 1H), 2.30 (s, 3H) md MSGMS (ESI) m / z 386.1 (M + H, 2), 193.7 (100). DSGMS (FAB) calculated 386.172933, found 386.173388.

example

1- (3-Amidinophenyl) -3-methyl-5 - [(4 '- (2' -sulfonylmethyl) phenoxyphenyl) aminocarbonyl] pyrazole

Part A: Preparation of 1- (3-Cyanophenyl) -3-methyl-5 - [(4 '- (2' -sulfonylmethyl) phenoxyphenyl) aminocarbonyl] pyrazole

Co-coupling of 4- (2'-sulfonylmethyl) phenoxy-1-aminophenyl with 1- (3cyano) phenyl-3-methyl-5-pyrazolecarboxylic acid according to standard chloro anhydride procedures described above yields the desired compound: ¹ H NMR (ODCI ₃ ) δ:

8.05 (d, 1H), 7.82 (s, 1H), 7.78 (d, 1H), 7.65 (d, 2H), 7.55 (m, 4H), 7.10 (d) , 2H), 6.95 (d, 2H), 6.65 (s, 1H), 3.32 (s, 3H), 2.40 (s, 3H) md; mass spectrum of ammonia, m / z (relative intensity) 490 (M + NH ₄ ⁺ , 100).

Part B: Preparation of 1- (3-Amidinophenyl) -3-methyl-5- (4 '- (2-sulfonylmethyl) phenoxyphenyl) aminocarbonylpyrazole

Standard Pinner amidine reaction with Part D product gives the desired product which, after purification by preparative HPLC (acetonitrile / water with 0.05% TFA), is colorless crystals. 1 H NMR (DMSO-d ₆ ) δ: 10.64 (s, 1H), 9.43 (s, 2H), 9.08 (s, 2H), 7.95 (m, 2H), 7.83 (d, 1H), 7.75 (d, 2H), 7.67 (m, 2H), 7.34 (t, 2H), 7.17 (d, 2H), 7.03 (s, 1H) ). 6.98 (d, 1H), 3.35 (s, 3H), 2.34 (s, 3H) md; ESI mass spectrum: m / z (rel intensity) 490 (M + H, 100); high resolution mass spectrum: calcd. for CHNSO 490.153564, found 490.153759.

example

1- (3-Amidinophenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) methylcarbonyl] pyrazole

Part A: Preparation of 1- (3-cyanophenyl-5-F (4'-bromophenyl) methylcarbonyl-3-methylpyrazole) Zinc dust (0.19 g, 2.9 mmol) in THF (3 mL) was treated with a few drops of dibromoethane, and mixture was brought to reflux for 5 min., then cooled to 0 C. ^c I ŠJ activated zinc in 5 minutes. 4brombenzilbromido was added dropwise (0.59 g, 2.3 mmol) in THF (6 ml). the reaction mixture was stirred at 0 ° At room temperature for 2 hours, then add a solution of LiCl (0.2 g, 4.7 mmol) and CuCN (0.21 g, 2.3 mmol) in THF (5 mL) at -78 ° C. At -10 ° C for 5 min, then cool to -78 ° C and add a solution of 1- (3-cyanophenyl) -5-carboxy-3-methylpyrazole chlorohydride (0.45 g, 1.98 mmol) in THF (5 mL) The reaction mixture was allowed to warm to room temperature overnight, diluted with ethyl acetate and washed with saturated NaHCO ₃ , brine, and dried (Na ₂ SO ₄ ), after purification by flash chromatography on silica gel, eluting with When using hexanes / ethyl acetate (2: 1) to give 0.15 g (17%) solid: ¹ H NMR (CDCl) δ: 7.67 (dd, J = 1.83, 6.96 Hz, 1 H) , 7.62 (s, 1H), 7.54 (m, 2H), 7.49 (d, J = 8.42 Hz, 2H), 7.13 (d, J = 8.42 Hz, 2H). , 6.90 (s, 1H), 4.10 (s, 2H), 2.39 (s, 3H); MS (NH 3) m / z 380-382 (M + H) ⁺ , 397-399 (M + NH 4) ⁺ .

Part B: Preparation of 1- (3-cyanophenyl) -5-F2'-t-butylaminosulfonyl-n, 1'1-biphen-4-yl) methylcarbonine-3-methylpyrazole

The above bromide (0.14 g, 0.37 mmol), 2M Na ₂ CO 3 (1 mL), 2-butylsulfonimidoboric acid (0.13 g, 0.50 mmol) and 1: 1 ethanol / toluene (15 mL) were added. ml) The mixture is degassed for 15 min. Tetrakis (triphenylphosphine) palladium (2 mg) is added and the reaction mixture is refluxed for 18 hours. The mixture was concentrated, the residue was dissolved in ethyl acetate, washed with water and dried (MgSO ₄ ). Purification by flash chromatography on silica gel eluting with hexanes / ethyl acetate (2: 1) gave 0.19 g (100%) of a clear viscous oil: ¹ H NMR (CDCl ₃ ) δ: 8.18 (dd, J = 1) , 46, 7.69 Hz, 1H), 7.68 (m, 2H), 7.58 (m, 2H), 7.52 (d, J = 8.40 Hz, 2H), 7.51 (m , 2H), 7.34 (d, J = 8.05 Hz, 2H), 7.33 (m, 1H), 6.95 (s, 1H), 4.21 (s, 2H), 3.48 (s, 1H), 2.40 (s, 3H), 0.97 (s, 9H); MS (ESI) m / z 535.19 (M + Na) ⁺ .

Part C: Preparation of 1- (3-Amidinophenyl) -3-methyl-5-f2'-aminosulfonyl-1,1''-biphen-4-yl) methylcarbonylpyrazole

This compound is obtained in 37% yield using the standard Pinner amidine reaction sequence described above. 1 H NMR (DMSO-d ₆ ) δ: 9.39 (s,

1.5H), 9.03 (s, 1.5H), 8.03 (dd, J = 7.32, 1.83 Hz, 1H), 7.85 (m, 2H), 7.68 (m , 2H), 7.59 (m, 2H), 7.44 (s, 1H), 7.36 (m, 7H), 4.34 (s, 2H), 2.34 (s, 3H); MS (ESI) m / z 474.18 (M + H) ⁺ .

example

1- (3-amidinophenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] 1,2,3-triazole

This compound is obtained in the form of colorless crystals from N-1- (mephacyanophenyl) -1,2,3-triazole-2-carboxylic acid (Sheehan et al., J. Amer. Chem. Soc. 1951, 73, 1207) according to the general procedure previously described. . ¹ H NMR (DMSO-d ₆ ) δ: 10.9 (s, 1H), 9.49 (pl.s, 1.5H), 9.20 (pl.s, 1.5H), 9.60 ( s, 1H), 8.11 (s, 1H), 8.06-7.95 (m, 3H), 7.88-7.80 (t, 1H), 7.69-7.56 (m, 3H), 7.38 (d, 2H), 7.29 (pl.s, 3H) m, d; ESI mass spectrum, m / z (rel intensity) 463 (M + H, 100); high resolution mass spectrum: calcd. for C21H19N8SO3 463,130084, found 463.129575.

example

1- (3-Amidinophenyl) -5 - ((2'-trifluoromethyl- [1,1 '] - biphen-4-yl) aminocarbonyl) tetrazole trifluoroacetic acid salt

Part A: Preparation of 1- (3-Cyanophenyl) -5-r (4'-bromophenyl) aminocarbonyltetrazole

4-Bromanyline is dissolved in CH ₂ Cl ₂ (25 mL). Trimethylaluminium (2M in heptane, 7.0 mL, 14 mmol) was added slowly. The mixture was stirred at room temperature under N _{2 for} 15 min. A solution of 1- (3-cyanophenyl) -5-carbethoxy-tetrazole (0.77 g, 3.16 mmol) (prepared in Example 24, Part A) in CH ₂ Cl ₂ (25 mL) was then added. The mixture was stirred at room temperature over the weekend. This reaction mixture was carefully quenched with 1N HCl. It is diluted with CH ₂ Cl ₂ , washed with water and brine, dried over MgSO ₄ , concentrated and chromatographed over silica gel (eluting with CH ₂ Cl ₂ ); 0.30 g of the expected product is obtained. ¹ H NMR (DMSO-d ₆ ) δ: 6.05 (quart, 4H), 7.85 (t, 1H), - 8.10 (t, 2H), 8.35 (s, 1H), δ , 5 (s, 1H); MS (NH ₃ Cl) 386 (M + NH ₄ ) ⁺ .

Part B: 1- (3-cyanophenyl) -5 - ((2'-trifluoromethyl-f1,1 ¹ biphen-4-yl) receiving aminokarboniDtetrazolo

Part A material (0.30 g, 0.813 mmol) and 2-trifluoromethylphenylboronic acid (0.2 g, 1.06 mmol) were dissolved in EtOH / toluene (4.2 mL / 10 mL). This mixture was stirred at room temperature for 30 min under N ₂ bubbles.

K2CO3 (0.82 mL 2M, 1.63 mmol), tetrabutylammonium bromide (13 mg, 0.04 mmol) and tetrakis (triphenophosphine) palladium (0) (46 mg, 0.04 mmol) were then added.

The mixture is refluxed under N _{2 for} 4 hours. The reaction mixture was cooled and filtered through celite. The solvent is evaporated.

The residue was dissolved in EtOAc, washed with water, brine, dried over MgSO ₄ , concentrated and chromatographed on silica gel (eluting with CH ₂ Cl ₂ ); 0.35 g of the title compound is obtained. ¹ H NMR (CDCl 3) δ: 7.15-7.95 (m, 12H), 9.15 (s, 1H). MS (NH 3 -Cl) 452 (M + NH ₄ ) ⁺ .

Part C; Preparation of 1- (3-Amidinophenyl) -5 - ((2'-trifluoromethyl-1,1,1'-biphen-4-iDaminocarbonyltetrazole) trifluoroacetic acid salt

The substance from Part B is dissolved in 10 ml of anhydrous CHCl 3 and 10 ml of anhydrous CH ₃ OH. The mixture is cooled in an ice bath and HCl gas is bubbled through until the solution is saturated. The reaction mixture is sealed and refrigerated for 12 hours. The solvent is evaporated off and the solid is dried under vacuum. This solid was redissolved in 20 mL of anhydrous CH ₃ OH and ammonium acetate (0.63 g, 10 equiv.) Was added. The mixture was sealed and stirred at room temperature for 12 hours. The solvent is evaporated. The solid is dissolved in CH ₃ CN / H ₂ O / TFA and purified by reverse phase HPLC; 150.0 mg of the desired product are obtained. ¹ H NMR (DMSO-d ₆ ) δ: 7.30-8.25 (m,

12H), 9.20 (s, 1H), 9.50 (s, 1H), 11.55 (s, 1H). MS (ESI) 452.2 (M + H) &lt; + &gt;.

example

1- (3-Amidinophenyl) -5 - ((2'-aminosulfonyl-3-chloro- [1,1 ']' biphen-4-yl) methylthio) tetrazole trifluoroacetic acid salt

Part A: Preparation of 1- (3-Cyanophenyl) -5-thiotetrazole m-Cyanophenylthioisocyanate (3.20 g, 20 mmol) is dissolved in 40 mL of CHCl ₃ .

Warm the mixture to dissolve the starting material and add a solution of NaN ₃ (2.64 g, 80 mmol) in 30 mL of water. The mixture was refluxed under N _{2 for} 1.5 h. The mixture is cooled and the layers are separated.

The aqueous layer is almost acidified. HCl. The white precipitate is filtered off and dried to give 3.33 g of the desired product. ¹ H NMR (acetone-d ₆ ) δ; 7.86 (t, 1H), 7.97 (d, 1H), 8.38 (d, 1H), 8.53 (s, 1H).

Part B: Preparation of 2'-t-Butylaminosulfonyl-4-bromomethyl-3-chloro-f,1,1'-biphenyl

2'-i-Butylaminosulfonyl-3-chloro-4-methyl- [1,1 '] - bisphenyl is converted to the bromo compound by boiling in NBS / CCU.

Part C: Preparation of 1- (3-cyanophenyl) -5 - ((2'-t-butylaminosulfonyl-3-chloro-1,1'-biphen-4-yl) methylthio) tetrazole

1- (3-Cyanophenyl) -5-thiotetrazole (0.22 g, 1.08 mmol) and 2'-f-butylaminosulfonyl-4-bromomethyl-3-chloro- [1,1] Biphenyl (0.45 g, 1) , 08 mmol) was added together with 20 mL of THF. Triethylamine (0.15 mL, 1.08 mmol) was added and the mixture was refluxed under N _{2 for} 30 min. The solvent was evaporated, the residue was dissolved in CH ₂ Cl ₂ and chromatographed on silica gel, eluting with 30% EtOAc in hexane; 0.40 g of a white foam is obtained. ¹ H NMR (CDCl ₃ ) δ: 1.03 (s, 9H), 3.58 (s, 1H), 4.82 (s, 2H), 7.26 (d, 1H), 7.37 (d , 1H), 7.53 (m, 3H), 7.75 (d, 2H), 7.82-7.92 (m, 3H), 8.16 (d, 1H). MS (ESI) 539.3 (M + H) &lt; + &gt;.

Part D; Preparation of 1- (3-Amidinophenyl) -5 - ((2'-aminosulfonyl-3-chloro-1,1,1'-biphen-4-yl) methylthio) tetrazole trifluoroacetic acid salt

1- (3-Cyanophenyl) -5 - ((2'-t-butylaminosulfonyl-3-chloro- [1, T] -biphen-4-yl) methylthio) tetrazole (0.24 g, 0.45 mmol) is dissolved 20 mL CHCl ₃ and 2 mL anhydrous CH ₃ OH. The mixture is cooled in an ice bath and HCl gas is bubbled through until the solution is saturated. The reaction mixture was sealed and stirred at room temperature for 12 hours. The solvent is evaporated off and the solid is dried under vacuum. This solid was redissolved in 10 mL anhydrous CH3OH and ammonium acetate (0.21 g, 6 equiv.) Was added. The mixture was sealed and stirred at room temperature for 12 hours. The solvent is evaporated. The solid is dissolved in CH ₃ CN / H ₂ O / TFA and purified by reverse phase HPLC; 0.11 g of the expected product is obtained. ¹ H NMR (DMSO-d ₆ ) δ: 4.79 (s, 2H), 7.30-7.69 (m, 8H), 7.90 (t, 1H), 8.02 (m, 3H). , 8.11 (s, 1H), 9.20 (s, 2H), 9.48 (s, 2H). MS (ESI) 500.2 (M + H) &lt; + &gt;.

and 23 examples

1- (3-Amidinophenyl) -5 - [(2'-aminosulfonyl-3-chloro- [1,1 '] - biphen-4-yl) methylsulfoxide] tetrazole trifluoroacetic acid salt (Example 22) and 1- ( 3-Amidinophenyl) -5 - [(2'-aminosulfonyl-3-chloro- [1,1 '] - biphen-4-yl) methylsulfonyl] tetrazole trifluoroacetic acid salt (Example 23)

1- (3-Amidinophenyl) -5 - [(2'-aminosulfonyl-3-chloro- [1,1 '] - biphen-4-yl) methylthio] tetrazole trifluoroacetic acid salt (80.0 mg, 0.13 mmol) ) is dissolved in 10 ml of methanol. Oxone (0.32 g, 0.52 mmol) was added. The mixture was stirred at room temperature under N _{2 for} 72 h. The mixture was filtered and the solid was washed with methanol. The filtrate is concentrated, then dissolved in CH ₃ CN / H ₂ O / TFA and purified by reverse phase HPLC; 48 mg of sulfoxide and 23 mg of sulfone are obtained. ¹ H NMR (Sulfoxide, CH 3 OH-d 4) δ: 5.08 (sq, 2H), 7.25-7.32 (m, 4H), 7.50-7.63 (m, 4H), 7, 85 (m, 2H), 8.00-8.10 (m, 3H). MS (ESI) 500.2 (M + H) &lt; + &gt;. ¹ H NMR (sulfone, DMSO-d 6) δ: 5.37 (s, 2H), 7.30-7.69 (m, 7H), 7.82-8.10 (m, 5H), 8.20 (s, 1H), 9.18 (s, 2H), 9.52 (s, 2H). MS (ESI) 532.2 (M + H) &lt; + &gt;.

example

1- (3-Amidinophenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] tetrazole trifluoroacetic acid salt

Part A; Preparation of 1- (3-Cyanophenyl) -5-carbethoxytetrazole

3-Aminobenzonitrile (5.0 g, 42.3 mmol) was dissolved in CH ₂ Cl ₂ (100 mL).

Triethylamine was added followed by ethyl oxalyl chloride (4.73 mL, 42.3 mmol). The mixture was stirred at room temperature under N _{2 for} 15 min. It is diluted with CH ₂ Cl ₂ and washed with water and saturated NaCl solution. The CH ₂ Cl ₂ solution was dried over MgSO ₄ and concentrated to a tan solid (6.33 g). This amide (3.00 g, 13.72 mmol) was then refluxed for 20 hours. with a solution of triphenylphosphine (5.4 g, 20.58 mmol) in 50 mL CCI ₄ . This solution was stirred at 0 ° C for 15 min before addition of the amide. The reaction mixture was cooled and hexane was added. The precipitate is filtered off. The filtrate is concentrated to a solid. It is then dissolved in 100 mL of CH ₃ CN and NaN ₃ (0.89 g, 1 eq.) Is added. The mixture was stirred at room temperature under N _{2 for} 12 h. The solvent is evaporated. The solid was dissolved in EtOAc and washed with water and saturated NaCl solution. The solution was dried over MgSO ₄ , concentrated, and chromatographed on silica gel (eluting with CH ₂ Cl ₂ ) to give 2.50 g of the desired product. ¹ H NMR (acetone-d ₆ ) δ: 1.24 (t, 3H), 4.38 (s, 2H), 7.90 (t, 1H), 8.11 (m, 2H), 8.24 (s, 1H). MS (DCI-NH ₃ ) 261 (M + NH ₄ ) ⁺ .

Part B: Preparation of 1- (3-cyanophenyl) -5-r (2'-t-butylaminosulfonyl-T1-biphen-4-yl) aminocarbonyltetrazole

2'-t-Butylaminosulfonyl-4-amino- [1,1'T] -biphenyl (0.25 g, 0.82 mmol) was dissolved in 10 mL of anhydrous CH ₂ Cl ₂ and trimethylaluminum (1.64 mL of 2.0M solution) was added slowly. heptane). The mixture was stirred at room temperature under N _{2 for} 15 min before 1- (3-cyanophenyl) -5-carbethoxytetrazole (0.20 g, 0.82 mmol) was added. The reaction mixture was stirred at room temperature under N _{2 for} 18 h. The reaction was quenched by the careful addition of 0.1 N aqueous HCl. The mixture was diluted with CH ₂ Cl ₂ and washed with water and saturated NaCl solution. The organic solution was dried over MgSO ₄ , concentrated, and chromatographed on silica gel (5% EtOAc / CH ₂ Cl ₂ ) to afford 0.22 g of the desired product. MS (ESI) 502.3 (M + H) &lt; + &gt;.

Part C: Preparation of the trifluoroacetic acid salt of 1- (3-Amidinophenyl) -5- f (2'-aminosulfonyl-1,1'-biphen-4-yl) aminocarbonyltetrazole

Part B was dissolved in 20 ml of anhydrous CHCl ₃ and 2 ml of anhydrous CH ₃ OH. The mixture is cooled in an ice bath and HCl gas is bubbled through until the solution is saturated. The reaction mixture was sealed and stirred at room temperature for 12 hours. The solvent is evaporated off and the solid is dried under vacuum. This solid was dissolved in 10 mL of anhydrous CH ₃ OH and ammonium acetate (0.34 g, 10 equiv.) Was added and the mixture was sealed and stirred at room temperature for 12 h. The solvent is evaporated. The solid is dissolved in CH ₃ CN / H ₂ O / TFA and purified by reverse phase HPLC to give 80.0 mg of the desired product. ¹ H NMR (DMSO-d ₆ ) δ: 7.28 (m,

3H), 7.37 (d, 2H), 7.60 (m, 2H), 7.78 (d, 2H), 7.89 (t, 1H), 8.02 (t, 2H), 8, 15 (d,

1H), 8.20 (s, 1H), 9.14 (s, 2H), 9.50 (s, 2H), 11.52 (s, 1H) MS (ESI) 463.3 (M + H) ⁴ .

The compounds of Examples 25-48 shown in Table 1a below were prepared using the procedures described above.

example

3-Methyl-1- (3-amidinophenyl) -5- (4 '- (4' -chlorophenyl) thiazol-2'-yl) aminocarbonyl) pyrazole

Part A: Preparation of 3-Methyl-1- (3-cyanophenyl) -5- (4 '- (4-chlorophenyl) thiazol-2'-yl) aminocarbonylpyrazole

1- (3-Cyanophenyl) -3-methylpyrazole-5-carboxylic acid (70 mg, 0.31 mmol) was treated with 2-amino-4- (4'-chlorophenyl) thiazole (168 mg, 0.8 mmol) in DMAP ( 191 mg, 1.5 mmol) and BOP reagent (benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, 442 mg, 1 mmol) in DMF (5 mL) at 60 ° C for 16 h to give the title compound (100 mg, 77%).

Part B: 3-Methyl-1- (3-amidinophenyl) -5- (4 '- (4-chlorophenyl) ^thiazol-2? -Yl) · Receipt aminokarboniPpirazolo

This compound (39 mg, 17%) was subjected to a Pinner reaction following standard procedures. ¹ H NMR (CD ₃ OD) δ: 7.93 (d, J = 1.8 Hz, 1H), 7.90 (d, J = 8.8 Hz, 2H), 7.86 (dd, J = 7.3 Hz, J = 1.8 Hz, 1H), 7.797.77 (m, 1H), 7.70 (t, J = 7.7 Hz, 1H), 7.44 (s, 1H), 7 , 38 (d, J = 8.4 Hz, 2H),

7.07 (s, 1H), 2.38 (s, 3H); DSGMS: 437.0951 (M + H) ^- .

example

1- (3-amidino) phenyl-3-methyl-5 - [(2'-trifluoromethylsulfide- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole

Part A: Preparation of 2'-Trifluoromethylthio-1-aminobiphenyl

Palladium-catalyzed Suzuki 4-aminotrifluoromethylacetyl-phenylboronic acid cross-coupling with 2-bromo-1-trifluoromethylthiobenzene in 72% yield gives 1-aminotrifluoromethylacetyl-biphenyl; ¹ H NMR (CDCl 3) δ: 8.53 (m.p., 1H), 7.78 (d, J = 8 Hz, 1H), 7.62 (d, J = 8 Hz, 2H), 7.487.60 (m, 1H), 7.29-7.46 (m, 5H) md; ¹⁹ F NMR (CDCl 3) δ: -42.5 (s, 3F) and -76.2 (s, 3F); mass spectrum of ammonia Cl m / z (rel intensity) 383 (M + NH ₄ ⁺ , 100), 366 (M + H, 100). Then saponification (1N NaOH in methanol) in 80% yield gives the title compound; ¹ H NMR (CDCl 3) δ: 7.77 (d, J = 8 Hz, 1H), 7.30-7.55 (m, 4H), 7.09 (d, J = 4 Hz, 2H), 6 , 70 (d, J = 8Hz, 2H), 3.69-3.80 (ss, 2H); mass spectrum for ammonia Cl / m / z (relative intensity) 256 (M + H, 100); ¹⁹ F NMR (CDCl 3) δ: -42.5 md

Part B: Preparation of 1- (3-cyanophenyl) -3-methyl-5 - [(2'-trifluoromethylsulfide-1,1''-biphen-4-yl) aminocarbonyl] pyrazole

Co-coupling of the product of Part A with pyrazole chlorohydride according to the procedure described in Example 10 gives the desired copolished phenyl nitrile analog in 75% yield; ¹ H NMR (CDCl 3) δ: 8.13 (pl.s, 1H), 7.70 (dd, J = 1.8 and 7.4 Hz, 1H), 7.51 (m, 2H), 7 48 (t, J = 7.7 Hz, 2H), 7.38 (t, J = 7.6 Hz, 2H), 7.28 (m, 2H), 6.67 (s, 1H), 2, 36 (s, 3H) md; ESI mass spectrum m / z (rel intensity) 501 (M + Na, 92), 479 (M + H, 100); ¹⁹ F NMR (CDCl 3) δ: -42.5 md

Part C: According to the Pinner amidation reaction procedure described in Example 10, the desired benzamidine is obtained in 50% yield which, after preparative HPLC (reverse phase, CH ₃ CN: water), is colorless crystals; ¹ H NMR (DMSO-d 6) δ: 10.7 (s, 1H), 9.43 (pl.s, 1.5H), 9.07 (pl.s, 1.5H), 7.98 (s) , 1H), 7.89-7.65 (m, 8H), 7.58-7.49 (m, 2H), 7.35 (d, J = 8 Hz, 2H), 7.04 (s, 1H),

2.37 (s, 1H) ppm; ESI mass spectrum m / z (rel intensity) 496 (M + H, 100); DSGMS calcd for C25H21N5F3SO 496.141892, found 496.142995.

and 52 examples

1- (3-amidino) phenyl-3-methyl-5 - [(2'-trifluoromethylsulfoxide- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole (Example 51) and 1- (3-amidino) phenyl- 3-Methyl-5 - [(2'-trifluoromethylsulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole (Example 52) The product obtained in Part C of Example C is oxidized with ΟΧΟΝΕ® (10 eq) in methanol / water 9 : 1 and a mixture of sulfoxide and sulfonyl products is obtained. Prepared by HPLC (reverse phase, CH ₃ CN; water) 45% yield pure sulfoxide (after freeze drying colorless crystals); ¹ H NMR (DMSO-d 6) δ: 9.40 (m.s, 1.5H), 9.04 (m.s, 2H), 8.08 (J = 8 Hz, 1H), 7.96 (s, 1H), 7.84-7.68 (m, 8H), 7.50 (m, 3H), 7.04 (s, 1H), 2.35 (s, 3H) md; ESI mass spectrum m / z 512. A sulfonyl product was also obtained (15% yield, after freeze drying colorless crystals): ¹ H NMR (DMSO-d 6) δ: 9.43 (pl.s, 1.5 H), 9 , 07 (m.p., 2H), 8.23 (d, 1H), 7.99 (m, 1H) 7.98 (s, 1H). 7.89-7.69 (m, 7H), 7.55 (d, J = 8Hz, 1H), 7.26 (d, J = 8Hz, 1H), 7.04 (s, 1H), 2.37 (s, 2H)

m. d .; ESI mass spectrum m / z 528.1.

example

1- (3-amidino) phenyl-3-methyl-5- [4 '- (carboxymethyl) phenylaminocarbonyl] pyrazole

Methyl 4-aminobenzoate is coupled with pyrazole chloro anhydrides according to the procedure described in Example 10 to give a benzonitrile copolymer product in quantitative yield. ¹ H NMR (CDCl ₃ ) δ: 8.01 (d, J = 8 Hz, 2H), 7.97 (s, 1H), 7.80 (s, 1H), 7.78-7.53 (m , 4H), 6.70 (s, 1H), 3.90 (s, 2H),

2.39 (s, 3H) ppm; ESI mass spectrum m / z (rel intensity) 361 (M + H, 100); This nitrile is then subjected to a Pinner's amidine reaction sequence as

100 is shown in Example 10 and the title product (colorless crystals) is obtained after separation by preparative HPLC in 50% yield; ¹ H NMR (DMSOd ₆ ) δ; 9.40 (m.p., 1.5H), 9.18 (m.p., 1.5H), 7.91 (m, 3H), 7.86-7.64 (m, 6H), 7. 08 (s, 1H), 3.81 (s, 3H), 2.37 (s, 2H) md; ESI mass spectrum m / z (rel intensity) 378 (M + H, 100); HRMS calculated for C ₂ oH ₂ on ₅ 03 378.156615, found 378.158283.

example

1- (3-amidino) phenH-3-methyl-5- [4 '- (N, N-dimethylaminocarbonyl) phenylaminocarbonyl] pyrazole <·

The above copolymerized benzonitrile pyrazo-methyl ester is saponified (LiOH, THF / water) then acidified (1N HCl) to give the corresponding carboxylic acid which is converted to the dimethylamide derivative via its chloro anhydride. According to Pinner's amidine reaction procedures taken from Example 10, the desired product, which is colorless crystals, is obtained in 50% yield; ¹ H NMR (DMSO-d ₆ ) δ: 10.7 (s, 1H), 9.40 (ss, 2H), 9.04 (ss, 2H), 7.96 (s, 1H) , 7.84-7.68 (m, 6H), 7.38 (d, J = 8.0 Hz, 2H), 7.03 (s, 1H), 2.95 (s, 6H), 2.36 (s, 3H) md; ESI mass spectrum m / z (rel intensity) 391 (M + H, 100).

example

1- (3-amidino) phenyl-3-methyl-5- [4 '- (N, N-dimethylaminosulfonyl) phenylaminocarbonyl] pyrazole

Copulation of 4-amino-N, N-dimethylbenzenesulfonamide with the pyrazole chlorohydride obtained in Example 10 gives the desired benzonitrile-pyrazole copolished product in 90% yield. Δ NMR (CDCl3) δ: 8.09 (s, 1H), 7.80-7.65 (m, 7H), 7.54 (m, 1H), 6.77 (s, 1H), 2.71. (s, 6H), 2.40 (s, 3H) md; ammonia Cl mass spectrum (relative intensity) 410 (M + H, 100). Treatment of the above nitrile according to the Pinner's amidine reaction procedure as shown in Example 10 affords the desired product in 70% yield which, after purification

101 are colorless crystals by preparative HPLC (reverse phase, acetonitrile: water). ¹ H NMR (DMSO-d ₆ ) δ: 10.8 (s, 1H), 9.39 (pl.s, 1.5H), 9.17 (pl.s, 1.5H), 7.89 ( m, 3H), 7.79 (m, 1H), 7.77-7.63 (m, 4H), 7.06 (s, 1H), 2.30 (s, 3H), 2.45 (s) (3H) md; ESI mass spectrum m / z (rel intensity) 426 (M + H, 100).

and 57 examples

1- (3-amidino) phenyl-3-methyl-5 - [(4'-tert-butylaminosulfonylphenyl) aminocarbonyl] pyrazole (Example 56) and 1- (3-amidino) phenyl-3-methyl-5 [(4'- aminosulfonylphenyl) aminocarbonyl] pyrazole (Example 57)

Co-coupling of 4-amino-N-tert-butylbenzenesulfonamide with pyrazole chlorohydride obtained in Example 10 affords the desired benzonitrile precursor in 80% yield. ¹ H NMR (CDCl 3) δ: 8.35 (m.p., 1H), 7.77 (m, 4H), 7.71 (m, 1H), 7.697.64 (m, 3H), 7.53 ( t, 1H), 6.89 (s, 1H), 2.39 (s, 3H), 1.20 (s, 9H) md; ESI mass spectrum m / z (rel intensity) 460 (M + Na, 100), 438 (M + H, 20). Treatment of the above nitrile according to the Pinner amidine reaction procedure as shown in Example 10 gives the desired product in 5% yield which, after purification by preparative HPLC (reverse phase, acetonitrile: water), is colorless crystals. ¹ H NMR (DMSO-d 6) δ: 10.8 (s, 1H), 9.41 (pl.s, 1.5H), 9.20 (pl.s, 1.5H), 7.97 (s) , 1H), 7.84-7.77 (m, 9H), 7.47 (s, 1H), 7.08 (s, 1H), 3.73 (s, 1H), 2.35 (s, 3H) md; ESI mass spectrum m / z (rel intensity) 455 (M + H, 100). De-tert-butylated sulfonamide was obtained in 30% yield (colorless crystals); ¹ H NMR (DMSO-d 6) δ: 10.85 (s, 1H),

9.40 (ss, 4H), 7.95 (s, 1H), 7.89-7.66 (m, 7H), 7.07 (s, 1H), 2.34 (s, 3H) md; ESI mass spectrum 381.3.

example

1- (3-Amidino) phenyl-3-methyl-5 - [(4'-trifluoromethylphenyl) aminocarbonyl] pyrazole

102

Copulation of 4-amino-1-trifluoromethylbenzene with the chloro anhydride obtained in Example 10 affords the desired benzonitrile precursor in 80% yield, ¹ H NMR (CDCl 3) δ: 8.17 (s, 1H), 7.79 (s, 1H), 7.75 -7.50 (m, 7H), 6.73 (s, 1H), 2.39 (s, 3H) md; Ammonia Ci mass spectrum 388 (M + NH 4, 34), 371 (M + H, 100). Treatment of the above nitrile according to the Pinner amidine reaction procedure as shown in Example 10 gives the desired product in 60% yield which, after purification by preparative HPLC (reverse phase, acetonitrile: water), is colorless crystals. ¹ H NMR (DMSO-d 6) δ: 9.40 (m.s, 1.5H), 9.20 (m.s, 1.5H), 8.09 (s, 1H), 7.90 (s) , 1H), 7.83-7.75 (dd, J = 7.6 and 8.4 Hz), 7.68-7.53 (m, 4H), 6.97 (s, 1H), 2, 29 (s, 2H) md; ESI mass spectrum m / z (rel intensity) 388.1 (M + H, 100): DSGMS calculated for C ₉ H ₇ N ₅ F ₃ O 388.138520, found 388.139013.

example

1- (3-amidino) phenyl-3-methyl-5 - [(4'-benzylsulfonylpiperidyl) aminocarbonyl] pyrazole

Co-coupling of 4-amino-1-benzylsulfonylpiperidine with the chloro-anhydride obtained in Example 10 affords the desired copolymer which, following the Pinner's amidine reaction procedure as shown in Example 10, yields the desired product after purification by preparative HPLC (reverse). phases, acetonitrile: water) are colorless crystals. ¹ H NMR (DMSO-d 6) δ: 9.40 (pl.s, 1.5H), 9.00 (pl.s, 1.5H), 8.59 (d, J = 8 Hz, 1H), 7.86 (s, 1H), 7.77 (m, 1H), 7.75 (m, 3H), 7.38 (m, 5H), 6.79 (s, 1H), 4.40 (s) , 2H), 3.50 (pi.d, 2H), 2.73 (m) 2H), 1.74 (m, 2H), 1.50 (m, 2H), 2.28 (s, 3H) md; ESI mass spectrum m / z (rel intensity) 481 (M + H, 100); DSGMS calcd for C ₂₄ H ₂₉ N ₆ 481.202186, found 481.201227.

example

1- (3-Amidinophenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) -N-methylaminocarbonyl] -3-methylpyrazole trifluoroacetic acid salt

103

Part A: Synthesis of 1- (3-Cyanophenyl) -5- f (2'-aminosulfonyl-n, T1-biphen-4-yl) -N-methylaminocarbonine-3-methylpyrazole

Standard coupling of 1- (3-cyanophenyl) -3-methylpyrazol-5-ylcarboxylic acid and 2-tert-butylsulfonamide-1-biphenyl-N-methylaniline yields a yellow foam (67%); . ¹ H NMR (CDCl ₃ ) δ: 8.16 (d, J = 7.69 Hz, 1H), 7.63 (m, 6H), 7.33 (m, 3H), 6.83 (m.p. , 2H), 6.23 (s, 1H), 3.43 (s and m, 4H),

2.27 (s, 3H), 1.02 (s, 9H); MS (ESI) m / z 528.4 (M + H) ⁺ , 550.4 (M + Na) ⁺ .

Part B: The Pinner amidine reaction procedure described in Example 10 gives the desired product. ¹ H NMR (DMSO-d ₆ ) δ: 9.45 (s, 1.5H), 9.12 (s, 1.5H), 8.16 (d, J = 7.69 Hz, 1H), δ , 81 (m, 7H), 7.30 (m, 5H), 7.15 (m, 2H), 3.10 (s, 3H), 2.12 (s, 3H) md; DSGMS 489.170886 (calculated), 489.170289 (found); Analysis: Calculated for C ₂₅ H ₂₄ N ₆ O ₃ S (TFA) 1.1 (H ₂ O) 0.3 C: 52.74, H: 4.18, N: 13.57; Found: C, 52.67; H, 4.28; N, 13.57.

example

1- (3-Amidinophenyl) -5 - [(4'-fluoro- [1,1 T] -biphen-4-yl) aminocarbonyl] -3-methylpyrazole trifluoroacetic acid salt

Part A: Preparation of 2-tert-Butylsulfonamide-4-fluoro-1-biphenyltrifluoroacetamide

1-Bromo-2-tert-butylsulfonamide-4-fluorobenzene. Indian Chem. Soc., Vol. 38, No.2, 1961, 117) standard Suzuki copulation with 4-trifluoroacetamid-1-phenylboronic acid yields a solid (57%). 1 H NMR (CDCl 3) δ: 8.11 (dd, J = 2.19, 6.59 Hz, 1H), 8.03 (s, 1H), 7.76 (m, 1H), 7.70 ( d, J = 8.79 Hz, 2H), 7.61 (d, J = 8.79 Hz, 2H), 7.30 (m, 1H), 4.78 (s, 1H),

1.27 (s, 9H) md; MS (DCI) m / z 436 (M + NH ₄ ) ⁺ ; Analysis: Calculated for C 21 H 17 F 3 O 4 S, C: 51.67, H: 4.34, N: 6.70; Found: C: 51.66, H: 4.26, N: 6.65.

Part B: Preparation of 2-tert-Butylsulfonamide-4-fluoro-1-biphenylaniline {Compound A (0.93 g, 2.2 mmol) in methanol was added with 0.5 M LiOH (8 mL, 4 mmol) and refluxed. refrigerator for 2 hours. The reaction mixture was cooled and concentrated. The aqueous residue is extracted with CH ₂ Cl ₂ .

104

The combined organic layers were washed with water, brine, dried (MgSO ₄ ) to give 0.7 g (98%) of a solid; melt temp. 158-160 ° C; Ή NMR (CDCl ₃ ) δ; 8.07 (dd, J = 2.2, 6.96 Hz, 1H), 7.66 (m, 1H),

7.40 (d, J = 8.43 Hz, 2H), 4.75 (s, 1H), 3.80 (s, 2H), 1.25 (s, 9H) md; MS (DCI) m / z 340 (M + NH ₄ ) ⁺ .

Part C: Standard coupling of 1- (3-cyanophenyl) -3-methyl-pyrazol-5-ylcarboxylic acid with 2-tert-butylsulfonamide-4-fluoro-1-biphenylaniline in 85% yield gave the crude nitrile which was used in the following. stage. MS (DCI) m / z 531 (M + H) ⁺ , 549 (M + NH ₄ ) ⁺ .

Part D: Part C nitrile undergoes a standard Pinner reaction to give the desired amidine; ¹ H NMR (DMSO-d _s) δ: 10.7 (s, 1H), 9.43 (s, 1.5H), 9.01 (s, 1.5H), 7.99 (m, 3H) , 7.81 (d, J = 7.69 Hz, 2H), 7.81 (m, 5H),

7.68 (d, J = 8.79 Hz, 2H), 7.55 (t, J = 8.79 Hz, 1H), 7.06 (s, 1H), 2.27 (s, 3H); DSGMS 493.1455814 (calculated), 493.145228 (found).

example

1- (3-Amidinophenyl) -5 - [[5- (2'-aminosulfonylphenyl] pyridin-2-yl] aminocarbonyl] 3-methylpyrazole trifluoroacetic acid salt

Part A; 1- (3-cyanophenyl) -5-rf5- (2 ^l -t-bUtilaminosulfonilfeniljpiridin iljaminokarbonilj-2-methylpyrazole-3-Synthesis of

Standard coupling of 1- (3-cyanophenyl) -3-methyl-pyrazol-5-ylcarboxylic acid with 2-t-butylsulfonamide-pyridylphenylaniline affords the title compound (44%); ¹ H NMR (CDCl 3) δ: 8.59 (s, 1H), 8.37 (m, 1H), 8.23 (t, J = 8.42 Hz, 2H), 7.94 (m, 7H). ), 6.77 (s, 1H), 3.94 (s, 1H), 2.41 (s, 3H), 1.10 (s, 9H) md; MS (ESI) 514 (M + H) &lt; ^{+ &gt};.

Part B: Standard Pinner reaction and HPLC purification (35%) with the compound described above; ¹ H NMR (DMSO-d 6) δ: 11.21 (s, 1H), 9.44 (s, 1.5H), 9.23 (s, 1.5H), 8.37 (t, J = 1 , 47 Hz, 1H), 8.07 (dd, J =)

105

7.30, 1.47 Hz, 1H), 7.99 (d, J = 7.69 Hz, 2H), 7.85 (m, 1H), 7.79 (dd, J = 9.52, 2 , 20 Hz, 2H), 7.73 (d, J = 7.69 Hz, 1H), 7.69 (m, 2H), 7.44 (s, 2H), 7.40 (dd, J = 2 , 20, 7.69 Hz, 1H), 7.18 (s, 1H), 2.33 (s, 3H) md; DSGMS 476.150485 (calcd), 476.149493 (found): Analysis: Calculated for C ₂₃ H ₂₁ N ₇ O ₃ S (TFA) 1.9 C: 46.51, H: 3.33, Ν.Ί4. 17; Found: C: 46.60, H: 3.51,

N: 14.17.

example

1- (3-Cyanophenyl) -5 - [[5- (2'-aminosulfonylphenyl) pyridin-2-yl] aminocarbonyl] -3-methylpyrazole trifluoroacetic acid salt

1- (3-Cyanophenyl) -5 - [[5- (2'-t-butylaminosulfonylphenyl) pyridin-2-yl] aminocarbonyl] -3-methylpyrazole (0.18 g, 0.28 mmol) was refluxed with trifluoroacetic acid in acid (6 mL) for 15 min. The reaction mixture was concentrated and the residue was purified by HPLC to give 69 mg (43%) of the title compound. ¹ H NMR (DMSO-d ₆ ) δ: 11.15 (s, 1H), 8.37 (d, J = 2.20 Hz, 1H), 8.07 (m, 3H), 7.89 (d , J = 7.69 Hz, 1H), 7.82 (m, 2H), 7.70 (d, J = 8.05 Hz, 1H), 7.67 (m, 2H), 7.42 (s) , 2H), 7.40 (dd, J = 1.83, 6.69 Hz, 2H), 7.18 (s, 1H), 2.32 (s, 3H) md; DSGMS 459.123936 (calculated), 459.122035 (found); Analysis: Calculated for C ₂₃ H ₃₁ N ₆ O ₃ S (TFA) 0.6: C: 55.16, H: 3.56, N.15.95; Found: C, 54.89; H, 3.69; N, 15.67.

example

1- (3-Amidinophenyl) -5 - [(2'-trifluoromethyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methylpyrazole trifluoroacetic acid salt

Part A: 2-Trifluoromethylbromobenzene and 4-trifluoroacetamidophenylboronic acid were combined under standard Suzuki reaction conditions and purified by silica gel flash chromatography eluting with hexanes / ethyl acetate (6: 1) to give 2-trifluoromethyl-1-biphenyl trifluoride. ¹ H NMR (CDCl ₃ ) δ: 7.90 (s, 1H), 7.77 (d, J = 7.69

Hz, 1H), 7.64 (d, J = 8.43 Hz, 2H), 7.58 (d, J = 6.59 Hz, 1H), 7.51 (m, 1H),

106

7.39 (d, J = 8.42 Hz, 2H), 7.33 (m, 1H) md; MS (ESI) m / z 334 (M + H) &lt; ^{+ &gt};. 2-Trifluoromethyl-1-biphenyltrifluoroacetamide is hydrolyzed with a base according to the procedure described above to give the free aniline (90%) which is used without further purification. MS (DCI) m / z 238.1 (M + H) ⁺ , 255.1 (M + NH ₄ ) ⁺ .

Part B: Preparation of 1- (3-Cyanophenyl) -5 - [(2'-trifluoromethyl-1,1'-biphen-4-yl) aminocarbonyl] -3-methylpyrazole

Standard coupling of 1- (3-cyanophenyl) -3-methylpyrazol-5-ylcarboxylic acid with 2-trifluoromethyl-1-biphenylaniline gives a yellow foam (50%) which is used in the crude step. MS (ESI) m / z 447.3 (M + H) &lt; + &gt;.

Part C: Part B nitrile is subjected to the standard Pinner reaction, purified by HPLC, lyophilized to give the title compound (32%). Ή NMR (DMSO-d ₆₎ δ: 10.68 (s, 1H), 9.44 (s, 1.5H), 9.10 (s, l, 5H), 7.97 (s, 1H) 7.84 (d, J = 7.7 Hz, 1H), 7.76 (m, 5H), 7.67 (m, 1H), 7.40 (d, J = 7.33 Hz, 1H), 7.31 (d, J = 8.40 Hz, 1H), 7.04 (s, 1H), 2.35 (s, 3H)

m. d .; DSGMS 464.169820 (calculated), 464.171171 (found); Analysis: Calculated for C 25 H 20 F 3 N 5 O (TFA): C: 56.16, H: 3.67, N: 12.13; Found: C: 55.77, H: 3.79, N: 11.85.

example

1- (3-aminocarbonylphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methylpyrazole 1- (3-cyanophenyl) -5 - [(2') Concentrated sulfuric acid (5 mL) was added to -f-butylaminosulfonyl- [1,1'J-biphen-4-yl-aminocarbonyl] -3-methylpyrazole (0.18 g, 0.36 mmol) and the reaction mixture was stirred for 48 h. After addition of ice and water, a precipitate precipitates out, and the mixture is extracted with ethyl acetate, washed with a saturated sodium bicarbonate solution and dried (MgSO ₄ ), purified by flash chromatography on silica gel using 1-10% eluant.

107 methanolic solution in methylene chloride to give 88 mg (52%) of the title compound. ¹ H NMR (DMSO-d ₆ ) δ: 10.63 (s, 1H), 8.12 (s, 1H), 8.04 (m, 2H), 7.90 (m, 1H),

7.69 (d, J = 8.42 Hz, 1H), 7.62 (m, 5H), 7.36 (d, J = 8.42 Hz, 2H), 7.32 (m, 1H), 7.24 (s, 2H), 6.93 (s, 1H), 2.50 (s, 3H) md; DSGMS 476.139251 (calculated), 476.139200 (found).

example

1- (3-amidinophenyl) -5 - [(2'-aminosulfonyl) -3-chloro- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methylpyrazole

Part A; 1- (3-Cyanophenyl) -3-methyl-pyrazol-5-ylcarboxylic acid is co-coupled with 4-bromo-2-chloroaniline under standard conditions (67%). ¹ H NMR (CDCl ₃ ) δ:

8.27 (d, J = 8.79 Hz, 1H), 8.17 (s, 1H), 7.82 (t, J = 1.80 Hz, 1H), 7.75 (m, 2H), 7.59 (m, 2H), 7.42 (dd, J = 8.78, 2.2 Hz, 1H), 6.72 (s, 1H), 2.41 (s, 3H) md

Part B: Mix Part A bromo compound (0.4 g, 0.96 mmol), 2-t-butylsulfonamidophenylboronic acid (0.32 g, 1.2 mmol), 2M sodium carbonate (1 mL) and 1: 1 toluene / ethanol and degassed with nitrogen. Tetrakistriphenylphosphine palladium (O) (1 mg) is added and the reaction mixture is refluxed for 18 hours. The mixture was filtered, concentrated, extracted with ethyl acetate and dried (MgSO ₄ ). Purification by silica gel flash chromatography using 1: 1 helsanes / ethyl acetate as eluent afforded 0.43 g (81%). ¹ H NMR (CDCl ₃ ) δ: 8.45 (d, J = 8.42 Hz, 1H), 8.32 (s, 1H), 8.18 (dd, J = 1.47, 7.69 Hz) , 1H), 7.85 (d, J = 1.83 Hz, 1H), 7.79 (d, J = 8.05 Hz, 1H), 7.72 (d, J = 7.69 Hz, 1H) ), 7.61 (m, 4H), 7.39 (dd, J = 2.20, 8.79 Hz, 1H), 7.28 (m, 1H), 6.76 (s, 1H), 3 , 67 (s, 1H), 2.43 (s, 3H), 1.07 (s, 9H) md; MS (ESI) m / z 548.3 (M + H) ⁺ , 570.0 (M + Na) ⁺ .

Part C: Part B nitrile undergoes a standard Pinner reaction to give amidine (43%). ¹ H NMR (DMSO-d _s) δ: 10.36 (s, 1H), 9.43 (s,

1.5H), 9.09 (s, 1.5H), 8.05 (dd, J = 6.96, 2.20 Hz, 1H), 7.96 (s, 1H), 7.82 (d) , J

108 = 7.32 Hz, 2H), 7.71 (m, 1H), 7.65 (m, 2H), 7.57 (d, J = 6.59 Hz, 1H), 7.54 (s) , 1H), 7.46 (s, 2H), 7.39 (m, 2H), 7.06 (s, 1H), 2.35 (s, 3H) md; DSGMS 509.116263 (found), 509.117360 (found); Analysis: Calculated for C ₂₄ H ₂₁ CIN ₆ O ₃ S (TFA) (H ₂ O); C, 48.72; H, 3.77; N, 13.11; Found: C, 48.56; H, 3.53; N, 12.75.

example

1- (3-Amidinophenyl) -5 - [(2'-trifluoromethyl) -3-chloro- [1,1 T] -biphen-4-yl) aminocarbonyl] -3-methylpyrazole trifluoroacetic acid salt

Part A: N- (2-Chloro-4-bromophenyl) -1- (3-cyanophenyl) -3-methylpyrazole carboxamide (0.4 g, 0.96 mmol), 2-t-Butylsulfonamidophenylboronic acid (0.24 g) , 1.2 mmol), 1M sodium carbonate (1 mL) and 1: 1 toluene / 'ethanol (10 mL) are degassed with nitrogen. Tetrakistriphenylphosphine palladium (O) (1 mg) is added and the reaction mixture is refluxed for 18 hours. The mixture was filtered, concentrated, extracted with ethyl acetate and dried (MgSO ₄ ). Purification by flash chromatography on silica gel eluting with 1: 1 hexanes / ethyl acetate afforded 0.41 g (90%). Δ NMR (CDCl3) δ: 8.40 (d, J = 8.42 Hz, 1H), 8.29 (s, 1H), 7.85 (d, J = 1.83 Hz, 1H), δ, 79 (d, J = 8.05 Hz, 2H), 7.71 (d, J = 7.60 Hz, 1H), 7.60 (t, J = 8.05 Hz, 2H), 7.52 (t, J = 7.69 Hz, 1H), 7.42 (d, J = 1.84 Hz, 1H), 7.29 (m, 1H), 6.75 (s, 1H), 4.11 (s, 1H), 2.42 (s, 3H) md; MS (ESI) m / z 481.2 (M + H) ⁺ , 503 (M + Na) ⁺ .

Part B: Part A nitrile undergoes a standard Pinner reaction to give amidine (36%). ¹ H NMR (DMSO-d ₆ ) δ: 10.4 (s, 1H), 9.43 (s,

1.5H), 9.13 (s, 1.5H), 7.96 (d, J = 1.83 Hz, 1H), 7.87 (m, 3H), 7.76 (m, 3H), 7.62 (d, J = 8.06 Hz, 1H), 7.52 (d, J = 1.83 Hz, 1H), 7.47 (d, J = 7.69 Hz, 1H), 7, 34 (dd, J = 8.42, 1.83 Hz, 1H), 7.07 (s, 1H), 2.35 (s, 3H) md; DSGMS 498.130848 (calculated), 498.128257 (found); Analysis: Calculated for C ₂₅ H ₉ ClF ₃ N ₅ O (TFA): C: 53.00, H: 3.29, N: 11.44; Found: C, 53.33; H, 3.36; N, 11.55.

Example 109

1- (3-Amidinophenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3n-butylpyrazole trifluoroacetic acid salt

Part A: Synthesis of ethyl 1- (3-cyanophenyl) -3-n-butyl-pyrazol-5-ylcarboxylate

Ethyl 2-methoxyimino-4-oxooctanoate (W. T. Aston, et al., J. Het.

Chem., 30 (1993) 2, 307) (0.69 g, 3.0 mmol) and 3-cyanophenylhydrazine hydrochloride (0.66 g, 3.9 mmol) were mixed in acetic acid (15 mL) and refluxed. 18 or. The reaction mixture was concentrated and the residue partitioned between ethyl acetate and 1N HCl. The organic layer was washed with water and dried (MgSO ₄ ). The resulting mixture of regioisomers (ca. 9: 1) was subjected to silica gel flash chromatography eluting with 4: 1 hexanes / ethyl acetate to give 0.56 g (63%) of the desired isomer as a yellow oil. ¹ H NMR (CDCl ₃ ) δ: 7.77 (d, J = 1.83 Hz, 1H),

7.70 (d, J = 7.69, 1.83 Hz, 2H), 7.58 (t, J = 7.69 Hz, 1H), 6.88 (s, 1H), 4.30 (s) ., J = 6.96 Hz, 2H), 2.72 (t, J = 7.69 Hz, 2H), 1.71 (m, 2H), 1.45 (m, 2H), 1.32 ( t, J = 6.96 Hz, 3H), 0.98 (t, J = 7.33 Hz, 3H) md; MS (DCI) m / z 298 (M + H) &lt; ^{+ &gt};.

Part B: Preparation of 1- (3-cyanophenyl) -3-n-butyl-pyrazol-5-ylcarboxylic acid

Part A ester (0.96 g, 3.2 mmol) was hydrolyzed with 1N NaOH (5 mL)

THF / water (5 mL) for 18 h. After acid-base treatment, 0.8 g (92%) of the acid is obtained. ¹ H NMR (CDCl ₃ ) δ: 7.79 (d, J = 1.83 Hz, 1H), 7.75 (dd, J = 1.1, 8.05 Hz, 1H), 7.66 (d , J = 7.69 Hz, 1H), 7.56 (t, J = 7.69 Hz, 1H), 6.88 (s, 1H), 2.71 (t, J = 7.32 Hz, 2H) ), 1.70 (m, 2H), 1.45 (m, 2H), 0.97 (t, J = 7.32 Hz, 3H) md; MS (DCI) m / z 270 (M + H) +

Part C: Preparation of 1- (3-cyanophenyl) -5-F (2'-t-butylaminosulfonyl-1,1'-biphen-4-yl) aminocarbonyl-3-n-butylpyrazole

Standard coupling of ethyl 1- (3-cyanophenyl) -3-n-butylpyrazol-5-ylcarboxylate with 2-t-butylsulfonamide-1-biphenylaniline gives a yellow solid

110 material (73%). ¹ H NMR (CDCl ₃ ) δ: 8.17 (dd, J = 1.1, 7.69 Hz, 1H), 8.03 (s, 1H), 7.82 (s, 1H), 7.77 (d, J = 8.06 Hz, 1H), 7.68 (s + d, J = 7.69 Hz, 3H), 7.55 (m, 5H), 7.31 (dd, J = 1, 4.7.7 Hz, 1H), 6.76 (s, 1H), 3.64 (s, 1H), 2.77 (t, J = 7.69 Hz, 2H), 1.75 (m , 2H), 1.44 (m, 2H), 1.03 (s, 9H), 1.00 (t, J = 7.69 Hz, 3H) md

Part D: Part C nitrile undergoes a standard Pinner reaction to give the desired amidine (57%). ¹ H NMR (DMSO-d ₆ ) δ: 10.65 (s, 1H), 9.44 (s, 1.5H), 9.08 (s, 1.5H), 7.83 (m, 3H) , 7.70 (d, J = 9.15 Hz, 2H), 7.37 (d, J = 8.42 Hz, 2H), 7.32 (d, J = 7.32 Hz, 1H), 7 , 28 (s, 2H), 7.06 (s, 1H), 2.72 (t, J = 7.69 Hz, 2H), 1.71 (m, 1H), 1.43 (m, 2H) , 0.97 (t, J = 7.33 Hz, 3H) md; DSGMS 517.202186 (calculated), 517.201333 (found); analysis; Calculated for C ₂₇ H ₂₈ N ₆ O ₃ S (TFA) (H ₂ O) 0.8: C: 54.00, H: 4.78, N: 13.03; Found: C, 54.23; H, 4.46; N, 12.80.

example

1- (3-Amidinophenyl) -5 - [(2'-trifluoromethyl- [1,1 T] -biphen-4-yl) aminocarbonyl] -3-N-butylpyrazole trifluoroacetic acid salt

Part A; Preparation of 1- (3-cyanophenyl) -5-i (2'-trifluoromethyl-1,1'-biphen-4-yl) aminocarbonine-3-N-butylpyrazole

Standard coupling of ethyl 1- (3-cyanophenyl) -3-N-butyl-pyrazol-5-ylcarboxylate with 2-trifluoromethyl-1-biphenylaniline gives the nitrile. ¹ H NMR (CDCl ₃ ) δ: 7.86 (s, 1H), 7.74 (m, 3H), 7.66 (m, 2H), 7.56 (m, 4H), 7.33 (m , 3H), 6.69 (s, 1H), 2.76 (t, J = 7.96 Hz, 2H), 1.75 (m, 2H), 1.44 (m, 2H), 0.98 (t, J = 7.32 Hz, 3H) md; MS (ESI) m / z 489 (M + H) &lt; ^{+ &gt};.

Part B: 1- (3-Amidinophenyl) -5 - [(2'-trifluoromethyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-N-butylpyrazole is prepared from Part A nitrile according to standard Pinner' reaction conditions. ¹ H NMR (DMSO-d ₆ ) δ; 10.00 (s, 1H),

9.43 (s, 1.5H), 9.02 (s, 1.5H), 7.96 (s, 1H), 7.84-7.70 (m, 7H), 7.63 (t, J = 7.69 Hz, 1H), 7.40 (d, J = 7.33 Hz, 1H), 7.31 (d, J = 8.42 Hz, 2H), 7.08 (s, 1H) ,

111

2.72 (t, J = 7.33 Hz, 2H), 1.73 (m, 2H), 1.45 (m, 2H), 0.97 (t, J = 7.33 Hz, 3H) md ; DSGMS 506.216771 (calculated), 506.214378 (found); Analysis: Calculated for C 23 H ₂₆ F ₃ N ₅ O (TFA) (H ₂ O) 0.8; C, 56.84; H, 4.55; N, 11.05; Found: C: 56.99, H: 4.41, N: 10.99.

example

1- (3-Amidinophenyl) -5 - [[5- (2'-aminosulfonylphenyl) pyridin-2-yl] aminocarbonyl] 3-n-butylpyrazole trifluoroacetic acid salt

Part A: Preparation of 1- (3-Cyanophenyl) -5 - [[5- (2'-tert-butylsulfonaminocarbonylphenyl) pyridin-2-yl] -1-aminocarbonine-3-n-butypyrazole

Standard coupling of 1- (3-cyanophenyl) -3-n-butyl-pyrazol-5-ylcarboxylic acid with 5- (2'-tert-butylsulfonaminocarbonylphenyl) pyridin-2-ylamine gives nitrile (25%). Ή NMR (CDCl ₃₎ δ: 8.59 (s, 1H), 8.37 (d, J = 2.20 Hz, 1H), 8.24 (m, 2H), 7.85 (m, 2H) , 7.78 (m, 1H), 7.76 (m, 1H), 7.70 (m, 3H), 7.30 (dd, J = 1.47, 9.15 Hz, 1H), 6, 79 (s, 1H), 3.95 (s, 1H), 2.76 (t, J = 7.33 Hz, 2H), 1.73 (m, 2H), 1.47 (m, 2H), 1.10 (s, 9H), 0.98 (t, J = 7.33 Hz, 3H) md; MS (ESI) m / z 557.29 (M + H) ⁺ , 579.27 (M + NH ₄ ) ⁺ .

Part B: 1- (3-Amidinophenyl) -5 - [[5- (2'-aminosulfonylphenyl) pyridin-2-yl] aminocarbonyl] -3-n-butylpyrazole trifluoroacetic acid salt (51%) is prepared from Part A nitrile according to standard Pinner reaction conditions. ¹ H NMR (DMSO-d ₆ ) δ: 11.21 (s, 1H), 9.43 (s, 1.5H), 9.04 (s, 1.5H), 8.37 (d, J = 2.20

Hz, 1H), 8.07 (dd, J = 1.83, 7.32 Hz, 1H), 8.02 (d, J = 8.79 Hz, 1H), 7.96 (s,

1H), 7.84 (m, 3H), 7.73 (d, J = 7.69 Hz, 1H), 7.86 (m, 2H), 7.44 (s, 2H), 7.40 ( dd, J = 1.83, 6.96 Hz, 1H), 7.24 (s, 1H), 2.70 (t, J = 7.32 Hz, 2H), 1.69 (m,

2H), 1.45 (m, 2H), 0.97 (t, J = 7.32 Hz, 3H) ppm; DSGMS 518.197435 (found), 518.195873 (found); Analysis: Calculated for C26H27N7O3S (TFA) 1.5: C: 50.58, H: 4.17, N: 14.24; Found: C, 50.76; H, 4.12; N, 14.26.

example

112

1- (3-Amidinophenyl) -5 - [(2'-trifluoromethyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-trifluoromethyl-4-methoxypyrazole trifluoroacetic acid salt

Part A: 1 - (3-cyanophenyl) -3-trifluoromethyl-4-methoxy-5 - [(2'-trifluoromethyl- [1,1 '] biphen-4-yl) aminocarbonyl] pyrazole, ¹ H NMR (CDCl ₃ δ: 8.97 (s, 1H), 7.80 (t, J = 1.83 Hz, 1H), 7.76 (s + m, 3H), 7.61 (d + m, J = 8) , 70 Hz, 4H), 7.50 (t, J = 7.32 Hz, 1H), 7.34 ((d + m, J = 8.0 Hz, 3H), 4.17 (s, 3H) md; MS (DCI) m / z

531.2 (M + H) ⁺ .

Part B: The trifluoroacetic acid salt of 1- (3-Amidinophenyl) -5 - [(2'-trifluoromethyl- [1,1 '] -biphen-4-yl) aminocarbonyl] -3-trifluoromethyl-4-methoxypyrazole is prepared from Part A nitrile under standard Pinner conditions. ¹ H NMR (DMSO-d 6) δ: 11.06 (s, 1H), 9.47 (s, 1.5H), 9.15 (s, 1.5H), 8.03 (s, 1H), 7.92 (m, 4H), 7.75 (m, 1H), 7.70 (m, 3H), 7.40 (d, J = 7.33 Hz, 1H), 7.33 (d, J = 8.42 Hz, 2H), 3.96 (s, 3H) md; HRMS 548.152120 (calculated) 548.150458 (found): Analysis: calculated for C26H19F6N5O2 (TFA) 1.3 (H ₂ O) 0.5: 0: 48.75, H: 3.05, N: 9 , 94; Found: 0: 49.04, H: 2.70, N: 9.85.

example

1- (3-Amidinophenyl) -5 - [(2'-trifluoromethyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-trifluoromethylpyrazole trifluoroacetic acid salt

Part A: Preparation of 1- (3-cyanophenyl) -3-trifluoromethyl-5- (4-bromobenzene) aminocarbonylpyrazole

Standard coupling of 1- (3-cyanophenyl) -3-trifluoromethyl-pyrazol-5-ylcarboxylic acid with 4-bromoaniline in 77% yield gives the title compound: MS (DCI) m / z 452-454 (M + H) ⁺ .

Part B: Preparation of 1- (3-cyanophenyl) -3-trifluoromethyl-5-i (2'-trifluoromethyl-1,1 '' - 1-biphen-4-yl) aminocarbonylpyrazole

Part A bromo compound and 2-trifluoromethylphenylboronic acid standard

Suzuki copulation yields the desired compound (80.7%). 1 H NMR (CDCl ₃ ) δ: 7.88

113 (m, 5H), 7.65 (d, J = 8.06 Hz, 1H), 7.59 (m, 4H), 7.35 (d, J = 8.79 Hz, 2H), 7, 29 (s, 1H), 7.15 (s, 1H) md; MS (ESI) m / z 501.2 (M + H) ⁺ .

Part C: The trifluoroacetic acid salt of 1- (3-amidinophenyl) -5 - [(2'-trifluoromethyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-trifluoromethylpyrazole is prepared from Part B nitrile according to standard Pinner 's terms. ¹ H NMR (DMSO-d 6) δ: 10.86 (s, 1H), 9.46 (s, 1.5H), 9.11 (s, 1.5H), 8.05 (s, 1H), 7.95 (d, J = 8.06 Hz, 2H), 7.84 (d, J = 9.16 Hz, 1H), 7.78 (m, 3H), 7.73 (d, J = 8 , 43 Hz, 2H), 7.63 (m, 1H), 7.40 (d, J = 7.69 Hz, 1H), 7.32 (d, J = 8.43 Hz, 2H) md ,; DSGMS 518.141555 (calculated), 518.141456 (found); Analysis: Calculated for C ₂₅ H ₁₇ F ₆ N ₅ O (TFA) 1.1: C: 50.82, H: 2.84, N: 10.89; found (3: 50.57, H: 2.96,

N: 10.75.

example

1- (3-Amidinophenyl) -5 - [(2'-sulfonylmethyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-trifluoromethylpyrazole trifluoroacetic acid salt

Part A: 1- (3-Cyanophenyl) -5- r (2'-sulfonylmethyl-1,1 '' - 1-biphen-4-yl) aminocarbonine-3-trifluoromethylpyrazole

Standard coupling of (3-cyanophenyl) -3-trifluoromethylphenyl with 2sulfonyl-1-biphenylaniline gives nitrile in 65% yield. ¹ H NMR (CDCl 3) δ: 9.81 (s, 1H), 8.24 (d, J = 8.06 Hz, 1H), 7.86 (d, J = 1.83 Hz, 1H), δ , 82 (m, 4H), 7.66 (m, 3H), 7.46 (s, 1H), 7.44 (d, J = 6.23 Hz, 2H), 7.37 (dd, J = 7.30, 1.46 Hz, 1H), 2.68 (s, 3H) md; MS (ESI) 533.11 (M + Na) &lt; + &gt;.

Part B: The desired compound is prepared from Part A nitrile under standard Pinner conditions. ¹ H NMR (DMSO-d 6) δ: 10.92 (s, 1H), 9.47 (s, 1.5H), 9.27 (s, 1.5H), 8.11 (dd, J = 7 , 69, 1.1 Hz, 1H), 8.06 (s, 1H), 7.97 (m, 2H), 7.79 (m, 6H), 7.41 (s + m, 2H), 2 , 85 (s, 3H) md; DSGMS 528.131721 (calculated), 528.1331 (found); Analysis: Calculated for C ₂₅ H ₂₀ F ₃ N ₅ O ₃ S (TFA) (H ₂ O) 0.6: C, 49.71, H, 3.43, N, 10.74; Found: C, 49.48; H, 3.35; N, 10.97.

Example 114

1- (3-Amidinophenyl) -5 - [(2'-aminosulfonyl-3-bromo- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methyl-pyrazole trifluoroacetic acid salt

Part A: Synthesis of 1- (3-Cyano) phenyl-3-methyl-5-r (2'-t-butylaminosulfonyl-3-bromo-1,1'-biphen-4-yl) aminocarboninpyrazole

This compound was prepared by co-coupling standard 1- (3-cyanophenyl) -3-methylpyrazole carboxylic acid chloro-anhydride with 4-amino-2'-ibutylaminosulfonyl-3-bromo- [1,1 '] - biphen-4-yl (71%). ¹ H NMR (CDCl ₃ ) δ: 8.44 (d, J = 8.79 Hz, 1H), 8.34 (s, 1H), 8.18 (dd, J = 1.47, 7.69 Hz) , 1H), 7.84 (m, 1H), 7.75 (d, J = 1.83 Hz, 1H), 7.69 (m, 1H), 7.61 (m, 3H), 7.43 (dd, J = 1.83,

8.43 Hz, 1H), 7.28 (m, 1H), 6.77 (s, 1H), 3.66 (s, 1H), 2.43 (s, 3H), 1.08 (s, 9H) md; MS (ESI) 614-616 (M + Na) &lt; + &gt;.

Part B: The desired compound is prepared from Part A nitrile under standard Pinner conditions. ¹ H NMR (DMSO-d ₆ ) δ: 10.35 (s, 1H), 9.43 (s, 1.5H), 9.08 (s, 1.5H), 8.05 (m, 1H) , 7.97 (s, 1H), 7.81 (m, 2H), 7.74 (d, J = 7.69 Hz, 1H), 7.74 (d, J = 7.69 Hz, 1H). , 7.70 (d, J = 1.83 Hz, 1H), 7.65 (m, 2H), 7.53 (d, J = 8.5 Hz, 1H), 7.46 (m, 3H) , 7.37 (m, 1H), 7.05 (s, 1H), 2.35 (s, 3H) md; DSGMS 553.065747 (calculated), 553.066135 (found); analysis:

calcd. for C ₂₄ H ₂₁ BrN ₆ O ₃ S (TFA) (H ₂ O) 0.5: C: 46.16, H: 3.43, N: 12.42; Found: C: 46.06, H: 3.15, N: 12.14.

example

1- (3-Aminocarbonylphenyl) -5 - {(2'-aminosulfonyl-3-bromo- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methyl-pyrazole trifluoroacetic acid salt cooled to 0 ° C 1- (3-cyano) phenyl-3-trifluoromethyl-5 - [(2'-fbutylaminosulfonyl-3-bromo- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole (Example 74, Part A) ( 82 mg, 0.14 mmol) was added almost. sulfuric acid (5 mL). The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. Water is added and the mixture is extracted with methylene chloride.

115

Purification by HPLC gave 35 mg (46%) of the desired amide. ¹ H NMR (DMSO-d 6) δ: 10.27 (s, 1H), 8.11 (s, 1H), 8.05 (m, 2H), 7.90 (d, J = 7.32 Hz) 1H). 7.68 (d, J = 1.84 Hz, 1H), 7.64 (m, 3H), 7.56 (dd, J = 8.4, 2.2 Hz, 2H), 7.51 (s) , 1H), 7.44 (m, 3H), 7.36 (m, 1H), 6.96 (s, 1H), 2.34 (s, 3H) md; DSGMS 554.049762 (calculated), 554.051045 (found).

example

1- (3-3ΠΉάΐηοίβηίΙ) -3-ΓηθΝΙ-5 - [(2'-3Γηϊηο5υΙίοηΐΙ- [1, Γ] -1οίίθη-4-ιΊ) methylcarbonylpyrazole trifluoroacetic acid salt

Part A: Preparation of 1- [3- (cyanophenyl) -5- (4-bromophenyl) acetyl] -3-methylpyrazole

To zinc dust (0.56 g, 8.6 mmol) in THF (10 mL) was added 5 drops of 1,2-dibromoethane. The mixture was refluxed for 5 min, then cooled to 0 ° C and a solution of 4-bromobenzyl bromide (1.85 g, 7.4 mmol) in THF (15 mL) was added dropwise. The reaction mixture was stirred at 0 ° C for 2 h. followed by a suspension of LiCl (0.6 g, 1.4 mmol), CuCN (0.62 g, 7.0 mmol) and THF (20 mL). After warming to 20 ° C for 5 min, the reaction mixture is again cooled to -78 ° C and freshly prepared 1- (3-cyanophenyl) -3-methylpyrazol-5-ylcarboxylic acid chloro anhydride (1.4 g, 5.7 mmol) in THF (15 g) is added. ml). The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The mixture was diluted with ethyl acetate, washed with brine and dried (Na ₂ SO ₄ ). Purification by silica gel chromatography eluting with 2: 1 hexanes / ethyl acetate gave 0.62 g (28%) of the title compound. Ή NMR (CDCl ₃₎ δ: 7.67 (dd, J = 1.83, 6.96 Hz, 1H), 7.62 (s, 1H), 7.54 (m, 2H), 7.49 ( d, J = 8.42 Hz, 2H), 7.13 (d, J = 8.42 Hz, 2H), 6.90 (s, 1H), 4.10 (s, 2H), 2.39 ( s, 3H) md: MS (NH ₃ -Cl) 380-382 (M + H) ⁺ , 397-399 (M + NH ₄ ) ⁺ .

Part B: To the product of Part A (0.6 g, 1.6 mmol) was added 2-fbutylaminosulfonylphenylboronic acid (0.57 g, 2.2 mmol), 2M sodium carbonate (3 mL) in 1: 1 ethanol / toluene. The reaction mixture is degassed with nitrogen for 15 min. Tetrakistriphenylphosphine palladium (0.3 g) is added and the reaction mixture is added

The 116 is refluxed for 24 hours. The reaction mixture was cooled, filtered, and concentrated. The aqueous residue was extracted with ethyl acetate, washed with brine and dried (MgSO ₄ ). Purification by silica gel chromatography using 3: 1 hexanes / ethyl acetate as eluent gave 0.62 g (77%) of the title compound. 1 H NMR (CDCl 3) δ: 8.18 (dd, J = 1.46, 7.69 Hz, 1H), 7.68 (m, 2H), 7.58 (m, 2H), 7.52 ( d + m, J = 8.40 Hz, 4H), 7.34 (d + m, J = 8.05 Hz, 3H), 6.95 (s, 1H), 4.21 (s, 2H), 3.48 (s, 1H), 2.40 (s, 3H), 0.97 (s, 9H) md; MS (ESI) 513.2 (M + H) &lt; + &gt;

535.2 (M + Na) ⁺ .

Part C: The standard Pinner's amidine reaction sequence then yields the desired compound, which is colorless crystals. ¹ H NMR (DMSO-d 6) δ: 9.39 (s, 1.5H), 9.03 (s, 1.5H), 8.03 (dd, J = 7.32, 1.83 Hz, 1H ), 7.85 (m, 2H), 7.68 (m, 2H),

7.44 (s, 1H), 7.36 (m, 7H), 4.34 (s, 2H), 2.34 (s, 3H) md; HRMS 474.159987 (calculated) 474.161536 (found): Analysis: calculated for C25H23N5O3S (TFA) (H ₂ O) 0.5: C: 54.36, H: 4.22, N: 11.74; Found: C, 54.39,

H, 3.87; N, 11.65.

example

1- (3-Aminocarbonylphenyl) -5- [5 - [(2'-aminosulfonylphen-1-yl) pyridin-2-yl] aminocarbonyl] -3-methylpyrazole trifluoroacetic acid salt

1- (3-Cyanophenyl) -5- [5 - [(2'-t-butylaminosulfonylphen-1-yl) pyridin-2-yl] aminocarbonyl] -3-methylpyrazole is converted to the desired amide according to the procedure described previously (Example 75). : ¹ H NMR (DMSO-d ₆ ) δ; 11.15 (s, 1H), 8.35 (d, J = 2.19 Hz, 1H), 8.12 (m, 4H), 7.90 (m, 1H), 7.81 (dd, J) = 2.20, 8.79 Hz, 1H), 7.66 (m, 2H), 7.55 (m, 2H), 7.48 (s, 1H), 7.41 (m, 3H), 7 , 08 (s, 1H) md; DSGMS 477.134500 (calculated), 477.135223 (found).

example

1- (3-Amidinophenyl) -5 - [[5- (2'-t-butylaminosulfonylphenyl) pyrimidin-2-yl] aminocarbonyl] -3-trifluoromethylpyrazole trifluoroacetic acid salt

117

Part A: 1- (3-Cyanophenyl) -5 - [[5- (2'-t-butylaminosulfonylphenyl) pyrimidin-2-yl] aminocarbonyl] -3-trifluoromethylpyrazole is prepared according to standard coupling procedures, ¹ H NMR (CDCl ₃ ) δ: 9.13 (s, 1H), 8.64 (s, 2H), 8.22 (dd, J = 1.47, 7.69 Hz, 1H), 7.89 (m, 1H), 7 , 85 (m, 1H, 7.75 (dd, J = 1.46, 6.59 Hz, 1H), 7.65 (m, 3H), 7.30 (m, 2H), 4.60 (s , 1H), 1.13 (s, 9H) md, MS (ESI) 570.1 (M + H) ⁺ , 592.1 (M + Na) ⁺ .

Part B: The standard Pinner's amidine reaction sequence then yields the desired compound, which is colorless crystals. ¹ H NMR (DMSO-d 6) δ: 11.64 (s, 1H), 9.46 (s, 1.5H), 9.11 (s, 1.5H), 8.63 (s, 2H), δ , 09 (dd, J = 7.69, 1.83 Hz, 1H), 8.04 (s, 1H), 7.96 (m, 2H), 7.81 (m, 2H), 7.76 ( m, 2H), 7.42 (dd, J = 1.46, 8.79 Hz, 1H), 7.32 (s, 1H), 1.03 (s, 9H) md; DSGMS 587.180069 (calculated), 587.177999 (found); Analysis: Calculated for C 26 H 25 F 3 N 3 O 3 S (TFA) 1.1: C: 47.57, H: 3.69, N: 15.74; Found: C, 47.51; H, 3.54; N, 15.41.

example

1- (3-Amidinophenyl) -5 - [[5- (2'-aminosulfonylphenyl) pyrimidin-2-yl] aminocarbonyl] -3-trifluoromethylpyrazole trifluoroacetic acid salt

1- (3-Cyanophenyl) -5 - [[5- (2'-i-butylaminosulfonylphenyl) pyrimidin-2-yl] aminocarbonyl] -3-trifluoromethylpyrazole (0.275 g, 0.39 mmol) was refluxed in TFA 1. or. Removal of TFA and purification by HPLC afforded 0.2 g (80%) of the title compound. ¹ H NMR (DMSO-d 6) δ: 11.63 (s, 1H), 9.46 (s, 1.5H), 9.42 (s, 1.5H), 8.66 (s, 2H), 8.08 (m, 2H), 7.96 (m, 2H), 7.83 (s, 1H), 7.81 (m, 1H), 7.72 (m, 2H), 7.54 (s) , 2H), 7.45 (m, 1H) md; DSGMS 531.117468 (calculated), 531.1177523 (found); Analysis: Calculated for C 22 H ₁₇ F ₃ N ₈ O ₃ S (TFA) 1.1 (H ₂ O) 0.5: C: 43.71, H: 2.9, N: 16.85; Found: C: 43.99, H: 2.62, N: 16.54.

example

1- (3-Aminocarbonylphenyl) -5 - [[5- (2'-Aminosulfonylphenyl) pyrimidin-2-yl] aminocarbonyl] -3-trifluoromethylpyrazole

118

1- (3-Cyanophenyl) -5 - [[5- (2'-t-butylaminosulfonylphenyl) pyrimidin-2-yl] aminocarbonyl] -3-trifluoromethylpyrazole (0.5 g, 0.8 mmol) is cooled to 0 ° C. C and attached almost. H ₂ SO ₄ (5 mL). The reaction mixture is kept cold for 24 hours. Ice-water is added, the precipitate was filtered off, dissolved in ethyl acetate and the solution dried (MgSO _4). Purification was achieved by chromatography on silica gel, eluting with 1-10% methanol in methylene chloride, followed by HPLC to give 72 mg (14%) of the desired amide. Ή NMR (DMSO-d6) δ: 11.59 (s, 1H), 8.64 (s, 2H), 8.16 (s, 1H), 8.03 (s, 3H), 7.72 (m , 4H), 7.64 (d, J = 7.33 Hz, 1H), 7.58 (m, 1H), 7.51 (s, 2H), 7.43 (d, J = 7.33 Hz) (1H) md; DSGMS 532.096112 (calculated), 532.098037 (found); analysis; calculated for C ₂₂ H ₁₆ F ₃ N ₇ O ₄ S (TFA) 0.5: C: 46.99, H: 2.83, Ν.Ν6.16; Found: C, 46.86; H, 2.74; N, 16.35.

example

1- (3-Cyanophenyl) -5 - [((4 '- (imidazol-1-yl) phenyl) aminocarbonyl] -3-trifluoromethylpyrazole trifluoroacetic acid salt

Part A: 1- (3-Cyanophenyl) -3-trifluoromethyl-pyrazol-5-ylcarboxylic acid (0.5 g,

1.8 mmol) is coupled with 4-imidazoyl aniline (0.3 g, 1.8 mmol) according to standard procedures and purified by HPLC to give 0.67 g (71). Ή NMR (DMSO-d6) δ: 9.55 (s, 1H), 8.22 (d, J = 5.49 Hz, 2H), 8.04 (d, J = 7.69 Hz, 1H). , 7.96 (d, J = 8.06 Hz, 1H), 7.89 (s + d, J = 8.79 Hz, 3H), 7.80 (m, 4H) md; DSGMS 423.118119 (found), 423.116015 (found); analysis; calcd for C ₂₁ H ₁₃ F ₃ N ₆ O (TFA): C: 51.50, H: 2.63, N: 15.67; Found: C: 51.52, H: 2.71, N: 15.49.

Part B: This is followed by standard Pinner reaction and purification with 1- (3-cyanophenyl) -5 - ((4 '- (imidazol-1-yl) phenyl) aminocarbonyl) -3-trifluoromethylpyrazole to give the desired amidine (79%). ) as colorless crystals. ¹ H NMR (DMSO-ds) δ: 11.02 (s, 1H), 9.46 (s, 1.5H), 9.42 (s, 1H), 9.22 ( s, 1.5H), 8.17 (s, 1H), 8.06 (s, 1H), 7.97 (t, J = 7.69 Hz, 2H),

119

7.88 (d, J = 8.79 Hz, 2H), 7.80 (m, 3H), 7.79 (d, J = 9.0 Hz, 2H) m.d .; DSGMS 440.144668 (calculated), 440.144557 (found).

and 83 examples

1- (3-Amidinophenyl) -5 - [(4 '- (morpholin-1-yl) phenyl) aminocarbonyl] -3-trifluoromethyl-pyrazole trifluoroacetic acid salt (Example 82) and 1- (3aminocarbonylphenyl) -5 - [(4' - ( Morpholin-1-yl) phenyl) aminocarbonyl] -3-trifluoromethylpyrazole trifluoroacetic acid salt (Example 83)

Part A: 1- (3-Cyanophenyl) -3-trifluoromethylpyrazol-5-ylcarboxylic acid (0.34 g,

1.2 mmol) is coupled with 4- (4-morpholino) aniline (0.22 g, 1.2 mmol) under standard conditions to give 0.53 g (69%) of product. ¹ H NMR (CDCl 3) δ: 9.63 (s, 1H), 7.85 (d, J = 1.46 Hz, 1H), 7.79 (m, 1H), 7.74 (d, J =

7.69 Hz, 1H), 7.60 (t, J = 8.06 Hz, 1H), 7.53 (d, J = 8.79 Hz, 2H), 7.37 (s, 1H),

6.89 (d, J = 9.15 Hz, 2H), 3.87 (m, 4H) md; MS (ESI) 442.1 (M + H) &lt; + &gt;.

Part B: Synthesis of the trifluoroacetic acid salt of 1- (3-Arnidinophenyl) -5- (4 '- (morpholin-1-yl) phenyl) aminocarbonyl-1,3-trifluoromethylpyrazole

Part A nitrile undergoes a standard Pinner reaction and 65% yield of amidine which is colorless crystals. ¹ H NMR (DMSO-d ₆ ) δ: 10.56 (s, 1H), 9.45 (s, 1.5H), 9.13 (s, 1.5H), 8.02 (s, 1H) , 7.94 (m, 2H), 7.79 (t, J = 7.69 Hz, 1H), 7.69 (s, 1H), 7.51 (d, J = 9.16 Hz, 2H) , 6.94 (d, J = 8.80 Hz, 2H), 3.74 (m, 4H), 3.08 (m, 4H) md; DSGMS 459.175634 (calcd), 459.173592 (found); Analysis: Calculated for C 22 H ₂₁ F 3 N ₆ O ₂ (TFA) 2.7 (H ₂ O) 0.1: C: 42.85, H: 3,, 14, N: 10.94; Found: C, 42.87; H, 2.78; N, 10.80.

Part C: In Part B, an amide was also isolated from the Pinner reaction. ^1H

NMR (DMSO-d ₆₎ δ: 10.54 (s, 1H), 8.15 (m, 2H), 7.68 (m, 1H), 7.60 (s, 1H), 7.55 (m , 1H), 7.50 (d, J = 8.78 Hz, 2H), 6.94 (d, J = 8.78 Hz, 2H), 3.73 (m, 4H), 3.07 (m (4H) md; MS (ESI) 460.1 (M + H) &lt; + &gt;, 482 (M + Na) &lt; + &gt;.

and 85 examples

120

Trifluoroacetic acid salt of 1- (3-amidinophenyl) -5- I [5- (2'-aminosulfonylphenyl) pyridin-2-yl] aminocarbonyl] 3-trifluoromethylpyrazole (Example 84) and 1- (3aminocarbonylphenyl) -5 - [[5 - (2'-Aminosulfonylphenyl) pyridin-2-yl] aminocarbonyl] -3-trifluoromethylpyrazole trifluoroacetic acid salt (Example 85)

Part A; 1- (3-Cyanophenyl) -5 - [[2- (2'-t-butylaminosulfonyl) -1-yl) pyridin-2-yl] aminocarbonyl] -3-trifluoromethylpyrazole. ¹ H NMR (CDCl ₃ ) δ; 8.75 (s, 1H), 8.35 (d, J = 1.83 Hz, 1H), 8.21 (m, 2H), 7.87 (m, 4H), 7.66 (t, J = 7.69 Hz, 1H), 7.59 (m, 2H), 7.29 (m, 2H), 4.30 (s, 1H), 1.11 (s, 9H) md; MS (ESI) 569.1 (M + H) ⁺ , 591.1 (M + Na) ⁺ .

Part B: The standard Pinner's amidine reaction sequence then yields the desired compound which is colorless crystals; ¹ H NMR (DMSO-d 6) δ; 11.46 (s, 1H), 9.47 (s, 1.5H), 9.21 (s, 1.5H), 8.39 (d, J = 1.84 Hz, 1H), 8.06 (m, 2H), 7.97 (m, 4H), 7.82 (m, 2H), 7.68 (m, 2H), 7.45 (s, 2H), 7.40 (dd, J = 2.20 Hz, 7.69 Hz, 1H) md; MS (ESI) 530.1 (M + H) &lt; ⁺ &gt; Analysis: Calculated for C ₂₃ H ₈ F ₃ N ₇ O ₃ S (TFA) ₂ : C: 42.81, H: 2.66, N: 12.44; Found: C, 42.99; H, 2.44; N, 12.77.

Part C: In Part B, an amide was also isolated from the Pinner reaction. ^1H

NMR (DMSO-d ₆₎ δ; 11.42 (s, 1H), 8.37 (d, 1H), 8.06 (s, 1H), 8.03 (m, 4H), 7.82 (m, 2H), 7.70 (m , 4H), 7.56 (s, 1H), 7.42. (s, 2H), 7.39 (dd, J = 7.69, 2.2 Hz, 1H) md; DSGMS 531.106235 (calculated), 531.108937 (found).

example

1- (3-Amidinophenyl) -5 - [(4 '- (3-methyltetrazol-1-yl) phenyl) aminocarbonyl] -3-trifluoromethylpyrazole trifluoroacetic acid salt

Part A; Synthesis of 4-Tetrazoylnitrobenzene

4-Nitrobenzonitrile (2 g, 13.5 mmol), sodium azide (0.92 g, 14 mmol) and tributyltin chloride (3.8 mL, 14 mmol) were mixed in toluene (30 mL) and the mixture was refluxed 18 or. The reaction mixture was extracted with 1N

121

Excess NaOH. The aqueous layer is cooled, almost acidified. The HCl precipitated solid was filtered off and dried in vacuo. The aqueous layer was extracted with ethyl acetate, mixed with the solid and dried (MgSO ₄ ); 1.4 g (56%) are obtained. ¹ H NMR (DMSO-d 6) δ: 8.48 (d, J = 8.79 Hz, 2H), 8.34 (d, J = 8.79 Hz, 2H) md MS (ES-) 190.0 (MH).

Part B: 60% Sodium Hydride (0.29 g) in 4-Tetrazolifnitrobenzene (1.16 g, 6.1 mmol) and iodomethane (0.53 mL, 8.5 mmol) in DMF (10 mL) was added at 0 ° C. , 7.3 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 24 hours. The reaction was quenched with water, extracted with ethyl acetate and dried (MgSO ₄ ). Purification by silica gel chromatography using 4: 1 hexanes / ethyl acetate as eluent afforded 0.9 g (72%) of the main isomer, 4- (3-methyltetrazol) nitrobenzene. ¹ H NMR (CDCl ₃ ) δ: 8.38 (d, J = 9.16 Hz, 2H), 8.35 (d, J = 9.52 Hz, 2H), 4.45 (s, 3H) md ; MS (NH ₃ -Cl) 206 (M + H) ⁺ , 176 (M + HNO).

Part C: 4- (3-Methyltetrazol) nitrobenzene (0.67 g, 3.3 mmol) was added to ethanol (15 mL) and trifluoroacetic acid (1 mL). A catalytic amount of 10% palladium on carbon is added and hydrogen is bubbled through the mixture. The reaction mixture was stirred for 4 hours, then filtered and concentrated. The resulting 4- (3-methyltetrazol) aniline trifluoroacetic acid salt (MS 176 (M + H) ⁺ ) is used directly in the next step. The salt of 4- (3-methyltetrazolyl) aniline trifluoroacetic acid and 1- (3-cyanophenyl) -3-trifluoromethylpyrazol-5-ylcarboxylic acid are copied under standard conditions to give 1- (3-cyanophenyl) -1-5 - [(4 '- (3-methyltetrazol) -1-yl) phenylaminocarbonyl] -3-trifluoromethylpyrazole ¹ H NMR (CDCl ₃ ) δ: 10.45 (s, 1H), 8.11 (d, J = 8.79 Hz,

2H), 7.86 (s, 1H), 7.82 (d, J = 8.79 Hz, 2H), 7.77 (dd, J = 7.69, 1.46 Hz, 2H),

7.63 (t, J = 7.69 Hz, 1H), 7.50 (s, 1H), 4.40 (s, 3H) md; MS (ESI) 439 (M + H) &lt; ⁺ &gt;, 460.9 (M + Na) &lt; ⁺ &gt;.

122

Part D: Part C nitrile is reacted under standard Pinner reaction conditions to give the trifluoroacetic acid salt of i- (3-amidinophenyl) -5 - [(4 '- (3-methyltetrazol-1-yl) phenyl) aminocarbonyl] -3-trifluoromethylpyrazole. . ¹ H NMR (DMSO-d _s) δ: 10.97 (s, 1H), 9.47 (s, 1.5H), 9.24 (s, 1.5H), 8.07 (d, J =

8.79 Hz, 2H), 8.06 (m, 1H), 7.97 (m, 2H), 7.86 (d, J = 8.78 Hz, 2H), 7.80 (m.

2H), 4.41 (s, 3H) ppm; DSGMS 456.150816 (calcd), 456.152474 (found); Analysis: Calculated for C 20 H 16 F 3 N 9 O (TFA) 1.2: C: 45.43, H: 2.93, N: 21.29; Found: C: 45.37, H: 3.18, N: 21.39.

example

Trifluoroacetic acid salt of 1- (3-amidinophenyl) -5- (2'-naphthylaminosulfonyl) -3-methylpyrazole

Part A: To 5-amino-1- (3-cyanophenyl) -3-methylpyrazole (0.5 g, 2.5 mmol) in methylene chloride (15 mL) was added 2-naphthylsulfonyl chloride (0.63 g, 2.8 mmol) ) and triethylamine (0.46 mL, 3.3 mmol). The reaction mixture was stirred for 18 hours at room temperature, but TLC did not complete the reaction. A few crystals of Ν, Ν-dimethylaminopyridine are added and the mixture is refluxed for 5 hours. The reaction mixture was cooled, diluted and washed with 1N HCl, saturated NaHCO ₃ , saturated NaCl, and dried (MgSO ₄ ). NMR and mass spectra of the crude product show that the major product is bissulfonamide, MS (ESI) 579 (M + H) ⁺ , 601 (M + Na) ⁺ .

Part B: Standard for Part A bis-sulfonamide crude

The Pinner reaction and purification by HPLC afforded 0.3 g (50%) of the desired monosulfonamide. ¹ H NMR (DMSO-d ₆ ) δ: 9.36 (s, 1.5H), 9.07 (s, 1.5H), 8.29 (s, 1H), 8.14 (d, J = 7.69 Hz, 1H), 8.09 (t, J = 8.79 Hz, 2H), 7.86 (s, 1H), 7.79 (m, 6H), 7.60 (d, J = 7.69 Hz, 1H), 5.79 (s, 1H), 2.12 (s, 3H) md; DSGMS 406.133772 (calculated), 406.133617 (found).

example

123

1- (3-Amidinophenyl) -5 - [(4-bromophenyl) aminosulfonyl] -3-methylpyrazole trifluoroacetic acid salt

Part A; To 5-amino-1- (3-cyanophenyl) -3-methylpyrazole (0.5 g, 2.5 mmol) in methylene chloride (15 mL) was added 4-bromobenzenesulfonyl chloride (0.7 g, 2.8 mmol) and triethylamine. (0.46 mL, 3.3 mmol). The reaction mixture was stirred for 18 hours at room temperature, but TLC did not complete the reaction. A few crystals of Ν, Ν-dimethylaminopyridine are added and the mixture is refluxed for 5 hours. The reaction mixture is cooled, diluted and washed with 1N HCl, saturated NaHCO3, brine and dried (MgSO _4). NMR and mass spectra of the crude product show that the major product is bissulfonamide, MS (ESI) 643-636.6 (M + H) ⁺ , 655-657.2 (M + Na) ⁺ .

Part B: Standard for Part A bis-sulfonamide crude

The Pinner reaction and purification by HPLC afforded 0.22 g (44%) of the desired monosulfonamide. ¹ H NMR (DMSO-d ₆ ) δ: 9.40 (s, 1.5H), 9.18 (s, 1.5H), 7.88 (s, 1H), 7.79 (m, 1H) , 7.74 (d, J = 8.40 Hz, 2H), 7.69 (m, 2H), 7.53 (d, J =

8.42 Hz, 2H), 5.89 (s, 1H), 2.17 (s, 3H) ppm; DSGMS 434.028633 (calculated), 434.029892 (found).

example

Trifluoroacetic acid of 1- (3-aminomethylphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4yl) aminocarbonyl] -3-methylpyrazole to 1- (3-cyanophenyl) -5 - [( 2'-Aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methylpyrazole (0.19 g, 0.41 mmol) was added with ethanol (20 mL), TFA (0.5 mL) and 10% palladium on carbon (10 mg). The mixture was stirred under H ₂ atmosphere (1 atm pressure) for 18 h. The reaction mixture was filtered, concentrated, and purified by HPLC; 17 mg (9%) of the title compound is obtained. ¹ H NMR (DMSO-d _s) δ: 10.66 (s, 1H), 8.22 (br s, 2H), 8.03 (dd, J = 1.47, 6.22 Hz, 1H) ,

7.70 (d, J = 8.79 Hz, 2H), 7.67 (m, 2H), 7.64 (m, 5H), 7.37 (d, J = 8.43 Hz,

124

2H), 7.32 (m, 2H), 6.93 (s, 1H), 4.13 (d, J = 4.03 Hz, 2H), 2.33 (s, 3H) m.d .; DSGMS 462.159987 (calculated), 462.158938 (found).

example

1- (3-aminomethyl) -5 - [(2'-aminosulfonyl [1,1 '] - bit ^e n-4-yl) aminocarbonyl] -3-trifluoromethyl-pyrazolo trifluoroacetic acid salt

The hydrogenation of 1- (3-cyanophenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-trifluoromethylpyrazole was reduced to the desired compound. ¹ H NMR (DMSO-d ₆ ) δ: 10.89 (s, 1H), 8.25 (ss, 1H), 8.04 (d, J = 7.33 Hz, 1H), 7.75 (s, 1H), 7.69 (d + s, J = 6.96 Hz, 3H), 7.60 (m, 4H), 7.39 (d, J = 8.43 Hz, 2H), 7 , 32 (s + d, J = 6.94 Hz, 3H), 4.17 (d, J = 5.49 Hz, 2H) ¹ H NMR (DMSOds) δ: 10.97 (s, 1H), 9 , 47 (s, 1.5H), 9.24 (s, 1.5H), 8.07 (d, J = 8.79 Hz, 2H), 8.06 (m, 1H), 7.97 ( m, 2H), 7.86 (d, J = 8.78 Hz, 2H), 7.80 (m, 2H), 4.41 (s, 3H) md; DSGMS 516.131721 (calculated), 516.130109 (found); analysis; Calculated for C24H20F3N5O3S (TFA) 1.2; C, 48.61; H, 3.28; N, 10.74; Found: C, 48.35, H, 3.18, N, 10.69.

example

1- (3-Amidinophenyl) -3-methyl-5 - [((2'-trifluoromethylphenyl) pyrid-2-yl) aminocarbonyl] pyrazole trifluoroacetic acid salt

This compound (colorless crystals) is prepared according to the standard Pinner amidine reaction sequence and purification procedures described above. ¹ H NMR (DMSO-d 6) δ: 11.21 (s, 1H), 9.39 (s, 2H), 9.11 (s, 2H), 8.31 (s, 1H), 8.00 ( d, 1H), 7.93 (s, 1H), 7.86-7.63 (m, 7H), 7.75 (d, 1H), 7.16 (s, 1H), 2.29 (s) (3H) md; LRMS (ESI) 465.3 (M + H) ⁺ HRMS ₂ C 4 H ₂ F ₃ oN ₆ 0 465.165069 (calculated) 465.165566 (found).

example

1- (3-Amidinophenyl) -3-methyl-5 - [((2'-aminosulfonyl-1-yl) pyrimidin-5-yl) aminocarbonyl] pyrazole trifluoroacetic acid salt

125

This compound (colorless crystals) is prepared according to the standard Pinner amidine reaction sequence and purification procedures described above. ¹ H NMR (DMSO-d 6) δ: 11.39 (s, 1H), 9.43 (s, 2H), 9.08 (s, 2H), 8.65 (s, 2H), 8.08-. 8.05 (m, 1H), 7.96 (s, 1H), 7.83 (m, 1H), 7.78-7.68 (m, 4H), 7.54 (s, 2H), 7 46-7.43 (m, 1H); 7.9 (s, 1H); 2.33 (s, 3H) md; MSGMS (ESI) 477.2 (M + H) ⁺ , DSGMS C ₂₂ H ₂₁ N ₈ O ₃ S 477.148419 (calcd.), 477.146755 (found).

example

1- (3-Amidinophenyl) -3-methyl-5 - [(2'-fluoro- [1,1 '] - biphen-4-yl) -aminocarbonyl] pyrazole trifluoroacetic acid salt

This compound (colorless crystals) is prepared according to the standard Pinner amidine reaction sequence and purification procedures described above. Ή NMR (DMSO-d6) δ: 10.68 (s, 1H), 9.43 (s, 2H), 9.13 (s, 2H), 7.96 (s, 1H), 7.83-7 , 67 (m, 6H), 7.55 (d, 2H), 7.41 (m, 1H), 7.33-7.27 (m, 2H), 7.05 (s, 1H), 2, 35 (s, 3H) md; MSGMS (ESI) 414.3 (M + H) &lt; ⁺ &gt;, DSGMS C 24 H 34 N 3 O 4 414.173014 (calculated), 414.172475 (found).

example

1- (3-Amidinophenyl) -3-methyl-5- [3-chloro- (2'-fluoro- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole trifluoroacetic acid salt

This compound (colorless crystals) is prepared according to the standard Pinner amidine reaction sequence and purification procedures described above. ¹ H NMR (DMSO-d 6) δ: 10.43 (s, 1H), 9.43 (s, 2H), 9.10 (s, 2H), 7.95 (s, 1H),

7.82 (m, 2H), 7.73 (m, 2H), 7.68-7.54 (m, 3H), 7.46 (m, 1H), 7.38-7.30 (m, 2H), 7.07 (s, 1H), 2.35 (s, 3H) md; LRMS (ESI) 448.2 (M + H) ^+, HRMS C ₂ 4H ₂ oN ₅ OPCI 448.134041 (calculated) 448.133737 (found).

example

126

1- (3-Amidinophenyl) -3-methyl-5- [3-fluoro- (2'-fluoro- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole trifluoroacetic acid salt

This compound (colorless crystals) is prepared according to the standard Pinner amidine reaction sequence and purification procedures described above. ¹ H NMR (DMSO-d 6) δ: 10.47 (s, 1H). 9.43 (s, 2H), 9.09 (s, 2H), 7.96 (s, 1H), 7.87-7.60 (m, 6H), 7.52 (m, 1H), 7 , 46 (d, 1H), 7.30 (d, 1H), 7.18 (d, 1H), 7.07 (s, 1H), 2.34 (s, 3H) md; MSGMS (ESI) 482.2 (M + H) &lt; + &gt;, DSGMS

C ₂₅ H ₂₁ N ₅ OF4 482.160398 (calcd), 482.157655 (found).

example

1- (3-Amidinophenyl) -3-methyl-5- [3-fluoro- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole trifluoroacetic acid salt

This compound (colorless crystals) is prepared according to the standard Pinner amidine reaction sequence and purification procedures described above. ¹ H NMR (DMSO-d ₆ ) δ: 10.45 (s, 1H), 9.43 (s, 2H), 9.09 (s, 2H), 8.04 (m, 1H), 7.96 (s, 1H), 7.80 (m, 2H), 7.73 (d, 1H), 7.65 (m, 3H), 7.43 (s, 2H), 7.36-7.29 (m, 2H), 7.22 (m, 1H), 7.06 (s, 1H), 2.34 (s, 3H) md; MSGMS (ESI) 493.2 (M + H) ⁺ , DSGMS C 24 H 22 N 6 O 3 SF 493.145814 (calcd.), 493.146092 (found).

example

1- (3-AmidinophenH) -3-methyl-5- [5- (2'-fluorophen-1-yl) pyrid-2-yl] aminocarbonyl] pyrazole trifluoroacetic acid salt

This compound (colorless crystals) is prepared according to the standard Pinner amidine reaction sequence and purification procedures described above. ¹ H NMR (DMSO-d ₆ ) δ: 11.25 (s, 1H), 9.43 (s, 2H), 9.09 (s, 2H), 8.59 (s, 1H), 8.10 -8.07 (d, J = 8.79 Hz, 1H), 8.02-7.96 (m, 2H), 7.85-7.79 (m, 2H), 7.737.70 (d, J = 8.06 Hz, 1H), 7.64-7.59 (m, 1H), 7.49-7.44 (m, 1H), 7.39-7.31 (m,

127

2H), 7.21 (s, 1H), 2.33 (s, 3H) md; MSGMS (ESI) 415.2 (M + H) ⁺ , DSGMS C ₂₃ H ₂₁ ON _s F 415.168263 (calculated), 425.168444 (found).

example

1- (3-Amidinophenyl) -3-methyl-5 - [[5- (2'-tert-butylaminosulfonylphenyl) pyrimid-2-ylaminocarbonyl] pyrazole trifluoroacetic acid salt

This compound (colorless crystals) is prepared according to the standard Pinner amidine reaction sequence and purification procedures described above. Ή NMR (DMSO-d6) δ: 11.40 (s, 1H), 9.43 (s, 2H), 9.08 (s, 2H), 8.62 (s, 2H), 8.09-8 , 06 (m, 1H), 7.95 (s, 1H), 7.83-7.65 (m, 6H), 7.43-7.40 (m, 1H), 7.08 (s, 1H) ), 2.32 (s, 3H), 1.04 (s, 9H) md; MSGMS (ESI) 533.3 (M + H) ⁺ , DSGMS C ₂₆ H ₂₉ N ₈ O ₃ S 533.208334 (calcd.), 533.207170 (found).

example

1- (3-Amidinophenyl) -3-methyl-5 - [[5- (2'-aminosulfonylphenyl) - [1,6] dihydropyrimidin-2-yl] aminocarbonyl] pyrazole trifluoroacetic acid salt

This compound (colorless crystals) is prepared according to the standard Pinner amidine reaction sequence and purification procedures described above. Ή NMR (DMSO-d ₆₎ δ: 9.95 (s, 1H), 9.38 (s, 2H), 9.29 (s, 1H), 9.25 (s, 2H), 7,95- 7.92 (m, 2H), 7.84 (d, J = 7.81 Hz, 1H), 7.79 (d, J = 8.79 Hz, 1H), 7.707.66 (t, J = 8 , 06 Hz, J = 7.81 Hz, 1H), 7.58-7.56 (t, J = 7.57 Hz, 1H), 7,547.49 (t, J = 7.57 Hz, 1H), 7.48 (s, 2H), 7.40 (d, J = 7.57 Hz, 1H), 6.86 (s, 1H), 6.13 (s, 1H), 4.24 (s, 2H) ), 2.28 (s, 3H) md; MSGMS (ESI) 579.2 (M + H) ⁺ , DSGMS C ₂₂ H ₂₃ N ₅ O ₃ S 579.161384 (calcd), 579.161293 (found).

Example 100

1- (3-Amidinophenyl) -3-methyl-5 - [(4- (pyrid-3'-yl) phen-1-yl) aminocarbonyl] pyrazole trifluoroacetic acid salt

128

This compound (colorless crystals) is prepared according to the standard Pinner amidine reaction sequence and purification procedures described above. Ή NMR (DMSO-d ₆₎ δ: 10.71 (s, 1H), 9.43 (s, 2H), 9.11 (s, 2H), 8.98 (s, 1H), 8.64 (m, 1H), 8.28-8.25 (d, J = 8.43 Hz, 1H), 7.97 (s, 1H), 7.84-7.06 (m, 8H), 7, 06 (s, 1H), 2.35 (s, 3H) md; MSGMS (ESI) 379.2 (M + H) ⁺ , DSGMS C ₂₃ H ₂ N ₆ O 379.177685 (calcd.), 379.176514 (found).

Example 101

1- (3-Amidinophenyl) -3-methyl-5 - [[2- (2'-pyridyl) ethyl] aminocarbonyl] pyrazole trifluoroacetic acid salt

This compound (colorless crystals) is prepared according to the standard Pinner amidine reaction sequence and purification procedures described above. ¹ H NMR (DMSO-d 6) δ: 9.40 (s, 2H), 9.16 (s, 2H), 8.81 (m, 1H), 8.68 (m, 1H), 8.09 ( m, 1H), 7.85 (s, 1H), 7.80-7.77 (d, J = 8.06 Hz, 1H), 7.64-7.54 (m, 4H), 6.72 (s, 1H), 3.61-3.55 (kv, 2H), 3.09-3.05 (t, 2H), 2.26 (s, 3H) md; LRMS (ESI) 349.1 (M + H) ⁺ HRMS C19H ₂ iN ₆ O 349.177685 (calculated) 349.175374 (found).

Example 102

1- (3-Amidinophenyl) -3-methyl-5 - [(3-phenylpropyl) aminocarbonyl] pyrazole trifluoroacetic acid salt

This compound (colorless crystals) is prepared according to the standard Pinner amidine reaction sequence and purification procedures described above. ¹ H NMR (DMSO-d 6) δ: 9.41 (S, 2Η), 9.11 (s, 2H), 8.72 (m, 1H), 7.88 (s, 1H), 7.81-. 7.77 (m, 1H), 7.68 (m, 2H), 7.31-7.18 (m, 5H), 6.77 (s, 1H), 3.21-3.14 (kv, J = 6.60 Hz, 2H), 2.62-2.57 (t, J = 7.69 Hz, 2H), 2.28 (s, 3H), 1.82-1.73 (kv, J = 7.32 Hz, 2H) md; LRMS (ESI) 362.1 (M ⁺ H), HRMS C ₂₁ H 4 N ₅ O ₂ 362.198086 (calculated) 362.197157 (found).

Example 103

129

1- (3-Amidinophenyl) -3-methyl-5- [4- (pyrid-2'-yl) phenyl-1-ylaminocarbonyl] pyrazole trifluoroacetic acid salt

This compound (colorless crystals) is prepared according to the standard Pinner amidine reaction sequence and purification procedures described above. Ή NMR (DMSO-d ₆₎ δ 10.7 (s, 1H), 9.43 (s, 2H), 9.08 (s, 2H), 8.66 (m, 1H), 8.10 ( m, 2H), 7.96-7.88 (m, 3H), 7.84-7.76 (m, 4H), 7.73 (m, 1H), 7.38 (m, 1H), 7 , 06 (s, 1H), 2.35 (s, 3H) md; MSGMS (ESI) 397.1 (M + H) ⁺ , DSGMS C ₂₃ H ₂₁ N ₅ O 397.177685 (calcd.), 397.179670 (found).

Example 104

1- (3-Amidinophenyl) -3-methyl-5 - [(4- (isopropyloxy) phenyl) aminocarbonyl] pyrazole trifluoroacetic acid salt

This compound (colorless crystals) is prepared according to the standard Pinner amidine reaction sequence and purification procedures described above. 1 H NMR (DMSO-d 6) δ: 10.40 (s, 1H), 9.42 (s, 2H), 9.06 (s, 2H), 7.94 (s, 1Η),

7.82 (d, J = 7.32 Hz, 1H), 7.75-7.65 (m, 2H), 7.54 (d, J = 9.16 Hz, 2H), 6.97 (s , 1H), 6.89 (d, J = 8.79 Hz, 2H), 4.57-4.53 (m, 1H), 2.32 (s, 3H), 1.25 (s, 3H) 1.23 (s, 3H) md; LRMS (ESI) 378.1 (M ⁺ H), HRMS C ₂₁ H ₅ O ₂ 4N ₂ 378.193000 (calculated) 378.194610 (found).

Example 105

1- (3-Amidinophenyl) -3-methyl-5 - [(5- (2'-trifluoromethylphenyl) pyrimidin-2-yl) aminocarbonyl] pyrazole trifluoroacetic acid salt

This compound (colorless crystals) is prepared according to the standard Pinner amidine reaction sequence and purification procedures described above. Ή NMR (DMSO-d6) δ: 11.45 (s, 1H), 9.43 (s, 2H), 9.09 (s, 2H), 8.69 (s, 2H), 7.96 (s) , 1H), 7.93 (d, J = 8.06 Hz, 1H), 7.84-7.67 (m, 5H), 7.57 (d, J = 7.69 Hz, 1H), 7 , 10 (s, 1H), 2.32 (s, 3H) md; MSGMS (ESI) 466.1 (M + H) ⁺ , DSGMS C23H19N7F3O 466.163004 (calcd), 466.161823 (found).

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Example 106

1- (3-Amidinophenyl) -3-methyl-5 - [(4- (piperidinosulfonyl) phenyl) aminocarbonyl] pyrazole trifluoroacetic acid salt

This compound (colorless crystals) is prepared according to the standard Pinner amidine reaction sequence and purification procedures described above. 1 H NMR (DMSO-d 6) δ: 10.90 (s, 1H), 9.42 (s, 2H), 9.19 (s, 2H), 7.95 (m, 3H), 7.80 ( m, 2H), 7.70 (m, 3H), 7.08 (s, 1H), 2.85 (m, 4H), 2.35 (s, 3H), 1.54 (m, 4H), 1.35 (pi.d, 2H) md; MSGMS (ESI) 467.1 (M + H) ⁺ ;

Example 107

1- (3-Amidinophenyl) -3-methyl-5 - [(4- (piperidinocarbonyl) phenyl) aminocarbonyl] pyrazole trifluoroacetic acid salt

This compound (colorless crystals) is prepared according to the standard Pinner amidine reaction sequence and purification procedures described above. 1 H NMR (DMSO-d ₆ ) δ: 10.69 (s, 1H), 9.43 (s, 2H), 9.12 (s, 2H), 7.95 (s, 1H),

7.83 (m, 1H), 7.77-7.96 (m, 4H), 7.37 (d, J = 8.79 Hz, 2H), 7.04 (s, 1H), 3.31 (pi.d, 2H), 3.54 (pi.d, 2H), 2.34 (s, 3H), 1.60 (pi.d, 2H), 1.50 (pi.d, 4H) md ; MSGMS (ESI) 431.1 (M + H) &lt; + &gt;.

Examples 108 and 109

1- (3-Amidino-4-fluorophenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4yl) aminocarbonyl] pyrazole trifluoroacetic acid salt (Example 108) and 1- (3) -aminocarbonyl-4-fluorophenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen4-yl) aminocarbonyl] pyrazole trifluoroacetic acid salt (Example 109)

Part A: Preparation of 2-Fluoro-5-aminobenzonitrile To a solution of 2-fluoro-5-nitrobenzonitrile (2.0 g, 12 mmol) in ethyl acetate (50 mL) was added tin chloride (27.0 g, 120 mmol). The reaction mixture was stirred and

Reflux for 1.5 hours and then cool to room temperature. The mixture was partitioned between ethyl acetate (150 mL) and saturated sodium bicarbonate solution (150 mL). The organic phase was separated and washed with water (5 x 75 mL), brine (75 mL), dried over sodium sulfate (anhydrous), filtered and concentrated to give 2-fluoro-5-aminobenzonitrile (1.4 g) as a pure compound.

Part B: Preparation of 3-Cyano-4-fluorophenylhydrazine tin chloride in a solution of 2-fluoro-5-aminobenzonitrile (1.4 g, 10.3 mmol) in HCl (almost 15 mL) at 0 ° C is added dropwise to sodium nitrite (0). , 71 g, 10.3 mmol) in cold water (3 mL). After the addition was complete, the mixture was stirred at 0 ° C for 0.5 h, and a solution of tin chloride (6.95 g, 30.9 mmol) in cold water (5 mL) was added dropwise. The suspension was cooled in a refrigerator overnight, the solid was filtered and washed with saturated NaCl solution (20 mL), petroleum ether: ether (2: 1, 30 mL) and air-dried to give 3-cyano-4-fluorophenylhydrazine tin chloride (2.5 g). .

Part C: Preparation of ethyl 1- (3-cyano-4-fluorophenyl) -3-methyl-pyrazol-5-ylcarboxylate into 3-cyano-4-fluorophenylhydrazine tin chloride (0.9 g, 2.65 mmol) and acetic acid (15 mL) of the mixture was added oxime. The reaction mixture was refluxed overnight. The acetic acid is evaporated off under a rotary evaporator under reduced pressure. The residue was partitioned between ethyl acetate (30 mL) and acidic sodium carbonate (25 mL). The organic phase is separated off, washed with water (3 x 20 mL), dried over sodium sulfate, filtered and concentrated by flash chromatography (ethyl acetate: hexane, 1: 5) to give ethyl 1- (3-cyano-4'-fluorophenyl) -3-. methylpyrazol-5-ylcarboxylate (0.7 g).

Part D: 1- (3-cyano-4-fluorophenyl) -3-methyl-5-f ^(2! -Fref butiiaminosulfonili1,1'l-biphen-4-yl) receiving aminokarboninpirazolo

132

To a solution of biphenylamine (167 mg, 0.55 mmol) in methylene chloride (5 mL) at 0 ° C was added trimethylaluminum (2.0 M in hexane, 0.55 mL, 1.1 mmol) via syringe. The mixture is slowly warmed to room temperature and stirred for 20 min, then a solution of ethyl 1- (3-cyano-4'-fluorophenyl) -3-methyl-pyrazol-5-ylcarboxylate (100 mg, 0.37 mmol) in methylene chloride is added portionwise. 5 ml). The reaction mixture was stirred at 45 ° C under nitrogen overnight. Methylene chloride was evaporated, the residue was partitioned between HCl (10%, 5 mL) and partitioned between ethyl acetate (20 mL) and HCl (10%, 15 mL). The organic phase was separated and washed with HCl (10%, 3 x 10 mL) and water (2 x 10 mL), dried over sodium sulfate; 1- (3-cyano-4-fluorophenyl) -3-methyl-5 - [(2'-tert-butylaminosulfonyl- [1,1'] -biphen-4-yl) aminocarbonyl] pyrazole (150 mg) is left after filtration and concentration. ), which is a pure compound. ¹ H NMR (CDCl ₃ ) δ: 8.21 (s, 1H), 8.17-8.14 (m. 1H), 7.75 (d, 1H), 7.72 (t, 1H), 7 , 66 (d, 2H), 7.60-7.46 (m, 5H), 7.31-7.28 (m, 2H), 6.78 (s, 1H), 3.67 (s, 1H). ), 2.41 (s, 3H), 1.03 (s, 9H) md; ESI m / z (rel intensity) 554 (Mt-Na, 100).

Part E: 1- (3-Amidino-4-fluorophenyl) -3-methyl-5 - [(2'-aminosulfonyl-1,1,1'-biphen-4-yl) aminocarbonyl] pyrazole trifluoroacetic acid salt and 1- (3-carboxamido- Preparation of 4-fluorophenyl) -3-methyl-5 - [(2'-aminosulfonyl-1,1'-biphen-4'-aminocarbonyl] pyrazole

1- (3-Cyano-4-fluorophenyl) -3-methyl-5 - [(2'-tert-butylaminosulfonyl- [1,1 '] - biphen4-yl) aminocarbonyl] pyrazole (150 mg) was dissolved in anhydrous HCl in anhydrous methanol. (10 mL). The reaction mixture was stirred at room temperature for 24 hours. The methanol is then evaporated. The residue was redissolved in methanol (10 mL) and excess ammonium carbonate was added. The reaction mixture was stirred at room temperature overnight. Methanol was evaporated and the residue purified by HPLC to give 1- (3-amidino-4-fluorophenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole TFA in the form of a salt (20 mg); ¹ H NMR (CD ₃ OD) δ: 8.07-8.04 (m, 3H), 7.63 (d, 2H), 7.58 (d, 2H), 7.42-7.55 (m , 2H), 7.38 (d, 2H), 7.35 (d, 2H), 6.80 (s, 1H), 2.34 (s, 3H) md; ESI m / z (relative intensity) 493 (M + H, 100); and 1- (3-aminocarbonyl-4-fluorophenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) amino-133-carbonyl] pyrazole (10 mg). ¹ H NMR (DMSO-d 6) δ; 10.59 (s, 1H), 7.99 (dd, 1H), 7.81 (pi, 1H), 7.72-7.67 (m, 2H), 7.63 (d, 2H), 7.60-7.49 (m, 4H), 7.377.26 (m, 4H), 7.21 (s, 2H), 6.90 (s, 1H), 2.29 (s, 3H). High-resolution mass spectrum; calcd for C 24 H 20 FN 5 O 4 S (M + H); 494.129829, found 494.131923.

Example 110

1-Methyl-3- (3-amidino) phenyl-4 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole

Part A: A mixture of ethyl 3-cyanobenzoylacetate (2.01 g) and N, N-dimethyldiethylacetal (50 ml) was gently heated under reflux overnight. Evaporation of the solvent in vacuo gave a viscous, viscous pink oil, which was dissolved in anhydrous methanol (50 mL). Nmethylhydrazine (0.43 g) is then added dropwise to this solution. The reaction mixture was stirred at room temperature overnight, then concentrated to a viscous oil containing a mixture of pyrazole regioisomers. This crude mixture of pyrazoles (0.45 g, 1.79 mmol) was added to 2'-tert-butylsulfonamide-1-aminobiphenyl (0.54 g, 1.79 mmol) and trimethylaluminum (5.37 mL, 10.7 mmol). ) in dichloromethane (50 mL). The reaction mixture was stirred at room temperature overnight, then quenched with dilute HCl (1N). The organic material was extracted with ethyl acetate (2 x 50 mL), dried (MgSO ₄ ) and evaporated to a colorless residue. Chromatography on a silica gel column (dichloromethane: MeOH, 9: 1) yields regioisomeric mixtures of the copolished pyrazoles. Reverse-phase preparative HPLC (acetonitrile; water gradient flow) allows the isolation of pure 1-methyl-3- (3-cyano) phenyl-4 - [(2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl). aminocarbonyl] pyrazole, which is a colorless oil (0.35 g); Δ NMR (CDCl3) δ: 8.14 (d, 1H), 8.01 (s, 1H), 7.83-7.65 (m, 4H), 7.60-7.41 (m, 6H). , 7.27 (m, 2H), 3.78 (s, 3H), 3.63 (s, 1H), 1.00 (s, 9H)

m. d .; ESI mass spectrum 536 (M + Na, 45), 514 (M + H, 100).

134

Part B: The product of Part A is then subjected to a Pinner's amidine reaction sequence as described in Example 10 and separation by preparative HPLC and lyophilization to give colorless crystals of the title compound (0.15 g); ¹ H NMR (DMSO-d 6) δ: 9.90 (s, 1H), 9.37 (pl.s, 1.5H), 9.29 (pl.s, 1.5H), 8.24 (s , 1H), 8.00 (d, 1H), 7.90 (ss, 2H), 7.84 (d, 1H), 7.73 (m, 1H), 7.69-7.50 ( m, 4H), 7.37-7.27 (m, 3H), 7.17 (m.s, 1H), 3.98 (s, 3H) md; ESI mass spectrum m / z (rel intensity) 475.3 (M + H, 100).

Example 111

1- (3-Amidinophenyl) -5 - [(4-pyrazol-4'-yl) phen-1-yl] aminocarbonylpyrazole trifluoroacetic acid salt

Part A: 4-Iodopyrazole (20 mmol) is treated with Et ₃ N (30 mmol) and (Boc) ₂ O (22 mmol) in THF (60 mL) at room temperature for 2 hours to give N-Boc-4-iodopyrazole (5.88) g, 100%). N-Boc-4-iodopyrazole in THF (100 mL) was treated with hexamethyl tin (20 mmol) in Pd (Ph ₃ P) ₄ (1.1 g, 1 mmol) under a nitrogen atmosphere at 78 ° C overnight. Aqueous 10% KF was added to the mixture and stirred for 30 min, then filtered through a pad of celite. The filtrate was extracted with EtOAc. The EtOAc layer was washed with water and dried over MgSO ₄ . Filtration and concentration followed by column purification gave a 3-trimethyltin-pyrazole derivative (5 g, 75%) as a white solid.

Part B: Part A product (10 mmol) was treated with 4-nitrobromobenzene (10 mL) in Pd (Ph ₃ P) ₄ (0.36 g, 0.3 mmol) under nitrogen at 78 ° C overnight, then treated with See above for the 4-pyrazole-nitrobenzene derivative (0.95 g, 33%). Hydrogenation (0.85 g, 2.94 mmol) in MeOH (150 mL) in Pd (5% on C, 0.09 g) at room temperature for 16 h gave an aniline derivative (0.76 g, 100%).

Part C: Standard co-coupling of Part B product with pyrazole acid anhydride under reflux for 1.5 hours. in Et ₃ N (1 mL) followed by

135 routine work-up and purification yields the copolymerized amide pyrazo-benzonitrile derivative (255 mg, 55%) which is subjected to Pinner's amidine reaction sequence to give the title compound, which is colorless crystals (148 mg, 70%). 1 H NMR (CD ₃ OD) δ: 7.93 (m.p., 2H), 7.907.87 (m. 1H), 7.80 (td, J = 7.4 Hz, J = 1.2 Hz , 2H), 7.70 (t, J = 7.8 Hz, 1H), 7.57 (d, J = 7.4 Hz, 2H), 7.60-7.54 (m, 2H), 6 , 93 (d, J = 1.9 Hz, 1H), 2.38 (s, 3H); ¹³ C NMR (CD ₃ OD) δ: 167.92, 159.84, 151.36, 142.27, 139.28, 137.30, 131.43, 131.07, 130.51, 128.33, 126.99, 125.48, 122.48, 110.77, 13.29; ESMS: m / z 386.3 (M + H, 100); DSGMS: Calcd. For C21H20N7O1 386.1729, found 386.1738.

Example 112

1- (3-Amidinophenyl) -3-methyl-5 - ([5- (2'-methylsulfonylphenyl) pyrid-2-yl] aminocarbonyl) pyrazole trifluoroacetate

Part A: Preparation of 2- (tert-Butoxycarbonyl) amino-5-bromopyridine and 2-trans-bis -refbutoxycarbonyl) amino-5-bromopyridine in a solution of 2-amino-5-bromopyridine (5.0 g, 29 mmol) in THF (75 mL). Sodium hydride (1.27 g, 60%, 32 mmol) was added at 0 ° C. The ice bath is removed and the reaction mixture is stirred for 25 min. at room temperature. Di-t-butyl dicarbonate (6.94 g, 32 mmol) is added and the reaction mixture is refluxed for 15 hours. After cooling, the reaction mixture is carefully quenched with water and extracted with EtOAc. The combined organic layers were washed with saturated NH ₄ Cl and saturated aqueous NaHCO _3, dried over Na ₂ SO _4l filtered and evaporated. The crude mixture was chromatographed on silica gel (5-7.5% EtOAc / hexanes followed by 100% CHCl ₃ ) to give mono-blocked (2.85 g, 36%) and bis-blocked (1.87, 17%). products. ¹ H NMR (mono-, CDCl 3) δ: 8.32 (d, 1H, J = 2.2 Hz), 8.13 (ds, 1H), 7.91 (d, 1H, J = 8, 8 Hz), 7.75 (dd, 1H, J = 8.8, J '= 2.2 Hz), 1.54 (s, 9H); ¹ H NMR (bis-, CDCl 3) δ: 8.53 (d, 1H, J = 2.5 Hz), 7.84 (dd, 1H, J = 8.5, J '= 2.5 Hz), 7.18 (d, 1H, J = 8.4 Hz), 1.45 (s, 18H).

136

Part B: Preparation of 2-rBis (freN-butoxycarbonyl) amino-1- (2'-methylthiophenyl) pyridine

2- [Bis (tert-butoxycarbonyl) amino] -5-bromopyridine (1.87 g, 5.0 mmol) was dissolved in benzene (120 mL). 2-Methylthiophenylboronic acid (1.95 g, 11.5 mmol), aqueous sodium carbonate (12 mL, 2.0 M, 24 mmol), tetrabutylammonium bromide (80 mg, 0.25 mmol) and bis (triphenylphosphine) are added. (ll) chloride (175 mg, 0.25 mmol) was evacuated, the mixture was purged with argon and refluxed for 16 hours. The cooled mixture was diluted with EtOAc and water. The layers were separated and the organic layer was washed with brine, dried over Na2S _4, filtered and evaporated. The crude product is chromatographed on silica gel (1020% EtOAc / hexanes) to give a viscous oil (1.82 g, 87.1%). ¹ H NMR (CDCl 3) δ: 8.51 (d, 1H, J = 2.2 Hz), 7.83 (dd, 1H, J = 8.1, J '= 2.2 Hz), 7.30 (m, 5H), 2.35 (s, 3H), 1.47 (s, 18H),

Part C: Preparation of 2-rBis (tert -butoxycarbonylamino) -5- (2'-methylsulfonylphenyl) pyridine

2- [Bis (tert-butoxycarbonyl) amino] -5- (2'-methylthiophenyl) pyridine (1.69 g,

4.1 mmol) was dissolved in MeOH (20 mL). In a separate beaker, prepare a solution of oxone (10 g) by diluting with 49 ml of water. Gets a part of this solution (14.5 mL, 4.8 mmol), and determined its pH 4 Na3PO ₄ saturated solution (4.0 mL). The mixture was poured into the reaction and stirred for 22 hours. at room temperature. The resulting mixture was diluted with water, extracted with CHCl 3, dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was chromatographed on silica gel (40-75% EtOAc / hexanes) to give the broth (1.19 g, 65%). ¹ H NMR (CDCl 3) δ: 8.48 (d, 1H, J = 1.8 Hz), 8.26 (dd, 1H, J = 8.1, J '= 1.5 Hz), 7.95 (dd, 1H, J = 8.1, J '= 2.2 Hz), 7.71 (td, 1H, J = 7.4, J' = 1.5 Hz), 7.64 (td, J = 7.7, J '= 1.4 Hz), 7.40 (dd, 1H, J = 7.3, J' = 1.4 Hz), 7.36 (d, 1H, J = 8, 8 Hz), 2.68 (s, 3H), 1.48 (s, 18H).

Part D: Preparation of 2-Amino-5- (2'-methylsulfonylphenyl) pyridine hydrochloride

137

2- [Bis (fref -butoxycarbonyl) amino] -5- (2'-methylsulfonylphenyl) pyridine (1.18 g, 2.6 mmol) and 2- (freFbutoxycarbonyl) amino-5- (2'-methylsulfonylphenyl) pyridine (1.62 g, 4.6 mmol) were suspended in HCl / dioxane (30 mL, 4.0 M) and stirred for 23 h. at room temperature. The resulting mixture was diluted with Et ₂ O and filtered to give a tan solid (2.27 g, 100%). ¹ H NMR (DMSO-d ₆ ) δ: 8.09 (m, 3H), 7.98 (d, 1H, J = 1.8 Hz), 7.90 (dd, 1H, J = 9.1, J '= 2.2 Hz), 7.75 (m, 2H), 7.45 (dd, 1H, J = 7.3, J' = 1.1 Hz), 6.98 (d, 1H, J =

9.1 Hz), 3.04 (s, 3H).

Part E: Preparation of 1- (3-cyanophenyl) -3-methyl-5- (f- (2'-methylsulfonylphenyl) pyrid-2-ylaminocarbonylpyrazole from 1- (3-cyanophenyl) -3-methylpyrazole-5-carboxylic acid (300 mg, 1.3 mmol) of CH ₂ Cl ₂ (5 mL) was added oxalyl chloride (175 μΙ, 2.0 mmol) and DMF (2 drops) and stirred under argon for 160 min. The resulting solution was evaporated and redissolved in CH ₂ Cl ₂ (5 mL) Add 4-dimethylaminopyridine (484 mg, 4.0 mmol) and 2-amino-5- (2'-methylsulfonylphenyl) pyridine hydrochloride (376 mg, 1.3 mmol) and stir at room temperature under argon for several days. The reaction mixture was evaporated and chromatographed on silica gel (50-100% EtOAc / hexanes followed by 1% MeOH / EtOAc) to give the desired product (300 mg, 50%). ¹ H NMR (CDCl ₃ ) δ: 8.54 ( s, 1H), 8.39 (d, 1H, J =)

2.2 Hz), 8.25 (d, 2H, J = 8.4 Hz), 7.82 (m, 2H), 7.66 (m, 5H), 7.37 (dd, 1H, J = 7, 7, J '= 1.5 Hz), 6.76 (s, 1H), 2.75 (s, 3H), 2.41 (s, 3H).

Part F: Preparation of 1- (3-Amidinophenyl) -3-methyl-5 - ([5- (2 ^, methylsulfonylphenyl) pyrid-2-ylaminocarbonyl) pyrazole trifluoroacetate

1- (3-Cyanophenyl) -3-methyl-5 - ([5- (2'-methylsulfonylphenyl) pyrid-2-yl] -aminocarbonyl) pyrazole (300 mg, 0.66 mmol) was dissolved in dry CHCL (15 mL). and dry MeOH (5 mL) and cooled to 0 ° C. to this solution for 90 min. gaseous HCl was bubbled through the addition of H ₂ SO ₄ (45 mL) to NaCl (200 g). The gas generator is removed, the reaction vessel is sealed and stored in a refrigerator (4 ° C) overnight. The reaction mixture was evaporated and redissolved in dry MeOH (10 mL). Ammonium carbonate (316 mg,

3.3 mmol), the reaction mixture was stirred at room temperature for 20 hours. and is suppressed. The crude product was purified by preparative chromatography on a C-18 reverse phase column (10-70% MeCN / H2O / 0.05% TFA) to give a white powder (161 mg, 42%). ¹ H NMR (DMSO-d ₆ ) δ: 11.21 (s, 1H), 9.38 (s, 2H), 8.96 (s, 2H), 8.36 (s, 1H), 8.07 (d, 1H, J = 7.3 Hz), 7.99 (d, 1H, J = 8.5 Hz), 7.92 (s, 1H), 7.73 (m, 6H), 7.42 (d, 1H, J = 7.7 Hz), 7.16 (s, 1H), 2.92 (s, 3H), 2.29 (s, 3H). DSGMS: Calcd. For C24H23NSO3S: 475.1552, found 475.1554.

Examples 113, 114, and 115

1- (3-amidinophenyl) -3-methyl-5 - ([5- (2'-methylsulfonylphenyl) pyrimidin-2-yl] aminocarbonyl) pyrazole trifluoroacetate (Example 113), 1- (3-cyanophenyl) 3-methyl- 5 '([5- (2'-Methylsulfonylphenyl) pyrimidin-2-yl] aminocarbonyl) pyrazole (Example 114) and 1- (3-aminocarbonylphenyl) -3-methyl-5 - ([5- (2'-methylsulfonylphenyl) pyrimidine) -2-yl] aminocarbonyl) pyrazole (Example 115)

Part A: Preparation of 2-methylthiophenylboronic acid

2-Bromothioanisole (29.0 g, 143 mmol) was dissolved in dry THF (400 mL) and cooled to -75 ° C. Within 50 min, n-BuLi (62.0 mL, 2.5 M in hexane, 155 mmol) was added. After stirring for 25 minutes, within 35 minutes. triisopropylborate (46 mL, 199 mmol) was added. The cooling bath is removed and the reaction mixture is stirred at room temperature for 16 hours. The resulting solution was cooled in an ice bath and 6M HCl (100 mL) was added. The mixture was stirred at room temperature for 5 hours. and is concentrated to about half its original volume. The concentrated solution is partitioned between Et ₂ O and water. The organic layer was extracted with 2M NaOH, which was then acidified with 6M HCl and re-extracted several times with Et ₂ O. These Et ₂ O extracts were dried over Na ₂ SO ₄ , filtered and evaporated to give a tan solid (20.4 g, 85%). ¹ H NMR (CDCl ₃ ) δ: 8.01 (dd, 1H, J = 7.3, J '= 1.4 Hz), 7.53 (dd, 1H, J = 7.7, J' = 1 , 1 Hz), 7.43 (td, 1H, J = 7.3, J '= 1.8 Hz), 7.34 (td, 1H, J = 7.3, J' = 1.5 Hz) , 6.22 (s, 2H), 2.50 (s, 3H).

139

Part B; Preparation of 2- t -Bis (tert-butoxycarbonyl) amino-5-bromopyrimidine

2-Amino-5-bromopyrimidine (10.0 g, 57 mmol) in dry THF (500 mL) at 0 ° C was treated twice with sodium hydride (5.06 g, 60%, 127 mmol). After stirring for 30 min, di-t-butyl dicarbonate (27.6 g, 126 mmol) was added. The resulting mixture was refluxed for 17 hours, carefully quenched with water and concentrated. The concentrated mixture was diluted with EtOAc and extracted with water. The combined aqueous layers were extracted with EtOAc. All organic layers were combined, dried over Na ₂ SO ₄ , filtered and evaporated. The crude product is chromatographed on silica gel (10-15% EtOAc / hexanes) to give the desired product (15.48 g, 72%). ¹ H NMR (CDCl 3) δ: 8.78 (s, 2H), 1.47 (s, 18H).

Part C: Preparation of 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), tetrabutylammonium bromide (86 mg, 0.26 mmol) and bis (triphenylphosphine) are added. (ll) chloride (190 mg, 0.27 mmol) is suctioned off, the mixture is purged with argon and refluxed for 17 hours. The cooled mixture was diluted with EtOAc and water. The layers were separated, the organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product is chromatographed on silica gel (50% EtOAc / hexanes), evaporated, and chromatographed a second time on silica gel (30-50% EtOAc / hexanes); The title product is obtained (2.13 g, 96%). ¹ H NMR (CDCl 3) δ: 8.81 (s, 2H), 7.41 (m, 2H), 7.25 (m, 2H), 2.39 (s, 3H), 1.49 (s, 18H).

Part D: Preparation of 2-tis-bis (tert-butoxycarbonyl) amino-5- (2'-methylsulfonylphenyl) pyrimidine

140

2- [Bis (tert-Butoxycarbonyl) amino] -5- (2'-methylthiophenyl) pyrimidine (2.13 g, 5.1 mmol) was dissolved in MeOH (20 mL) and cooled to 0 ° C. In a separate beaker, prepare a solution of oxone (5.49 g) by diluting with 27 ml of water. Gets a part of this solution (17 mL, 5.6 mmol) and the pH determined in 4.2 Na3PO ₄ saturated solution (4.7 mL). This mixture was poured into the reaction and stirred for 23 hours. at room temperature. The resulting mixture was diluted with water and extracted with CHCl ₃ . The organic layers were combined, washed with water and brine, dried over Na ₂ SO ₄ , filtered and evaporated. The crude product is chromatographed on silica gel (50-100%

EtOAc / hexanes) to give the sulfone (1.28 g, 56%). ¹ H NMR (CDCl ₃ ) δ: 8.81 (s, 2H), 8.28 (dd, 1H, J = 7.6, J 1 = 1.4 Hz), 7.72 (m, 2H), 7.39 (dd, 1H, J = 7.3, J '= 1.4 Hz), 2.76 (s, 3H), 1.50 (s, 18H).

Part E: Preparation of 2-Amino-5- (2'-methylsulfonylphenyl) -irimidine hydrochloride

2- [Bis (tert-butoxycarbonyl) amino] -5- (2'-methylsulfonylphenyl) pyrimidine (1.28 g, 2.8 mmol) was suspended in HCl / dioxane (10 mL, 4.0 M) and stirred for 20 h. at room temperature. The resulting mixture was triturated with Et ₂ O and filtered to give a white solid (772 mg, 95%). ¹ H NMR (CDCl ₃ + a few drops of MeOD) δ: 8.53 (s, 2H), 8.22 (dd, 1H, J = 7.7, J '= 1.8 Hz), 7.77 ( m, 2H), 7.40 (dd, 1H, J = 7.4, J '= 1.5 Hz), 2.94 (s, 3H).

Part F: Preparation of 1- (3-Cyanophenyl) -3-methyl-5- (1'5% 2'-methylsulfonylphenyl) pyrimidin-2-ylaminocarbonylpyrazole

To 1- (3-cyanophenyl) -3-methylpyrazole-5-carboxylic acid (300 mg, 1.3 mmol) in CH ₂ Cl ₂ (5 mL) was added oxalyl chloride (175 μΙ, 2.0 mmol) and DMF (2 drops). ) and stirred under argon for 120 min. The resulting solution was evaporated and redissolved in CH ₂ Cl ₂ (5 mL). 4-Dimethylaminopyridine (480 mg, 3.9 mmol) and 2-amino-5- (2'-methylsulfonylphenyl) pyrimidine hydrochloride (377 mg, 1.3 mmol) were added and stirred at room temperature under argon for 5 days. The crude reaction mixture is chromatographed on silica gel (2-5% MeOH / CHCl ₃ ) to give the crude product which is dissolved in CHCl ₃ and extracted with 1M HCl. The organic layer was dried over Na ₂ SO ₄ ,

141 was filtered and the pure product was obtained (486 mg, 80%). ¹ H NMR (CDCl ₃ ) δ: 8.69 (s, 2H), 8.64 (s, 1H), 8.25 (dd, 1H, J = 7.7, J '= 1.5 Hz), 7.84 (m, 1H), 7.73 (m, 4H), 7.55 (t, 1H, J = 7.6 Hz), 7.35 (dd, 1H, J = 7.3, J ' = 1.4 Hz), 6.79 (s, 1H), 2.80 (s, 3H), 2.42 (s, 3H).

Part G; 1- (3-Amidinophenyl) -3-methyl-5- (f5- (2'-methylsulfonylphenyl) pyrimid-2-ylaminocarbonylpyrazole trifluoroacetate and 1- (3-aminocarbonylphenyl) -3-methyl-5- (f5 (2'- methylsulfonylphenyl) pyrimid-2-ylaminocarbonyl) pyrazole

1- (3-Cyanophenyl) -3-methyl-5 - ([5- (2'-methylsulfonylphenyl) pyrimidin-2-yl] -aminocarbonyl] pyrazole (471 mg, 1.0 mmol) was dissolved in dry CHCl ₃ (15 mL) and in dry MeOH (5 mL) and the solution cooled to 0 ^{° c} c to the solution for 30 minutes. bubbled gaseous HCl was prepared by adding H2SO4 (45 ml) and NaCl (480 g). the gas generator is removed, the reaction vessel was sealed and stored in a refrigerator (4 ° C) for 18 h The reaction mixture was evaporated and redissolved in dry MeOH (15 mL), ammonium carbonate (487 mg, 5.1 mmol) was added and the reaction mixture was stirred at room temperature for 20 h and evaporated. MeCN in water, TFA, DMS and MeOH The solvent was purified by preparative chromatography using a ΟΙ8 reverse phase column (10-70% MeCN / H2O / 0.05% TFA) to give the desired amidine as the TFA salt (0, 31 g, 51%) ¹ H NMR (DMSO) δ; 11.38 (s, 1H), 9.39 (s, 2H), 9.00 (s, 2H), 8.67 (s) 2H), 8.10 (dd, 1H, J = 8.1, J ^! = 1.5 Hz), 7.92 (m, 1H), 7.74 (m, 5H), 7.49 (dd, 1H, J = 7.3, J '= 1.1 Hz), 7, 06 (s, 1H), 3.03 (s, 3H), 2.29 (s, 3H). DSGMS; calculated for C23H ₂₂ N ₇ O ₃ S: 476.1505, found 476.1529. The second product was isolated from preparative HPLC and mixed with the above insoluble solid for purification over silica gel (10% MeOH / CHCl ₃ ). This crude amide is suspended in toluene and filtered. The white solid thus obtained is the desired amide (52 mg, 11%), ¹ H NMR (DMSO) δ: 11.33 (s, 1H), 8.64 (s, 2H), 8.08 (m, 2H). , 7.92 (s, 1H), 7.77 (m, 3H), 7.48 (m, 4H), 6.95 (s, 1H), 3.01 (s, 3H), 2.27 ( s, 3H). DSGMS; calcd. for C ₂₃ H ₂ iN ₆ O ₄ S: 477.1345, found 477.1350.

142

Example 116

1- (3- (N-Aminoamidino) phenyl) -3-methyl-5 - [(2'-tert-butylaminosulfonyl · [1,5] biphen-4-yl) aminocarbonyl] pyrazole trifluoroacetic acid salt

1- (3-Cyanophenyl) -3-methyl-5 - [(2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole (150 mg) is dissolved in anhydrous CH ₃ OH and the solution is cooled to 0 ° C. Within 15 minutes bubbles allowed to dry HCl. The resulting solution was allowed to warm to room temperature and allowed to stand for 18 hours. The mixture is concentrated in vacuo. MSGMS (M + H) &lt; ⁺ &gt; = 489 C25H23N5O4Si. 50 mg of this material are dissolved in 10 ml of anhydrous CH3OH. Hydrazine (0.10 mL) was added and the resulting mixture was stirred at room temperature for 4 h. This mixture was concentrated in vacuo. Purify by HPLC to give 2.5 mg (98% purity by HPLC). DSGMS: C 28 H 31 N 7 O 3 Si (M + H) ⁺ calcd 490.162947, found 490.164868. ¹ H NMR (CD 3 OD) δ: 1.02 (s, 9H), 2.38 (s, 3H), 6.94 (s, 1H), 7.305 (d, 1H, J = 7.69 Hz), δ , 53 (t, 1H, J = 7.69Hz), 6.64-7.85 (m, 7H), 8.085 (d, 1H, J = 8.06Hz).

Example 117

1- (3- (N-Aminoamidino) phenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4yl) aminocarbonyl] pyrazole trifluoroacetic acid salt

3- [4- (2-N-Butylaminosulfonyl) phenyl) aminophenyl-3-methyl-5-carboxypyrazole) cyanophenyl (1.0 g) was dissolved in anhydrous CH ₃ OH and the solution cooled to 0 ° C. Through it.-15 min. bubbles allowed to dry HCl. The resulting solution was allowed to warm to room temperature and allowed to stand for 18 hours. The mixture is concentrated in vacuo. MSGMS (M + H) &lt; ⁺ &gt; = 489 C25H23N5O4Si. 300 mg of this material are dissolved in 10 ml of anhydrous CH3OH. Hydrazine (0.023 mL) was added and the resulting mixture was stirred at room temperature for 4 h. This mixture is concentrated in vacuo. Purification by HPLC gave 23 mg (98% purity by HPLC). DSGMS: C 24 H 23 N 7 O 3 Si (M + H) ⁺ calcd 546.228735, found 546.228088. Ή NMR (CD3OD) δ: 2.38

143 (s, 3H), 6.94 (s, 1H), 7.31 (d, 1H, J = 7.33 Hz), 7.495 (d, 2H, J = 7.33 Hz), 7.59- 7.86 (m, 7H), 8.08 (d, 1H, J = 7.69 Hz).

Example 118

1- (3- (N-Methyl-N-hydroxyamidino) phenyl) -3-methyl-5 - [(2'-t-butylaminosulfonyl [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole trifluoroacetic acid salt

3- [4- (2- (i-Butylaminosulfonyl) phenyl) aminophenyl-3-methyl-5-carboxypyrazole) cyanophenyl (300 mg) was dissolved / suspended in 25 mL of CH ₃ OH. Triethylamine (0.098 mL) was added along with N, N-methylhydroxylamine hydrochloride (0.048 g). The reaction mixture was stirred at 50 ° C for 15 h. The mixture is concentrated in vacuo. Purification by chromatography on silica gel using 10% CH ₃ OH / CH ₂ Cl ₂ as the eluent gave 360 mg of product. DSGMS: C 24 H 34 N 2 O 4 S, (M + H) ⁺ calcd 561.228401, found 561.22987. ¹ H NMR (CD ₃ OD) δ: 1.02 (s, 9H), 2.38 (s, 3H), 3.40 (s, 3H), 3.62 (s, 1H), 6.96 ( s, 1H), 7.305 (d, 1H, J = 7.69 Hz), 7.42 (d, 2H, J = 8.79 Hz), 3.53 (t, 1H, J = 8.06 Hz). , 7.60 (t, 1H, J = 7.32 Hz), 7.65 (d, 2H, J = 8.06 Hz), 7.70-7.78 (m, 4H), 8.085 (d, 1H, J = 7.69 Hz).

Example 119

1- (3- (N-Methylamidino) phenyl) -3-methyl-5 - [(2'-tert-butylaminosulfonyl- [1,1 '] biphen-4-yl) aminocarbonyl] pyrazole trifluoroacetic acid salt

1- (3- (N-Methyl-N-hydroxyamidino) phenyl) -3-methyl-5 - [(2'-n-butylaminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole (300 mg) dissolved in acetic acid (25 ml). Trifluoroacetic anhydride (0.106 mL) was added and the reaction mixture was stirred at room temperature for 35 min. Add 10% Pd / C (300 mg) and the reaction vessel placed in a Parr shaker (344.7 kPa H ₂₎ 17 h. The reaction mixture was filtered through celite and concentrated in vacuo. Purification by HPLC gives 33 mg (97% purity by HPLC). DSGMS: C ₂₉ H ₃₂ N ₆ O ₃ Si (M + H) ⁴ calcd 545.233486, found 545.233079. ¹ H NMR (CD ₃ OD) δ: 1.02 (s, 9H), 2.38 (s, 3H), 3.09 (s, 3H), 6.94

144 (s, 1H), 7.30 (d, 1H, J = 7.33 Hz), 7.425 (d, 2H, J = 8.42 Hz), 7.50 (t, 1H, J = 7.69 Hz), 7.57-7.64 (m, 3H), 7.685 (d, 1H, J = 7.32 Hz), 7.73-7.77 (m, 2H), 7.87 (s, 1 H), 8.085 (d, 1H, J = 7.70 Hz).

Example 120

1- (3- (N-Methylamidino) phenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole trifluoroacetic acid salt

1- (3 '- (N-Methyl-N-hydroxyamidino) phenyl) -3-methyl-5 - [(2'-n-butylaminosulfonyl- [1,1'] - biphen-4-yl) aminocarbonyl] Pyrazole (347 mg) was dissolved in trifluoroacetic acid (10 mL) and stirred at 50 ° C for 1 h. The mixture was concentrated in vacuo (346 mg). MSGMS C25H24N6O4S1 (M + H) ⁺ '= 505. This material was dissolved in acetic acid (100 mL). Trifluoroacetic anhydride (0.116 mL) was added and the reaction mixture was stirred at room temperature for 35 min. Add 10% Pd / C (300 mg) and the reaction vessel placed in a Parr shaker (344.7 kPa H ₂₎ for 18 h. The reaction mixture was filtered through celite and concentrated in vacuo. Purification by HPLC gives 80 mg (98% purity by HPLC). DSGMS: C 25 H 24 N 6 O 3 S 1 (M + H) ⁺ calcd 489.172971, found 489.172971. ¹ H NMR (CD 3 OD) δ: 2.38 (s, 3H), 3.08 (s, 3H), 6.94 (s, 1H), 7.31 (d, 1H, J = 7.33 Hz). , 7.395 (d, 2H, J = 8.79 Hz), 7.51 (t, 1H, J = 7.32 Hz), 7.57-7.68 (m, 6H), 8.085 (d, 1H , J = 7.47 Hz).

Example 121

1- (3-Amidinophenyl) -5 - [(2'-aminosulfonylphenyl) pyridin-2-yl] aminocarbonyl] tetrazole trifluoroacetic acid salt

This compound (colorless crystals) is prepared according to the standard Pinner amidine reaction sequence and purification procedures described above. ¹ H NMR (DMSO) δ: 8.40-6.95 (m, 11H), 9.25 (s, 1H), 9.50 (s, 1H), 11.55 (s, 1H). MS (ESI) 464.17 (M + H) &lt; + &gt;.

145

Example 122

1- (3-Aminocarbonylphenyl) -5 - {[5- (2'-Aminosulfonylphenyl) pyridin-2-yl] aminocarbonyl} tetrazole

This compound (colorless crystals) is prepared according to the standard Pinner amidine reaction sequence and purification procedures described above. 1 H NMR (DMSO) δ: 8.40-7.39 (m, 11H), 11.55 (s, 1H). MS (ESI) 465.11 (M + H) &lt; + &gt;.

Example 123

1- (3-Amidinophenyl) -5 - {[5- (2'-trifluoromethylphen-1-yl) pyridin-2-yl] aminocarbonyl} tetrazole trifluoroacetic acid salt

This compound (colorless crystals) is prepared according to the standard Pinner amidine reaction sequence and purification procedures described above. 1 H NMR (DMSO) δ: 8.40-7.49 (m, 11H), 9.5 (s, 1H), 11.60 (s, 1H). MS (ESI) 453.20 (M + H) &lt; + &gt;.

Example 124

1- (3-Amidinophenyl) -5 - [(4'-bromophen-1-yl) aminocarbonyl] tetrazole trifluoroacetic acid salt

This compound (colorless crystals) is prepared according to the standard Pinner amidine reaction sequence and purification procedures described above. 1 H NMR (DMSO) δ: 8.20-7.55 (m, 11H), 9.20 (s, 1H), 9.5 (s, 1H), 11.55 (s, 1H). MS (ESI) 386.03 (M + H) &lt; + &gt;.

Example 125

- (3-Aminocarbonylphenyl) -5 - {[5- (2'-trifluoromethylphen-1-yl) pyridin-2-yl] aminocarbonyl] tetrazole

146

This compound (colorless crystals) is prepared according to the standard Pinner amidine reaction sequence and purification procedures described above. Δ NMR (DMSO) δ: 8.40-7.50 (m, 11H), 11.60 (s, 1H). MS (ESI) 454.12 (M + H) &lt; + &gt;.

Example 126

5- (3-Amidinophenyl) '1 - [(2'-trifluoromethyl- [1,1'] - biphen-4-yl) methyl] tetrazole trifluoroacetic acid salt

Part A: Preparation of N- (4-bromophenylmethyl) -3-cyanobenzamide

4-Bromobenzylamine HCl (3.36 g, 15.1 mmol) was dissolved in CH ₂ Cl ₂ (1.00 mL). Triethylamine (8.4 mL, 60 mmol) was added followed by 3-cyanobenzyl chloride (2.50 g, 15.1 mmol). The mixture was stirred at room temperature under N _{2 for} 15 min. It is diluted with CH ₂ Cl ₂ and washed with water and saturated NaCl solution. The CH ₂ Cl ₂ solution is dried over MgSO ₄ and concentrated to give 3.5 g of the desired product. 1 H NMR (CDCl ₃ ) δ: 4.6 (d, 2H), 7.0 (s, 1H), 7.20-8.20 (m, 8H); MS (DCI-NH ₃ ) 315 (M + H) ⁺ .

Part B: Preparation of 1- (4-Bromophenylmethyl) -5- (3-cyanophenyl) tetrazole

Part A material (3.2 g, 10 mmol) was dissolved in CH ₃ CN (100 mL) and NaN ₃ (0.7 g, 10 mmol) was added. The mixture was cooled in an ice bath and trifluoro anhydride (1.7 mL, 10 mmol) was added. The ice bath is then removed and stirred at room temperature under N ₂ overnight. The reaction mixture was diluted with EtOAc and washed with water and saturated NaCl solution. It is dried over MgSO ₄ , concentrated and chromatographed over silica gel (CH ₂ Cl ₂ ); 2.0 g of the expected product are obtained. 1 H NMR (CDCl ₃ ) δ: 5.60 (s, 2H), 7.05-7.90 (m, 8H); MS (NH 3 -Cl) 342 (M + H) ⁺ .

Part C: Administration of 5- (3-Cyanophenyl) -1-r (2'-trifluoromethyl-1,1,1'-biphen-4-yl) methyltetrazole

Part B material (0.36 g, 1.06 mmol) and 2-trifluoromethylphenylboronic acid (0.24 g, 1.26 mmol) were dissolved in benzene (30 mL). The mixture is stirred

147 at room temperature with bubbling N _{2 for} 30 min. K2CO3 (2 mL 2M, 4 mmol), tetrabutylammonium bromide (50 mg, 0.15 mmol) and tetrakis (triphenylphosphine) palladium (0) (200 mg, 0.17 mmol) were then added. The mixture is refluxed under N _{2 for} 4 hours. The solvent is evaporated. The residue was dissolved in CH ₂ Cl ₂ and washed with water and saturated NaCl solution. The solution was dried over MgSO ₄ , concentrated and the residue chromatographed on silica gel (eluting with CH ₂ Cl ₂ ); 0.41 g of the expected product is obtained. 1 H NMR (CDCl ₃ ) δ: 5.70 (s, 2H), 7.10-7.85 (m, 12H); MS (NH 3 -Cl) 406.1 (M + H) ⁺ .

Part D: 5- (3-amidinophenyl) -1-r (2'-trifluoromethyl-f1,1 ¹ biphen-4-yl) metintetrazolo trifluoroacetic acid salt The

Part C is dissolved in 10 ml of anhydrous CHCl ₃ and 10 ml of anhydrous CH ₃ OH. The mixture is cooled in an ice bath and bubbled with HCl gas until the solution is saturated. The reaction mixture was sealed and stored at 0 ° C for 12 hours. The solvent was evaporated and the solid dried in vacuo. The resulting solid is re-dissolved in 20 m! anhydrous CH ₃ OH and ammonium acetate (0.77 g, 10 equiv.) was added. The mixture was sealed and stirred at room temperature for 12 hours. The solvent is evaporated. The solid is dissolved in CH ₃ CN / H ₂ O / TFA and purified by reverse phase HPLC to give 150.0 mg of the desired product. 1 H NMR (DMSO-d ₆ ) δ: 5.95 (s, 1H), 7.19-8.20 (m, 12H), 9.35 (s, 1H), 9.50 (s, 1H) ; MS (ESI) 423.17 (M + H) &lt; + &gt;.

Example 127

1 - [(3-Amidinophenyl) methyl] -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole trifluoroacetic acid salt

Part A: Preparation of ethyl 1- [3- (cyanophenyl) methyl] -3-methylpyrazole-5-carboxylate

To a solution of ethyl 3-methylpyrazole-5-carboxylate (2.0 g, 13.0 mmol) in 50 mL of dimethylformamide was added 3-cyanobenzyl bromide (2.54 g, 13.0 mmol) and potassium iodide (6.46 g, 38 mL). , 9 mmol). The resulting mixture was stirred at 65 ° C for 16 h. The reaction mixture was cooled to room temperature

148 temperature, diluted with ethyl acetate, washed with saturated aqueous sodium thiosulfate (2 times) and brine (2 times), dried (MgSO ₄ and concentrated in vacuo. The residue was purified by flash chromatography (eluting with 1: 1 hexanes / ethyl acetate) to give 2, 5 g (71%) of the title compound MS (ESI) 270 (M + H) ⁺ .

Part B: Preparation of 1- [3- (cyanophenyl) methyl] -3-methylpyrazole-5-carboxylate from ethyl 1 - [(3-cyanophenyl) methyl] -3-methylpyrazole-5-carboxylate (2.37 g, 8.80) sodium hydroxide (0.70 g, 17.6 mmol) was added and the resulting solution was stirred at room temperature for 16 h. The mixture was acidified with 10% aqueous HCl, diluted with ethyl acetate, washed with brine (2x), dried (MgSO ₄ ), and concentrated in vacuo to give the title compound (1.9 g, 90%) which was used without further purification. MS (ESI) 242 (M + H) &lt; ^{+ &gt};.

Part C: Preparation of 1 - [(3-cyanophenyl) methyl] -3-methyl-5-r (2'-tert-butylaminosulfonyl-1S-biphen-4-yl) aminocarbonyl] pyrazole by yielding 1 - [(3-cyanophenyl) methyl] - To a solution of 3-methylpyrazole-5-carboxylate (1.80 g, 7.46 mmol) in 20 mL of dimethylformamide was added (2'-freebutylaminosulfonyl [1,1 '] - biphen-4-yl) amine (2.50 g, 8.21 mmol), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent, 4.95 g, 11.19 mmol) and triethylamine (1.13 g, 11.19 mmol). The resulting mixture was stirred at 60 ° C for 16 h. The reaction mixture was allowed to cool to room temperature, then diluted with ethyl acetate, washed with brine (4 times), dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by flash chromatography (eluting with 1: 1 hexanes: ethyl acetate) to give 1.9 g (49%) of the title compound. MS (ESI) 528 (M + H) &lt; + &gt;.

Part D: Preparation of the trifluoroacetic acid salt of 1- (3-amidinophenyl) methine-3-methyl-5 - [(2'-aminosulfonyl-1,1'-biphen-4-yl) aminocarbonyl] pyrazole

149

J 1 - [(3-cyanophenyl) methyl] -3-methyl-5 - [(2'-tert-butylaminosulfonyl- [1T] -biphen4-yl) aminocarbonyl] pyrazole (1.77 g, 3.35 mmol ), anhydrous methanol (1.36 mL, 33.5 mmol) was added to 40 mL of methyl acetate. Cool the solution to 0 ° C. Thereafter, this solution was stirred for 15 min. bubbles bubbling dry HCI gas. The solution is capped and stirred overnight at room temperature. Volatiles are evaporated in vacuo. The residue is dried under deep vacuum for 1 hour. The residue is then dissolved in 100 ml of anhydrous methanol. Ammonium carbonate (1.93 g, 20.21 mmol) was added and the reaction mixture was stirred at room temperature overnight. The volatiles are evaporated in vacuo and the residue is purified by preparative HPLC (C18 reverse phase column, eluting with H ₂ O / CH ₃ CN with 0.5% TFA gradient) to give the title compound as a white powder. MS (ESI) 489 (M + H) &lt; ^{+ &gt};

Example 128

1 - [(4-Amidinophenyl) methyl] -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole trifluoroacetic acid salt

Part A: Preparation of ethyl 1-F (4-cyanophenyl) methine-3-methylpyrazole-5-carboxylate

Ethyl 3-methylpyrazole-5-carboxylate (2.50 g, 16.21 mmol) was treated with 4-cyanobenzibromide (3.18 g, 16.21 mmol) and potassium iodide (8.07 g, 48.65 mmol) to give 3, 1 g (70%) of the desired product. MS (ESI) 270 (M + H) &lt; ^{+ &gt};.

Part B: Preparation of 5-Carboxy-1-f (4-cyanophenyl) methine-3-methylpyrazole

Ethyl 1 - [(4-cyanophenyl) methyl] -3-methylpyrazole-5-carboxylate (2.96 g, 10.99 mmol) was converted to 2.4 g (91%) of the title compound according to the procedure previously described; MS (ESI) 242 (M + H) &lt; ^{+ &gt};.

Part C: Preparation of 1- [f (4-cyanophenyl) methine-3-methyl-5-i (2'-tert-butylaminosulfonyl-1,1 '] biphen-4-yl) aminocarboninpyrazole

5-Carboxy-1 - [(4-cyanophenyl) methyl] -3-methylpyrazole (2.29 g, 9.49 mmol) is converted to 2.0 g (40%) of the title compound according to the procedure previously described;

MS (ESI) 528 (M + H) &lt; ^{+ &gt};.

150

Part D: Preparation of trifluoroacetic acid salt of 1- [1- (4-Amidinophenyl) methyl] -3-methyl-5-F- (2'-aminosulfonyl-1,1'-biphen-4-yl) aminocarbonylpyrazole

1 - [(4-Cyanophenyl) methyl] -3-methyl-5 - [(2'-freibutylaminosulfonyl- [1,1 '] - biphen4-yl) aminocarbonyl] pyrazole (0.78 g, 1.47 mmol) converted to the desired compound according to the procedure previously described; MS (ESI) 489 (M + H) &lt; ^{+ &gt};.

Example 129

1- (3-Amidinophenyl) -2 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] imidazole trifluoroacetic acid salt

Part A: 3-Fluorobenzonitrile (4.84 g, 40 mmol) was heated with imidazoles (2.72 g, 40 mmol) in K2CO3, DMF at 100 ° C for 8 h to give a copolitated product which was white. solid. ¹ H NMR (CDCl 3) δ: 7.89 (s, 1H), 7.70 (d, J = 0.8 Hz, 1H), 7.68-7.58 (m, 3H), 7.30 ( d, J = 1.0 Hz, 1H), 7.26 (s, 1H); MSGMS: 170 (M + H) &lt; + &gt;.

Part B: The product from Part A (1.52 g, 9 mmol) was slowly treated with π-BuLi (1.6

M, 6.3 mL) in THF (60 mL) at -78 ° C for 40 min followed by slow decomposition at the same temperature with chloromethyl formate (942 mg, 10 mmol). The resulting mixture was stirred at -78 ° C for 2 hours, then warmed to room temperature. It is then poured into a mixture of water and ethyl acetate. The organic layer was separated and washed with water, brine, and dried over MgSO ₄ . Evaporation of the ethyl acetate gave a residue which was purified by column chromatography eluting with ethyl acetate: methylene chloride (1: 1) to give 2-imidazolylphenylethyl ester derivative (1.33 g, 65%) as a white solid. ¹ H NMR (CDCl 3) δ: 7.80-7.77 (m, 1H), 7.65-7.61 (m, 3H), 7.33 (s, 1H), 7.20 (s, 1H); MSGMS: 228 (M + H) &lt; + &gt;.

Part C: A stirred solution of 4 - [(o-SO ₂ fBu) -phenyl] aniline (304 mg, 1 mmol)

CH ₂ Cl ₂ (20 mL) at 0 ° C was slowly added trimethylaluminium (2M in hexane, 1 mL) and the resulting mixture was warmed to room temperature over

151 mins A solution of the product from Part B in CH 2 Cl 2 (5 mL) was added dropwise and the resulting mixture was refluxed for 2 hours. The mixture was quenched with water, diluted with ethyl acetate and filtered through celite. The organic layer was separated, washed with water, brine, and dried over MgSO ₄ . Evaporation of the ethyl acetate gave a residue which was purified by column chromatography eluting with ethyl acetate: methylene chloride (1: 1) to give the title product as a white solid (260 mg, 52%). ¹ H NMR (CDCl 3) δ: 9.41 (s, 1H), 8.15 (dd, J = 7.7 Hz, J = 1.5 Hz, 1H), 7.78 (dd, J = 7, 3 Hz, J = 1.1 Hz, 1H), 7.74-7.57 (m, 6H), 7.55 (td, J = 7.7 Hz, J = 1.1 Hz, 1H), 7 , 49 (dd, J = 8.8 Hz, J = 1.8 Hz, 2H), 7.29 (dd, J = 8.1 Hz, J = 1.5 Hz, 1H), 7.28 (d , J = 0.8 Hz, 1H), 7.22 (d, J = 0.8 Hz, 1H), 3.64 (s, 1H), 0.99 (s, 9H); MSGMS: 500.1 (M + H) ⁺ .

Part D: The desired product (120 mg, 50%) is obtained using standard Pinner amidine preparation and purification procedures; ¹ H NMR (CD 3 OD) δ: 8.08 (dd, J = 7.7 Hz, J = 1.1 Hz, 1H), 7.91-7.88 (m, 2H), 7.83 (dd, J = 8.4 Hz, J = 1.5 Hz, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7 , 58 (dd, J = 7.3 Hz, J = 1.1 Hz, 1H), 7.50 (s, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.32 (s, 1H), 7.30 (dd, J = 7.3 Hz, J = 1.1 Hz, 1H); ESMS: 461 (M + H) &lt; + &gt;.

Example 130

1- (3-Amidinophenyl) -4-methyl-2 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] imidazole

Ethyl 1- (3-cyanophenyl) -4-methylimidazolyl-2-carboxylate was prepared according to the standard copulation procedure described above. This compound was copolymerized under standard Weinreb conditions (trimethylaluminium), further subjected to Pinner's amidine reaction procedures, purified by conventional techniques to give the desired compound as colorless crystals. ¹ H NMR (CD ₃ OD) δ: 8.09 (dd, J = 8.1 Hz, J = 1.1 Hz, 1H), 7.89 (t, J = 1.5 Hz, 1H), 7.87 (d, J = 1.8 Hz, 1H), 7.81-7.78 (m, 1H), 7.72 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.57 (dd, J = 7.7 Hz, J = 1.5 Hz, 1H), 7.50 (td,

152

J = 7.7 Hz, J = 1.5 Hz, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.30 (dd, J = 7.7 Hz, J = 1, 5 Hz, 1H), 7.26 (s, 1H), 2.33 (s, 3H); ¹³ C NMR (CDCl ₃ OD) δ: 167.73, 158.04, 143.04, 141.49, 140.47, 139.62, 138.64, 137.53, 133.65, 133.45, 132.93, 132.76, 132.35, 131.25, 130.55, 129.09, 128.74, 128.63, 126.69, 120.87, 13.27; ESMS: m / z 475.19 (M + H, 100) DSGMS: Calcd. For C ₂₄ H ₂₃ N ₆ O ₃ Si 475.1552, found 475.1548.

Example 131

1- (3-Amidinophenyl) -5-chloro-4-methyl-2 - [(2'-aminosulfonyl- [1,1 '] - biphen-4'-yl) aminocarbonyl] imidazole

Chlorination of ethyl 1- (3-cyanophenyl) -4-methylimidazolyl-2-carboxylate in NCS by refluxing in carbon tetrachloride affords the 5-chlorimidazole derivative, which is then subjected to Pinner's amidine reaction procedures purified by conventional methods. to give the title compound as colorless crystals (145 mg, 34.8%). ¹ H NMR (CD 3 OD) δ: 8.07 (d, J = 7.7 Hz, 1H), 7.96 (d, J = 7.3 Hz, 1H), 7.82 (s, 1H), δ , 78 (d, J = 7.7 Hz, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 8.8 Hz, 1H), 7.49 (td, J = 7.7 Hz, J = 1.5 Hz, 1H), 7.37 (d, J = 8.4 Hz, 2H) ), 7.29 (d, J = 7.7 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 2.32 (s, 3H); ¹³ C NMR (CDC 3 OD) δ: 167.63, 157.41, 143.05, 141.47, 139.26, 138.46, 138.32, 137.59, 135.51, 134.27, 133, 63, 132.91, 131.48, 131.22, 130.84, 129.98, 128.74, 128.61, 128.43, 120.98,

12.22; ESMS: m / z 509.1 (M + H, 100). DSGMS: Calcd

C ₂₄ H ₂₂ CIN ₆ O ₃ Si 509.1163, found 509.1172.

Example 132

5- (3-Amidinophenyl) -2-methyl-4 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] imidazole

Part A: Ethyl 2-methyl-4- (3'-cyano) phenyl-5-carboxylate is prepared in 20% yield by reaction with ethyl 2-bromo- (3-cyano) benzoyl acetate and ammonium acetate in acetic acid. ¹ H NMR (CDCl ₃ ) δ: 10.03 (pl.s, 1H), 8.25 (pl.s, 1H),

153

8.17 (pi.d, 1H), 7.40 (d, 1H), 7.44 (t, 1H), 4.30 (s, 2H), 2.50 (s, 3H), 1.30 (t, 3H) md; ammonia Cl mass spectrum 272 (M + H, 100).

Part B: Coagulation of Veinreb product of Part A with 2'-tert-butylaminosulfonyl-1-aminobiphenyl and trimethylaluminium yields the desired copolymer product, which is then subjected to Pinner's amidine reaction procedures, purified by conventional techniques to give the desired compound as colorless crystals. . ¹ H NMR (CD ₃ OD) δ: 8.29 (s, 1H), 8.10 (dd, J = 7.9, Hz, J = 1.2 Hz, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.70 (s, 2H) ), 7.61 (td, J = 7.6 Hz, J = 1.5 Hz, 1H), 7.52 (td, J = 7.6 Hz, J = 1.5 Hz, 1H), 7, 42 (d, J = 6.8Hz, 2H), 7.33 (dd, J = 7.6Hz, J = 1.2Hz, 1H), 2.53 (ss, 3H); ESMS: m / z 475.1 (M + H, 100) for C 5 H 5 N 5 O 5 S.

Examples 133 and 134

1- (3-amidinophenyl) -3-methyl-5 - [(4 '- (benzimidazol-1-yl) phenyl-1-yl) aminocarbonyl] pyrazole and 1- (3-aminocarbonylphenyl) -3-methyl-5- [(4 '(Benzimidazol-1-yl) phen-1-yl) aminocarbonyl] pyrazole

Part A: Preparation of N- (4-nitrophenyl) benzimidazole

A suspension of 1.26 g of 4-bromonitrobenzene and 0.74 g of benzimidazole is prepared in 50 ml of anhydrous dimethylformamide. 0.94 g of potassium carbonate is added to the reaction mixture. The reaction mixture was heated at 80 ° C for 72 h. The mixture was diluted with 100 ml water and extracted 3 times with 50 ml portions of ethyl acetate. The extracts are mixed and dried. Filtration and concentration of the organic material in vacuo affords a crude product. MSGMS (NH ₃ -Cl): 240 (M + H, 100); Ή NMR (CDCl ₃ ) δ: 8.50 (d, 2H), 8.20 (s, 1H), 7.93 (complex, 1H), 7.75 (d, 2H), 7.63 (complex, 1H), 7.42 (complex, 2H).

Part B: Preparation of N- (4-aminophenyl) benzimidazole

Prepare a slurry of 0.6 g of crude N- (4-nitrophenyl) benzimidazole and a catalytic amount of 10% palladium on carbon in 20 ml of methanol.

154

The reaction mixture is placed in 1 atmosphere of hydrogen gas and stirred for 15 hours. The reaction mixture was passed through a pad of celite (25.4 mm) and the filtrate concentrated in vacuo to give a crude product. MSGMS (NH ₃ -Cl): 210 (M + H, 100); ¹ H NMR (DMSO-d ₆ ) δ: 9.25 (s, 1H), 7.83 (complex, 1H), 7.60 (complex, 1H), 7.47 (complex, 2H), 7.35 (d, 2H), 6.80 (d, 2H).

Part C: Preparation of N- (3-cyanophenyl) -3-methyl-5 - [(4 '- (benzimidazol-1-yl) phen-1-yl) aminocarbonyl] arazole

To 0.16 g of N- (3-cyanophenyl) -3-methyl-pyrazole-5-carboxylic acid and 2 ml of dichloromethane are added 0.07 ml of oxalyl chloride and 2 drops of DMF. The reaction is carried out overnight. Concentration of the reaction mixture and maintaining the residue in a deep vacuum yields the crude chloro anhydride, which is then coupled with the product of Part B under standard conditions to give the crude N- (3-cyanophenyl) -3-methyl-5 - [(4 '- (N-benzimidazole). 1-yl) phen-1-yl) aminocarbonyl] pyrazole. MSGMS (ESI): 419 (M + H, 20), 210 (M + 2H) ⁺⁺ .

Part D: Preparation of N- (3-amidinophenyl) -3-methyl-5 - [(4 '- (benzimidazol-1-yl) phen-1-yl) aminocarbonyl] pyrazole

The standard transformation of benzonitrile from part C through ethylimidate into 0.24 g of crude benzonitrile after standard purification by HPLC is converted to 0.02 g of benzamidine bis-TFA salt: MSGMS (ES +): 436.21 (M + H), DSGMS (FAB): calculated: 436.188584, found mass 436.191317; and 0.003 g of benzamide; MSGMS (ES +): 437 (M + H), 459 (M + Na); DSGMS (NH 3 -Cl): calcd: 437.172599, found 437.173670. ¹ H NMR (DMSO-d 6, 300 MHz) δ: 10.76 (s, 1H), 9.40 (s, 2H), 9.02 (s, 2H), 8.59 (s, 1H), 7.94 (s, 1H), 7.88 (d, 2H), 7.76 (complex, 3H), 7.64 (complex, 4H), 7.32 (complex, 2H), 7.05 (s) , 1H), 2.30 (s, 3H).

Examples 135 and 136

155

1- (3-amidinophenyl) -3-methyl-5 - [(4 '- (2-methylimidazolyl) phenyl) aminocarbonyl] pyrazole and 1- (3-aminocarbonylphenyl) -3-methyl-5 - [(4' - ( 2-methylimidazolyl) phenyl) aminocarbonyl] pyrazole

Part A: Preparation of N- (4-nitrophenyl-2-methylimidazole

2-Methylimidazole (1.04 g) was treated with 0.56 g of a 60% sodium hydride suspension in oil in 60 ml of DMF under cooling. After 0.33 or. per 0.5 or. three portions of 4-bromonitrobenzene are added. The reaction mixture was allowed to warm to room temperature and kept overnight. The mixture was diluted with 100 mL of 1.0 M HCl solution and extracted three times with 30 mL of ethyl acetate. The extracts were mixed and dried over magnesium sulfate. The resulting organic matter is concentrated in vacuo. Purification of the crude material by standard chromatography gives a pure product which is a crystalline solid. MSGMS (NH ₃ -Cl): 204 (M + H, 100); ¹ H NMR (CDCl ₃ ) δ: 8.40 (sd 12), 7.50 (d, 2H), 7.05 (d, 2H), 2.43 (s, 3H).

Part B; Preparation of 1- (4-aminophenyl) -2-methylimidazo [a]

N- (4-nitrophenyl) -2-methylimidazole (0.47 g) is treated with a catalytic amount of 10% palladium on carbon in 15 ml of methanol. The reaction mixture was placed in a hydrogen atmosphere, stirred for 3 hours, and then passed through a 25.4 mm layer of celite. The resulting filtrate is concentrated in vacuo to give the title compound. MSGMS (NH ₃ -Cl): 174 (M + H, 100); ¹ H NMR (CDCl 3) δ: 7.05 (d, 1H), 6.97 (d, 2H), 6.77 (d, 2H), 6.60 (d, 2H), 5.34 (s, 2H), 2.13 (s, 3H).

Part C: Preparation of N- (3-cyanophenyl) -3-methyl-5 - [(4 '- (2-methylimidazolyl) phenyl) aminocarbonyl] pyrazole, 0.24 g of N- (3-cyanophenyl) -3-methyl- of pyrazole-5-carboxylic acid and 20 mL of dichloromethane are added 0.14 mL of oxalyl chloride and 2 drops of DMF. The reaction is carried out overnight. Concentration of the reaction mixture and maintenance of the residue under deep vacuum affords the crude chloro anhydride, which is then copolymerized with the product of Part B under standard conditions to give the desired compound, which is isolated as the hydrochloride salt. MSGMS (ESI):

156

383 (M + H, 100). ¹ H NMR (DMSO-d 6) δ: 10.90 (s, 1H), 7.95 (s, 1H), 7.90 (d, 2H), 7.83 (m, 2H), 7.75 ( m, 2H), 7.63 (m, 1H), 7.57 (d, 2H), 7.10 (s, 1H), 2.49 (s, 3H), 2.30 (s, 3H).

Part D: 1- (3-Amidinophenyl) -3-methyl-5-r (4 '- (2-methylimidazolyl) phenyl) aminocarbonyl] pyrazole and 1- (3-aminocarbonylphenyl) -3-methyl-5-r (4'- Preparation of (2-methylimidazolyl) phenyl) aminocarbonylpyrazole

N- (3-cyanophenyl) -3-methyl-5 - [(4 '- (2-methylimidazolyl) phenyl) aminocarbonyl] pyrazole is converted to the corresponding benzamidine according to Pinner's synthesis and amidation by stepwise imidate treatment with ammonium carbonate. The crude material is then purified by standard HPLC to give benzamidine which after lyophilization is a white solid. MSGMS (ES +): 400 (M + H, 100); DSGMS: Calculated: 400.1888584, Found: 400.188113; ¹ H NMR (DMSO-d 6, 300 MHz) δ: 10.87 (s, 1H), 9.40 (s, 2H), 9.30 (s, 2H), 7.95 (s, 1H), 7 , 89 (d, 2H), 7.80 (m, 2H), 7.75 (m, 2H), 7.65 (m, 1H), 7.55 (d, 2H), 7.05 (s,

H), 2.47 (s, 3H), 2.30 (s, 3H). During the purification, the corresponding benzamide was isolated as a by-product. MSGMS (ES &lt; + &gt;): 401 (M + H); DSGMS (NH ₃ Cl): calculated 401.172599, found mass: 401.170225; ¹ H NMR (DMSOds, 300 MHz) δ: 10.77 (s, 1H), 8.78 (s, 1H), 8.09 (s, 1H), 7.94 (s, 1H), 7.87 (m, 3H), 7.77 (m, 1H), 7.65 (d, 2H), 7.63 (m, 1H), 7.50 (complex, 3H), 7.36 (m, 2H) ), 6.95 (s, 1H), 2.30 (s, 3H).

Example 137

1- (3-Amidinophenyl) -3-methyl-5 - [[4 '- (1,2,4-triazol-2-yl) phenyl] aminocarbonyl] pyrazole

Part A: 1- (3-Cyanophenyl) -3-methyl-5-trans-4 '- (1,2,4-triazolyl) pheninaminocarbonylpyrazole

The standard method provides the pyrazole acid anhydride and copied with 0.18 g of commercial 4- (1-N-1,2,4-triazole) aniline using standard DMAP copying; 1- (3-cyanophenyl) -3-methyl-5 - [[4 '(1,2,4-triazol-1-yl) phenyl] aminocarbon () pyrazole is obtained.

157 is recrystallized from a 2: 1 mixture of methylene chloride and methanol to give the product as a white solid. MSGMS (NH ₃ -Cl): 370 (M + H); ¹ H NMR (DMSO-d 6, 300 MHz) δ: 10.57 (s, 1H), 9.20 (s, 1H), 8.19 (s, 1H), 7.97 (s, 1H), δ , 80 (complex, 6H), 7.65 (t, 1H), 7.00 (s, 1H), 2.29 (s, 3H).

Part B: Preparation of 1- (3-Amidinophenyl) -3-methyl-5-trans-4 '- (1,2,4-triazolyl) pheninaminocarbonylpyrazole

The standard transformation of benzonitrile from Part A into ethyl imidate to 0.13 g of benzonitrile after standard HPLC purification is converted to the bis-TFA salt of benzamidine; MSGMS (ES +): 387 (M + H), DSGMS (NH ₃ -Cl): Calc'd: 387.168182, Found 387.1666790; ¹ H NMR (DMSO-d 6, 300 MHz) δ: 10.70 (s, 1H), 9.39 (s, 2H), 9.20 (s, 2H), 9.02 (s, 2H), δ , 19 (s, 1H), 7.91 (s, 1H), 7.79 (m, 5H), 7.70 (m, 2H), 7.02 (s, 1H), 2.31 (s, 3H).

Example 138

1- (3-Amidinophenyl) -3-methyl-5 - ((4'-cyclohexylphenyl) aminocarbonyl) pyrazole

Part A: Preparation of 1- (3-Cyanophenyl) -3-methyl-5 - ((4'-cyclohexylphenyl) aminocarbonyl) pyrazole

The standard method generates pyrazole acid chloro anhydride and copolymers with 0.19 g of commercial 4-cyclohexaniline using standard DMAP copulation; 1- (3-cyanophenyl) -3-methyl-5 - ((4'-cyclohexylphenyl) aminocarbonyl) pyrazole is obtained. MSGMS (NH 3 -Cl): 385 (M + H), 402 (M + NH ₄ ); Ή NMR (DMSO-d _6, 300 MHz) δ: 10.40 (s, 1H), 7.92 (s, 1H), 7.82 (d, 1H), 7.72 (d, 1H); 7.61 (t, 1H), 7.50 (d, 2H), 7.13 (d, 2H), 6.92 (s, 1H), 3.31 (s, 1H), 2.25 ( s, 3H), 1.71 (complex, 5H), 1.13 (complex, 5H).

Part B: Preparation of 1- (3-Amidinophenyl) -3-methyl-5 - ((4'-cyclohexylphenyl) aminocarbonyl) pyrazole

The standard transformation of the benzonitrile from Part A through ethyl imidate converts the crude benzonitrile to the TFA salt of benzamidine. The crude product is purified by standard HPLC. MSGMS (ES &lt; + &gt;): 402

158 (M + H), DSGMS (NH 3 -Cl): calculated: 402.229386, found 402.227504; ¹ H NMR (DMSO-d _s, 300 MHz) δ: 10.30 (s, 1H), 9.38 (s, 2H), 9.07 (s, 2H), 7.90 (s, 1H) 7.77 (m, 1H), 7.69 (m, 2H), 7.50 (d, 2H), 7.12 (d, 2H), 6.93 (s, 1H), 3.31 (m , 1H), 2.28 (s, 3H), 1.71 (complex, 5H), 1.32 (complex, 5H).

Example 139

1- (3-Amidinophenyl) -3-methyl-5 - [[1,1 '] - biphen-4-ylaminocarbonyl] pyrazole

Part A: Preparation of 1- (3-Cyanophenyl) -3-methyl-5-phenyl-1,1'-biphen-4-ylaminocarboninpyrazole

The standard method generates pyrazole acid chloro anhydride and copulates with 0.19 g of commercial 4-aminobiphenyl using standard DMAP copulation; 1- (3-cyanophenyl) -3-methyl-5 - [[1, T] -biphen-4-ylaminocarbonyl] pyrazole is obtained. MSGMS (NH ₃ -Cl): 379 (M + H), 396 (M + NH ₄ ); DSGMS (NH 3 -Cl): calculated: 396.182436, found 396.181736; ¹ H NMR (DMSO-d 6, 300 MHz) δ: 10.57 (s, 1H), 9.20 (s, 1H), 8.19 (s, 1H), 7.97 (s, 1H), δ , 80 (complex, 6H), 7.65 (t, 1H), 7.00 (s, 1H), 2.29 (s, 3H).

Part B: Preparation of 1- (3-Amidinophenyl) -3-methyl-5-yn, 1'1-biphen-4-ylaminocarbonyl] pyrazole

The standard transformation of the benzonitrile from Part A through ethyl imidate converts the crude benzonitrile to the TFA salt of benzamidine. The crude product is purified by standard HPLC. MSGMS (ES &lt; + &gt;): 396 (M + H); DSGMS (NH ₃ -Cl) :; calculated: 396.181736, found mass 396.182436; ¹ H NMR (DMSO-d ₆ , 300 MHz) δ: 10.60 (s, 1H), 9.40 (s, 2H), 8.99 (s, 2H), 7.91 (m, 1H), 7.80 (complex, 5H), 7.61 (m, 2H), 7.30 (m, 1H), 7.00 (s, 1H), 2.29 (s, 3H).

140 Example

1- (3-amidinophenyl) -3-methyl-5 - ((4'-morpholinophenyl) aminocarbonyl) pyrazole

159

Part A: 1- (3-cyanophenyl) -3-methyl-5 - ^((4, -morfolinofenil) aminocarbonyl) pyrazole

The standard method generates pyrazole acid chloro anhydride and copolymers with 0.26 g of commercial 4-morpholinaniline using standard DMAP copulation; 1- (3-cyanophenyl) -3-methyl-5 ((4'morpholinophenyl) -aminocarbonyl] pyrazole is obtained. MSGMS (NH ₃ -Cl): 388 (M + H), 1 H NMR (DMSO-d ₆ , 300 MHz) δ: 10.30 (s, 1H), 7.90 (m, 1H), 7.82 (d, 1H), 7.71 (m, 1H), 7.62 (t, 6H), 7 , 49 (d, 2H), 6.89 (s, 1H), 6.87 (d, 2H), 3.69 (t, 4H), 3.02 (t, 4H), 2.25 (s, 3H).

Part B: The standard transformation of the benzonitrile obtained in Part A through ethyl imidate converts the crude benzonitrile to the bis-TFA salt of benzamidine. The crude product is purified by standard HPLC. MSGMS (ES &lt; + &gt;): 405 (M + H); DSGMS (NH 3 -Cl): calcd .: 405.203899, found 405.201545; 1 H NMR (DMSO-d 6, 300 MHz) δ: 10.38 (s, 1H), 9.40 (s, 2H), 7.90 (s, 1H), 7.78 (d, 1H), 7 , 68 (m, 2H), 7.49 (d, 2H), 6.92 (s, 1H), 6.90 (d, 2H), 3.80 (t, 4H), 3.01 (t, 4H), 2.29 (s, 3H.

Example 141

1- (3-amidinophenyl) -3-methyl-5 - [(4 '- ((2-trifluoromethyl) tetrazol-1-yl) phenyl) aminocarbonyl] pyrazole

Part A: Preparation of 4- (2-Trifluoromethyltetrazole-Dnitrobenzene)

3.0 g of commercial 4-nitroaniline is trifluoromethylacetylated in the presence of trifluoroacetic anhydride to give crude N-trifluoroacetyl-4-nitroaniline. MSGMS (NH 3 -Cl): 252 (M + NH ₄ ); Δ NMR (DMSO-d6, 300 MHz) δ: 11.75 (s, 1H), 8.28 (d, 2H), 7.92 (d, 2H). The crude material is then treated with triphenylphosphine in carbon tetrachloride to give the chlorimine. 1 H NMR (CDCl 3, 300 MHz) δ: 8.35 (d, 2H), 7.15 (d, 2H). The crude chlorimine is cyclized to 4- (2-trifluoromethyl-tetrazole) nitrobenzene with sodium azide in acetonitrile. 1 H NMR (CDCl 3, 300 MHz) δ: 8.54 (d, 2H), 7.80 (d, 2H). The crude 2-trifluoromethyl-tetrazolaniline is rubbed to give a semi-pure product,

160 which is catalytically reduced to aniline by 10% palladium on carbon. MSGMS (NH 5 -Cl): 230 (M + H), 247 (M + NH ₄ ); ¹ H NMR (DMSO-d ₆ , 300 MHz) δ: 7.256 (d, 2H), 6.65 (d, 2H).

Part B: Preparation of 1- (3-cyanophenyl) -3-methyl-5 - [(4 '- ((2-trifluoromethyl) tetrazolyl) phenyl) aminocarbonylpyrazole

The standard method generates the pyrazole acid chloro anhydride and copulates with 0.49 g of 4- (2-trifluoromethyltetrazolyl) aniline using standard DMAP copying; 1- (3-cyanophenyl) -3-methyl-5 - ((4 '- (2-trifluoromethyltetrazol-1-yl) phenyl) aminocarbonyl) pyrazole is obtained. MSGMS (NH ₃ -Cl): 439 (M + H), 461 (M + Na) ⁺ , 877 (2 M + H), 899 (2 M + Na); Ή NMR (DMSO-d _6, 300 MHz) δ: 10.87 (s, 1H), 8.00 (s, 1H), 7.91 (d, 2H), 7.84 (m, 1H), 7 , 77 (m, 1H), 7.69 (d, 2H), 7.63 (t, 1H), 7.02 (s, 1H), 2.29 (s, 3H).

Part C: Preparation of 1- (3-Amidinophenyl) -3-methyl-5 - [(4 '- ((2-trifluoromethyl) tetrazole-1-phenyl] aminocarbonyl) pyrazole

The standard transformation of the benzonitrile from Part B through ethyl imidate to the crude benzonitrile is followed by conversion to the TFA salt of benzamidine by HPLC purification. MSGMS (ES +): 456 (M + H): DSGMS (NH ₃ -Cl): Calcd .: 456.150816, Found 456.150428; ¹ H NMR (DMSO-d 6, 300 MHz) δ: 10.92 (s, 1H), 9.40 (s, 2H), 9.18 (s, 2H), 7.90 (complex, 3H), 7.78 (m, 2H), 7.67 (complex, 3H), 7.08 (s, 1H), 2.32 (s, 3H).

Example 142

1- (3-Aminomethylphenyl) -3-methyl-5 - [(4 '- ((2-trifluoromethyl) tetrazol-1-yl) phenyl) aminocarbonyl] pyrazole

0.06 g of 1- (3-cyanophenyl) -3-methyl-5 - ((4 '- (2-trifluoromethyl) tetrazolyl) phenyl) aminocarbonyl) pyrazole is treated with 10% palladium on carbon in TFA / methanol under a hydrogen atmosphere. After a few hours, the reaction mixture was filtered through

25.4 mm layer of celite. The filtrate is concentrated under reduced pressure and the residue is purified by standard HPLC to give the title compound.

161

MSGMS (NH 4 -Cl): 443 (M + H); DSGMS (NH 4 -Cl): calcd: 443.155557 mass determined 443.155557; ¹ H NMR (DMSO-d _s, 300 MHz) δ: 10.90 (s, 1H), 8.20 (br s, 2H), 7.90 (d, 2H), 7.69 (d, 2H ), 7.62 (s, 1H), 7.42 (complex, 3H), 6.97 (s, 1H), 4.09 (m, 2H), 2.29 (s, 3H).

Example 143

1- (3-Amidinophenyl) -3-methyl-5 - [((4 '- (N, N-dimethylamino) carbonylamino) phenyl) aminocarbonyl] pyrazole

Part A: Preparation of 4 - ((N, N-dimethylamino) carbonylamino) -1-nitrobenzene

1.56 g of 4-nitroaniline are treated with 0.50 g of sodium hydride% oil dispersion DMF at 0 ° C. After 20 minutes 1.04 ml of N, N-dimethylcarbamyl chloride are added dropwise. The mixture was allowed to warm to room temperature and kept overnight. The reaction mixture is poured into 150 ml of ice water. Support 1 or. Vacuum filtration separates the precipitate. MSGMS (NH 3 -Cl): 210 (M + H), 227 (M + NH ₄ ); ¹ H NMR (DMSO-d ₆ , 300 MHz) δ: 8.97 (s, 1H), 8.12 (d, 2H), 7.70 (d, 2H), 2.91 (s, 6H).

Part B: Preparation of 1-Amino-4 - ((N, N-dimethylamino) carbonylamino) benzene

1.66 g of 4-N, N-dimethylureanitrobenzene are subjected to a catalytic amount of% palladium on carbon in methanol under a hydrogen pressure of 241.3 kPa for 1 hour. Passing through a layer of 25.4 mm celite, concentrating the filtrate and maintaining the residue in a deep vacuum, gives a solid. MSGMS (NH ₃ -Cl): 18 (M + H).

Part C: Preparation of 1- (3-Cyanophenyl) -3-methyl-5-1 '(4' - ((N, N-dimethylamino) carbonylamino) phen-1 '-propaminocarbonylpyrazole

0.37 g of 4-N, N-dimethylcarbamidaniline is copolished with 0.46 g of N- (3-cyanophenyl) -3-methyl-pyrazole-5-carboxylic acid chlorohydride according to standard

DMAP copulation methodology in dichloromethane. Several drops of DMF are added to catalyze the reaction. N- (3-cyanophenyl) -3-methyl-pyrazole-5-carboxylic acid chloro anhydride is prepared according to the procedure described previously. Wanted

162 products are purified according to standard purification procedures. MSGMS (ES +): 389 (M + H), 411 (M + Na) ⁺ , 777 (2M + H) 7.99 (2M + Na); ¹ H NMR (DMSO-d ₆ , 300 MHz) δ: 10.35 (s, 1H), 8.22 (s, 1H), 7.91 (s, 1H), 7.82 (d, 1H), 7.71 (d, 1H), 7.63 (t, 1H), 7.46 (d, 2H), 7.37 (d, 2H), 6.91 (s, 1H), 2.88 (s) , 6H), 2.29 (s, 3H).

Part D: Preparation of 1- (3-Amidinophenyl) -3-methyl-5 - [(4 ^, - ((N, N-dimethylamino) carbonylamino) phen-1'-iDaminocarbonyl] pyrazole

The standard transformation of the benzonitrile from part C through ethyl imidate to the crude benzonitrile is followed by conversion to the TFA salt of benzamidine by HPLC purification. MSGMS (ES +): 406 (M + H), 811 (H + -dimer); DSGMS (NH ₃ Cl): calculated: 406.199148 mass determined 406.198887: ¹ H NMR (DMSO-d ⁶ , 300 MHz) δ: 10.37 (s, 1H), 9.40 (s, 2H), 9 , 02 (s, 2H), 8.23 (s, 1H), 7.91 (s, 1H), 7.78 (d, 1H), 7.68 (m, 2H), 7.43 (d, 2H), 7.38 (d, 2H), 6.95 (s, 1H), 2.87 (s, 6H), 2.29 (s, 3H).

Examples 144 and 145

1- (3-amidinophenyl) -3-methyl-5 - [(4 '- (N, N-diethylamino) phenyl) aminocarbonyl] pyrazole (Example 144) and 1- (3-aminocarbonylphenyl) -3-methyl-5 - [(4' - (N, N-diethylamino) phenyl) aminocarbonyl] pyrazole (Example 145)

Part A: Preparation of 1- (3-Cyanophenyl) -3-methyl-5 - ['(4' - (N, N-diethylamino) phenyl) aminocarbonyl] pyrazole

The standard method generates pyrazole acid chloro anhydride and copulates with 0.24 g of commercial N, N-diethyl-1,4-phenylenediamine using standard DMAP copulation; 1- (3-cyanophenyl) -3-methyl-5 - ((4'-N, N-diethylaminoaniline) aminocarbonyl) pyrazole is obtained. MSGMS (NH 3 -Cl): 374 (M + H), 747 (2M + H); ¹ H NMR (DMSO-d 6, 300 MHz) δ: 10.16 (s, 1H), 7.90 (s, 1H), 7.81 (m, 1H), 7.71 (m, 1H), δ , 60 (t, 1H), 7.37 (d, 2H), 6.88 (s, 1H), 6.59 (d, 2H), 3.26 (m, 4H), 2.25 (s, 3H), 1.02 (t, 6H).

163

Part B: Preparation of 1- (3-Amidinophenyl) -3-methyl-5-i (4 '- (N, N-diethylamino) phenyl) aminocarbonylpyrazole

The standard transformation of benzonitrile from Part A through ethylimidate to 0.24 g of crude benzonitrile is purified by HPLC to give 0.256 g of benzamidine bis-TFA salt. MSGMS (ES &lt; + &gt;): 391 (M + H); DSGMS (NH ₃ Cl): calcd .: 391.224635 mass determined 391.224109. HPLC purification also yields 0.017 g of benzamide. MSGMS (ESI +): 392 (M + H); DSGMS (NH 3 -Cl): Calcd .: 392.208650 Mass determined 392.207700.

Examples 146 and 147

1- (3-amidinophenyl) -3-methyl-5 - [(4 '- (1-tetrazolyl) phenyl) aminocarbonyl] pyrazole (Example 146) and 1- (3-aminocarbonylphenyl) -3-methyl-5 - [(4' - ( 1-Tetrazolyl) phenyl) aminocarbonyl] pyrazole (Example 147)

Part A: Preparation of 4-N-formylaminonitrobenzene

0.69 g of 4-aminonitrobenzene at 0 ° C are treated with acetic acid anhydride in THF. The reaction mixture was then heated at 55 ° C for 2 h. Concentrating the mixture under reduced pressure and maintaining the residue in a deep vacuum yields an impure product. MSGMS (NH 3 -Cl): 184 (M + NH ₄ ).

Part B: Preparation of 4- (1-Tetrazolyl) nitrobenzene

A solution of the above compound, 2.63 g of triphenylphosphine, 1.15 g of TMS azide and 1.75 g of DEAD reagent in THF is prepared. Stir for 24 hours. The reaction mixture was diluted with water and extracted with methylene chloride. Drying and concentration of the organic extracts yields a crude product which is purified by standard chromatographic techniques. MSGMS (NH ₃ -Cl): 209 (M + NH ₄ ); ¹ H NMR (DMSO-d ₆ , 300 MHz) δ: 10.35 (s, 1H), 8.48 (d, 2H), 8.20 (d, 2H).

Part C:

4- (Preparation of 1-Tetrazolylaniline)

164

4- (1-Tetrazolyl) nitrobenzene is exposed to 10% palladium on carbon in methanol and stored under a hydrogen pressure of 275.8 kPa for 2 hours. The reaction mixture was passed through a pad of celite (25.4 mm) and the filtrate concentrated to give a crude product. MSGMS (NH ₃ -Cl): 162 (M + H), 179 (M + NH ₄ ): ¹ H NMR (DMSO-d ₆ , 300 MHz) δ; 9.79 (s, 1H), 7.42 (d, 2H), 6.67 (d, 2H).

Part D: Preparation of 1- (3-Cyanophenyl) -3-methyl-5-if4 '- (1-tetrazolyl) phenyl) aminocarbonylpyrazole

The standard method generates the pyrazole acid chloro anhydride and copulates with 0.26 g of 4- (1-tetrazolyl) aniline using standard DMAP copulation; 1- (3-cyanophenyl) -3-methyl-5 - [(4 '- (1-tetrazolyl) () phenyl) aminocarbonyl] pyrazole is obtained This crude material is used in the next step.

Part E: Preparation of 1- (3-Amidinophenyl) -3-methyl-5 - [(4'- (1-tetrazolyl) phenyl) aminocarbonyl] -irazole

The standard transformation of the benzonitrile obtained in Part D through ethyl imidate to the crude benzonitrile by HPLC purification yields 0.014 g of benzamidine TFA salt. MSGMS (ES +); 388 (M + H); DSGMS (NH 3 -Cl); deducted; 388.163431, found mass 388.165343. ¹ H NMR (DMSO-d 6, 300 MHz) δ: 10.79 (s, 1H), 10.01 (s, 1H), 9.40 (ss, 2H), 8.99 (s, s) 2H), 7.93 (s, 1H), 7.85 (m, 4H), 7.77 (m, 2H), 7.67 (m, 1H), 7.04 (s, 1H), 2, 31 (s, 3H). HPLC purification also gives 0.007 g of benzamide. MSGMS (ESI +); 799 (2M + Na), 777 (2M + H); DSGMS (NH 3 -Cl); deducted; 389.147447, found mass 389.149952; ¹ H NMR (DMSO-d 6, 300 MHz) δ: 10.77 (s, 1H), 10.00 (s, 1H), 7.94 (m, 1H), 7.87 (m, 6H), δ , 51 (m, 1H), 6.96 (s, 1H), 2.30 (s, 3H).

Examples 148, 149, and 150

1- (3-amidinophenyl) -3-methyl-5 - [(4 '- (N-acetylpiperazine-1-H) phenyl) aminocarbonyl] pyrazole, 1- (3-amidinophenyl) -3-methyl-5 - [(4' - (N-fref165 butyloxycarbonylpiperazin-1-yl) phenyl) aminocarbonyl] pyrazole and 1- (3amidinophenyl) -3-methyl-5 - ((4'-piperazin-1-yl) phenyl) aminocarbonyl) pyrazole

Part A: 1- (3-cyanophenyl) -3-methyl-5-f (4 ^l - (N-tert-receiving butiloksikarbonilpiperazin1 -iOfeniDaminokarbonilIbirazolo

The standard method generates the pyrazole acid anhydride and copulates it with 0.23 g of 4- (N-boc-piperazine) aniline (which is readily obtained from commercially available 1- (4-nitrophenyl) piperazine) using standard DMAP copying to give 1- (3) crude. -cyanophenyl) -3-methyl-5 - [(4 '- (Neryl-butyloxycarbonylpiperazin-1-yl) phenyl) aminocarbonyl] pyrazole. This product is purified by standard chromatographic techniques. MSGMS (NH ₃ -Cl): 487 (M + H); Ή NMR (DMSO-d _6, 300 MHz) δ: 10.60 (s, 1H)

7.90 (s, 1H), 7.81 (m, 1H), 7.73 (m, 1H), 7.61 (t, 1H), 7.47 (d, 2H), 6.90 (s) , 1H), 6.88 (d, 2H), 3.41 (complex, 4H), 3.01 (complex, 4H), 2.28 (s, 3H), 1.37 (s, 9H).

Part B: Preparation of 1- (3-amidoxymphenyl) -3-methyl-5-i (4 '- (N-tert-butyloxycarbonylpiperazin-1-ylphenyl) aminocarbonylpyrazole

0.29 g of 1- (3-cyanophenyl) -3-methyl-5 - [(4 '- (N-ire-butyloxycarbonylpiperazin-1-yl) phenyl) aminocarbonyl] pyrazole are treated with 0.15 g of hydroxylamine hydrochloride and 0.11 g of sodium carbonate in ethanol / water mixture. The reaction mixture was refluxed for 5 hours. Treatment of the reaction mixture and extraction of the aqueous fractions, drying of the resulting organic layer and concentration in vacuo afforded the crude amidoxime.

Part C: 1- (3-Amidinophenyl) -3-methyl-5-i (4 '- (N-tert-butyloxycarbonylpiperazin-1-yl) phenyl) aminocarboninpyrazole and 1- (3-amidinophenyl) -3-methyl- Preparation of 5-r (4 '(N-acetylpiperazin-1-ylphenylarninocarbonylpyrazole)

The crude amidoxime is treated with acetic acid and acetic anhydride for 0.5 h. A catalytic amount of 10% palladium on carbon is added to the reaction mixture, and the mixture is placed on a Parr hydrogenator in the presence of

344.7 kPa for 4 hours. Passed through a 25.4 mm layer of celite, and

Concentration of the filtrate yields crude benzamidine. Purification by standard HPLC procedure. MSGMS (ES +) for N-acetyl Compound: 446 (M + H, 100): DSGMS (FAB +): Calculated: 446.230448, Found 446.231327. Ή NMR (DMSO-d6, 300 MHz) δ: 10.33 (s, 1H), 9.39 (p.s. 2H), 9.04 (p.s. 2H),

7.90 (s, 1H), 6.77 (d, 1H), 7.68 (m, 2H), 7.48 (d, 2H), 6.94 (s, 1H), 6.90 (d) , 2H), 3.52 (m, 4H), 3.02 (m, 4H), 2.28 (s, 3H), 2.00 (s, 3H). 1- (3-Amidinophenyl) 3-methyl-5 - [(4 '- (N-acetylpiperazin-1-yl) phenyl) aminocarbonyl] pyrazole was isolated as a by-product to the N-boc compound. MSGMS (ES +): 504 (M + H); DSGMS (NH 3 -Cl): calculated: 504.272313, found 504.272536; 1 H NMR (DMSO-d 6, 300 MHz) δ: 10.34 (s, 1H), 9.38 (p.s. 2H), 9.05 (p.s. 2H),

7.90 (m, 1H), 7.77 (m, 1H), 7.67 (m, 2H), 7.47 (d, 2H), 6.94 (s, 1H), 6.90 ( d, 2H), 3.42 (m, 4H), 3.00 (m, 4H), 2.29 (s, 3H), 1.37 (s, 9H).

Part D: Preparation of 1- (3-Amidinophenyl) -3-methyl-5 - [(4'-piperazin-1-i-phenyl) aminocarbonylpyrazole

0.043 g of 1- (3-amidinophenyl) -3-methyl-5 - [(4 '- (N-tert-butyloxycarbonylpiperazin-1-yl) phenyl) aminocarbonyl] pyrazole is treated with TFA at room temperature for 3 hours. Concentration of the reaction mixture under reduced pressure affords the crude product. The material is purified by standard HPLC. MSGMS (ES &lt; + &gt;): 404 (M + H); DSGMS (NH ₃ -Cl): calculated: 404.219884, found 404.221193; 1 H NMR (DMSO-d 6, 300 MHz) δ: 10.36 (s, 1H), 9.39 (p.s. 2H), 9.18 (p.s. 2H), 7.90 (s) , 1H), 7.77 (d, 1H), 7.67 (m, 2H), 7.01 (d, 2H), 6.92 (m, 3H), 3.22 (m, 8H), 2 , 29 (s, 3H).

Example 151

1- (3-Amidinophenyl) -3-trifluoromethyl-5 - ((4'-cyclohexylphenyl) aminocarbonyl) pyrazole

Part A: Preparation of 1- (3-Cyanophenyl) -3-trifluoromethyl-5 - ((4'-cyclohexylphenyl) aminocarbonylpyrazole

According to a standard procedure, 0.25 g of N- (3-cyanophenyl) -3-methylpyrazole-5-carboxylic acid is converted into its chloro anhydride and treated with 0.15 g of 4167 cyclohexaniline in DMAP in methylene chloride; work up and purification by standard chromatographic techniques affords the title compound. MSGMS (ES +): 461 (M + Na) ⁺ , 899 (Na ⁺ -dimer); ¹ H NMR (DMSO-d ₆ , 300 MHz) δ: 10.57 (s, 1H), 8.13 (s, 1H), 7.95 (d, 1H), 7.86 (d, 1H), 7.69 (t, 1H), 7.65 (s, 1H), 7.50 (d, 2H), 7.15 (d, 2H), 2.41 (complex, 1H), 1.70 (complex) , 5H), 1.25 (complex, 5H).

Part B: Preparation of 1- (3-Amidinophenyl) -3-trifluoromethyl-5 - ((4'-cyclohexylphenyl) aminocarbonylpyrazole

This cyano-derivative is converted to the amidino-derivative via amidoxime as described previously. The amidoxime is reduced to the corresponding benzamidine by converting it to the corresponding acetate using acetic acid / acetic anhydride and catalytic reduction with 10% palladium on carbon, also described above. The crude product is purified by standard HPLC and the TFA salt is obtained. MSGMS (ES +): 456 (M + H); DSGMS (NH 3 -Cl): calculated: 456.199783, found 456.201120; ¹ H NMR (DMSO-d ₆ , 300 MHz) δ: 10.62 (s, 1H), 9.40 (s, 2H), 9.16 (s, 2H), 7.99 (s, 1H), 7.88 (m, 2H), 7.72 (t, 1H), 7.69 (s, 1H), 7.50 (d, 2H), 7.14 (d, 2H), 2.41 (complex , 1H), 1.69 (complex, 5H), 1.25 (complex, 5H).

Example 152

1- (3-Amidinophenyl) -3-methyl-5 - [(4 '- (N-morpholino) -3'-chlorophenyl) aminocarbonyl] pyrazole

Part A: Preparation of 1- (3-Cyanophenyl) -3-methyl-5 - [(4 '- (N-morpholino) -3'-chlorophenyl) aminocarbonyl] pyrazole

According to the standard procedure, N- (3-cyanophenyl) -3-methylpyrazole-5-carboxylic acid is converted into its chloro-anhydride. 0.30 g of this anhydride is treated with 0.26 g of commercially available 2-chloro-4-morpholinaniline in DMAP, methylene chloride, and the product obtained after treatment and purification by standard chromatographic techniques, MSGMS (ES +): 422 (M + H): ¹ H NMR (DMSO-d _s, 300 MHz) δ: 10.57 (s, 1H), 8.13 (s, 1H), 7.95 (d, 1H), 7.86 (d, 1H), 7 , 69 (t, 1H),

168

7.65 (s, 1H), 7.50 (d, 2H), 7.15 (d, 2H), 2.41 (complex, 1H), 1.70 (complex, 5H), 1.25 (complex , 5H).

Part B: Preparation of 1- (3-Amidinophenyl) -3-methyl-5 - [(4 '- (N-morpholino) -3'-chlorophenyl) aminocarbonyl] pyrazole

This cyano-derivative is converted to the amidino-derivative via amidoxime as described previously. The amidoxime is reduced to the benzamidine by converting it to the corresponding acetate using acetic acid / acetic anhydride and catalytic reduction with 10% palladium on carbon as described above. The crude product was purified by standard HPLC to give the bis-TFA salt. MSGMS (ES +): 439 (M + H); DSGMS (NH ₃ -Cl): calculated: 439.164927, found 439.163814; 1 H NMR (DMSO-d ₆ , 300 MHz) δ: 10.54 (s, 1H), 9.38 (s, 2H), 9.06 (s, 2H), 7.89 (s, 1H), 7.78 (m, 2H), 7.67 (m, 2H), 7.51 (dd, 1H), 7.12 (d, 1H), 6.96 (s, 1H), 3.69 (t , 4H), 2.88 (t, 4H), 2.46 (m, 3H).

Example 153

1- (3-Amidinophenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] 3- (methylthio) pyrazole trifluoroacetic acid salt

Part A: Preparation of ethyl-N- (3-cyanophenyl) glycine

A solution of 15.11 g (128 mmol) of 3-aminobenzonitrile in 200 ml of DMF under N ₂ is added with 23.50 g (141 mmol) of ethyl bromoacetate and 14.95 g (141 mmol) of anhydrous sodium carbonate. The mixture is heated at 70 ° C for 5 hours, then cooled to room temperature. water (500 mL) was added and the mixture was stirred vigorously until a precipitate formed. This solid was filtered off, washed with 100 mL water, then dried in vacuo to give 19.97 g (76%) of the title compound as a yellow-orange solid; 1 H NMR (CDCl ₃ ) δ: 7.26 (t, 1H), 7.03 (d, 1H), 6.81 (d, 1H), 6.79 (s, 1H), 4.53 (m.p. 1 H, 4.03 (s, 2H), 3.92 (d, 2H), 1.21 (t, 3H).

Part B:

Preparation of N- (3-cyanophenyl) glycine

169 L of a solution of 17.00 g (83.2 mmol) of ethyl N- (3-cyanophenyl) glycine in 100 mL of THF N ₂ are added 3.67 g (87.4 mmol) of lithium hydroxide monohydrate in 20 mL of water. After 15 or. the mixture is acidified to pH 3 with concentrated hydrochloric acid to give a precipitate. This solid was filtered off, washed with 100 mL water, then dried in vacuo to give 14.15 g (97%) of the title compound as a yellowish solid; ¹ H NMR (CDCl ₃ ) δ: 7.28 (dt, 1H), 7.05 (dd, 1H), 6.83 (dd, 1H), 6.82 (d, 1H), 4.00 (s) , 2H).

Part C: Preparation of N- (3-cyanophenyl) -N-nitrosoqlycine

To a suspension of N- (3-cyanophenyl) glycine (14.15 g, 80.3 mmol) in 65 mL of water under N ₂ is added sodium nitrite (5.54 g, 80.3 mmol) in 15 mL of water. The mixture was stirred at room temperature for 14 hours. The solution is acidified to pH 3 with concentrated hydrochloric acid and a precipitate is formed. This solid was filtered off, washed with 50 mL water, then dried in vacuo to give 16.06 g (98%) of the title compound as a gray solid; ¹ H NMR (CDCl ₃ ) δ: 13.22 (ss, 1H), 8.10 (dd, 1H), 7.99 (dd, 1H), 7.87 (dd, 1H), 7.72 (t, 1H), 4.78 (s, 2H).

Part D: Preparation of 1- (3-Cyanophenyl) -4-oxy-1,2,3-oxadiazole

N- (3-cyanophenyl) -N-nitrosoglycine (6.97 g, 34 mmol) was dissolved in 32 mL of acetic anhydride and heated at 70 ° C for 5 h. The reaction mixture is cooled and then poured into 200 ml of ice water. After stirring for 30 min to decompose the excess acetic anhydride, the reaction mixture was filtered to give 5.99 g (94%) of a white solid. ¹ H NMR (CDCl ₃ ) δ: 8.08 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 7.7 Hz, 1H). , 7.82 (dd, J = 8.4, 7.7 Hz, 1H), 9.81 (s, 1H).

Part E: Preparation of 1- (3-cyanophenyl) -4-oxy-5-methylthio-1,2,3-oxadiazole

1- (3-Cyanophenyl) -4-oxy-1,2,3-oxadiazole (1.48 g, 7.9 mmol) was dissolved in 30 mL of dry DMSO and cooled to 0 ° C. A very slow injection of acetyl chloride (1.25 g, 15.9 mmol) under the surface of the liquid under N ₂ . The reaction mixture was stirred at room temperature

At 170 for 14 hours. The mixture is diluted with 100 mL of Et ₂ O and washed twice with 25 mL of saturated aqueous NaHCC> 3. The DMSO is then washed 3 times with 25 mL of water. The organic extracts are dried over MgSO ₄ and concentrated in vacuo to give 1.5 g of a red solid which is used without further purification. MS (NH ₃ -Cl) m / z 234.0 (M + H).

Part F: Preparation of methyl 1- (3-cyanophenyl) -3-methylthiopyrazole-5-carboxylate

The crude 1- (3-cyanophenyl) -4-oxy-5-methylthio-1,2,3-oxadiazole (0.95 g, 3.90 mmol) and methylpropiolate (3.28 g, 39.1 mmol) are dissolved in 40 ml of CH ₂ Cl ₂ and the quartz reaction vessel purged with N ₂ . The reaction mixture is irradiated in a Rayonet RPR-100 photochemical reactor for 14 hours. The crude product is concentrated in vacuo, then chromatographed on silica gel using 20% eluant.

EtOAc / hexanes to give 0.34 g (32%) of a yellow solid. ¹ H NMR (CDCl 3) δ: 7.77 (t, J = 1.8 Hz, 1H), 7.70 (m, 2H), 7.57 (t, J = 8.1 Hz, 1H), δ , 94 (s, 1H), 3.83 (s, 3H), 2.57 (s, 3H).

Part G: Preparation of 1- (3-cyanophenyl) -5-i (2'-t-butylaminosulfonyl-f 1,1 '1-biphen-4-yl) aminocarbonine-3- (methylthio) pyrazole

4-Amino-2'-methylsulfonyl- [1,1 '] - biphenyl (65.7 mg, 0.216 mmol) is suspended in 2 mL of CH ₂ Cl ₂ and 0.51 mL of 2M trimethylaluminum in heptane is added slowly via syringe. The reaction mixture was stirred for 30 min. at room temperature followed by the addition of methyl 1- (3-cyanophenyl) -3-methylthiopyrazole-5-carboxylate (56.2 mg, 0.206 mmol). The reaction mixture was stirred at room temperature for another 14 hours. The aluminum reagent is decomposed by the careful addition of 1N HCl to pH 2. The reaction mixture is then extracted three times with 10 mL of CH ₂ Cl ₂ . The combined organic extracts were washed with water, brine, dried over MgSO _4, and the solvent was evaporated. Chromatography on silica gel eluting with 30% EtOAc / hexanes afforded the desired product (83 mg, 74%). ¹ H NMR (CDCl ₃ ) δ: 8.16 (dd, J = 7.7, 1.5 Hz, 1H), 7.84 (ss, 1H), 7.84 (t, J = 1 , 8 Hz, 1H), 7.76 (m, 1H), 7.70171

7.46 (m, 8H), 7.50 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 7.5 Hz, 1H), 6.81 (s, 1H), 2.62 (s, 3H).

Part H: Preparation of the trifluoroacetic acid salt of 1- (3-amidinophenyl) -5- f (2'-aminosulfonyl-1,1'-biphen-4-yl) aminocarbonyl-3- (methylthio) pyrazole

- (3-Cyanophenyl) -5 - [(2'-t-butylaminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3- (thiomethyl) pyrazole (83 mg, 0.15 mmol) is dissolved 5 ml of methanol and 10 ml of chloroform. The reaction mixture was cooled in an ice bath and kept for 30 min. HCl gas was bubbled through it to saturate the solution. The mixture was sealed and stirred at room temperature for 14 hours. The solvents are evaporated in vacuo and the resulting solid is used in the next step.

The above imidate is added to a solution of 0.15 g (1.6 mmol) of ammonium carbonate in 10 ml of methanol. The mixture was stirred under N _{2 for} 14 h. The solvent is evaporated off under reduced pressure. The crude benzamidine was purified by HPLC (C18 reverse phase column) eluting with 0.5% TFA in H2O / CH3CN to afford 64 mg (84%) of the desired salt. ¹ H NMR (DMSO-d 6) δ: 10.66 (s, 1H), 9.41 (p.s. 2H), 8.97 (p.s. 2H), 7.96 (m, 2H), 7.797.76 (m, 7H), 7.63 (d, J = 9.0 Hz, 2H), 7.56 (t, J = 6.6 Hz, 1H), 7.33 (d, J = 9) , 0 Hz, 2H), 7.27 (m, 1H), 7.19 (s, 1H), 2.55 (s, 3H). DSGMS 507.1268 (M + H).

Examples 154 and 155

1- (3-Amidinophenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] 3- (methylsulfinyl) pyrazole trifluoroacetic acid salt (Example 154) and 1- (3- amidinophenyl) -5 - [(2'-aminosultonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] 3- (methylsulfonyl) pyrazole trifluoroacetic acid salt (Example 155) and 1- (3-amidinophenyl) -5- [(2'-Aminosulfonyl- [1,1'] -biphen-4-yl) aminocarbonyl] 3- (methylthiopyrazole trifluoroacetic acid salt (54 mg, 0.11 mmol) in 10 mL of methanol was added Oxone® (66 mg, 0, 11 mol) and the reaction mixture is stirred for 14 hours and the solvent is evaporated off under reduced pressure.

The sulfoxide 172 was purified by HPLC (C18 reverse phase column) eluting with 0.5% TFA in H ₂ O / CH ₃ CN to afford 22 mg (38%) of the desired salt. ¹ H NMR (DMSO-d 6) δ; 10.84 (s, 1H), 9.43 (s, 2H), 9.00 (s, 2H), 8.00 (s, 1H), 7.99 (m, 1H), 7 , 87 (m, 2H), 7.75 (m, 2H), 7.65 (d, J = 9.6 Hz, 2H), 7.56 (m, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.27 (m, 3H), 2.99 (s, 3H); DSGMS: 523.1220 (M + H). Another product, the sultan (28 mg, 47%), was isolated from the column. ¹ H NMR (DMSO-d 6) δ: 10.89 (s, 1H), 9.52 (pl.s, 2H), 9.09 (s.s, 2H), 8.09 (s, 1H), 8.06 (d, J = 7.3 Hz, 1H), 7.98 (m, 2H), 7.86 (s, 1H), 7.84 (t, J = 9.0 Hz, 1H), 7.72 (d, J = 8.8 Hz, 2H), 7.64 (m, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.33 (m, 3H), 3.45 (s, 3H); DSGMS: 539.1175 (M + H).

Example 156

1- (3-Aminocarbonylphenyl) -5 - [(2'-trifluoromethyl- [1,1 '] - biphen-4-yl) methyl] tetrazole

This compound is prepared by the method described above. ¹ H NMR (DMSO d ₆ ) δ: 5.85 (s, 2H), 7.10-8.25 (m, 12H); MS (ESI) 424.14 (M + H) &lt; + &gt;.

157 Example

1- (3-Aminocarbonylphenyl) -5 - {[(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) methyl] tetrazole

This compound is prepared by the method described above. ¹ H NMR (DMSO d ₆ ) δ: 5.85 (s, 2H), 7.15-8.25 (m, 12H); MS (ESI) 435.12 (M + H) &lt; + &gt;.

158 Example

1- (3-Amidinophenyl) -5 - [(4'-cyclopentyloxyphenyl) aminocarbonyl] -3-methylpyrazole trifluoroacetic acid salt

Part A: 4-Cyclopentyloxyaniline (obtained by reaction of 4-fluoronitrobenzene with the cyclopentanol anion and after catalytic reduction (10% Pd / C) in methanol) is copolished according to the standard procedure with chlorohydride,

173 derived from N 1 - (3-cyanophenyl) -3-methylpyrazole-5-carboxylic acid to give an amide precursor which is a yellowish oil; ¹ H NMR (CDCl 3) δ: 7.79 (s, 1H), 7.75-7.50 (m, 7H), 6.95 (d, 1H), 4.75 (m, 1H), 1.95-1.70 (m, 6H), 1.60 (m, 2H), 2.30 (m, 3H) m, d; ESI mass spectrum m / z (rel intensity) 378 (M + H, 100).

Part B: The title compound (colorless crystals) is obtained by purification (according to standard procedures) of the product obtained by standard Pinner's amidine reaction sequence. ¹ H NMR (DMSO-d 6) δ: 10.39 (s, 1H), 9.42 (pl.s, 2H), 9.05 (pl.s, 2H), 7.94 (s, 1H). , 7.82-7.68 (complex, 3H), 7.71 (d, 2H), 6.97 (s, 1H), 6.88 (d, 2H), 4.77 (m, 1H), 2.33 (s, 3H), 1.84-1.59 (complex, 8H) md; ESI mass spectrum m / z (rel intensity) 404.2 (M + H, 100).

159 Example

1- (3-Amidinophenyl) -5 - [(3 - ((pyrid-2-yl) methylamino) phenyl] aminocarbonyl] -3-methylpyrazole trifluoroacetic acid salt

Part A: Standard 3 - ((pyrid-2-yl) methylamino) aniline [produced in two steps (condensation and reduction) from 3-nitroaniline and 2-pyridylcarboxaldehyde] to give the desired bis-aniline derivative; ¹ H NMR (CDCl ₃ ) δ: 8.58 (d, J = 5.13 Hz, 1H), 7.67 (t, J = 7.69 Hz, 1H), 7.35 (d, J = 7 , 69 Hz, 1H),

7.19 (m, 1H), 6.99 (t, J = 7.69, 8, 06 Hz, 1H), 6.14 (m, 2H), 6.01 (m, 1H), 4.66 (pi.d, 1H), 4.44 (s, 2H), 3.56 (pi.d, 2H) md; mass spectrum (NH 3 -Cl) 200 (M + H, 100)] copulation with chloro-anhydride obtained from. 1- (3-Cyanophenyl) -3-methyl-pyrazole-5-carboxylic acid gives a copolymerized benzonitrile precursor which is then subjected to the standard Pinner amidine reaction sequence to give the desired benzamidine which is colorless crystals. ¹ H NMR (DMSO-d _s) δ: 10.28 (s, 1H), 9.42 (s, 2H), 9.08 (s, 2H), 8.58 (d, J = 4.39 Hz , 1H), 7.83 (m, 3H), 7.72 (m, 2H), 7.46 (d, J = 8.06 Hz, 1H), 7.40 (t, J = 5.49, 6.59 Hz, 1H), 7.01 (m, 3H), 6.88 (d, J = 8.05 Hz, 1H), 6.34 (d, J = 8.06 Hz, 1H), 4 , 39 (s, 2H), 2.31 (s, 3H) md; ESI mass spectrum m / z (relative intensity) 426.1

174 (M + H, 100); DSGMS: C 24 H 24 N 7 O 426.204234 (calcd.), 426.201998 (found).

160 Example

1- (3-amidinophenyl) -3-methyl-5 - [(4 '- (N-imidazolyl) phenyl) aminocarbonyl] pyrazole

Part A: Preparation of N- (4-nitrophenyl) imidazole

4-lmidazolonitrobenzene (5 g) was hydrogenated (10% Pd / C) in 200 mL of methanol for 20 h. The reaction mixture is filtered through a pad of celite to give 3.99 g of crude material which is used directly in the next step. Mass spectrum (H ₂ O-GC / MS): 160 (M + H, 100).

Part B: Preparation of 1- (3-Cyanophenyl) -3-methyl-5-F (4 '- (N-imidazolyl) phenyl) aminocarbonyl · pyrazole

The product of Part A is then coupled with 1- (3-cyanophenyl) -3-methylpyrazole-5-carboxylic acid using the chloro anhydride methodology described above to give the desired amide which is then purified by standard reverse phase HPLC to give the desired product. ¹ H NMR (DMSO-d ₅ , 300 MHz) δ: 10.73 (s, 1H), 9.35 (ss, 2H), 8.13 (s, 1H), 7.95 (s, 1H) ), 7.90-7.60 (complex, 8H), 7.0 (s, 1H), 2.30 (s, 3H) md; ESI mass spectrum m / z (rel intensity) 369 (M + H, 100); DSGMS: 369.146384 (calculated), 369.145884 (found).

Part C: 1- (3-amidinophenyl) -3-methyl-5-f (4 ^- (N-imidazolyl) phenyl) receiving aminokarbonilĮpirazolo

The B product is then subjected to the standard Pinner amidine reaction sequence and purified by HPLC to give the desired benzamidine. ¹ H NMR (DMSO-d 6, 300 MHz) δ: 10.65 (s, 1H), 9.40 (pl.s, 2H), 9.00 (s.s, 2H), 8.19 (s, 1H), 7.90 (s, 1H), 7.80-7.55 (complex, 8H), 7.06 (s, 1H), 2.30 (s,

175

3H) ppm; ESI mass spectrum m / z (rel intensity) 386 (M + H, 100); DSGMS (FAB): 386.172933 (calculated), 386.173388 (found).

Example 161

1- (3-Amidinophenyl) -3-trifluoromethyl-5 - [(4 '- (N-morpholinyl) -3-chlorophenyl) aminocarbonyl] pyrazole

Part A: 1- (3-Cyanophenyl) -3-trifluoromethyl-5 - [(4 '- (N-morpholino) -3-chlorophenylaminocarbonyl] pyrazole

Co-commercialization of commercial 2-chloro-4-morpholinaniline with N- (3-cyanophenyl) -3-trifluoromethylpyrazole-5-carboxylic acid using chloro anhydride under standard conditions yields the desired copolished product. ¹ H NMR (DMSO-d ₆ , 300 MHz) δ: 10.66 (s, 1H), 8.12 (s, 1H), 7.97 (d, 1H), 7.87 (d, 1H), 7.70 (complex, 3H), 7.50 (dd, 1H), 7.14 (d, 2H), 3.70 (m, 4H), 2.90 (m, 4H) md; ESI mass spectrum m / z (rel, intensity) 476 (M + H, 100).

Part B: Preparation of 1- (3-Amidinophenyl) -3-trifluoromethyl-5-i (4 '- (N-morpholino) -3-chlorophenyl-aminocarbonylpyrazole

The cyano compound of part A is converted to the amidine derivative via amidoxime as described above. The amidoxime is reduced to the desired compound (acetic acid / acetic anhydride and catalytic reduction of acetate with 10% palladium on carbon in hydrogen atmosphere) as described above. The crude product is purified by standard HPLC techniques to afford the desired compound as the bis-TFA salt. 1 H NMR (DMSO-d 6, 300 MHz) δ: 10.73 (s, 1H), 9.41 (pl.s, 2H), 9.09 (pl.s, 2H), 7.98 (s, 1H), 7.89 (m, 2H), 7.73 (complex, 3H), 7.50 (d, 1H), 7.14 (d, 1H), 3.69 (complex, 4H), 2, 89 (complex, 4H) md; ESI mass spectrum m / z (rel intensity) 493 (M + H, 100); DSGMS (FAB +): 493.136666 (calculated), 493.136951 (found).

Example 162

1- (3-Amidinophenyl) -3-methyl-5 - [(4 '- (N-pyrrolidinocarbonyl) -3'-chlorophenyl) aminocarbonyl] pyrazole

176

Part A: Preparation of 4'-Pyrrolidinocarbonyl-3-chloronitrobenzene

To a solution of 4-nitro-3-chlorobenzoic acid (1.61 g) in dichloromethane was added N-methylmorpholine (1.93 mL) and isobutyl chloroformate (1.04 mL), followed by pyrrolidine (0.67 mL), and the reaction mixture was kept at room temperature. Concentration of the reaction mixture, treatment with water and extraction with ethyl acetate yields a crude product which is used directly in the subsequent reaction. MSGMS (NH ₃ -Cl): 255 (M + H).

Part B: Preparation of 4'-Pyrrolidinocarbonyl-3-chloroaniline

The crude 4'-pyrrolidinocarbonyl-3-chloronitrobenzene is treated with a catalytic amount of 10% palladium on carbon in 20 ml of methanol and placed under a hydrogen atmosphere at 68.9 kPa for 15 hours. The mixture is passed through a 25.4 mm celite layer and concentrated in vacuo. Recrystallization from methylene chloride / methanol gives 1.8 g of crystalline 4'-carboxamidopyrrolidine-3-chloroaniline. ¹ H NMR (DMSO-d ₆ , 300 MHz) δ: 16.94 (d, 1H, J = 8.42 Hz), 6.66 (d, 1H, J = 1.83 Hz), 6.47 ( dd, 1H, J = 8.43, J = 7.69 Hz), 3.36 (t, 2H, J = 6.23, J = 6.95 Hz), 3.09 (t, 2H, J = 6.22, J = 6.23 Hz), 1.78 (m, 4H) md; mass spectrum (NH ₃ -Cl): 225 (M + H, 100).

Part C: 1- (3-Cyanophenyl) -3-methyl-5 - [(4 '- (N-pyrrolidinocarbonyl) -3'-chlorophenyl] aminocarbonylpyrazole

Standard coupling of the product of Part B with chloro-anhydride derived from 1- (3-cyanophenyl) -3-methylpyrazole-5-carboxylic acid gives the desired copolished product. ¹ H NMR (DMSO-d 6,; 300 MHz) .δ: 10.71 (s, 1H), 7.97 (d, 1H), 7.84 (m, 2H), 7.76 (m 1H), 7.63 (m, 2H), 7.32 (d, 1H), 7.00 (s, 1H), 3.42 (t, 2H), 3.06 (t, 2H), 2.29 (s) , 3H), 1.80 (m, 4H) md; ESI mass spectrum m / z (rel intensity) 434 (M + Na, 100).

Part D; 1- (3-Amidinophenyl) -3-methyl-5 - [(4 '- (N-pyrrolidinocarbonyl) -3'chlorophenyl) aminocarbonyl] pyrazole

177

Part C benzonitrile is then converted to the desired benzamidine under the standard conditions described above. Purification by reverse-phase HPLC affords the title compound as the trifluoroacetic acid salt. ¹ H NMR (DMSO-d ₆ , 300 MHz) δ: 10.73 (s, 1H), 9.38 (s, 2H), 9.04 (s, 2H), 7.91 (s, 1H), 7.85 (s, 1H), 7.79 (d, 1H), 7.74 (d, 1H), 7.67 (d, 1H), 7.62 (m, 1H), 7.02 (s) , 1H), 3.41 (t, 2H), 3.06 (t, 2H), 2.30 (s, 3H), 1.82 (m, 4H) md ,; ESI mass spectrum m / z (rel intensity) 451 (M + H, 100); DSGMS (Cl): 451.164788 (found), 451.164927 (calcd).

Example 163

1- (3-Amidinophenyl) -3-methyl-5 - [(4 '- (N-morpholinocarbonyl) -3-chlorophenyl) aminocarbonyl] pyrazole

Part A: Preparation of 4- (N-morpholinocarbonyl) -3-chloronitrobenzene

To a solution of 4-nitrobenzoyl chloride (2.41 g) in dichloromethane at 0 was added a solution of morpholine (3.40 mL) in 75 mL of methylene chloride. The reaction mixture was warmed to room temperature and kept for 20 hours, then diluted with water (100 mL). The organic layer was separated, washed with water (50 mL), 1.0 M HCl (50 mL), dried (magnesium sulfate) and concentrated in vacuo. The crude material is used in the next step without further purification. Mass spectrum (NH ₃ -Cl): 237 (M + H, 100). The product obtained above is then catalytically reduced (10% palladium on carbon, 60 mL methanol, held at 413.7 kPa hydrogen pressure for 3 h), filtered through a pad of celite, and evaporated to give the desired aniline derivative. ¹ H NMR (DMSO-d 6, 300 MHz) δ: 7.09 (d, 2H), 6.50 (d, 2H), 3.54 (t, 4H), 3.44 (t, 4H), 3 , 29 (s, 2H) md; Mass Spectrum (NH ₃ -Cl): 207 (M + H, 100).

Part B: Preparation of 1- (3-Cyanophenyl) -3-methyl-5-r (4 '- (N-morphplinocarbonyl) -3-chlorophenyl) aminocarbonylpyrazole

Standard coupling of Part A product with chloro-anhydride derived from 1- (3-cyanophenyl) -3-methylpyrazole-5-carboxylic acid, after conventional work-up and

178 chromatography on a silica gel column gives the desired product (oil). 1 H NMR (DMSO-d 6, 300 MHz) δ: 10.63 (s, 1H), 7.94 (s, 1H), 7.83 (d, 1H, J = 7.69 Hz), 7.75 (dd, 1H, J = 8.06, J = 8.06 Hz), 7.70 (d, 2H, J = 8.42 Hz), 7.63 (t, 1H, J = 7.69, J = 8.05 Hz), 7.37 (d, 2H, J = 8.06 Hz), 6.98 (s, 1H), 3.28 (d, 8H, J = 6.96 Hz), 2, 28 (s, 3H) md; ESI mass spectrum m / z (rel intensity) 438 (M + Na), 416 (M + H, 100).

Part C; Preparation of 1- (3-Amidinophenyl) -3-methyl-5 - [(4 '- (N-morphplinocarbonyl) -3-chlorophenyl) aminocarbonyl] pyrazole

Standard conversion of Part B product to benzamidine and purification by reverse phase HPLC affords the desired product. 1 H NMR (DMSO-d 6, 300 MHz) δ; 10.66 (s, 1H), 9.38 (s, 2H), 9.04 (s, 2H), 7.90 (d, 1H, J = 9.52 Hz), 7.78 (d, 1H, J = 7.33 Hz), 7.73-7.62 (complex, 4H), 7.37 (d, 2H, J = 8.42 Hz), 7.00 (s, 1H) , 3.55-3.46 (complex, 8H); ESI mass spectrum m / z (rel intensity): 433 (M + H, 100); DSGMS: 433.199045 (found), 433.198814 (calculated).

Example 164

1- (3-Cyanophenyl) -5 - [(4 '- (N-imidazolyl) phenyl) aminocarbonyl] -3-trifluoromethylpyrazole trifluoroacetic acid salt

1- (3-Cyanophenyl) -3-trifluoromethyl-pyrazol-5-ylcarboxylic acid (0.5 g, 1.8 mmol) is copolished with 4-imidazolylaniline (0.3 g, 1.8 mmol) under standard conditions and purified by HPLC 0.67 g (71%) of product is obtained. 1 H NMR (DMSO-d ₆ ) δ: 10.99 (s, 1H), 9.55 (s, 1H), 8.22 (d, J = 5.49 Hz, 2H), 8.04 (d , J = 7.69 Hz, 1H), 7.96 (d, J = 8.06 Hz, 1H), 7.89 (s + d, J = 8.79 Hz, 3H), 7.80 (m (4H) md; DSGMS: 423.118119 (calculated), 423.116015 (found); Analysis: Calculated for C 21 H 13 F ₃ N ₅ O (TFA) C: 51.50, H: 2.63, N: 15.67, Found: C: 51.52, H: 2.71, N: 15.49.

Example 165

1- (3-amidinophenyl) -5 - [(4 '- (N-imidazolyl) phenyl) aminocarbonyl] 179

Trifluoroacetic acid salt of 3-trifluoromethylpyrazole

1- (3-Cyanophenyl) -5 - [(4'-imidazol-1-ylphenyl) aminocarbonyl-3-trifluoromethylpyrazole is subjected to standard Pinner amidine reaction sequence conditions and purified under standard conditions to give the desired amidine (79%). Ή NMR (DMSO-d ₆₎ δ: 11.02 (s, 1H), 9.46 (s, 1.5H), 9.42 (s, 1.5H), 8.17 (s, 1H) 8.06 (s, 1H), 7.97 (t, J = 7.69 Hz, 2H), 7.88 (d, J = 8.79 Hz, 2H), 7.80 (m, 3H), 7.79 (d, J = 9.0 Hz, 2H) md; DSGMS: 440.144668 (calculated), 440.144557 (found); Analysis: Calculated for C ₂₁ H ₁₆ F ₃ N ₇ O (TFA) 2 (H ₂ O) 1: C: 43.81, H: 2.94, N: 14.30, Found: C: 43.76, H : 2.70, N: 13.95.

Example 166

1- (3-Amidinophenyl) -5 - [(4 '- (N-methyltetrazolon-1-yl) phenyl) aminocarbonyl] 3-trifluoromethylpyrazole trifluoroacetic acid salt

Part A: 4-Nitrobenzoic acid is converted to 4-nitrophenyltetrazolone according to Toselli, M and Zaneratio, P., JCS Perk. Trans. 1992, 1, 1101. ¹ H NMR (DMSO-d ₆ ) δ: 8.46 (d, J = 9.15 Hz, 2H), 8.22 (d, J = 9.16 Hz, 2H).

Part B: To 4-nitrophenyltetrazolone (0.8 g, 3.9 mmol) in DMF (10 mL) was added iodomethane (0.38 mL) and 60% sodium hydride (0.23 g) at 0 ° C. The reaction mixture was allowed to warm to room temperature and stirred for 24 hours. The reaction was quenched with water, extracted with ethyl acetate and dried (MgSO 4). The crude product is chromatographed on silica gel and recrystallized from methylene chloride / hexanes to give 0.35 g (41%) of product: MS (DCI) m / z 192 (M + H-NO) ⁺ , 209 (M + NH ₄ -NO) ^+. .

Part C: The nitro compound of Part B (0.215 g, 0.97 mmol) is hydrogenated under an atmosphere of hydrogen and a catalytic amount of 10% palladium on carbon to aniline. Mass spectrum (DCI) m / z 192 (M + H) ⁺ , 209 (M + NH ₄ ) ⁺ .

180

Part D: 1- (3-Cyanophenyl) -3-trifluoromethylpyrazol-5-ylcarboxylic acid (0.38 g, 1.4 mmol) was cloned with Part C aniline according to standard procedure to give the nitrile in 43% yield. ¹ H NMR (CDCl 3) δ: 8.04 (s, 1H), 7.95 (d, J = 9.16 Hz, 2H), 7.85 (s, 1H), 7.79 (m, 2H) ), 7.67 (m, 3H), 7.21 (s, 1H), 3.71 (s, 3H) md; MS (ESI) m / z = 454.9 (M + H) ⁺ , 477 (M + Na) ⁺ .

Part E: Part N nitrile is subjected to standard Pinner reaction conditions and the desired amidine is obtained in 53% yield. ¹ H NMR (DMSO-d ₆ ) δ: 10.63 (s, 1H), 9.46 (s, 1.5H), 9.12 (s, 1.5H), 8.04 (s, 1H) , 7.95 (d, J = 7.69 Hz, 2H), 7.84 (s, 4H), 7.81 (m, 2H), 3.61 (s, 3H) md; DSGMS: 472.145731 (calculated), 472.145205 (found); Analysis: Calculated for C 20 H 16 F 3 N 9 O 2 (TFA) 1.2: C: 44.23, H: 2.85, N: 20.73, Found C: 44.40, H: 2.85, N: 20.15.

Example 167 1-ia'-Aminocarbonylphenyl-S-liz'-aminosulfonylphenyl-yl (1'-biphenyl) methylcarbonyl] -3-methylpyrazole

This amide is isolated from the Pinner reaction by HPLC isolation techniques. ¹ H NMR (DMSO-d ₆ ) δ: 10.63 (s, 1H), 8.06 (s, 1H), 8.03 (dd, J = 2.19, 7.32 Hz, 1H), δ , 87 (s, 1H), 7.61 (m, 2H), 7.53 (m + d, J = 7.33 Hz, 3H), 7.44-7.26 (m, 6H), 7, 21 (s, 2H), 4.33 (s, 2H), 2.33 (s, 3H) md; ESI mass spectrum m / z (rel intensity) 497 (M + Na, 100), 433 (M + H).

Example 168

1- (3-Amidinophenyl) -5- [4 '- (pyrrolidinomethyl) phenyl) aminocarbonyl] -3-methylpyrazole trifluoroacetic acid salt

Standard coupling of 4- (pyrrolidinomethyl) aniline with chloro-anhydride derived from 1- (3-cyanophenyl) -3-methyl-pyrazole-5-carboxylic acid yields a copolymerized benzonitrile precursor followed by Pinner's amidine reaction sequence and purification. the desired product (colorless crystals) is obtained. ^1H

NMR (DMSO) δ: 10.69 (s, 1H), 9.42 (s, 2H), 9.20 (s, 2H), 7.96 (s, 1H), 7.84 (m,

181

1H), 7.75-7.68 (m, 4H), 7.48 (d, 2H, J = 8.79 Hz), 7.04 (s, 1H), 4.31 (m, 2H), 3.35 (pi, 2H), 3.05 (pi, 2H), 2.34 (s, 3H), 2.05 (pi, 2H), 1.85 (pi, 2H) md; ESI mass spectrum m / z (rel intensity) 403 (M + H, 100) DSGMS: C23H27N6O 403.224635 (calcd.), 403.222719 (found).

Example 169

1- (3-Aminophenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 T] -biphen-4-yl) aminocarbonyl] pyrazole

Part A: To commercially available 3-nitrophenylhydrazine hydrochloride (1.00 g, 5.27 mmol) in 15 mL of absolute ethanol was added 1,1,1-trichloro-4-methoxy-3penten-2-one (1.15 g, 5, 27 mmol) and the reaction mixture was refluxed for 12 hours. The solvent was evaporated and the residue was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in hexanes. The first elution fraction contains the desired ethyl (3-nitrophenyl) -3-methyl-5-pyrazolecarboxylate. MS (ES +) 276.1 (M + H) &lt; + &gt; (100%). This ester (110 mg, 0.400 mmol) is coupled with (2'-tert-butylaminosulfonyl- [1, b] biphen-4-yl) amine (122 mg, 0.400 mmol) using the Veinreb trimethylaluminum method. 1- (3-nitrophenyl) -3-methyl-5 - [(2'-tert-butylaminosulfonyl- [TT] -biphen-4-yl) (178.2 mg, 83%) is obtained after preparative TLC (50% ethyl acetate / hexanes eluent). ) aminocarbonyl] pyrazole which is a colorless solid. MS (ES +) 551.24 (M + NH ₄ ) ⁺ (30%); 556.18 (M + Na) ⁺ (100%).

Part B: 170.5 mg (0.320 mmol) of the product from Part B in 5 ml of trifluoroacetic acid was refluxed for 12 hours. Preparative TLC (10% methanol / chloroform as eluent) gives 1- (3-nitrophenyl) -3-methyl-5 - [(2'-aminosulfonyl- [TT] -biphen-4-yl) aminocarbonyl] pyrazole as a colorless solid material. MS (ES +) 478.23 (M + H) &lt; + &gt;(30%); 500.21 (M + Na) ⁺ (100%). DSGMS (FAB +) (M + H) +: Calculated: 478.118616, Found: 478.117673.

182

Part C: 64.3 mg (0.135 mmol) of the product from Part B are catalytically hydrogenated (5% Pd / C in ethanol at 1 atm hydrogen pressure) to give the title compound as a colorless solid. ¹ H NMR (CD 3 OD) δ: 8.08 (d, J = 7.7 Hz, 1H), 7.61-7.30 (m, 8H), 7.13 (t, J = 7.7 Hz) , 1H), 6.72 (m, 3H), 2.33 (s, 3H). MS (ESI +): 448.11 (M + H) &lt; + &gt;(35%); 470.16 (M + Na) ⁺ (100%). DSGMS (FAB +) (M + H) ⁺ : Calc'd 448.144337, Found 448.144965.

Example 170

1- (2'-Aminophenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole

This compound was prepared in a similar manner to Example 169. ¹ H NMR (CD 3 OD) δ: 8.14-8.03 (m, 2H), 7.58-6.74 (m, 11H), 2.47 (s, 3H). MS (ESI +): 448.12 (M + H) ⁺ (60%); 470.16 (M + Na) ⁺ (100%).

Example 171

1- (3-amino-4'-chlorophenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1, r] ^_B 'f * ^en 4-i ·) aminocarbonyl

This compound was prepared in a similar manner to Example 169. Δ NMR (CD3OD) δ: 8.08 (d, J = 6.9 Hz, 1H), 8.07-7.23 (m, 8H), 6.91 (d, J = 2.2 Hz, 1H), 6.79 (s, 1H), 6.66 (dd, J = 8.43, 2.56 Hz, 1H), 2.22 (s, 3H). MS (ESI +): 482.0 (M + H) &lt; + &gt;(80%); 484.0 (30%), 504.0 (M + Na) ⁺ (100%), 506 (40%).

Example 172

1- (3-Amino-4'-fluorophenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole

This compound was prepared in a similar manner to Example 169. Ή NMR (CD ₃ OD) δ: 8.14 to 8.03 (m, 2H), 7.58 to 6.74 (m, 11 H), 2.47 (s, 3H). MS (ES +): 466.0 (M + H) &lt; + &gt;(5%); 488.0 (M + Na) ⁺ (100%).

183

Example 173

1- (3-Amino-4'-methoxyphenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole

This compound was prepared in a similar manner to Example 169. ¹ H NMR (CD ₃ OD) δ: 8.10 (d, J = 6.6 Hz, 1H), 7.63-7.31 (m, 7H), 6.89-6.72 (m, 4H ), 3.88 (s, 3H), 2.34 (s, 3H). MS (ES +): 478.1 (M + H) &lt; + &gt;(25%); 500.0 (M + Na) ⁺ (100%).

Example 174

1- (3-Amino-4'-chlorophenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] tetrazole trifluoroacetic acid salt

Part A: Preparation of 1- (3-Nitro-4-chlorophenyl) -5-carboethoxytetrazole

4-Chloro-3-nitroaniline (10.36 g, 60 mmol) was dissolved in CH ₂ Cl ₂ (100 mL). Triethylamine (10 mL, 70 mmol) was added followed by oxalyl chloride (6.8 mL, 60 mmol). The mixture was stirred at room temperature under N _{2 for} 15 min. It is then diluted with CH ₂ Cl ₂ , washed with water and brine. The CH ₂ Cl ₂ solution was dried over MgSO ₄ and concentrated to a yellowish solid (15.53 g). This amide (5.5 g, 20.2 mmol) was refluxed for 4 h. with a solution of triphenylphosphine (7.87 g, 30 mmol) in 100 mL CCI ₄ . (The solution is stirred at 0 ° C for 15 min before the amide is added). The reaction mixture is cooled and the precipitate is filtered off. The filtrate is concentrated to a solid. This material was dissolved in 100 mL CH ₃ CN and NaN ₃ (1.31 g, 1 eq) was added. The mixture was stirred at room temperature under N _{2 for} 12 h. The solvent is evaporated. The solid was dissolved in EtOAc and the solution was washed with water and saturated NaCl solution. Dry over MgSO ₄ , concentrate, and chromatograph over silica gel (CH ₂ Cl ₂ ) to give 3.19 g of the desired product. ¹ H NMR (CDCl ₃ ) δ: 1.35 (t, 3H), 4.42 (kv, 2H), 7.50-7.70 (m, 2H), 8.10 (s, 1H). MS (DCI-NH ₃ ) 315 (M + NH ₄ ) ⁺ .

184

Part B: Preparation of 1- (3-Nitro-4'-chlorophenyl) -5- f (2'-t-butylaminosulfonyl-n ', biphen-4'-aminocarbonyltetrazole

2'-t-Butylaminosulfonyl-4-amino- [1,1 '] - biphenyl (1.33 g, 4.37 mmol) was dissolved in 40 mL of anhydrous CH ₂ Cl ₂ and trimethylaluminum (11 mL of a 2M solution in heptane) was added slowly. The mixture was stirred at room temperature under N _{2 for} 15 min. A solution of part A (1.30 g, 4.37 mmol) in anhydrous CH ₂ Cl ₂ (40 mL) was then added. The mixture was stirred at room temperature under N _{2 for} 18 h. The reaction mixture was carefully quenched with 1N HCl. It is diluted with CH ₂ Cl ₂ and washed with water and saturated NaCl solution. The organic solution was then dried over MgSO ₄ , concentrated, and chromatographed on silica gel (CH ₂ Cl ₂ ) to give 1.5 g of the desired product. MS (ESI) 554.1 (MH ⁺ ).

Part C: Preparation of 1- (3-Nitro-4-chlorophenyl) -5- f (2'-aminosulfonyl-1,1,1'-biphen-4-yl) aminocarbonyl] tetrazole

Part B material (1.5 g, 2.7 mmol) and trifluoroacetic acid (20 mL) were stirred at room temperature under N ₂ overnight. Trifluoroacetic acid was evaporated, and silica gel chromatography (10% EtOAc / CH ₂ Cl ₂ ) gave 0.72 g of the desired product. ¹ H NMR (DMSO-d ₆ ) δ: 7.25-8.20 (m, 11H), 8.69 (s, 1H), 11.55 (s, 1H). MS (ESI) 497.9: 499.9 (3: 1) (MH) ⁺ .

Part D: Preparation of 1- (3-Amino-4-chlorophenyl) -5- f (2'-aminosulfonyl-1,1,1'-biphen-4-yl) aminocarbonyltetrazole trifluoroacetic acid salt

Part C material (0.72 g, 1.44 mmol) was dissolved in EtOAc (30 mL). SnCl _2, 2H ₂ O (2.59 g, 11.52 mmol) was added. The reaction mixture was refluxed for 1 h, then cooled to room temperature. Saturated NaHCO ₃ solution to pH 8.0 was added to the mixture. The mixture was partitioned between EtOAc and NaHCO ₃ layers. The EtOAc layer was washed with water and saturated NaCl solution. It is dried over MgSO ₄ and concentrated. The solid is dissolved in CH ₃ CN7TFA and purified by reverse phase HPLC

185

300 mg of the desired product. ¹ H NMR (DMSO-d _g) δ: 6.80 to 8.00 (m, 11 H), 11.40 (s, 1H). MS (DCI-NH ₃ ) 470 (M + H) ⁺ .

Example 175

1- (3-Amino-4'-chlorophenyl) -5 - {[(2'-aminosulfonylphenyl) pyridin-2-yl] aminocarbonyl} tetrazole

This compound is prepared according to the procedure described in Example 171. 1 H NMR (DMSO-d 6) δ: 6.80-8.40 (m, 10H), 11.70 (s, 1H). MS (ESI) 471.20 (M + H) &lt; + &gt;.

Example 176

1- (3-Amino-4'-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1 T] -biphen-4-yl) aminocarbonyl] tetrazole trifluoroacetic acid salt

This compound is prepared according to the procedure described in Example 171. Δ NMR (DMSO-d6) δ: 6.80-8.05 (m, 11H), 11.15 (s, 1H). MS (ESI) 466.0 (M + H) &lt; + &gt;.

Example 177

1- (3-Aminomethylphenyl) -5 - [(2'-aminosulfonylphenyl) pyridin-2-yl) -aminocarbonyl] 3-methylpyrazole trifluoroacetic acid salt

Part A: Ethyl 1- (3-cyanophenyl) -3-methyl-5-pyrazolecarboxylate (2.7 g, 10.58 mmol) was dissolved in methanol (50 mL). glacial acetic acid (2 mL) and 10% palladium on carbon (cat.) are added to this solution. The reaction mixture was hydrogenated (344.7 kPa) for 12 hours, filtered through celite, and evaporated to give the crude benzylamine salt. This crude amine is converted to a carbobenzyloxy derivative by treatment with CBzCl in saturated sodium bicarbonate solution. The organic material was extracted with ethyl acetate (2 x 100 mL), dried over magnesium sulfate and evaporated to give the crude product (2.15 g). This oil is then hydrolyzed with LiOH (0.22 g, 5.5 mmol)

186 in aqueous THF for 16 h. The reaction mixture was quenched with water (500 mL) and the unreacted products were extracted with ethyl acetate (2 x 100 mL). The aqueous layer was carefully acidified (1N HCl), then extracted with ethyl acetate (2 x 100 mL), the extract dried (magnesium sulfate) and evaporated to give the pure acid (1.23 g); ESI (mass) 362 (M-H, 100).

Part B: Standard coupling of Part A product (TBTU, triethylamine in anhydrous THF) with 2-amino-5- (2'-tert-butylaminosulfonylphenyl) pyridine gives the desired amido derivative, which is hydrogenated (10% Pd / C, methanol, from a balloon) ) overnight. The reaction mixture was filtered through celite and evaporated to a yellowish oil. Purification according to the standard reverse-phase procedure gives the desired product which is colorless crystals; ¹ H NMR (DMSOds) δ: 8.35 (d, 1H), 8.19 (m.s, 1H), 8.00 (t, 1H), 7.78 (dd, 1H), 7.63 ( t, 2H), 7.77-7.37 (m, 6H), 7.06 (s, 1H), 4.13 (m, 2H), 2.30 (s, 3H) md; ESI mass spectrum m / z (rel intensity) 463.3 (M + H, 100).

Example 178

1- (3-Aminomethyl-4'-methylphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methylpyrazole trifluoroacetic acid salt

Part A: Ethyl 1- (3-cyano-4-methylphenyl) -3-methyl-5-pyrazolecarboxylate is prepared according to the standard condensation procedure described above (3-cyano-4-methylphenylhydrazine and ethyl 2- (N- (methoxy) imine). -4-oxopentanoate in acetic acid) ¹ H NMR (CDCl ₃ ) δ: 7.68 (s, 1H), 7.57 (dd, 1H), 7.58 (d, 1H), 6.82 (s, 1H), 4.24 (s, 2H), 2.40 (s, 3H), 2.37 (s, 3H), 1.27 (t, 3H) md; ESI mass spectrum 270 (M + H, 100) ).

Part B: The product of Part A is coupled with 1-amino-2'-tert-butylaminosulfonylbiphenyl according to the standard Veinreb copulation procedure to give the desired product. ¹ H NMR (CDCl ₃ ) δ: 8.30 (m.p.

1H), 8.13 (ss, 1H), 7.78-7.23 (m, 10H), 6.78 (s, 1H), 3.68 (s, 1H), 2.60 (s) ,

187

3H), 2.40 (s, 3H), 1.01 (s, 9H) ppm; ESI mass spectrum m / z (rel intensity) 550 (M + Na, 100).

Part C: The product from Part B is then hydrogenated according to the procedure described above at 344.7 kPa in acidic methanol, then treated with TFA (pure), and purified by standard reverse phase chromatography to give the title compound as colorless crystals. ¹ H NMR (DMSO-d ₆ ) δ: 10.6 (s, 1H), 8.14 (ds, 2H), 8.01 (d, 1H), 7.68 (d, 2H), 7 , 54 (m, 2H), 7.26 (m, 5H), 6.91 (s, 1H), 4.07 (pi.d, 1H), 2.38 (s, 3H), 2.33 ( s, 3H) md; ESI mass spectrum m / z (rel intensity) 476 (M + H, 100).

Example 179

1- (3-Aminomethyl-4'-fluorophenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methylpyrazole trifluoroacetic acid salt

This benzylamine is prepared from 3-cyano-4-fluorophenylhydrazine according to the procedures described above. 1 H NMR (DMSO-d 6) δ: 8.25 (pi.s, 3H), 8.00 (d, 1H), 7.78-7.23 (complex, 12H), 6.95 (s, 1H ), 4.14 (m, 2H), 2.30 (s, 3H) md; ESI mass spectrum m / z (rel intensity) 480 (M + H, 100).

Example 180

1- (3-Aminomethylphenyl) -5 - [(4 '- (N-pyrrolidinocarbonyl) phenyl) aminocarbonyl] -3-trifluoromethylpyrazole trifluoroacetic acid salt

A d a s: Preparation of 1- (3-Cyanophenyl) -5- [(4 '- (N-pyrrolidinocarbonyl) phenyl] aminocarbonyl-3-trifluoromethylpyrrolidone

- (3-Cyanophenyl) -3-trifluoromethylpyrazol-5-ylcarboxylic acid (0.5 g, 1.8 mmol) is coupled with 4- (N-pyrrolidinocarbonyl) aniline (0.3 g, 1.8 mmol) under standard conditions to give 0.4 g (56%) of a white solid. 1 H NMR (CDCl 3) δ: 9.72 (s, 1H), 7.78-7.72 (m, 4H), 7.61 (t, J = 7.69 Hz, 1H), 7.23 ( s, 4H), 3.67 (t, J = 6.59 Hz, 2H), 3.43 (t, J = 6.59 Hz, 2H), 1.98 (kv, J =

188

6.23 Hz, 2H), 1.89 (s, J = 6.23 Hz, 2H) ppm; ESI mass spectrum m / z (rel intensity) 476 (M + Na, 100), 454.1 (M + H).

Part B: Part A nitrile (0.4 g, 0.88 mmol), 10% palladium on carbon (50 mg) and ethanol (20 mL) were placed in a Parr apparatus and hydrogenated for 18 hours. at a pressure of 275.8 kPa. The reaction mixture was filtered and concentrated. The crude product was purified by reverse phase HPLC to afford 0.38 g (76%) of the desired amine after lyophilization. ¹ H NMR (DMSO-d ₆ ) δ: 10.91 (s, 1H), 8.23 (m.s, 2H), 7.73 (m, 3H), 7.71 (d, J = 8). 79 Hz, 2H), 7.59 (m, 2H), 7.54 (d, J = 8.42 Hz, 2H), 4.16 (d, J = 5.50 Hz, 2H), 3.45 (kv, J = 7.32 Hz, 4H), 1.83 (ppm, 4H) md; Analysis: Calculated for C 23 H ₂₂ F ₃ N ₅ O ₂ (TFA) 1 (H ₂ O) 0.5: C: 51.73, H: 4.27, N: 12.06, Found: C: 51.45, H: 3.95, N : 11.73.

Example 181

1- (3-Ethylcarboxamidinophenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methylpyrazole 1- (3-cyanophenyl) -5 - [(2 Ethyl chloroformate (0.017 mL, 0.17 mmol) was added to '-t-butylaminosulfonyl- [1,1'] - biphen-4-yl) aminocarbonyl] -3-methylpyrazole (88 mg, 0.15 mmol) in DMF (5 mL). ) and triethylamine (0.052 mL, 0.037 mmol) and the reaction mixture was stirred for 72 h. The mixture was diluted with ethyl acetate and washed with water, then brine and dried (MgSO _4). Purification by chromatography on silica gel eluting with 3-10% methanol / methylene chloride gave 27 mg (33%) of the title compound. ¹ H NMR (DMSO-d ₆ ) δ: 10.62 (s, 1H), 9.18 (s, 1H), 8.16 (s, 1H), 8.05 (m, 2H), 7.70 (d, 2H), 7.60 (m, 5H), 7.37 (d, 2H), 7.30 (d, 1H), 7.24 (s, 2H), 6.95 (s, 1H) , 4.10 (kv, 2H), 2.35 (s, 3H), 1.20 (t, 3H) md; DSGMS 547.176365 (calculated), 547.178880 (found).

Examples 182 and 183

1- (3- (r -imino-1 '- (N-morpholino) methyl) phenyl-5 - [(2'-tert-butylaminosulfonyl [1,1'] - biphen-4-yl) aminocarbonyl] -3-methylpyrazole of trifluoroacetic acid

189 salt and 1- (3- (1 Mmino-r- (N-morpholino) methyl) phenyl-5 - [(2'-aminosulfonyl [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methylpyrazole trifluoroacetic acid salt

Part A: The morpholine-amidine compound is prepared from its precursor nitrile by nucleophilic anhydrous morpholine synthesis using the standard Pinner reaction procedure. Purification by standard HPLC gives the desired morpholino-amidine compound as colorless crystals. ¹ H NMR (DMSO-d ₆ ) δ: 11.39 (s, 1H), 9.67 (s, 1H), 9.27 (s, 1H), 8.62 (s, 2H), 8.09 (d, J = 7.69 Hz, 1H), 7.79 (s, 1H), 7.73-7.61 (m, 5H), 7.42 (d, J = 7.32 Hz, 1H). , 7.30 (s, 1H), 7.08 (s, 1H), 3.81 (pi, 2H), 3.74 (pi, 2H), 3.63 (pi, 2H) 3, 37 (pi, 2H), 2.31 (s, 3H), 1.04 (s, 9H) md; ESI mass spectrum m / z (rel intensity) 603.2 (M + H, 100).

Part B: The f-butyl group is then cleaved by heating the product of Part A in TFA and purifying by standard HPLC techniques to give the desired morpholino-amidine as colorless crystals; ¹ H NMR (DMSO) δ: 11.38 (s, 1H), 9.67 (s, 1H), 9.27 (s, 1H), 8.65 (s, 2H), 8.08 (m, 1H), 7.78 (s, 1H), 7.737.67 (m, 5H), 7.62 (m, 1H), 7.55 (s, 1H), 7.45 (m, 1H), 7, 09 (s, 1H), 3.81 (pi, 2H), 3.74 (pi, 2H), 3.62 (pi, 2H), 3.37 (pi, 2H), 2.31 (pi, 2H) s, 3H) md; ESI mass spectrum m / z (rel intensity) 547.0 (M + H, 100), DSGMS C26H27N8O4S 547.187599 (calcd.), 547.186294 (found).

Example 184

1- [3- [N - ((5-methyl-2-oxo-1,3-dioxol-4-yl) methoxycarbonyl) amidino] phenyl] 5 - ((2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl) -3-methylpyrazole

Part A: 4-Hydroxymethyl-5-methyl-1,3-dioxol-2-one (0.227 g, 1.75 mmol) (Alpegiani, M. et al. Syn. Com. 1992, 22 (9), 1277 ) in chloroform (5 mL) at 0 ° C was added pyridine (0.15 mL) and 4-nitrophenyl chloroformate (0.387 g, 1.9 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was washed with water saturated with NaCl

190 solution and dried (Na ₂ SO ₄ ). The crude dioxolone is used in the next step.

Part B: 1- (3-Amidinophenyl) -5 - ((2'-aminosulfonyl- [1,1 '] -biphen-4-yl) aminocarbonyl) -3-methylpyrazole (80 mg, 0.14 mmol) in DMF (1 mL) of Part A dioxolone and triethylamine (0.038 mL) was added. The mixture is stirred for 18 hours. The reaction mixture was diluted with ethyl acetate, washed with water and dried (MgSO ₄ ). Purification by chromatography on silica gel eluting with 3-5% methanol in methylene chloride afforded 47 mg (55%) of the desired dioxolone. ¹ H NMR (DMSO) δ: 10.63 (s, 1H), 8.25 (s, 1H), 8.05 (t, 2H), 7.62 (d, 2H), 7.50 (m, 5H), 7.37 (m, 4H), 7.25 (s, 2H), 6.93 (s, 1H), 4.92 (s, 2H), 2.37 (s, 3H), 2, 15 (s, 3H) md; DSGMS 631.161109 (calculated), 631.160927 (found).

Example 185

1- (Pyrid-2-yl) -3-methyl-5 - [(3-fluoro-2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole

This compound is prepared according to the procedure described above using 2-pyridine hydrazine hydrochloride. MSGMS (M + H) @ ⁺ m / z: 452.

Example 186

1- (6-Bromopyridin-2-yl) -3-methyl-5 - [(3-fluoro-2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole

Using the procedure described above, ethyl 3-methyl-1- (pyridin-2-yl) -1H-pyrazolecarboxylate is obtained. This compound is then treated with Nbromo-succinimide according to the following procedure:

A mixture of 3-methyl-1- (pyridin-2-yl) -1H-pyrazolecarboxylic acid (7.0483 mmol, 1.63 g) and N-bromosuccinimide (2.51 g, 2.0 equiv.) In carbon tetrachloride (40 ml) is stirred at room temperature for 18 hours. The reaction mixture was filtered through celite to remove solid impurities and washed with carbon tetrachloride (30 mL). After evaporation of the filtrate and purification of the residue by flash chromatography over

A column of 191 silica gel (200 g) eluting with 3: 1 hexane: ethyl acetate afforded 0.258 g of pure 3-methyl-1- (6-bromopyridin-2-yl) -1H-pyrazolecarboxylic acid (12%).

The 3-methyl-1- (6-bromopyridin-2-yl) -1H-pyrazolecarboxylic acid chloro anhydride is then coupled with 3-fluoro-4 - ((2N-i-butylsulfonamid) phenyl) aniline, blocking f-butyl group according to the procedures described above. cleavage under reflux in trifluoroacetic acid to give the title compound; MSGMS (M + H) <RTIgt; ^{+ <} /RTI> m / z 530.

Example 187

1- (3-Amino-4-chlorophenyl) -5 - [(2'-aminosulfonyl-3-chloro- [1,1 '] - biphen-4-yl) aminocarbonyl] tetrazole trifluoroacetic acid salt

This compound is prepared according to the procedure described in Example 174. ¹ H NMR (DMSO) δ: 10.90 (s, 1H), 8.02 (d, 1H), 7.78 (d, 1H), 7.62 (m, 2H), 7.55 (s, 1H), 7.26-7.34 (m, 5H), 7.03 (s, 1H), 6.81 (d, 1H), 5.89 (s, 2H). High resolution mass spectrum: 504.0412 calculated 504.0411 found.

Example 188

1- (3-Amino-4-chlorophenyl) -5 - [(4 '- (1-pyrrolidinocarbonyl) phenyl) aminocarbonyl] tetrazole trifluoroacetic acid salt

This compound is prepared according to the procedure described in Example 174. ¹ H NMR (DMSO) δ: 11.26 (m.p., 1H), 7.80 (t, 1H), 7.49 (d, J = 11.0 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.04 (d, J = 2.6 Hz, 1H), 6.79 (dd, J = 8.4 and 2.6 Hz, 1H), 3.45 (t, J = 6.2 Hz, 2H), 3.40 (t, J = 5.8 Hz, 2H), 1.85 (m, 4H). ESI mass spectrum m / z (rel intensity): 430.0 (M + H) ⁺ , 452.0 (M + Na) ⁺ .

Example 189

1- (3-Aminomethylphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] tetrazole trifluoroacetic acid salt

192

1- (3-Cyanophenyl) -5- [2 '- (t-butylaminosulfonyl- [1,1'] - biphen-4-yl) aminocarbonyl] tetrazole, prepared according to the procedure described in Example 24, Part B, (0.20 g, 0.40 mmol) was dissolved in 10 mL of EtOAc and 10 mL of EtOH. TFA (1 mL) and palladium on carbon (10%) are added. The mixture was hydrogenated at 206.8 kPa for 18 hours. The reaction mixture was filtered through celite and washed with EtOAc. The filtrate is concentrated to a brown oil. It is dissolved in 5 ml of TFA and the solution is refluxed under N _{2 for} 30 min. The solvent was evaporated in vacuo and the resulting material was purified by reverse phase HPLC to give 59.8 mg of the title compound of 98% purity. ¹ H NMR (DMSO-d 6) δ: 11.56 (s, 1H), 8.25 (ds, 3H), 8.02 (d, J = 6.3 Hz, 1H), 7.84 ( ss, 1H), 7.77 (t, J = 5.8 Hz, 2H), 7.72 (t, J = 6.9 Hz, 2H), 7.60 (m, 2H), 7, 39 (d, J = 8.8 Hz, 2H), 7.32 (m, 1H), 7.31 (s, 2H), 4.18 (ss, 2H); ESI mass spectrum m / z (rel intensity): 450.2 (M + H) ⁺ .

Example 190

1- (3-Aminomethylphenyl) -5 - [(2'-aminosulfonyl-3-fluoro- [1,1 '] - biphen-4-yl) aminocarbonyl] tetrazole trifluoroacetic acid salt

This compound is prepared according to the procedure described in Example 189. ¹ H NMR (DMSO-d ₆ ) δ: 11.28 (s, 1H), 8.23 (m.s, 3H), 7.99 (d, J = 6.6 Hz, 1H), 7.80 (e.g. s, 1H), 7.70 (m, 2H), 7.60 (m, 2H), 7.41 (s, 2H), 7.31 (d, J = 9.5 Hz, 2H). , 7.20 (d, J = 8.1 Hz, 1H), 4.14 (m, 2H). ESI mass spectrum m / z (rel intensity): 467.9 (M + H, 100) ⁺ .

Example 191

1- (3-Aminomethylphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] imidazole trifluoroacetic acid salt

Part A: A solution of 3-aminobenzonitrile (6.3 g, 53.4 mmol) in ethyl alcohol (50 mL) was treated with n-butylglyoxylate (7.0 g, 53.8 mmol). After stirring for 18 hours. at room temperature, the reaction mixture is concentrated under reduced pressure

The residue was purified by flash chromatography (hexane: ethyl acetate = 1: 1) to give the imine (4.0 g, 33%) as a colorless oil. ESI mass spectrum m / z (rel intensity): 232 (M + H, 100).

Part B: To a solution of Part A 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). mmol). The solution is stirred for 1 hour. at room temperature followed by evaporation of the solvent under reduced pressure. The residue is treated with a saturated sodium chloride solution and the mixture is extracted with methylene chloride. The organic extract is concentrated and the residue is triturated with methyl alcohol. Filtration and drying gave the desired methyl 1- (3-cyanophenyl) -imidazole-5-carboxylate (1.5 g, 94%). ESI mass spectrum m / z (rel intensity): 277 (M + H, 100).

Part C: To a solution of (2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl) amino (3.5 mmol) in methylene chloride (3 mL) was added dropwise to AIMe ₃ (2M in hexane, 1.8 mL) , 3.5 mmol). The resulting reaction mixture was stirred for 0.5 h. at room temperature, then treated with Part B product (0.16 g, 0.7 mmol) and stirred for 18 h. The mixture was carefully cleaved with 10% HCl, extracted with methylene chloride, dried over magnesium sulfate and concentrated. Purification by flash chromatography (methanol / methylene chloride, 1: 9) afforded a copolished amide derivative (0.22 g, 28%). ESI mass spectrum m / z (rel intensity): 500 (M ⁺ , 100). Reduction of this benzonitrile to benzylamine followed by purification by standard HPLC techniques described above gives the pure desired compound which is colorless crystals. ¹ H NMR (CD ₃ OD) δ: 8.61 (pl.s, 1H), 8.14 (pl.s, 1Η), 8.09 (dd, J = 7.7 Hz, 1H), 7.657 50 (m, 12H), 7.40 (dd, J = 8.8 Hz, 2H), 7.32 (dd, J = 7.3 Hz, 1H), 4.91 (s, 3H) m, d , ESI mass spectrum m / z (rel intensity): 448.2 (M + H, 100).

Example 192

194

1- (3-Aminomethylphenyl) -5 - [(2'-methylsulfonylmethyl- [1,1 '] - biphen-4-yl) aminocarbonyl] imidazole trifluoroacetic acid salt

This compound is prepared according to the procedure described in Example 191. ¹ H NMR (CD ₃ OD) δ: 8.57 (s, 1H), 8.15 (m, 2H), 7.72-7.58 (m, 12H), 7.40 (m, 3H), 4.22 (s, 2H), 2.72 (s, 3H) md ESI mass spectrum m / z (rel intensity): 447 (M + H, 100) ⁺ .

Example 193

1- (3-Amidinophenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) -aminocarbonyl] imidazole trifluoroacetic acid salt

The benzonitrile obtained in Example 191, Part C, is subjected to the Pinner amidine reaction procedure, and the product is purified by the methods described above to give the title compound as colorless crystals. ¹ H NMR (CD ₃ OD) δ: 8.76 (s, 1H), 8.21 (s, 1H), 8.07 (d, J = 7.7 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.79 (t, J = 7.7 Hz, 1H), 7.59 (m, 3H) , 7.50 (t, J = 7.7 Hz, 1H), 7.38 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.7 Hz, 1H) md ESI mass spectrum m / z (rel intensity): 461.2 (M + H, 100) ⁺ .

Example 194

1- [3- (Methylaminomethyl) phenyl] -5 - [(2'-aminosulfonyl-3-fluoro- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methylpyrazole trifluoroacetic acid salt

Part A: Preparation of ethyl 1- [3- (N-t-butoxycarbonylaminomethyl) phenyl] -3-methylpyrazolecarboxylate

To a solution of 1.52 g (5.14 mmol) of ethyl 1- [3- (aminomethyl) phenyl] -3-methylpyrazolecarboxylate hydrochloride in 10 mL of THF under N ₂ is added 1.49 g (14.7 mmol) of triethylamine and 1.35 g (6.17 mmol) of di-t-butyl dicarbonate. The mixture was stirred at room temperature for 16 hours. Water (25 mL) was added and the mixture was extracted three times with 25 mL ether. The combined organic extracts were dried over MgSO ₄ and evaporated to give the desired product

195 product (1.85 g, 74%) which is a white solid. 1 H NMR (CDCl 3) δ: 7.34 (m, 4H), 6.81 (s, 1H), 4.87 (ss, 1H), 4.37 (d, J = 7Hz, 2H). , 4.22 (sq, J = 7Hz, 2H), 2.35 (s, 3H), 1.45 (t, 9H), 1.24 (t, J = 7Hz, 3H).

Part B: Preparation of ethyl 1- [3- (N-butoxycarbonyl-N-methylaminomethyl) phenin-3-methylpyrazolecarboxylate] with 1.86 g (5.15 mmol) of ethyl 1- [3- (N-butoxycarbonylaminomethyl) -phenyl] -3-methylpyrazolecarboxylate 0.15 g (5.88 mmol) of 95% sodium hydride is added in 10 mL of THF under N ₂ . After 1 or. gas evolution ceases and 0.83 g (5.88 mmol) of methyl iodide is added. The mixture was stirred at room temperature for 16 hours. water (25 mL) was added and the mixture was extracted three times with 25 mL of ether. The combined organic extracts were dried over MgSO ₄ , the solvent was evaporated, and the residue was chromatographed on silica gel eluting with 20% EtOAc / hexanes to give the desired product (0.52 g, 27%) as a white solid. A further 0.83 g of unmethylated starting material is isolated. Δ NMR (CDCl3) δ: 7.40 (m, 4H), 7.30 (m, 3H), 6.81 (s, 1H), 4.47 (s, 2H), 4.22 (s) , J = 7Hz, 2H), 2.83 (ppm, 2H), 2.34 (s, 3H), 1.47 (s, 9H), 1.23 (t, J = 7Hz) , 3H).

Part C: Preparation of 1- [3- (N-butoxycarbonyl-N-methylaminomethyl) phenin-3-methylpyrazolecarboxylic acid into 0.52 g (1.39 mmol) of ethyl 1- [3- (Nf-butoxycarbonyl-N-methylaminomethyl) phenyl] To a solution of -3-methyl-pyrazolecarboxylate in 5 mL of THF was added 1.4 mL (1.4 mmol) of 1M aqueous lithium hydroxide. The mixture was stirred at room temperature for 6 hours. Water (10 mL) was added and the mixture was extracted with ether (3 x 25 mL). The aqueous layer was acidified with 1N HCl to pH 4 and extracted with ether (3 x 25 mL). The combined second extraction organic layers were dried over MgSO ₄ and evaporated the solvent to give the desired product (0.35 g, 74%) as a white solid. 1 H NMR (CDCl 3) δ: 7.38 (m, 4H), 6.87 (s, 1H), 4.46 (s, 2H), 2.83 (ppm, 3H), 2, 37 (s, 3H), 1.46 (s, 9H).

196

Part D: Preparation of the trifluoroacetic acid salt of 1- [3- (methylaminomethyl) phenyl] -5- [(2'-aminosulfonyl-3-fluoro-1,1'-biphen-4-yl) aminocarbonyl] -3-methylpyrazole

To a solution of 1- [3- (Ni-butoxycarbonyl-N-methylaminomethyl) phenyl] -3-methylpyrazole carboxylic acid (0.176 g, 0.509 mmol) in 10 mL of CH ₂ Cl _{2 was} added 10 μΙ of DMF and oxalyl chloride (97 mg, 0.763 mmol). The solution is stirred for 1.5 hours. Is the solvent then evaporated in a deep vacuum under a deep vacuum. The resulting solid was redissolved in 10 mL and triethylamine (0.15 g, 1.53 mmol) and 2 '- (t-butylaminosulfonyl) -3-fluoro- [1,1'] -biphenyl (0.172 g, 0.534) were added. mmol). After stirring for 16 h under Ar, the reaction mixture was poured into water and extracted with ethyl acetate. The solvent was evaporated and the mixture was dissolved in 5 mL TFA. This solution is heated at 50 ° C for 4 hours, cooled to room temperature and the solvent evaporated. The crude benzylamine was purified by HPLC (C18 reverse phase) eluting with 0.5% TFA in H ₂ O / CH ₃ CN to afford 60 mg (19%) of the desired salt. ¹ H NMR (DMSO-d ₆ ) δ: 8.75 (m.s, 2H), 8.00 (m. 1H), 7.63-7.15 (m, 10H), 6.94 (s , 1H), 4.15 (pl, J = 6Hz, 2H), 2.54 (t, J = 5Hz, 2H), 2.45 (s, 3H). ESI mass spectrum m / z (rel intensity): 494.1 (M + H, 100).

195 Example

1- [3- (Methylaminomethyl) phenyl] -5 - [(2'-methylsulfonyl-3-fluoro- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methylpyrazole trifluoroacetic acid salt of 1- [ To a solution of 3- (N-butoxycarbonyl-N-methylaminomethyl) phenyl] -3-methylpyrazole carboxylic acid (0.176 g, 0.509 mmol) in 10 mL of CH ₂ Cl _{2 was} added 10 μΙ of DMF and oxalyl chloride (97 mg, 0.763 mmol). The solution is stirred for 1.5 hours. Is the solvent then evaporated in the atmosphere under a deep vacuum. The resulting solid was redissolved in 10 mL and triethylamine (0.15 g, 1.53 mmol) and 2 '- (methylsulfonyl) -3-fluoro- [1,1'] -biphenyl (0.172 g, 0.534 mmol) were added. After stirring for 16 h under Ar, the reaction mixture was poured into water and extracted with ethyl acetate. The solvent was evaporated and the mixture was dissolved in 5 ml TFA. This solution is heated at 50 ° C for 4 hours, cooled to room temperature

197 and evaporated solvent. The crude benzylamine was purified by HPLC (C18 reverse phase) eluting with 0.5% TFA in H2O / CH3CN to afford 140 mg (45%) of the desired salt. ¹ H NMR (DMSO-d ₆ ) δ: 8.76 (m.p.

2H), 8.06 (dd, J = 8, 1 Hz, 1H), 7.77-7.61 (m, 4H), 7.52-7.31 (m, 5H), 7.19 ( dd, J = 8, 1.5 Hz, 1H), 6.95 (s, 1H), 4.17 (e.g., J = 6 Hz, 2H), 2.90 (s, 3H),

2.54 (t, J = 5Hz, 2H), 2.29 (s, 3H). ESI mass spectrum m / z (rel intensity): 492.2 (M + H, 100).

Example 196

1- (3-Aminomethylphenyl) -5 - [(2'-methylsulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] 4-methoxy-3-trifluoromethylpyrazole trifluoroacetic acid salt

Part A: To 1- (3-cyanophenyl) -4-methoxy-3-trifluoromethylpyrazole carboxylic acid (0.69 g, 2.2 mmol) was added CH 2 Cl 2 (15 mL), oxalyl chloride (0.27 mL, 3.1 mmol). and three drops of DMF. The reaction mixture was stirred for 2 hours. The solvents were evaporated, CH ₂ Cl ₂ (15 mL), 4-bromoaniline (0.38 g, 2.2 mmol) and DMAP (0.68 g, 5.5 mL) were added again and the reaction mixture was stirred for 18 h. It is diluted with CH ₂ Cl ₂ , washed successively with 1N HCl, saturated NaHCO ₃ , saturated NaCl solution, dried (MgSO ₄ ) and recrystallized from CH ₂ Cl ₂ / hexanes to give 0.5 g (48%) of pure product and 0.43 g - from the filtrate. ¹ H NMR (CDCl ₃ ) δ: 8.90 (s, 1H), 7.79 (m, 2H), 7.72 (dd, J = 1.83, 9.96 Hz, 1H), 7.63 (t, J =

8.06 Hz, 1H), 7.46 (s, 4H), 4.15 (s, 3H) ppm: ESI mass spectrum m / z (rel intensity): 482-484 (M + H, 100).

Part B: To Part B bromo compound (0.4 g, 0.86 mmol) was added 2-thiomethylphenylboronic acid (0.18 g, 1.1 mmol), 2M Na ₂ CO ₃ (1 mL), toluene (15 mL) and ethanol (15 mL). The mixture is degassed, tetrakistriphenylphosphine palladium (O) (40 mg) is added and the reaction mixture is refluxed for 18 hours. The reaction mixture was cooled, filtered, concentrated, extracted with ethyl acetate and dried (MgSO ₄ ).

The mixture was purified by chromatography on silica gel eluting with hexanes / ethyl acetate (4: 1) to give 0.195 g (46%) of a yellow solid.

198

Δ NMR (CDCl ₃ ) δ: 8.95 (s, 1H), 7.80 (m, 3H), 7.63 (d, J = 8.42 Hz, 2H), 7.61 (m, 1H) , 7.44 (d, J = 8.43 Hz, 2H), 7.34 (m, 2H), 7.20 (m, 2H), 4.15 (s, 3H), 2.37 (s, 3H) md

Part C: A solution of Part B product (0.19 g, 0.37 mmol) cooled to 0 ° C

CH ₂ Cl ₂ (15 mL) was added m-chloroperoxybenzoic acid (0.33 g, 1.1 mmol). The reaction mixture was warmed to room temperature and kept overnight. This mixture was washed with water, acid sodium sulfite solution, NaHCO 3 and dried (MgSO _4). The compound was purified by chromatography on silica gel eluting with hexanes / ethyl acetate (1: 1) to give 0.192 g (95%) of a yellow solid. 1 H NMR (CDCl 3) δ: 9.02 (s, 1H), 8.24 (dd, J = 1.46, 7.69 Hz, 1H), 7.80 (m, 3H), 7.66 (d, J = 8.06 Hz, 2H), 7.65 (m, 3H), 7.49 (d, J = 8.79 Hz, 2H), 7.37 (dd, J = 1.46, 7.69 Hz, 1H), 4.18 (s, 3H), 2.68 (s, 3H); ESI mass spectrum m / z (rel intensity): 563 (M + Na, 100).

Part D: Part C product is hydrogenated with EtOH / TFA with 10% palladium on carbon as catalyst at 344.7 kPa for 24 h. Purification by reverse-phase HPLC after lyophilization to give 0.16 g (69.6%) of the title compound Ή NMR (DMSO-d ₆₎ δ: 11.11 (s, 1H), 8.25 (br, s, 2H), 8.10 (d, J = 8.06 Hz, 1H), 7.77 (s + d, J = 8.79 Hz, 2H), 7.69 (s + d, J = 7.32). Hz, 3H), 7.60 (s + m, 3H), 7.41 (m, 3H), 4.15 (ss, 2H), 3.95 (s, 3H), 2.88 (s) (3H) md; DSGMS: 545.147037 (calculated), 545.146284 (found); Elemental analysis: calculated for C2 H23F _{S 3} N ₄ O ₄ S (TFA) (H ₂ O) 1.3: C: 49.31, H: 3.93, N: 8.22, Found C: 49.46 H, 3.62; N, 8.09.

197 Example

1- (3-Aminomethylphenyl) -5 - [(2-fluoro-4- (N-pyrrolidinocarbonyl) phenyl) aminocarbonyl] -3-trifluoromethylpyrazole trifluoroacetic acid salt

Part A: J 1- (3-Cyanophenyl) -3-trifluoromethylpyrazole carboxylic acid (0.29 g,

A solution of 1.0 mmol) in CH ₂ Cl ₂ (40 mL) was added with oxalyl chloride (0.135 mL, 1.6 mmol) and a few drops of DMF. The reaction mixture was stirred for 2 hours, then

199 concentrated. To this chloro anhydride was again added CH ₂ CH ₂ (40 mL), 2-fluoro-4- (N-pyrrolidinocarbonyl) aniline (0.22 g, 1 mmol) and DMAP (0.32 g, 2.6 mmol), and the reaction mixture was stirred for 18 hours. The mixture was washed successively with 1N HCl, followed by NaHCO 3 and dried (MgSO _4). The compound was purified by silica gel column chromatography eluting with hexanes / ethyl acetate (1: 1.5) to give 0.345 g (71%). Δ NMR (CDCl ₃ ) δ: 9.03 (s, 1H), 7.86 (m, 4H), 7.63 (t, J = 8.05 Hz, 1H), 7.55 (s, 1H) ), 7.21 (m, 2H), 3.67 (t, J = 8.05 Hz, 2H), 3.45 (t, J = 6.59 Hz, 2H), 2.02 (kv, J = 6.22 Hz, 2H), 1.92 (kv, J = 6.22 Hz, 2H) md; ESI mass spectrum m / z (relative intensity): 472.1 (M + H) ⁺ , 494 (M + Na) ⁺ .

Part B: Part A product is hydrogenated with EtOH / TFA with 10% palladium on carbon as catalyst at 344.7 kPa for 24 h. Purification by reverse phase HPLC and lyophilization afforded 0.34 g (80%) of the title compound. H NMR (DMSO-d _s) δ: 10.8 (s, 1H), 8.23 (s, 2H), 7.72 (m + d, J = 8.06 Hz, 3H), 7.59 (m, 3H), 7.49 (dd, J = 1.84, 11.36 Hz, 1H), 7.39 (dd, J = 8.06, 1.83 Hz, 1H), 4.15 (kv, J = 5.86 Hz, 2H), 3.47 (t, J = 6.6 Hz, 2H), 3.42 (t, J = 6.2 Hz, 2H), 1.89 (m (4H) md; ESI mass spectrum m / z: 476.2 (M + H) ⁺ ; elemental analysis: calculated for C ₂₃ H ₂ iF ₄ N ₅ O ₂ (TFA) (H ₂ O) 0.5: C: 50.17, H: 3.87, N: 11.70, found C: 50, 05, H: 3.87, N: 11.43.

198 Example

1- (3-Aminomethylphenyl) -5 - [(3-fluoro-4- (N-pyrrolidinocarbonyl) phenyl) aminocarbonyl] -3-trifluoromethylpyrazole trifluoroacetic acid salt

Part A: 1- (3-Cyanophenyl) -3-trifluoromethylpyrazolecarboxylic acid and 3-fluoro-4- (N-carbonylpyrrolidino) aniline are copolished via chloro anhydride as in the previous example; yield 81%. ¹ H NMR (CDCl ₃ ) δ: 10.01 (s, 1H), 7.79 (m, 4H), 7.61 (t, J = 7.69 Hz, 1H), 7.16 (dd, J = 1.84, 10.99 Hz, 1H), 7.06 (t,

J = 8.06 Hz, 1H), 6.93 (dd, J = 1.83, 8.05 Hz, 1H), 3.68 (t, J = 6.59 Hz, 2H), 3.34 ( t, J = 6.59 Hz, 2H), 2.00 (kv, J = 6.59 Hz, 2H), 1.94 (kv, J = 6.59 Hz, 2H) md; ES! mass spectrum m / z (relative intensity): 472.1 (M + H) ⁺ , 494 (M + Na) ⁺ .

200

Part B; Part A product is hydrogenated with EtOH / TFA with 10% palladium on carbon as catalyst at 344.7 kPa for 24 h. Purification by reverse-phase HPLC and lyophilization gave 0.38 g (84%) of product. ¹ H NMR (DMSO-d _s) δ: 11.07 (s, 1H), 8.24 (s, 2H), 7.73 (m, 3H), 7.63 (m, 3H), 7.50 (m, 2H), 4.16 (d, J = 5.49 Hz, 2H), 3.47 (t, J = 6.23 Hz, 2H), 3.23 (t, J = 6.23 Hz) , 2H), 1.89 (m, 4H) md; DSGMS: 476.170963 (calc.), 476.171044 (found); Elemental analysis: calculated for C23H21F4N5O2 (TFA) (H ₂ O) 0.5: C: 50.17, H: 3.87, N: 11.70, found C: 50.17, H: 3.85, N : 11.48.

199 Example

1- (3-Aminomethylphenyl) -5 - [(2'-sulfonylmethyl- [1,1 '] - biphen-4-ii) aminocarbonyl] 3-trifluoromethylpyrazole trifluoroacetic acid salt

1- (3-Cyanophenyl) -5 - [(2'-sulfonylmethyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-trifluoromethylpyrazole (synthesized previously) is hydrogenated with 10% palladium on carbon in EtOH / TFA as catalyst at 344.7 kPa for 24 hours. Purification by reverse-phase HPLC and lyophilization gave the title compound. ¹ H NMR (DMSO-d ₆ ) δ: 10.92 (s, 1H), 8.24 (m.s, 2H), 8.10 (d, J = 7.69 Hz, 1H), 7, 79 (m, 6H), 7.60 (m, 3H), 7.41 (s + d, J = 8.79 Hz, 3H), 4.14 (s, J = 5.12 Hz, 2H), 2.85 (s, 3H) md; DSGMS: 515.136472 (calc.), 515.136472 (found).

Example 200

1- (3-Aminomethylphenyl) -5 - [(2'-aminosulfonyl-3-fluoro- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-trifluoromethylpyrazole trifluoroacetic acid salt

Part A: 1- (3-Cyanophenyl) -3-trifluoromethylpyrazolecarboxylic acid and 1- (2'-freefutaminosulfonyl- [1,1 '] -3-fluorobiphenylaniline) are coupled via chloro anhydride as in the previous example, 76% yield. ¹ H NMR (CDCl 3) ) δ: 8.31 (t, J = 8.43 Hz, 1H), 8.18 (dd, J = 1.47, 7.69 Hz, 1H), 8.04 (s, 1H), 7, 88 (d, J = 1.46

201

Hz, 1H), 7.83 (m, 2H), 7.68 (d, J = 8.06 Hz, 1H), 7.62 (m, 2H), 7.42 (dd, J = 1.83). , 11.72 Hz, 1H), 7.29 (d, J = 1.47 Hz, 1H), 7.22 (m, 2H), 3.69 (s, 1H), 1.07 (s, 9H) ) md; ESI mass spectrum m / z (relative intensity): 607.9 (M + Na, 100).

Part B: Part A product is boiled in TFA for 30 min then hydrogenated

EtOHTTFA with 10% palladium on carbon as catalyst at 344.7 kPa for 24 h and then with platinum (II) oxide as catalyst at 344.7 kPa for 24 h. Purification by reverse-phase HPLC and lyophilization yielded 0.16 g of product. ¹ H NMR (DMSO-d ₆ ) δ: 10.71 (s, 1H), 8.24 (pl.s, 2H), 8.05 (dd, J = 1.47, 6.96 Hz, 1H). , 7.74 (s, 1H), 7.69 (s, 1H), 7.66 (m, 6H), 7.43 (s, 2H), 7.35 (m, 2H), 7.23 ( d, J = 8.42 Hz, 1H), 4.16 (kv, J = 5.49 Hz, 2H) md; ESMS 534.1 (M + H); Elemental Analysis: Calculated for C24H19F4N5O3S (TFA) 1.1: C: 46.99, H: 3.21, N: 10.46, Found C: 47.06, H: 2.86, N: 10.37.

Examples 201 and 202

1- (3-Aminomethylphenyl) -5 - [(5- (2'-aminosulfonylphenyl) - [1,6-dihydro] pyrimidin-2-yl) aminocarbonyl] -3-trifluoromethylpyrazole trifluoroacetic acid salt and 1- (3-aminomethylphenyl) - 5 - [(5- (2'-Aminosulfonylphenyl) pyrimidin-2-yl) aminocarbonyl] -3-trifluoromethylpyrazole trifluoroacetic acid salt

1- (3-Cyanophenyl) -5 - [(5- (2'-tert-butylaminosulfonylphenyl) -4-yl) pyrimidin-2-yl) aminocarbonyl] -3-trifluoromethylpyrazole (0.3 g, 0.5 mmol) (its synthesis described above) is hydrogenated in ethanol / acetic acid for 24 hours at 275.8 kPa, initially with 10% palladium on carbon, followed by the addition of platinum (II) oxide. The reaction mixture was filtered, concentrated, and refluxed in TFA for 30 min. Reverse phase HPLC purification and lyophilization yielded small amounts of the two products. The first product obtained is the dihydro compound (64.5 mg). ¹ H NMR (DMSO-d 6) δ: 9.76 (s, 1H), 9.10 (s, 1H). 8.22 (pi, 2H), 7.95 (dd, J = 1.10, 7.69 Hz, 1H), 7.65 (s, 1H), 7.61 (m, 5H), 7, 49 (s, 2H), 7.41 (dd, J = 1.46, 7.32 Hz, 1H), 7.19 (s, 1H), 6.10 (d, J

202 = 4.40 Hz, 1H), 4.22 (s, 2H), 4.15 (kv, J = 5.86 Hz, 2H) md; DSGMS 520.137869 (found), 520.138256 (found): Elemental Analysis: Calculated for C ₂₂ H ₂₀ F ₃ N ₇ O ₃ S (TFA) 2: C: 41.77, H: 2.97, N: 13.12, Found: C: 41.98, H: 3.02, N: 12.97. The second product is the pyrimidyl analog. ¹ H NMR (DMSO-d 6) δ: 11.61 (s, 1H), 8.66 (s, 1H), 8.24 (pi, 2H), 8.08 (dd, J = 2.20, 6.95 Hz, 1H), 7.73 (m, 4H), 7.60 (m, 5H), 7.48 (m, 1H), 4.16 (m, 2H) md; DSGMS 518.122219 (calcd), 518.122803 (found); Elemental Analysis: Calculated for C22H18F3N7O3S (TFA) 1.3: C: 43.79, H: 3.03, N: 14.53, Found: 0: 43.92, H: 2.99, Ν..34.37 .

Example 203

1- [3- (2'-Ethylaminophenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-trifluoromethylpyrazole trifluoroacetic acid salt

Part A: To 1- (3-cyanophenyl) -5-hydroxymethyl-3-trifluoromethylpyrazole (1.8 g, 6.7 mmol) in DMF (12 mL) was added tert-butyldimethylsilyl chloride (1 g, 7.1 mmol) and imidazole (0.94 g, 13.8 mmol). The reaction mixture was stirred for 3 h, then partitioned between ethyl acetate and water. After extraction with ethyl acetate, dried (MgSO ₄₎ and purified by chromatography on silica gel (4: 1) hexanes / ethyl acetate to yield 1.88 g (73%) of product.

Part B: Methyl magnesium chloride (0.9 mL, 2.6 mmol) was added at 0 ° C to a portion of the JA product (0.4 g, 1.0 mmol) in THF (15 mL) and the reaction mixture was stirred at room temperature for 2 h. After cooling to 0 ° C, methanol (25 mL) was added followed by sodium borohydride (0.2 g, 5 mmol) and the reaction mixture was stirred for 1 h. The reaction is quenched with water, filtered and concentrated. The residue was extracted with ethyl acetate and dried (MgSO ₄ ). The crude oil was dissolved in CH ₂ Cl ₂ , cooled to 0 ° C, and di-tert-butylcarbamate (0.23 g, 1.1 mmol) and triethylamine (0.15 mL) were added. The reaction mixture was stirred for 18 h., Then washed with saturated ammonium chloride, brine and dried (MgSO _4). The crude material was dissolved in THF and tetrabutylammonium fluoride in THF (1.46 mL) was added. The reaction mixture

203 is stirred for 3 hours, then concentrated. The residue was dissolved in CH 2 Cl 2, washed with water, brine and dried (MgSO ₄ ). Purification by chromatography on silica gel eluting with 2: 1 hexanes / ethyl acetate afforded 0.187 g (47%) of product. ¹ H NMR (CDCl 3) δ: 7.58 (s, 1H), 7.47 (m,

2H), 7.38 (m, 1H), 6.70 (s, 1H), 4.92 (pi, 1H), 4.78 (m, 1H), 4.65 (m, 2H), 2 , 91 (pi, 1H), 1.49 (d, J = 6.96 Hz, 3H), 1.40 (s, 9H) md; MS ESI mass spectrum m / z (rel. Intensity): 407.8 (M + Na, 100).

Part C: To a product of Part B (0.17 g, 0.44 mmol) in acetonitrile (5 mL) at 0 ° C was added several crystals of ruthenium (III) chloride and aqueous sodium periodate (0.2 g, 0.9 mmol) The reaction mixture was stirred for 18 hours, then filtered and concentrated, the aqueous residue was extracted with ethyl acetate and dried (MgSO ₄ ). ESI mass spectrum m / z (rel intensity): 398 (MH, 100).

Part D: 1-Ethyl-3- (3-dimethylaminopropyl) was added in Part C product (0.17 g, 0.4 mmol) and 4-bromoaniline (0.073 g, 0.4 mmol) in CH ₂ Cl ₂ (5 mL). carbodiimide hydrochloride (0.11 g, 0.57 mmol). The reaction mixture was stirred for 18 h., Then washed with water, brine and dried (MgSO _4). Filtration through a pad of silica gel eluting with hexanes / ethyl acetate (1: 1) gives 0.148 g of a white foam, ESI mass spectrum m / z (relative intensity): 575-577 (M + Na) ⁺ .

Part E; The product from Part D (0.14 g, 0.26 mmol) is coupled with 2-tert-butylsulfonamidophenylboronic acid according to standard Suzuki procedure. The crude product of this reaction was refluxed in TFA for 20 min. Purification by reverse phase HPLC and lyophilization gave 77 mg of product (46%). ¹ H NMR (DMSO-d _s) δ: 10.86 (s, 1H), 8.32 (br., 2H), 8.04 (dd,

J = 7.69, 1.42 Hz, 1H), 7.76 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.67 (m, 6H),

7.39 (d. J = R 7.9 H7 9H \ 7 99 ΜΗ .1 = 9 -I 99 N? -F 7 90 (e ΟΙ-Π A FC / m

204

530.148939 (found); Elemental Analysis: Calculated for C25H22F3N5O3S (TFA) 1.1: C: 49.88, H: 3.55, N: 10.69, Found: C: 49.49, H: 3.49, N: 10.60 .

Example 204

1- [3- (1-N-Morpholino) imino) phenyl] -5 - [(2'-aminosulfonyl-3-fluoro [1,1 '] - biphen4-yl) aminocarbonyl] -3-trifluoromethylpyrazole trifluoroacetic acid salt

To 1- (3-cyanophenyl) -5 - [(2'-tert-butylaminosulfonyl-3-fluoro- [1,1]] -biphen-4-yl) aminocarbonyl] -3-trifluoromethylpyrazole (0.23 g, 0.39 mmol) in (2: 1) CHCl ₃ / MeOH (30 mL) at 0 ° C for 15 min. was bubbled HCl gas. Stopper the flask and the assistance of the refrigerator for 18 h. the solvent was removed and added morpholine (0.2 ml) and of fresh methanol. the reaction mixture was stoppered and stirred for 48 h. the solvent was evaporated and the residue was refluxed in TFA for 15 minutes. Purification by reverse phase HPLC and lyophilization to give 0.146 g of product (51%). ¹ H NMR (DMSO-d _s) δ: 10.70 (s, 1H), 9.69 (s, 1H), 9.32 (s, 1H), 8.05 (dd, J = 6.96, 2.20 Hz, 1H), δ , 94 (s, 1H), 7.89 (d, J = 8.05 Hz, 1H), 7.80 (m, 2H), 7.65 (m, 3H), 7.42 (s, 2H) , 7.35 (d, J = 8.50 Hz, 2H), 7.23 (d, J = 9.52 Hz, 1H), 3.81 (pi, 2H), 3.74 (m.p. , 2H), 3.56 (pl.s, 2H), 3.32 (pl.s, 2H) md; ESMS 616.9 (M + H) Elemental analysis: calculated for C28H24F4NSO4S (TFA) 1.1 ( H ₂ O) 1 , 2: C: 47.50, H: 3.63, N: 11.01, found: C: 47.39, H: 3.28, N: 10.69.

Example 205

1- (3-Aminomethylphenyl) -5- [2- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) -1-hydroxyethyl] -3-trifluoromethylpyrazole trifluoroacetic acid salt

Part A: Oxalyl chloride (0.4 mL, 4.9 mmol) was added to 1- (3-cyanophenyl) -3-trifluoromethylpyrazole-5-carboxylic acid (1 g, 3.6 mmol) in CH ₂ Cl ₂ (40 mL). and a few drops of DMF. The reaction mixture was stirred for 3 hours, then the solvent was evaporated in vacuo. In a separate flask, dibromoethane (0.1 mL) was added to activate Zn (0.35 g, 5.3 mmol) in THF (5 mL). The mixture is refluxed for 5 minutes, then cooled to 0 ° C and slowly over 0.5 hour. 4205 bromobenzyl bromide (1.1 g, 4.3 mmol) in THF (5 mL) was added. The reaction mixture was maintained at 0 ° C for 3 h, then injected via tube into a mixture of CuCN (0.38 g, 4.3 mmol), LiCl (0.36 g, 8.5 mmol) and THF (10 mL). At 78 ° C. The reaction mixture was warmed to -20 ° C and maintained for 5 min then cooled again to -78 ° C. The solid chlorohydride is suspended in THF (20 mL) and added to the above chilled mixture. The reaction mixture was allowed to slowly warm to room temperature, then filtered and concentrated. Purification by chromatography on silica gel eluting with 2: 1 hexanes / ethyl acetate afforded 0.55 g (37%) of a white foam. MS (ESI) m / z = 433.9-432 (MH) ⁺ .

Part B: The product from Part A (0.53 g, 1.2 mmol) was copolished according to Suzuki standard procedures with 2-tert-butylaminosulfonylphenylboronic acid (0.39 g, 1.7 mmol). Purification by chromatography on silica gel eluting with (4: 1) hexanes / ethyl acetate afforded 0.32 g (46%) of the copolished ketonitrile product. MS (ESI) m / z = 565 (MH ⁺ ).

Part C: To Part B (0.05 g, 0.08 mmol) product CH ₂ Cl ₂ (10 mL) was added, tetra-N-butylammonium borohydride (0.08 g, 0.31 mmol) was added and the mixture was heated to reflux. refrigerator for 18 hours. The solvent was evaporated, replaced with 10% HCl and refluxed for 1 hour. The reaction mixture was cooled, extracted with diethyl ether, basified with 50% NaOH, extracted with ethyl acetate and dried (MgSO ₄ ). The diethyl ether layer contains fref-butyl-blocked intermediate. The ethereal layer was concentrated and the residue heated in TFA for 15 min. The whole product was mixed together, purified by reverse phase HPLC, lyophilized to give 0.01 g (18%) of product. ¹ H NMR (DMSO-d 6) δ:

8.23 (pi, 2H), 8.03 (d, J = 6.96 Hz, 1H), 7.63 (m, 6H), 7.28 (s + d, J = 7.69 Hz), 3H), 7.18 (s, 2H), 7.11 (s + d, J = 6.96 Hz, 3H), 5.83 (m, 1H), 4.81 (m, 1H),

4.15 (m, 2H); 3.09 (d, J = 6.60 Hz, 2H) ppm; DSGMS 517.152122 (calculated), 517.152222 (found).

206

Example 206

1- (3-Aminomethylphenyl) -5 - [(3-fluoro-2'-methylsulfonyl- [1,1]] -biphen-4-yl) aminocarbonyl] -3-trifluoromethylpyrazole trifluoroacetic acid salt

Part A: Oxalyl chloride (0.43 mL, 4.9 mmol) was added to 1- (3-cyanophenyl) -3-trifluoromethylpyrazole-5-carboxylic acid (1 g, 3.6 mmol) in CH ₂ Cl ₂ (40 mL). and a few drops of DMF. The reaction mixture was stirred for 18 h before the solvent was evaporated in vacuo. CH ₂ Cl ₂ (40 mL) was added again followed by 4-bromo-2-fluoroaniline (0.68 g, 3.6 mmol) and 4-dimethylaminopyridine (1.09 g, 8.9 mmol). After stirring for 18 h., The reaction mixture was washed with 1N HCl, saturated NaHCO 3, dried (Na ₂ SO _4), filtered and concentrated to afford 1.55 g crude bromide. ESI mass spectrum m / z (relative intensity) 450.8-452.8 (MH, 100).

Part B: Compound A bromide (0.5 g, 1.1 mmol), 2-thiomethylphenylboronic acid (0.26 g, 1.5 mmol) and 2M Na ₂ CO ₃ (2 mL) are added (1: 1). ethanol / toluene (20 mL), and the solution is degassed by purging with nitrogen gas for 30 min. Tetrakistriphenylphosphine palladium (O) (50 mg) is added and the reaction mixture is refluxed for 18 hours. The reaction mixture was cooled, concentrated, extracted with ethyl acetate and dried (MgSO ₄ ). The copolished product is purified by passing through a pad of silica gel eluting with hexane / ethyl acetate (1: 1) and used in the next step. The thiomethyl compound was dissolved in CH ₂ Cl ₂ (50 mL), cooled to 0 ° C, and MCPBA (0.67 g, 2.2 mmol) was added. The reaction mixture was stirred for 48 h., And then washed with aqueous acid sodium sulfite solution, brine and dried (MgSO _4). The broth was purified by passing through a pad of silica gel eluting with hexane / ethyl acetate (1: 1) to give 0.34 g. 1 H NMR (CDCl ₃ ) δ: 8.25 (t, 1H), 7.90-7.15 (m, 12H), 2.39 (s, 3H) md ESI mass spectrum m / z 550.7 ( M + Na) ⁺ , 526.7 (M + H) ⁺ .

Part C: Part B product (0.34 g, 0.6 mmol) was hydrogenated (1: 2) in methanol / ethanol (70 mL) and TFA (1 mL) with 10% palladium on carbon as

207 catalyst at 344.7 kPa for 24 hours. Purification by reverse-phase HPLC and lyophilization afforded 0.21 g (50%) of product. ¹ H NMR (DMSO-d ₆ ) δ: 10.75 (s, 1H), 8.23 (m, 3H), 8.11 (dd, J = 7.69, 1.46 Hz, 1H), δ , 96 (dd, J = 6.96, 1.47 Hz, 1H), 7.81 (m, 8H), 7.26 (dd, J = 1.47, 8.06 Hz, 1H), 4, 16 (kv, J = 5.49 Hz, 2H), 2.94 (s, 3H) md; ESI mass spectrum m / z 532.9 (M + H, 100). Elemental Analysis: Calculated for C 25 H 20 F 4 N 4 O 3 S (TFA) 1.1: 0: 49.65, H: 3.23, N: 8.52, Found: 0: 49.73, H: 2.98, N: 8.40 .

Example 207

1- (3-Aminomethylphenyl) -5 - [(5- (2'-methylsulfonylphenyl) pyrimidin-2-yl) aminocarbonyl] -3-trifluoromethylpyrazole trifluoroacetic acid salt

Part A: 1- (3-Cyanophenyl) -3-trifluoromethylpyrazole-5-carboxylic acid (2.2 g,

7.8 mmol) is refluxed in methanol containing almost. sulfuric acid (1 mL), 48 h. The solvent was evaporated, the residue was dissolved in ethyl acetate, washed with NaHCO ₃ (saturated), brine and dried (MgSO ₄ ). The ester is hydrogenated with MeOH / TFA with 10% palladium on carbon as catalyst at 276 kPa for 24 h. The reaction mixture was filtered and concentrated. The residue was suspended in CH ₂ Cl ₂ , cooled to 0 ° C, and 1N NaOH (35 mL) and benzyl chloroformate (1.2 mL, 8.6 mmol) were added. The reaction mixture is stirred for 2 hours, then the layers are separated, the organic layer is dried (MgSO ₄ ) - and concentrated. The residue was dissolved in MeOH, cooled to 0 ° C, and a solution of LiOH (0.5 g, 11.8 mmol) in water was added. The reaction mixture was stirred for 18 hours. The mixture was concentrated, the residue acidified, extracted with ethyl acetate, dried (MgSO ₄ ) to give 1.83 g (57%) of a white solid. ESI spectrum m / z (rel intensity): 417.9 (MH, 100).

Part B: Part A acid (0.46 g, 1.1 mmol) is coupled with 2-amino-5- (2'-methylsulfonylphenyl) pyrimidine (0.31 g, 1.1 mmol) according to the standard chloro-anhydride procedure to give 0. , 3 g (42%) of the carbobenzyloxy-blocked intermediate. This intermediate was refluxed with TFA

After 208 min and purification by reverse phase HPLC and lyophilization, 0.16 g (23% overall yield) of product is obtained. ¹ H NMR (DMSO-d ₆ ) δ: 11.65 (s, 1H), 8.72 (s, 2H), 8.24 (pi, 2H), 8.15 (d, J = 7.69). Hz, 1H), 7.87 (m, 4H), 7.58 (s + m, 3H), 7.54 (d, J = 7.32 Hz, 1H), 4.16 (kv, J = 5 , 49 Hz, 2H), 3.07 (s, 3H) md; DSGMS 517.126970 (calculated), 517.125600 (found). Elemental Analysis: Calculated for C23H19F3NSO3S (TFA) 1.2: C: 46.70, H: 3.12, N: 12.86, Found: C: 46.78, H: 3.04, N: 12.56 .

Example 208

1- (3-Amidinophenyl) -5 - [(3-fluoro-2'-methanesulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-trifluoromethylpyrazole trifluoroacetic acid salt

The nitrile prepared in Example 206 was subjected to standard Pinner reaction conditions and purified by reverse-phase HPLC and lyophilized to afford 0.067 g (27%) of the desired product. ¹ H NMR (DMSO-d ₆ ) δ: 10.74 (s, 1H), 9.45 (s, 1.5H), 9.13 (s, 1.5H), 8.11 (d, J = 7.69 Hz, 1H), 8.04 (s, 1H), 7.95 (d, J = 8.42 Hz, 2H), 7.81 (m, 5H), 7.44 (m, 2H) , 7.26 (d, J = 8.42 Hz, 1H), 2.94 (s, 3H) md ESI mass spectrum m / z (rel intensity): 546 (M + H, 100).

Example 209

1- (3-Amidinophenyl) -5 - [(3-fluoro-2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-trifluoromethylpyrazole trifluoroacetic acid salt

The nitrile prepared in Example 207 is subjected to standard Pinner reaction conditions and purified by reverse phase HPLC and lyophilized to afford 0.042 g (25%) of the desired product. DSGMS: 547.117549 (calcd), 547.117400 (found).

Example 210

1- (3-Aminomethyl) phenyl-5 - [(2'-aminosulfonyl- [1,1 T] -biphen-4-yl) aminocarbonyl] -3-trifluoromethylpyrazole trifluoroacetic acid salt

209

Part A: Oxalium chloride (1.5 mL, 16.7 mmol) and DMF (0) were added to N-carbobenzyloxy-blocked carboxylic acid (5 g, 11.9 mmol) (described in Example 207) in CH ₂ Cl ₂ (100 mL). , 5 mL). The reaction mixture was stirred for 18 h, then the solvents were evaporated and the resulting yellow solid was left for further use, and dibromoethane (0.3 mL) Zn (1.87 g, 28 mmol) in THF (30 mL) was added to a separate flask. The mixture is refluxed for 5 minutes, then cooled to 0 ° C and slowly over 0.5 hour. a solution of 4-bromobenzyl bromide (5.96 g, 24.9 mmol) in THF (45 mL) was added. The reaction mixture was maintained at 0 ° C for 3 h, then injected through a tube of a mixture of CuCN (2.24 g, 25 mmol), LiCl (1.52 g, 36 mmol) and THF (15 mL) at -78 ° C. . The reaction mixture was warmed to -20 ° C and maintained for 5 min then cooled again to -78 ° C. The solid chlorohydride is suspended in THF (50 mL) and poured into the above cooled mixture. The reaction mixture was maintained at -78 ° C for 1 h, at 0 ° C for 1 h, then at 20 ° C for 1 h. The reaction mixture was partitioned between saturated NH ₄ Cl, filtered, and extracted with ethyl acetate. The aqueous layer is carefully acidified, extracted with ethyl acetate and the combined organic layers are dried (Na ₂ SO ₄ ). Purification by chromatography on silica gel eluting with hexanes / ethyl acetate (1: 1) and recrystallization (CH 2 Cl 2 / hexanes) gives 2.8 g of pure product and 2.5 g of crude product from the filtrate. ¹ H NMR (CDCl ₃ ) δ: 7.47 (d, J = 8.4 Hz, 2H),

7.42 (m, 8H), 7.08 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 8.4 Hz, 1H), 5.13 (s, 2H),

4.43 (d, J = 5.9 Hz, 2H), 4.09 (s, 2H), 3.11 (AB, J = 13.5, 46.9 Hz, 2H) md: ESI (s) masses m / z (rel intensity) 569.7-571.6 (MH) ⁺ .

Part B: The product of Part A (0.5 g, 0.88 mmol) was copolished according to Suzuki standard procedures with 2-tert-butylaminosulfonylphenylboronic acid (0.3 g, 1.1 mmol). Purification by chromatography on silica gel eluting with hexanes / ethyl acetate (2: 1) yields 0.36 g of the copolished product. De-blocking by boiling in TFA (20 min), reverse-phase HPLC purification and lyophilization afforded 0.2 g (64%) of product. ¹ H NMR (DMSO-d _s) δ: 8.16 (m, 3H), 8.13

210 (dd, J = 6.9, 2.2 Hz, 1H), 7.61 (m, 5H), 7.45 (m, 1H), 7.33 (m, 7H), 4.45 (s) , 2H), 4.14 (d, J = 5.9 Hz, 2H) md; ESI mass spectrum m / z (rel intensity): 514.8 (M + H, 100); Elemental analysis: Calculated for C25H21F3N4O3S (TFA) 1.3: 0: 50.02, H: 3.39, N: 8.45, Found: C: 50.10, H: 3.35, N: 8.39 .

Example 211

1- (3-Aminomethyl) phenyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3- (methylsulfonylmethyl) pyrazole trifluoroacetic acid salt

Part A: The pyrazole (1 g, 3.92 mmol) obtained in Part B of Example 10 was dissolved in CCl ₄ , followed by the addition of NBS (1.1 g, 6.27 mmol) and benzoyl peroxide (0.038 g, 0.5 mmol). The mixture is refluxed for 18 hours. Evaporation of the solvent, 50 ml of water, extracted with EtOAc and the organic layer was washed with brine and dried over MgSO _4th Filtration and concentration of the filtrate in vacuo followed by purification by flash chromatography (2: 3 / hexane: methylene chloride) afforded 0.55 g of the desired bromomethyl product as a yellowish solid. ¹ H NMR (CDCl 3) δ: 7.77-7.69 (m, 3H), 7.61 (t, J = 7.69, 1H), 7.13 (s, 1H), 4.51 (s) , 2H), 4.32 (kv, J = 6.95 Hz, 2H), 1.33 (t, J = 6.96 Hz, 3H) md; mass spectrum of ammonia Cl / m / z (relative intensity): 334.0 (97) and 336.0 (100).

Part B: To the product from Part A (0.55 g, 1.65 mmol) was added DMF in KSMe (0.16 g, 1.81 mmol). The mixture is refluxed overnight. The solution was treated with water (100 mL) and extracted with EtOAc. The organic layer was washed with saturated NaCl solution and dried over MgSO ₄ . After filtration, 2 or. air was bubbled through the filtrate, then the filtrate was concentrated in vacuo and purified by flash chromatography (3: 2 / hexane: EtOAc); 0.14 g of the desired methylsulfonylmethyl compound is obtained which is a colorless oil. Ammonia Cl mass spectrum m / z (rel intensity): 334.1 (M + H, 100). ¹ H NMR (CDCl 3) δ: 7.77-7.69 (m, 4H), 7.61 (t, J = 8.05,

211

1H), 4.38 (s, 2H), 4.30 (kv, J = 6.95 Hz, 2H), 2.94 (s, 3H), 1.32 (t, J = 6.96 Hz), 3H) md

Part C: Co-coupling of the product from Part B with 2'-tert-butylaminosulfonyl [1,1 '] -biphenylaniline according to standard Veinreb coupling procedures followed by acid cleavage and flash chromatography on silica gel to give 0.13 g of the desired product. ESI mass spectrum m / z (rel intensity): 613.8 (75). ¹ H NMR (CDCl 3) δ: 8.35 (s, 1H), 8.16 (m, 1H), 7.82 (s, 1H), 7.75-7.55 (m, 8H), 7 50-7.45 (m, 2H), 7.30 (m, 1H), 7.16 (s, 1H), 4.42 (s, 2H), 3.00 (s, 3H), 1.02 (s, 9H) md

Part D: To Part C product (0.13 g, 0.22 mmol) dissolved in ethanol (50 mL) was added 10% Pd / C (20 mg) and 2 mL AcOH. Hydrogenation of this solution in a Parr apparatus at 344.7 kPa for 18 hours, followed by filtration through a pad of celite and concentration, afforded a crude reduced product which was subjected to TFA (6 mL) and refluxed for 50 min. Evaporation of the solvent, purification according to standard reverse-phase procedures and lyophilization yields the desired product which is a colorless solid. ESI mass spectrum m / z (rel intensity): 540.1 (M + H, 100).

Example 212

1- (3-Amidino) phenyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3 (methylaminosulfonylmethyl) pyrazole trifluoroacetic acid salt

Part A: To a product of Part A (Example 211) (1.1 g, 3.29 mmol) in DMF was added NaN ₃ (0.24 g, 3.62 mmol). The mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with water (200 mL) and extracted with EtOAc. The organic layer was washed with water, brine, and dried over MgSO ₄ . The mixture is filtered and concentrated to give 0.93 g of the crude azidomethyl compound. ESI mass spectrum m / z (rel intensity): 297.1 (M + H, 100). ¹ H NMR (CDCl ₃ ) δ: 7.77 (m, 3H),

212

7.59 (m, 1H), 7.08 (s, 1H), 4.44 (s, 2H), 4.30 (s, J = 7Hz, 2H), 1.31 (t, J = 7) Hz, 3H) md

Part B: To the product from Part A (0.54 g, 1.82 mmol) in THF was added PPh ₃ (0.53 g, 2.01 mmol). The reaction mixture was stirred at room temperature for 4 hours and the solvent was evaporated. HCl (1N, 50 mL) was added and the organics were extracted with EtOAc. The organic layer was washed with saturated NaCl solution and dried over MgSO ₄ . Evaporation in vacuo afforded the desired aminomethyl compound (0.32 g) as a white solid. ESI mass spectrum m / z (rel intensity): 271.1 (M + H, 100). ¹ H NMR (CDCl ₃ ) δ: 7.77 (s, 1H), 7.59 (m, 1H), 7.01 (s, 1H), 4.30 (s, J = 7 Hz, 2H). , 3.96 (s, 2H), 1.31 (t, J = 7Hz, 3H) md

Part C: Triethylamine (1.5 eq) was added to part JB product (0.43 g, 1.59 mmol) in CH 2 Cl 2. The reaction mixture was cooled to 0 ° C and CH ₃ SO ₂ Cl (1 eq) was added. The reaction mixture was stirred at room temperature for 18 h, diluted with CH 2 Cl 2 and washed with 1N HCl, NaHCO ₃ (saturated solution), brine, then dried over MgSO ₄ . Evaporation in vacuo followed by flash chromatography (4: 1 / hexane: EtOAc) afforded 0.42 g of the desired methylsulfonamide pyrazole precursor. Ammonia Cl mass spectrum m / z (rel intensity): 349.0 (M + H, 100). 1 H NMR (CDCl 3) δ: 7.76 (m, 2H), 7.73 (m, 1H), 7.61 (m, 1H), 7.08 (s, 1H), 4.44 (d J = 6.3 Hz, 2H), 4.29 (kv, J = 7.3 Hz, 2H), 3.325 (s, 1H), 1.31 (t, J = 7.3 Hz, 3H) md

Part D: Co-coupling of the product of Part B with 2'-tert-butylaminosulfonyl [1,1 '] -biphenylaniline according to standard Veinreb coupling procedures, followed by conventional acid cleavage and flash chromatography on silica gel to give the desired product. ESI mass spectrum m / z (rel intensity): 605.1 (M-H, 100). 1 H NMR (CDCl 3) δ: 8.55 (s, 1H), 8.16 (m, 1H), 7.74 (m, 5H), 7.56 (m, 6H), 7.30 (m, 1H), 7.02 (s, 1H), 4.46 (d, 2H), 3.81 (s, 1H), 3.06 (s, 3H), 1.04 (s, 9H) md

213

Part E: Reaction according to the standard Pinner amidine reaction procedure, purification by reverse phase HPLC and lyophilization yields the desired product which is colorless crystals. ¹ H NMR (CDCl 3) δ: 10.69 (s, 1H), 9.43 (s, 2H), 9.15 (s, 2H), 8.05 (m, 1H), 7.95 (s, 1H), 7.85 (m, 1H), 7.80 (m, 1H), 7.70 (m, 4H), 7.60 (m, 2H), 7.35 (m, 2H), 7 , 30 (m, 1H), 7.20 (m, 3H), 4.28 (d, J = 6.1 Hz, 2H), 2.97 (s, 3H) md ESI mass spectrum m / z (rel. . intensity): 568.0 (100). DSGMS for C25H26N7O5S2: 568.143686 (calculated), 568.145471 (found).

Example 213

1- (3-Aminomethyl) phenyl-5 - [(2'-aminosulfonyl-3-fluoro- [1,1 '] - biphen-4-yl) aminocarbonyl] -3- (methylaminosulfonylmethyl) pyrazole trifluoroacetic acid salt

Part A: Co-coupling of the product of Part C (Example 203) with 4-bromo-2-fluoroaniline according to the standard Veinreb copulation procedure gives the desired amide. ¹ H NMR (CDCl ₃ ) δ: 8.13 (t, J = 8.4 Hz, 1H), 7.90 (pi, 1H), 7.79 (m, 1H), 7.78 (m, 2H), 7.61 (m, 1H), 7.35 (m, 2H), 6.96 (s, 1H), 4.86 (m, 1H), 4.44 (d, J = 6.2). Hz, 2H), 3.04 (s, 3H) md. ESI mass spectrum (m / z): 489.8 (85) and 491.8 (100).

Part B: Co-coupling of the product of Part A with 2-thiomethylboronic acid according to Suzuki's standard coupling procedure gives the desired 2'-thiomethyl-biphenyl intermediate. Δ NMR (CDCl ₃ ) δ: 8.25 (pi, 1H), 8.00 (pi, 1H), 7.83 (s, 1H), 7.75 (m, 2H), 7.62 ( m, 1H), 7.35 (m, 6H), 6.96 (s, 1H), 4.85 (m, 1H), 4.48 (d, J = 5.9 Hz, 2H), 3, 05 (s, 3H), 2.39 (s, 1H) md ESI mass spectrum m / z (rel intensity): 557.9 (M + Na, 100). ESI mass spectrum m / z (relative intensity): 533.8 (MH-100).

Part C: To Part B product (0.54 g, 1.01 mmol) in CH ₂ Cl _{2 is} added

MCPBA (0.52 g, 3.03 mmol), and the reaction mixture was stirred at room temperature

At 214 overnight. CH ₂ Cl _{2 is} added to the mixture, washed with NaHCO 3 (saturated solution), acidic sodium sulfite, saturated NaCl solution and dried over MgSO ₄ . Filtration, concentration of the filtrate in vacuo and purification by flash chromatography (1: 1 / hexane: EtOAc) gives 0.53 g of the sulfonylmethyl derivative as a white solid. ¹ H NMR (CDCl ₃ ) δ: 10.53 (s, 1H), 8.07 (m, 1H), 7.97 (s, 1H), 7.85 (m, 1H), 7.8 (m , 6H), 7.41 (m, 1H), 7.35 (m, 1H), 7.23 (m, 2H), 4.23 (s, 2H), 2.94 (s, 3H), 2 , 89 (s, 3H) md ESI (mass) mass spectrum m / z (rel intensity): 565.8 (70).

Part D: The product of Part C is hydrogenated according to the procedure described above to give the desired benzylamine analog which, after purification by reverse phase HPLC and lyophilization, is colorless crystals. - ¹ H (DMSO) δ: 10.53 (s, 1H), 8.16 (br., 2H), 8.07 (m, 1H), 7.75 (m, 1H), 7.72 (m , 4H), 7.49 (m, 5H), 7.21 (m, 2H), 4.23 (d, J = 6.2 Hz, 2H), 4.09 (m, 2H), 2.93 (s, 3H), 2.90 (s, 3H) md ESI mass spectrum m / z (relative intensity): 571.9 (M + H, 100). DSGMS: calcd. For C ₂₆ H ₂₇ N ₅ O ₅ FS ₂ 572.143766 (calcd), 572.145154 (found).

Example 214

1- (3- (N-Carboxymethyl) amidinophenyl) -5 - [(5- (2'-aminosulfonylphenyl) pyrimidin-2-yl) aminocarbonyl] -3-methylpyrazole trifluoroacetic acid salt of Example 92 (100 mg, 0.19 mmol) a solution of DMF was added methyl chloroformate (36 mg, 0.38 mmol) and Et ₃ N. The mixture was stirred at room temperature for 2.5 h. Dilute with 100 mL of water, extract with EtOAc, wash the organic layer with water, brine, dry over MgSO ₄ , filter, concentrate in vacuo and purify by reverse phase HPLC to give the desired carbamate [ESI mass spectrum m / z (relative intensity): 590.9 (100)], which is then treated with TFA and refluxed for 0.5 hours. Evaporation of TFA, purification by reverse phase HPLC and lyophilization gave the title compound. ¹ H (DMSO) δ: 11.34 (s, 1H), 8.61 (s, 2H), 8.01 (m, 1H), 7.95 (m, 1H), 7.80 (m, 1H ), 7.69 (m,

215

1H), 7.64 (m, 3H), 7.49 (s, 2H), 7.40 (m, 1H), 7.03 (s, 1H), 3.79 (s, 3H), 2, 28 (s, 3H) md ESI mass spectrum m / z (relative intensity): 535.0 (M + H,

100). HRMS: calculated for C ₂₄ H ₂₂ N _o O ₃ S 535.151213 (calculated) 535.151600 (found).

Example 215

1- (3-Aminomethylphenyl) -5 - [(2'-methylsulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] 3-methylpyrazole trifluoroacetic acid salt

Part A: Standard Weinreb copulation of 2'-sulfonylmethylbiphenylamine with the pyrazole ester of Example 10 Part B, followed by standard workup and purification by silica gel chromatography, yields the desired copulated amidine precursor. ¹ H NMR (CDCl ₃ ) δ: 8.24 (d, J = 7.7 Hz, 1H), 7.87 (s, 1H),

7.81 (s, 1H), 7.76 (m, 1H), 7.69 (m, 6H), 7.45 (m, 2H), 7.35 (m, 1H), 6.71 (s, 1H), 2.68 (s, 3H), 2.42 (s, 3H) md ESI mass spectrum m / z (rel intensity): 478.9 (M + Na, 100). ESI mass spectrum m / z (rel intensity): 454.9 (M-H, 100).

Part B: To a product of Part A (0.48 g, 1.05 mmol) in EtOH was added 10%

Pd / C (80 mg) and 1 mL TFA. The mixture was hydrogenated in a Parr apparatus at 344.7 kPa for 18 hours. After filtration through a pad of celite and concentration of the filtrate in vacuo, the product is purified by reverse phase preparative HPLC to give the title compound. 1 H (DMSO) δ: 10.65 (s, 1H), 8.17 (pi, 2H), 8.06 (d, J = 7.7 Hz, 1H), 7.75 (m, 5H). , 7.49 (m, 6H), 6.92 (s, 1H), 4.10 (m, 2H),

2.81 (s, 3H), 2.29 (s, 3H) md ESI mass spectrum m / z (relative intensity): 460.9 (M + H, 100). HRMS: calculated for C ₂ 5H ₂₅ N ₄ O ₃ S 461.164738 (calculated) 461.164405 (found).

Example 216

1- (3-Aminomethylphenyl) -5 - [(2'-aminosulfonyl-3-methyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-trifluoromethylpyrazole trifluoroacetic acid salt

216

Part A: 2'-tert-Butylaminosulfonyl-2-methylbiphenylamine standard

Weinreb's copulation with the previously obtained pyrazole ester yields the desired copulated amide precursor. ¹ H NMR (CDCl ₃ ) δ: 8.13 (d, J = 7.7 Hz, 1H), 7.83 (m, 4H), 7.64 (m, 2H), 7.56 (m, 2H). ), 7.4 (m, 3H), 7.15 (s, 1H), 3.61 (s, 1H), 2.36 (s, 3H), 1.04 (s, 9H) md ES! mass spectrum m / z (rel intensity): 604.1 (M + Na, 100). ESI mass spectrum m / z (rel intensity): 580.3 (MH, 100).

Part B: Reduction of benzonitrile to benzylamide, cleavage and purification of the tert-butyl group by standard reverse phase HPLC affords the desired compound. ¹ H (DMSO) δ: 10.33 (s, 1H), 8.23 (br., 2H), 8.02 (m, 1H), 7.76 (s, 1H), 7.66 (m, 6H), 7.40 (d, J = 8.1 Hz, 1H), 7.31 (m, 5H), 4.15 (m, 2H), 2.25 (s, 3H) md ESI mass spectrum m / z (relative intensity): 530.2 (M + H, 100).

Example 217

1- (3-Aminomethylphenyl) -5 - [(3-fluoro-2'-methylsulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -1,2,3-triazole trifluoroacetic acid salt

Standard Weinreb co-coupling of 4-bromo-2-fluoroaniline with the previously obtained 1,2,3-triazole-4-carboxylic acid used to prepare the compound of Example 46 gives, after purification by flash chromatography on silica gel, a copolished amidotriazole derivative. ¹ H NMR (CDCl 3) δ: 8.23 (s, 1H), 8.11 (m, 1H), 7.86 (m, 4H), 7.68 (m, 1H), 7.34 (m, 2H) md ESI (s) mass spectrum m / z (ratio, intensity): 383.8 (100) and 385.8 (80). Standard Suzuki coupling of this intermediate with 2-thiomethylboronic acid followed by MCPBA oxidation in dichloromethane yields the desired biphenylsulfonyl derivative. ¹ H NMR (CDCl ₃ ) δ: 8.34 (m, 3H), 8.05 (pi, 1H), 7.93 (m, 3H), 7.74 (m, 3H), 7.37 ( m, 2H), 7.24 (m, 1H), 2.74 (s, 3H) md ESI (m / z) mass spectrum m / z (rel. intensity): 459.9 (MH, 100). This intermediate is then reduced to benzylamine and purified under standard conditions as described above. ¹ H (DMSO) δ: 10.76 (s, 1H), 8.53 (s, 1H), 8.21 (br.,

217

2H), 8.05 m, 1H), 7.77 (m, 7H), 7.39 (m, 2H), 7.22 (m, 1H), 4.14 (m, 2H), 2.89 (s, 3H) md ESI (s) mass spectrum m / z (relative intensity); 465.9 (M + H, 100). DSGMS: Calcd. For C23H21N5O3FS 466.134915 (calcd.), 466.136900 (found).

Example 218

- (S-Aminomethyl - N - methylphenyl-S - {^ - aminosulfonyl-1,1'-biphen-4-yl) aminocarbonyl] -3-methylpyrazole trifluoroacetic acid salt

Part A: To a cold (0 ° C) solution of 2-methyl-4-aminobenzonitrile (10 g, 78.12 mmol) in acidic (almost HCl, 100 mL) was added sodium nitrite (8.08 g, 117.19 mmol) in water. (20 mL). Cold temperature is maintained during addition of sodium nitrite solution. After stirring for a further 0.5 h, the SnCb solution is added dropwise. HCl (50 mL). Immediate precipitation occurs. The reaction mixture was stirred at 0 ° C for an additional 18 h, then filtered, washed with cold water (1000 mL) followed by petroleum ether / ether (2: 1, 500 mL). The residue is dried under vacuum overnight to give a total of 8.15 g of crude hydrazine tin salt.

Part B: The tin salt obtained in Part A is stirred in glacial acetic acid (100 ml). Methoxoxime from ethyl 2,4-dioxovalerate (4.59 g, 24.55 mmol) is then added to this solution. The reaction mixture was gently boiled under reflux overnight. The acetic acid is evaporated and the residue is taken up in water (200 ml). The organics were extracted with ethyl acetate (2 x 100 mL), washed with saturated sodium carbonate (2 x 50 mL), brine (50 mL), and dried (magnesium sulfate). Chromatography over a column (silica gel, ethyl acetate: hexane 2: 8) gives the desired pyrazole carboxylate (4 g), which is a yellowish oil which crystallizes on standing.

Part C: The product of Part B is then copolymerized with 2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-ylamine according to the standard procedure described above.

Weinreb's methodology for trimethylaluminium copulation. Impure material

218 is chromatographed on a silica gel column (methylene chloride: methanol, 9: 1) to give 90% pure product. ¹ H NMR (CDCl ₃ ) δ: 8.30 (pi, 1H), 8.13 (pi, 1H), 7.78-7.23 (m, 10H), 6.78 (s, 1H) , 3.68 (s, 1H), 2.60 (s, 3H), 2.40 (s, 3H), 1.01 (s, 9H) md ESI mass spectrum m / z (rel intensity): 528 (M + H, 100).

Part D: The product of Part C is then reduced (in a Parr apparatus) at

344.7 kPa hydrogen pressure in acidic medium (methanol, acetic acid) overnight using 10% palladium on carbon. The solvents were evaporated and the crude material was stirred in TFA (reflux) for 0.5 h, then evaporated to give crude benzylamine product which was purified by preparative HPLC (acetonitrile: water with 0.5% TFA, gradient), and the desired benzylamine is obtained which is flake-like crystals. ¹ H NMR (DMSO-d 6) δ: 10.6 (s, 3H), 8.14 (m.s, 2H), 8.01 (d, 1H), 7.68 (d, 2H (7), 64-7.54 (m, 2H), 7.38-7.26 (m, 5H), 6.91 (s, 1H), 4.07 (pi.d, 2H), 2.38 (s, 3 H), 2.33 (s, 3 H) md ESI mass spectrum m / z (rel intensity): 476.2 (M + H, 100).

Example 219

1- (3-Aminomethyl-4-fluoro) phenyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methylpyrazole trifluoroacetic acid salt

The pyrazole compound is prepared from the readily available 4-fluoro-3-cyanophenylhydrazine tin salt (obtained from the corresponding aniline) and oxime from ethyl 2,4-dioxovalerate according to the procedures described above. The standard Venereb copulation of this pyrazole with 2'-tert-butylaminosulfonyl [1,1 '] -biphen-4-ylamine yields the desired copolymed amide precursor, which is then treated according to a standard procedure (344.7 kPa hydrogen pressure, methanol: nitrogen). acid) using 10% palladium on carbon. After evaporation of the solvents followed by treatment with TFA for 0.5 h. and purification by preparative HPLC as described above affords the title compound as colorless crystals. ¹ H NMR (DMSO-d 6) δ: 8.25 (m.s, 3H), 8.00 (d, 1H), 7.78219

7.23 (complex, 12H), 6.95 (s, 1H), 4.14 (m, 2H), 2.30 (s, 3H) m, d. ESI mass spectrum m / z (rel intensity): 480.2 (M + H, 100).

Example 220

1- (3-Aminomethyl-4-chloro) phenyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methylpyrazole trifluoroacetic acid salt

The pyrazole compound is prepared from the readily available 4-chloro-3-cyanophenylhydrazine tin salt (obtained from the corresponding aniline) and oxime from ethyl 2,4-dioxovalerate according to the procedures described above. 1 H NMR (CDCl 3) δ: 7.78 (d, 1H), 7.86-7.55 (m, 2H), 6.86 (s, 1H), 4.24 (s, 2H), 2, 35 (s, 3H), 1.28 (t, 2H) md ESI mass spectrum m / z (rel intensity) 290 (M + H, 100). Pyrazole obtained above with a standard coupling VVeinreb'o IREF-2'-butylaminosulfonyl- ^[1,1] -biphen-4-ylamine to give the desired coupled amide precursor which is then treated with tetrabutylammonium borohydride (1.5 equiv.) In dichloromethane for 24 h . Evaporation of the solvent and purification by preparative HPLC as described above affords the title compound as colorless crystals. ¹ H NMR (DMSO-d _s) δ: 8.25 (br s, 3H), 8.00 (d, 1H), 7,787,23 (complex, 12H), 6.95 (s, 1H) 4 , 14 (m, 2H), 2.30 (s, 3H) md ESI mass spectrum m / z (rel intensity): 497.1 (M + H, 100).

Example 221

1- (3-Aminomethyl-4-fluoro) -phenyl-5 - [(2'-aminosulfonyl-3-fluoro- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-trifluoromethylpyrazole trifluoroacetic acid salt

Reduction of the benzonitrile precursor prepared according to the procedure described above (10% palladium on carbon, methanol / acetic acid, 344.7 kPa hydrogen pressure) affords the title compound which, after purification by para-HPLC and lyophilization, is colorless crystals. ¹ H NMR (DMSO-d 6) δ: 10.68 (s, 1H), 8.27 (ss, 2H), 8.02 (dd, 1H), 7.81 (m, 1H), 7 73 (s, 1H), 7.687.60 (m, 4H), 7.61-7.43 (m, 3H), 7.38-7.30 (m, 2H), 7.20 (dd, 2H). , 4.18 (pi.d, 2H) md ESI mass spectrum m / z (rel intensity): 551.9 (M + H, 100).

220

Example 222

1- (3-Aminomethyl) phenyl-5 - [(2'-aminosulfonyl-3-fluoro- [1,1]] -biphen-4-yl) aminocarbonyl] -3-methylpyrazole trifluoroacetic acid salt

Part A: Copulation of ethyl 1- (3-cyanophenyl) -3-methyl-5-carboxylate with 2'-tert-butylaminosulfonyl-3-fluoro- [1,1] -biphen-4-ylamine according to Weinreb's method described above the desired copolished amide compound. In this case, 1.5 equivalents of biphenyl analog was used to facilitate copulation. Purification by chromatography on silica gel (methylene chloride / methanol, 9/1) gives the pure amide (60%) which is a slightly yellowish oil. ¹ H NMR (CDCl 3) δ: 8.35 (t, 1H), 8.15 (dd, 1H), 7.96 (m, 1H), 7.82 (s, 1H), 7.787.68 (m, 4H), 7.60-7.48 (m, 4H), 7.20 (m, 1H), 6.74 (s, 1H), 3.67 (s, 1H), 2.04 (s, 3H) ), 1.04 (s, 9H) md ESI mass spectrum m / z (relative intensity)

553.9 (M + Na, 100). ESI (s) mass spectrum m / z (relative intensity)

529.9 (M-H, 100).

Part B: The product from Part A is then converted to the corresponding benzylamine using the reduction procedure described above (10% Pd / C, MeOH / AcOH, 344.7 kPa hydrogen pressure). Evaporation of the solvent, followed by standard cleavage of the tert-butyl group with TFA and purification by preparative HPLC afforded the pure title compound as colorless crystals (60%). H NMR (DMSO-d _s) δ: 10.42 (s, 1H), 8.20 (br s, 2H), 8.02 (dd, 1H), 7.70 to 7.59 (m, 4H), 7.55-7.29 (m, 6H), 7.19 (dd, 1H), 6.97 (s, 1H), 4.11 (pi.d, 2H), 2.50 (s) , 2H) md ESI mass spectrum m / z (rel intensity): 480 (M + H, 100).

Example 223

1- (3-Aminomethyl) phenyl-5 - [(3-fluoro-2'-methylsulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-trifluoromethylpyrazole trifluoroacetic acid salt

221

Part A: Copulation of ethyl 1- (3-cyanophenyl) -3-methyl-5-carboxylate with 2'-methylsulfonyl-3-fluoro- [1,1 '] - biphen-4-ylamine (prepared by pre-copying)

2-Thiomethylphenylboronic acid with 4-bromo-2-fluoroaniline according to Suzuki's copolymerization procedure according to Weinreb's method described above gives the desired copolymeric amide compound. Purification by chromatography on silica gel (methylene chloride / methanol 9/1) gives the pure amide (80%) as a colorless solid. This amide was also obtained by first coupling (Veinreb) 2-fluoro-4-bromoaniline with the above pyrazole carboxylate, followed by Suzuki coupling with 2-thiomethylphenylboronic acid and oxidation to the sulfonyl derivative. ¹ H NMR (CDCl ₃ ) δ: 8.39 (t, 1H), 8.20 (dd, 1H), 7.96 (pi.d, 1H), 7.83 (s, 1H), 7.78 -7.59 (m, 5H), 7.41-7.35 (t, 2H), 7.17 (d, 1H), 6.74 (s, 1H), 2.73 (s, 3H), 2.40 (s, 3H) md ESI mass spectrum m / z (rel intensity) 593 (M + Na, 100). ESI mass spectrum m / z 572 (MH, 100) (relative intensity).

Part B: Reduction of the product of Part A according to the procedures described above and purification by HPLC affords the title compound as colorless crystals (70%). ¹ H NMR (DMSO-d ₆ ) δ: 10.45 (s, 1H), 8.20 (m.s, 3H), 8.08 (dd, 1H), 7.80-7.66 (m, 4H), 7.55-7.37 (m, 5H), 7.21 (dd, 1H), 6.98 (s, 1H), 4.12 (s, 2H), 2.94 (s, 3H). ), 2.50 (s, 3H) md ESI mass spectrum m / z (rel intensity): 479 (M + H, 100).

Example 224

1- (3-Amidinophenyl) -3-methyl-5 - [(3-fluoro-4- (N-morpholino) phenyl) aminocarbonyl] pyrazole bis-trifluoroacetate

Part A: Preparation of N- (3-fluoro-4-nitrophenyl) morpholine by freezing (0 ° C) morpholine (6.03 mL, 69.14 mmol), diisopropylamine (11.83 mL, 67.89 mmol), and ml of ethyl acetate solution over 1.5 hours. 3,4-difluoronitrobenzene (10.0 g, 62.86 mmol) was added. The reaction mixture was allowed to warm to room temperature and left for 48 hours. The reaction mixture was diluted with 25 mL of methylene chloride, 100 mL of ethyl acetate and 50 mL of water.

222

The layers were separated and the aqueous layer was extracted with 2 x 25 mL EtOAc. The organic extracts are combined, dried over magnesium sulfate and concentrated under reduced pressure to give a yellow solid. This crude material is recrystallized from acetone and water to give 12.55 g of a yellow crystalline solid. ¹ H NMR (DMSO-d 6) δ: 7.99 (m, 2H), 7.14 (t, 1H, J = 8.79 Hz), 3.71 ppm, 4H, J = 4.56 Hz), 3.23 (e.g., 4H, J = 4.76 Hz). ESI mass spectrum m / z (rel intensity): 227 (M + H).

Part B: Preparation of N- (3-Fluoro-4-aminophenyl) morpholine

In a Parr flask, N- (3-fluoro-4-nitrophenyl) morpholine (6.01 g, 26.59 mmol) was suspended in methanol (100 mL) and the catalytic amount of palladium on carbon (10%). The reaction mixture is placed in a Parr hydrogenator at 413.7 kPa for 2 hours. The reaction mixture is passed through a pad of celite, and the filtrate is concentrated under reduced pressure to give 4.50 g of N (3-fluoro-4-aminophenyl) morpholine as a colorless solid. ¹ H NMR (DMSO-d 6) δ: 6.73 (t, 1H, J = 9.34 Hz), 6.28 (m, 2H), 3.64 (m.p., 4H, J = 4.58 Hz), 2.76 (e.g., 4H, J = 4.58 Hz). ESI mass spectrum m / z (rel intensity): 197 (M + H, 100). ¹⁹ F NMR (DMSO-d ₆ ) δ: -124.455.

Part C: Preparation of 1- (3-cyanophenyl) -3-methyl-5 - ((3-fluoro-4- (N-morpholino) phenyl) aminocarbonylpyrazole into 1- (3-cyanophenyl) -3-methylpyrazole-5-carboxylic acid To a solution of chloro anhydride (0.46 g, 1.88 mmol) and N- (3-fluoro-4-aminophenyl) morpholine (0.37 g, 1.88 mmol) in 20 mL of methylene chloride was added dimethylaminopyridine (0.28 g, 2 The reaction mixture was stirred at room temperature for 72 hours, then concentrated under reduced pressure to give a residue which was purified by flash chromatography to give 0.070 g of pure 1- (3-cyanophenyl) -3-methyl-5 - ((3-fluoro-) 4- (N-morpholino) phenyl) aminocarbonyl) pyrazole 1 H NMR (DMSO-d 6) δ: 10.50 (s, 1H), 7.93 (s, 1H), 7.83 (d, 1H, J = 7.33 Hz), 7.73 (d, 1H, J = 8.79 Hz), 7.62 (t, 1H, J = 7.87 Hz), 7.53 (m, 1H), 7, 34 (d, 1H, J = 9.15 Hz), 6.99 (t, 1H, J = 9.34 Hz), 6.93 (s, 1H), 3.69 (e.g., 4H, J = 4.58 Hz), 2.92 (e.g., 4H, J =

223

4.58 Hz), 2.28 (s, 3H). ESI mass spectrum m / z (rel intensity): 406 (M + H, 100), 833 (2M + Na). ¹⁹ F NMR (DMSO-d ₆ , 300 MHz) δ: -122,081.

Part D: Preparation of 1- (3-Amidinophenyl) -3-methyl-5 - ((3-fluoro-4- (N-morpholino) phenyl) aminocarbonylpyrazole

1- (3-Cyanophenyl) -3-methyl-5 - ((3-fluoro-4- (N-morpholino) phenyl) aminocarbonyl) pyrazole (0.070 g, 0.173 mmol) was dissolved in 2 mL of chloroform and 2 mL of ethanol at 0 ° C. at room temperature for 1 hour. gaseous hydrogen chloride is bubbled through. The reaction mixture was allowed to warm to room temperature and allowed to stand for 15 h, then concentrated under reduced pressure. The resulting solid was maintained under deep vacuum for 2 h. This crude imidate is then dissolved in 2 ml of ethanol and ammonium carbonate (0.25 g, 2.60 mmol) is added to the solution at room temperature. The reaction mixture was stirred for 72 h. and concentrated under reduced pressure. Purification of the crude product by standard HPLC affords 0.016 g of pure 1- (3amidinophenyl) -3-methyl-5 - ((3-fluoro-4- (N-morpholino) phenyl) aminocarbonyl) pyrazole.

Ή NMR (DMSO-d6) δ: 10.53 (s, 1H), 9.40 (s, 2H), 9.12 (s, 2H), 7.93 (d, 1H, J = 1.71 Hz) ), 7.81 (m, 1H), 7.70 (m, 2H), 7.53 (dd, 1H, J = 15 Hz), 7.35 (d, 1H, J = 8.79 Hz), 7.01 (m, 2H), 3.72 (pt, 4H, J = 4.52 Hz), 2.95 (pt, 4H, J = 4.6 Hz), 2.29 (s , 3H). ESI mass spectrum m / z (rel intensity): 423 (M + H, 100). ⁹ F NMR (DMSO-d ₆ ) δ: -73.790 and -121.040. DSGMS calculated for C ₂ H ₂₄ N ₆ O ₂ F ₁ : 423.194478, found 423.192755.

Example 225

1- (3-Aminomethylphenyl) -3-methyl-5 - [(3-fluoro-4- (N-morpholino) phenyl) aminocarbonyl] pyrazole bis-trifluoroacetate

Part A: Preparation of 1- (3-cyanophenyl) -3-methyl-5 - ((3'-fluoro-4 '- (N-morpholino) phenyl) aminocarbonylpyrazole) with N- (cyanophenyl) -3-methylpyrazole-5-carboxylic acid chlorohydride (0.30 g, 1.22 mmol) and N- (3-fluoro-4-aminophenyl) morpholine (0.24 g, previously described)

Dimethylaminopyridine (1.22 mmol) was added to 20 mL of methylene chloride

224 (0.18 g, 1.47 mmol). The reaction mixture was stirred at room temperature for 72 hours, then concentrated under reduced pressure. The resulting residue was purified by flash chromatography to give 0.070 g of pure 1- (3cianofenil) -3-methyl-5 - ((3'-fluoro-4 '- (N-morpholino) phenyl) aminocarbonyl) pyrazole, ¹ H NMR (DMSO -d6) δ: 10.50 (s, 1H), 7.93 (s, 1H), 7.83 (d, 1H, J = 7.33 Hz), 7.73 (d, 1H, J = 8 , 79 Hz), 7.62 (t, 1H, J = 7.87 Hz), 7.53 (m, 1H), 7.34 (d, 1H, J = 9.15 Hz), 6.99 ( t, 1H, J = 9.34 Hz), 6.93 (s, 1H), 3.69 (pt, 4H, J = 4.58 Hz), 2.92 (pt, 4H, J = 4.58 Hz), 2.28 (s, 3H). ESI mass spectrum m / z (relative intensity); 406 (M + H, 100), 833 (2M + Na). ¹⁹ F NMR (DMSO-d 6, 300 MHz) δ: -122,078.

Part B: Preparation of 1- (3-Aminomethylphenyl) -3-methyl-5 - ((3'-fluoro-4 '- (N-morpholino) phenyl) aminocarbonylpyrazole in 1 ml of methanol and 1 ml of trifluoroacetic acid is suspended in 1- (3-cyanophenyl) -3-Methyl-5 - ((3'-fluoro-4 '- (N-morpholine) phenylaminocarbonyl) pyrazole (0.21 g, 0.519 mmol) and a catalytic amount of palladium on carbon (10%). The hydrogenator was passed through a pad of celite under a pressure of 413.7 kPa for 20 hours and the filtrate was concentrated under reduced pressure to give pure 1- (3-aminomethylphenyl) -3-methyl-5 - (( 3'-Fluoro-4 '- (N-morpholino) phenylaminocarbonyl) pyrazole ¹ H NMR (DMSO-d 6) δ: 10.53 (s, 1H), 8.18 (m.p., 2H), 7.60 (s, 1H), 7.53 (dd, 1H, J = 15.0 Hz, J ₂ = 2.2 Hz), 7.44 (m, 2H), 7.33 (d, 2H, J = 7.33 Hz), 6.98 (dd, 1H, J = 9.3 Hz, J ₂ = 9.2 Hz), 6.86 (s, 1H), 4.07 (bt, 2H, J 1 = 2.9 Hz, J ₂ = 2.6 Hz), 3.69 (e.g., 4H, J 1 = 4.4 Hz, J ₂ = 4.8 Hz), 2.91 (e.g. t, J , = 4.9 Hz, J ₂ = 4.8 Hz), 2.47 (s, 3H). ESI mass spectrum m / z (rel intensity): 410 (M + H, 100). ¹⁹ F NMR (DMSO-d 6) δ: -122.105. DSGMS calculated for C C CHNNNeO ^: 410.199224, found 410.197598.

Example 226

225

1- (3-Aminomethylphenyl) -3-trifluoromethyl-5 - ((3-fluoro-4- (2-methylimidazol-1-yl) phenyl) aminocarbonyl) pyrazole bis-trifluoroacetate

Part A: Preparation of 3-Fluoro-4- (2-methylimidazol-1-iDnitrobenzene)

To a solution of 3,4-difluoronitrobenzene in 100 mL of DMF was added 2-methylimidazole (1.0 g, 12.18 mmol). Potassium carbonate (2.02 g, 14.61 mmol) was added to the reaction mixture and stirred vigorously for 24 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in 100 mL of ethyl acetate. The organics were washed with 6 x 50 mL water and 3 x 50 mL saturated NaCl solution. Drying the solution with magnesium sulfate and concentrating the resulting organic material under reduced pressure gives 1.66 g of crude

3-Fluoro-4- (2-methylimidazol-1-yl) nitrobenzene. ¹ H NMR (DMSO-d 6, 300 MHz) δ: 8.42 (dd, 1H, J 1 = 2.4 Hz, J 2 = 10 Hz), 8.21 (m, 1H), 7.86 (t, 1H, J = 8.4 Hz), 7.34 (s, 1H), 6.98 (s, 1H), 2.21 (s, 1H). ESI mass spectrum m / z (rel intensity): 221.9 (M + H, 100). ¹⁹ F NMR (DMSO-d 6) δ: -118.512.

Part B: Preparation of 3-Fluoro-4- (2-methylimidazol-1-yl) aniline

3 Fluoro-4-N- (2-methylimidazol-1-yl) nitrobenzene (1.66 g, 7.51 mmol) was added to a suspension of palladium on carbon (10%) in 30 mL of methanol. The reaction mixture was placed in a Parr hydrogenator at 413.7 kPa for 20 hours. The reaction mixture is filtered through a pad of celite, and the filtrate is concentrated under reduced pressure to give 1.40 g of crude 3-fluoro-4-N- (2-methylimidazol-1-yl) aniline. Ή NMR (DMSO-d _s, 300 MHz) δ: 7.02 (m, 2H), 6.83 (s, 1H), 6.43 (m, 2H), 5.70 (br s, 1H) , 2.07 (s, 3H). ESI mass spectrum m / z (relative intensity). ¹⁹ F NMR (DMSO-d 6) δ: -124,344.

Part C: Preparation of 1- (3-cyanophenyl) -3-trifluoromethyl-5 - ((3'-fluoro-4 '- (2-methylimidazol-1-yl) phenyl) aminocarbonyl) pyrazole

J N- (3-Cyanophenyl) -3-trifluoromethylpyrazole-5-carboxylic acid chloro anhydride (0.39 g, 1.30 mmol) and 3-fluoro-4- (2-methylimidazol-1-yl) aniline (0.25 g) , 1.30 mmol) of dimethylaminopyridine (0.19 g, 1.56 mmol) was added in 10 mL of methylene chloride. The reaction mixture was stirred

226 at room temperature for 5 hours, then concentrated under reduced pressure. The resulting residue was purified by flash chromatography to give 0.16 g of pure 1- (3-cyanophenyl) -3-trifluoromethyl-5 - ((3'-fluoro-4 '- (2-methylimidazol-1-yl) phenyl) aminocarbonyl). pyrazole. ESI mass spectrum m / z (relative intensity) 455.2 (M + H, 100).

Part D: Preparation of 1- (3-Aminomethylphenyl) -3-trifluoromethyl-5 - ((3'-fluoro-4 '- (2-methylimidazol-1-yl) phenyl) aminocarbonyl) pyrazole bis-trifluoroacetate

The standard transformation of the benzonitrile from Part C (0.16 g, 0.344 mmol) to benzylamine using catalytic hydrogenation affords 0.050 g of 1- (3-aminomethylphenyl) -3-trifluoromethyl-5 - ((3'-fluoro-4 ') after purification by HPLC. - (2-methylimidazol-1-yl) phenyl) aminocarbonyl) pyrazole bistrifluoroacetate. ¹ H NMR (DMSO-d 6, 300 MHz) δ: 11.25 (s, 1H), 7.91-7.52 (m, 10H), 4.12 (m, 2H), 2.43 (s, 3H). ESI mass spectrum m / z (rel intensity) 459.1 (M + H, 100). HRMS (NH ₃ lambda-cI) calculated for C 2 H _{2 1 4} 9N6OF: 459.155647, found 459.154688.

Example 227

1- (3-Cyanophenyl) -3-trifluoromethyl-5 - (([1,1 '] - biphen-4-yl) oxymethyl) pyrazole

Part A: Preparation of 1- (3-cyanophenyl) -3-trifluoromethyl-5 - ((1,1,1'-biphen-4-yl) oxymethyl) pyrazole into 1- (3-cyanophenyl) -3-trifluoromethyl- as described above. A solution of 5-hydroxymethylpyrazole (0.46 g, 1.73 mmol), 4-hydroxy- [1,1'J-biphenyl (0.44 g, 2.59 mmol) and triphenylphosphine (0.68 g, 2.59 mmol) 15 mL of THF per 1 h. diethyl azodicarboxylate (0.41 mL, 2.59 mmol) was added. The reaction mixture was stirred for 48 hours. The reaction mixture was diluted with 30 mL of water and extracted with ethyl acetate. The organic extracts were combined, dried over magnesium sulfate and purified by flash chromatography to give 0.040 g of pure 1- (3-cyanophenyl) -3-trifluoromethyl-5 - (([1,1-biphen-4-yl) oxymethyl) -pyrazole. . ¹ H NMR (DMSO-d 6) δ: 8.01 (m, 1H), 7.91 (m, 1H), 7.75 (m, 1H), 7.58 (m, 4H), 7.44 (m, 2H), 7.34 (m, 1H), 6.99 (m, 2H), 6.88

227 (s, 1H), 5.05 (s, 2H). ESI mass spectrum m / z (rel intensity) 420 (M + H, 100), 437 (M + NH ₄ , 63).

Examples 228 and 229

1- (3-amidinophenyl) -3-trifluoromethyl-5 - (([1,1 '] - biphen-4-yl) oxymethyl) pyrazole (Example 228) and 1- (3-carboxamidophenyl) -3-trifluoromethyl-5 - (([1, r] -biphen-4-yl) oxymethyl) pyrazole (Example 229)

Part A: 1- (3-Amidinophenyl) -3-trifluoromethyl-5 - ((1,1,1'-biphen-4-yl) oxymethyl) pyrazolyl] -1- (3-carboxamidophenyl-3-trifluoromethyl-5 - (( Preparation of ri, 1'1-biphen-4iPoxymethyl-pyrazole

- Standard Pinner amidine transformation of (3-cyanophenyl) -3-trifluoromethyl-5 - (([1,1 '] -biphen-4-yl) oxymethyl) -pyrazole according to the procedure described above, when purified by HPLC, gives 0. 22 g 1- (3-amidinophenyl) -3-trifluoromethyl-5 - (([1,1 ^l ] -biphen-4-yl) oxymethyl) pyrazole trifluoroacetate; ¹ H NMR (DMSO-d 6) δ: 9.42 (m.s, 2H), 9.16 (m.s, 2H), 8.06 (s, 1H), 8.01 (d, 1H, J = 8.1 Hz), 7.91 (d, 1H H. J = 8.1 Hz), 7.79 (t, 1H, J = 8.1 Hz), 7.56 (m, 4H), 7 , 39 (m, 2H), 7.28 (m, 1H), 7.23 (m, 1H), 7.01 (d, 2H, J = 8.79 Hz), 5.26 (s, 2H) ; ESI mass spectrum m / z (rel intensity) 437 (M + H, 100); DSGMS (NH ₃ Cl): calculated for C ₂₄ H ₂₀ O ₄ OF ₃ : 437.158921, found 437.157809; and 0.002 g of 1- (3-carboxamidophenyl) -3-trifluoromethyl-5 - (([1,1 '] -biphen-4-yl) oxymethyl) pyrazole;

Ή NMR (DMSO-d _6, 300 MHz) 5: 8.18 (s, 1 H), 7.99 (d, 1H, J = 7.7 Hz), 7.78 (d, 1H, J = 9 , 2 Hz), 7.68-7.52 (m, 5H), 7.39 (t, 2H, J = 7.7 Hz), 7.27 (dd, 2H, J 1 = 7.3 Hz, J ₂ = 7.0 Hz), 7.18 (s, 1H), 7.01 (d, 2H, J = 8.8 Hz), 5.21 (s, 2H); ESI mass spectrum m / z (rel intensity) 479 (M + H + MeCN); DSGMS (NH ₃ -Cl): calculated for C ₂₄ H ₂₀ N ₄ OF 3: 437.15892, found 437.157809.

Examples 230 and 231

1- (3-amidinophenyl) -3-trifluoromethyl-5 - ((2-fluoro-4- (N-morpholino) phenyl) aminocarbonyl) pyrazole bis-trifluoroacetate and 1- (3-carboxamidophenyl) -3-trifluoromethyl-5 - (( 2-Fluoro-4- (N-morpholino) phenyl) aminocarbonyl) pyrazole

228

Part A: Preparation of 2-Fluoro-4- (N-morpholine) aniline from 4-bromo-2-fluoroaniline (1.03 g, 5.42 mmol), Copper (I) bromide (0.039 g,

To a mixture of 0.27 mmol) and potassium carbonate (1.50 g, 10.84 mmol) was added morpholine (10.0 mL, 115 mmol). The reaction mixture is heated at 130 ° C for 48 hours, concentrated under reduced pressure and purified by flash chromatography to give 0.11 g of pure 2-fluoro-4- (Nmorpholine) aniline. ¹ H NMR (DMSO-d 6) δ: 6.73 (dd, 1H, J 1 = 8.8 Hz, J 2 = 9.9 Hz), 6.64 (dd, 1H, J 1 = 2.6 Hz, J 2 = 13.2 Hz), 6.57 (m, 1H), 3.85 (m, 4H), 3.02 (m, 4H). ESI mass spectrum m / z (rel intensity) 197 (M + H, 100). ¹⁹ F NMR (DMSO-d 6, 300 MHz) δ: -133.

Part B: Preparation of 1- (3-cyanophenyl) -3-trifluoromethyl-5 - ((2'-fluoro-4 '- (N-morpholino) phenylaminocarbonyl) pyrazole by stirring N- (3-cyanophenyl) -3-trifluoromethylpyrazole-5- of a solution of carboxylic acid chloro anhydride (0.17 g, 0.56 mmol) and dimethylaminopyridine (0.082 g, 0.67 mmol) in 10 mL of methylene chloride was added 2-fluoro- (N-morpholine) aniline (0.11 g, 0.56 mmol) ) solution of 5 ml of methylene chloride The reaction mixture is stirred at room temperature for 20 hours. Concentration of the reaction mixture under reduced pressure and purification by flash chromatography gives 0.19 g of pure 1- (3-cyanophenyl) -3-trifluoromethyl-5 - ((2 ') -fluoro-4 '- (Nmorpholino) phenyl) aminocarbonyl) pyrazole ¹ H NMR (DMSO-d 6) δ: 7.94 (m, 1H), 7.86 (s, 1H), 7.77 (m, 3H). ), 7.61 (dd, 2H, J = 7.7 Hz, J ₂ = 8.1 Hz), 7.12 (s, 1H), 3.85 (m, 4H), 3.14 (m , 4H).

Part C: 1- (3-Amidinophenyl) -3-trifluoromethyl-5 - ((2 ^, -fluoro-4 '- (N-morpholino) phenyl) aminocarbonyl) pyrazole bis-trifluoroacetate and 1- (3-carboxamide-phenyl) -3- Preparation of trifluoromethyl-5 - ((2'-fluoro-4 '- (Nmorpholino) phenyl) aminocarbonyl) pyrazole

Standard Pinner amidine transformation of 1- (3-cyanophenyl) -3-trifluoromethyl-5 - ((2'-fluoro-4 '- (N-morpholino) phenyl) aminocarbonyl) pyrazole yields 0.10 g. 1- (3-amidinophenyl) -3-trifluoromethyl-5 - ((2'-fluoro-4 '(N-morpholino) phenyl) aminocarbonyl) -pyrazole bis-trifluoroacetate: ¹ H NMR (DMSO229 d ₆ , 300 MHz) δ 10.35 (s, 1H), 9.40 (ss, 2H), 9.11 (s, 1H), 7.96 (s, 1H), 7.87 (t, 2H), 7.72 (t, 1H), 7.67 (s, 1H), 7.27 (t, 1H), 6.84-6.71 (m, 2H), 3.703.66 (m, 4H), 3 , 09-3.06 (m, 4H); ESI mass spectrum m / z (rel intensity) 476.5 (M + H, 100): DSGMS (Cl): calcd for C ₂ H ₂₁ N ₆ O ₂ F ₄ 477.166212, found 477.1666415: ¹⁹ F NMR ( DMSO-d6, 300 MHz) δ: -61.354, -74.722; and 0.002 g of 1- (3-carboxamidophenyl) -3-trifluoromethyl-5 - ((2'fluoro-4 '- (N-morpholino) phenyl) aminocarbonyl) pyrazole; 1 H NMR (DMSO-d 6) δ: 10.31 (s, 1H), 8.10 (s, 1H), 7.98-7.94 (m, 2H), 7.64-7.50 (m , 2H), 7.33-7.27 (m, 1H), 6.83-6.70 (m, 2H), 3.70-3.66 (m, 4H), 3.09-3.06 (m, 4H); ESI mass spectrum m / z (relative intensity) 477.5 (M + H, 100); ¹⁹ F NMR (DMSOds) δ: -61,274, -74,363; HRMS (Cl): calculated for C22H ₂₀ N ₅ O ₃ F4 478.150228, found 478.147507.

Example 232

1- (3-Aminomethylphenyl) -3-trifluoromethyl-5 - ((3-trifluoromethyl-4- (N-morpholino) phenyl) aminocarbonyl) pyrazole bis-trifluoroacetate

Part A: Preparation of 3-Trifluoromethyl-4-N-morpholininaniline To a palladium on carbon (10%) suspension of 25 ml of methanol is added 3-trifluoromethyl-4-N-morpholinonitrobenzene (1.0 g, 3.62 mmol), and the reaction mixture is charged atmospheric pressure H ₂ at room temperature for 24 hours. The reaction mixture is passed through a pad of celite and concentrated the filtrate under reduced pressure to give the desired aniline in quantitative yield. ¹ H NMR (DMSO-d ₆ ) δ: 7.20 (d, 1H, J = 7.2 Hz), 6.92 (d, 1H, J = 2.6 Hz), 6.81 (dd, 1H , J 1 = 2.9 Hz, J ₂ = 8.4 Hz), 3.80 (m, 4H), 3.74 (m.p., 2H), 2.83 (m.p., 4H, J = 4.4 Hz), 3.70-3.66 (m, 4H), 3.09-3.06 (m, 4H). Ammonia Cl mass spectrum m / z (relative intensity) 247 (M + H, 100).

Part B: Preparation of 1- (3-cyanophenyl) -3-trifluoromethyl-5 - ((3'-trifluoromethyl-4 '- (N-morpholino) phenyl) aminocarbonyl) oirazole: 3-Trifluoromethyl-4-N-morpholinaniline (O) , 41 g, 1.67 mmol) and N- (3-cyanophenyl) -3-trifluoromethylpyrazole carboxylic acid chloro anhydride (0.50 g, 1.67 mmol)

Dimethylaminopyridine (0.25 g, 2.01 mmol) was added to a suspension of 230 mmol) in 20 mL of methylene chloride. The reaction mixture was stirred at room temperature for 24 hours, concentrated under reduced pressure and purified by flash chromatography to give 0.38 g of pure 1- (3-cyanophenyl) -3-trifluoromethyl-5 - ((3'-trifluoromethyl-4 '- (N-morpholine)). -phenyl) aminocarbonyl) pyrazole. ¹ H NMR (DMSO-d 6, 300 MHz) δ: 7.79 (m, 5H), 7.62 (dd, 1H, J 1 = 7.7 Hz, J 2 = 8.1 Hz), 7.38 ( d, 1H, J = 8.4 Hz, 7.15 (s, 1H), 3.83 (pt, 4H, J = 4.4 Hz), 2.91 (pt, 4H, J = 4.4 Hz). Ammonia Cl mass spectrum m / z (relative intensity) 510 (M + H, 100). ¹⁹ FBMR (DMSO-d6) δ: -61.033 and -62.854.

Part C: Preparation of 1- (3-Amidinophenyl) -3-trifluoromethyl-5 - ((3-trifluoromethyl-4- (Nmorpholino) phenyl) aminocarbonyl) pyrazole bis-trifluoroacetate

1- (3-Cyanophenyl) -3-trifluoromethyl-5 - ((3'-trifluoromethyl-4 '- (N-morpholino) phenyl) aminocarbonyl) pyrazole (0.38 g, 0.75 mmol) is converted to the corresponding benzylamine. Standard catalytic reduction as described above and purification by HPLC gives 0.19 g of 1- (3-amidinophenyl) -3-trifluoromethyl-5 ((3'-trifluoromethyl-4 '- (N-morpholino) phenyl) aminocarbonyl) pyrazole bistrifluoroacetate. .

¹ H NMR (DMSO-d 6) δ: 10.92 (s, 1H), 7.99 (d, 1H, J = 2.6 Hz), 7.88-7.85 (m, 1H), 7 68 (s, 1H), 7.63 (s, 1H), 7.55-7.49 (m, 4H), 4.11 (e.g. s, 2H), 3.67-3.64 (m, 4H), 2.78 (i.e., 4H J = 4.4 Hz). ESI mass spectrum m / z (rel intensity) 514 (M + H, 100). ¹⁹ F NMR (DMSO-d 6, 300 MHz) δ: -59,557, 61.305 and -74,290. HRMS (Cl): calculated for C23H ₂ 2 N ₅ O ₂ F _6: 514.167770, found 514.166332.

Example 233

1- (3-Aminomethylphenyl) -3-ethyl-5 - [(3-fluoro-2'-tert-butylaminosulfonyl- [1,1 '] biphen-4-yl) aminocarbonyl] pyrazole

Part A: Preparation of ethyl 2,4-dioxohexanoate

Metallic sodium (16.50 g, 717.39 mmol) was dissolved in 200 mL of ethanol.

When the solution cools, 2-butanone (64.26 mL, 717.39 mmol) is added. After

231

0.10 or. diethyl oxalate (97.43 mL, 717.39 mmol) was added to the reaction mixture. The reaction mixture is heated at 65 ° C for 4 hours, concentrated under reduced pressure and treated with 200 ml of 1.0 M hydrochloric acid solution. Extract with 200 ml EtOAc and wash the organic layer with 2 x 150 ml water and 2 x 150 ml saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by flash chromatography to give 21.13 g of pure ethyl 2,4-dioxohexanoate. ¹ H NMR (CDCl ₃ ) δ: 14.40 (m.s, 1H), 6.38 (s, 1H), 4.40-4.32 (m, 2H), 2.54 (s, 2H, J = 7.7 Hz), 1.41-1.36 (m, 3H), 1.18 (t, 3H, J = 7.2 Hz).

Part B: Preparation of ethyl (2-methylimino) -4-oxohexanoate

Ethyl 2,4-dioxohexanoate (21.26 g, 0.12 mmol) and methoxylamine hydrochloride (10.26 g, 0.12 mmol) were added to a suspension of 3A molecular weight grids (30 g) in 500 mL of anhydrous ethanol. The reaction mixture was mechanically stirred for 24 hours. The suspension is then filtered through a pad of celite, and the resulting filtrate is concentrated to give a crude product. Flash chromatography of this crude product afforded 6.07 g of pure ethyl (2-methylimino) -4-oxohexanoate. ¹ H NMR (DMSO-d 6) δ: 4.33 (kv, 2H, J = 7.2 Hz), 4.06 (s, 3H), 3.71 (s, 3H), 2.51 (kv, 2H, J = 7.2Hz), 1.35 (t, 3H, J = 7.2Hz), 1.08 (t, 3H, J = 7.2Hz). Ammonia Cl mass spectrum m / z (relative intensity) 201 (M + H, 60), 219 (M + NH ₄ , 100).

Part C: Preparation of ethyl (N- (3-cyanophenyl) -3-ethyl) oirazole-5-carboxylate

To a solution of ethyl (2-methoxyimino) -4-oxohexanoate (1.0 g, 4.98 mmol) in 50 mL of glacial acetic acid was added 3-cyanophenylhydrazine hydrochloride (0.84 g, 4.98 mmol). The reaction mixture was refluxed for 4 hours, concentrated under reduced pressure and purified by flash chromatography to give 0.98 g of ethyl (N- (3-cyanophenyl) -3-ethyl) pyrazole-5-carboxylate. ¹ H NMR (DMSO-d 6) δ: 7.77-7.76 (m, 1H), 7.72-7.68 (m, 2H), 7.56 (t, 1H, J = 8.0 Hz) ), 6.89 (s, 1H), 4.30-4.23 (m, 2H), 2.73 (sq, 2H, J = 8.0 Hz),

232

1.33-1.27 (m, 6H). Ammonia Cl mass spectrum m / z (relative intensity) 270 (M + H, 100).

Part D: Preparation of 1- (3-cyanophenyl) -3-ethyl-5 - ((4-bromo-2-fluorophenyl) aminocarbonyl) pyrazole with 4-bromo-2-fluoroaniline (2.06 g, 10.82 mmol) and a solution of ethyl (3-cyanophenyl) -3-ethyl) pyrazole-5-carboxylate (0.97 g, 3.61 mmol) in 20 mL of methylene chloride over 0.3 h. trimethyl laium (2.0 M in hexanes, 5.41 mL, 10.82 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 72 h, carefully quenched with 1.0 M hydrochloric acid solution, washed with 4 x 50 mL 1.0 M hydrochloric acid solution, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to give 0.23 g of 1- (3-cyanophenyl) -3-ethyl-5 - [(4-bromo-2-fluorophenyl) aminocarbonyl] pyrazole. ¹ H NMR (DMSO-d 6) δ: 8.17 (t, 1H, J = 8.0 Hz), 7.82 (m, 2H), 7.71 (m, 2H), 7.56 (dd, 1H, J = 8.0 Hz, J ₂ = 7.7 Hz), 7.33 (m, 1H), 6.72 (s, 1H), 2.77 (m, 2H), 1.34 ( t, 3H, J = 7.7 Hz). Ammonia Cl mass spectrum m / z (relative intensity) 415 (M + H, 100).

Part E: Preparation of 1- (3-cyanophenyl) -3-ethyl-5 - [(3-fluoro-2-tert-butylaminosulfonyl-1,1,1'-biphen-4-yl) aminocarboninpyrazole

1- (3-Cyanophenyl) -3-ethyl-5 - [(4-bromo-2-fluorophenyl) aminocarbonyl] pyrazole (0.23 g, 0.56 mmol), 2-tert-butylaminosulfonylphenylboronic acid (1N), purified in gaseous nitrogen A solution of 0.17 g, 0.67 mmol) and sodium carbonate (0.12 g, 1.12 mmol) in 10 mL of ethanol and 20 mL of toluene was added with a catalytic amount of tetrakistriphenylphosphine palladium. The reaction mixture was heated at 80 ° C for 15 h, concentrated under reduced pressure and purified by flash chromatography to give 0.13 g of 1- (3-cyanophenyl) -3-ethyl-5 - [(3-fluoro-2 tert-butylaminosulfonyl). - [1,1 T] -biphen-4-yl) aminocarbonyl] pyrazole. ¹ H NMR (DMSO-d ₆ ) δ: 8.36 (t, 1H, J = 8.0 Hz), 8.16 (m, 1H), 7.97 (pi.d, 1H, J = 3, 0 Hz), 7.85 (s, 1H), 7.77 (d, 1H, J = 8.1 Hz), 7.70 (d, 1H, J = 7.8 Hz), 7.54 (m , 3H), 7.41 (dd, 1H, J = 1.8 Hz, J ₂ = 11.7 Hz), 7.25 (m, 2H), 6.76 (s, 1H), 3.67 (s, 1H), 2.79 (s, 2H, J = 8.0 Hz), 1.36 (t, 3H, J = 8.0 Hz), 1.06 (s, 9H).

233

Ammonia Cl mass spectrum m / z (relative intensity) 546 (M + H, 100). ¹⁹ F NMR (DMSO-d6, 300 MHz) δ: -130,963.

Part F: Preparation of 1- (3-Aminomethylphenyl) -3-ethyl-5-i (3-fluoro-2-phosphobutylaminosulfonyl, 11'-biphen-4-yl) aminocarboninpyrazole

Standard transformation of benzonitrile from Part E to benzylamine using catalytic reduction followed by treatment with trifluoroacetic acid 1- (3-cyanophenyl) -3-ethyl-5 - [(3-fluoro-2-tert-butylaminosulfonyl- [1, 1'-biphen-4-yl) aminocarbonyl] pyrazole is converted to 1- (3-aminomethylphenyl) -3-ethyl-5 - [(3-fluoro-2-tert-butylaminosulfonyl- [1,1'J-biphen-4-yl) aminocarbonyl]. pyrazole trifluoroacetate. The crude product is purified by standard HPLC procedure. ¹ H NMR (DMSO-d _s) δ: 8.01 to 7.98 (m, 1H), 7.63 to 7.56 (m, 4H), 7,457,25 (m, 5H), 7.16 ( d, 1H, J = 8.4 Hz), 6.96 (s, 1H), 3.95 (s, 2H), 2.66 (kv, 2H, J = 7.7 Hz), 1.24 (t, 3H, J = 7.7 Hz). ESI mass spectrum m / z (relative intensity) 493.9 (M + H, 100). HRMS (Cl): calculated for C 2 H _{5 2} 4 N ₅ O ₃ FS 493.158390, found 493.156279.

Example 234

1- (3-Aminomethylphenyl) -3-ethyl-5 - [(3-fluoro-2'-methylsulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole trifluoroacetate

Part A: Preparation of 1- (3-cyanophenyl) -3-ethylpyrazole-5-carboxylic acid chloro-anhydride by freezing (0 ° C) ethyl 1- (3-cyanophenyl) -3-ethylpyrazole-5-carboxylate (7.13 g, 26 Lithium hydroxide (1.33 g, 31.81 mmol) was added to a solution of (51 mmol) in 100 mL of water and 150 mL of tetrahydrofuran. The reaction mixture was allowed to warm to room temperature and allowed to stand overnight, then concentrated under reduced pressure. The resulting aqueous solution is washed with 3 x 100 ml of diethyl ether and acidified with concentrated hydrochloric acid to give a white precipitate which is filtered off with suction. This white solid is maintained under deep vacuum for 24 hours. and a portion (0.31 g, 1.27 mmol) of oxalyl chloride (0.17 mL, 1.90 mmol) and dimethylformamide

234 (0.1 mL) in 10 mL methylene chloride. After 24 hours at room temperature, the reaction mixture is concentrated and the solid obtained is maintained under deep vacuum to give crude 1- (3-cyanophenyl) -3-ethylpyrazole-5-carboxylic acid chloro anhydride. This chloro-anhydride is used in the downstream purification.

Part B: Preparation of 1- (3-cyanophenyl) -3-ethyl-5-i (3-fluoro-2'-methylsulfonyl-1,1''-1-biphen-4-yl) aminocarbonyl ariazole

To 2-fluoro-2'-methylsulfonylphenylaniline hydrochloride (0.38 g, 1.27 mmol) and crude 1- (3-cyanophenyl) -3-ethylpyrazole-5-carboxylic acid chloro anhydride (1.27 mmol) are added 10 mL of dichloromethane. dimethylaminopyridine (0.34 g, 2.79 mmol). The reaction mixture was stirred at room temperature for 24 hours, concentrated under reduced pressure, and purified by flash chromatography to give 0.23 g of 1- (3-clanophenyl) -3-ethyl-5 - [(3-fluoro-2'-methylsulfonyl- [1, 1 '] - biphen-4-yl) aminocarbonyl] pyrazole. ¹ H NMR (DMSO-d _s) δ: 10.42 (s, 1H), 8.06 (dd, 1H, J = 2.0 Hz, J ₂ = 8.0 Hz), 7.95 to 7 , 94 (m, 1H), 7.857.60 (m, 6H), 7.42-7.32 (m, 2H), 7.20 (dd, 1H, J ₁ = 2.0 Hz, J ₂ = 8, 0 Hz), 7.08 (s, 1H), 2.89 (s, 3H), 2.67 (s, 2H, J = 7.7 Hz), 1.24 (t, 3H, J = 7, 7 Hz). Ammonia Cl mass spectrum m / z (relative intensity) 489 (M + H, 100).

Part C: Preparation of 1- (3-Aminomethylphenyl) -3-ethyl-5 - [(3-fluoro-2'-methylsulfonyl-1,1'-biphen-4-yl) aminocarbonyl] pyrazole

To 1- (3-cyanophenyl) -3-ethyl-5 - [(3-fluoro-2'-methylsulfonyl- [1,1'J-biphen-4-yl) aminocarbonyl] pyrazole (0.103 g, 0.211 mmol) and cobalt chloride (0.003 g, 0.021 mmol) was added sodium borohydride (0.016 g, 0.422 mmol) in 10 mL of methanol. After 1 or. more sodium borohydride (0.016 g, 0.422 mmol) was added. The reaction mixture was stirred for 2 hours. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was dissolved in 1.0 M hydrochloric acid solution to give a white precipitate. Separation of the precipitate by vacuum filtration and purification of the solid by HPLC gives 0.030 g of pure 1- (3-aminomethylphenyl) -3-ethyl-5 - [(3-fluoro-2'-methylsulfonyl- [1,1 '] - biphen-4). -yl) -aminocarbonyl] pyrazole trifluoroacetate. 1 H NMR

235 (DMSO-d ₆₎ δ: 10.45 (s, 1H), 8.06 (dd, 1H, J _n = 2.0 Hz, J ₂ = 8.0 Hz), 7.77 to 7, 61 (m, 5H), 7.47-7.31 (m, 4H), 7.21-7.17 (m, 1H), 7.01 (s, 1H), 4.07-4.06 ( m, 2H), 2.90 (s, 3H), 2.66 (s, 2H, J = 7.7 Hz), 1.24 (t, 3H, J = 7.7 Hz). ESI mass spectrum m / z (relative intensity) 493 (M + H, 100). HRMS (Cl): calculated for C 6 H _{2 2 4} 6N O3FS 493.170966, found 493.172100.

Example 235

1- (3-Aminomethylphenyl) -3-ethyl-5 - [(2-fluoro-4- (2-methylsulfonylimidazol-1-yl) phenyl)] aminocarbonyl) pyrazole trifluoroacetate

Part A: Preparation of 4- (2'-Methylthioimidazol-1-iDnitrobenzene) In a stirred suspension of potassium carbonate (40.07 g, 22.60 mmol) in 175 ml of acetone was added 1- (4-nitrophenyl) imidazoline-2-thione (5, 0 g, 22.60 mmol) Add iodomethane (1.44 mL, 23.05 mmol) to the reaction mixture and reflux for 20 h, concentrate the reaction mixture under reduced pressure and dissolve the resulting solid in 200 mL of water. Extract three times with ethyl acetate.The combined extracts are dried over magnesium sulfate and concentrated in vacuo to give

5.29 g of crude 4- (2'-methylthioimidazol-1-yl) nitrobenzene. ¹ H NMR (DMSO-d 6) δ: 10.45 (s, 1H), 8.06 (dd, 1H, J = 2.0 Hz, J ₂ = 8.0 Hz), 8.38-8, 33 (m, 2H), 7.777.72 (m, 2H), 7.61 (d, 1H, J = 1.5 Hz), 7.14 (d, 1H, J = 1.5 Hz), 2.52 (s, 3H). ESI mass spectrum m / z (relative intensity) 236 (M + H, 100).

Part B: Preparation of 4- (2'-Methylsulfonylimidazol-1-iNitrobenzene)

To a stirred solution of 4- (2'-methylthioimidazole-1-iDnitrobenzene (1.05 g, 4.47 mmol) in dichloromethane (40 mL) was added meta-chloroperoxybenzoic acid (1.54 g, 8.94 mmol). The reaction mixture was allowed to warm to room temperature and allowed to stand for 20 h. The reaction mixture was washed with 3 x 75 mL of 1.0 M sodium hydroxide solution, dried over magnesium sulfate and concentrated in vacuo to give 0.98 g of crude 4- (2'-methylsulfonylimidazole). 1-yl) nitrobenzene ¹ H NMR (DMSOds) δ: 8.39 (d, 2H, J = 8.7 Hz), 7.73 (d, 2H, J = 8.7 Hz), 7.28- 7.23 (m, 2H),

236

3.43 (s, 3H). Ammonia Cl mass spectrum m / z (relative intensity) 268 (M + H, 100).

C d i s: Preparation of 4- (2'-Methylsulfonylimidazol-1-iDanylline)

Standard catalytic reduction of palladium on carbon (10%) in 4- (2'-methylsulfonylimidazol-1-yl) nitrobenzene (0.98 g, 3.67 mmol) yields 0.80 g of 4- (2'-methylsulfonylimidazol-1). -il) aniline. ¹ H NMR (CDCl 3) δ: 7.24 (d, 2H, J = 8.7 Hz), 7.15 (dd, 2H, J ₁ = 18.3 Hz, J ₂ = 18.6 Hz), 6, 72 (d, 2H, J = 8.7 Hz),

3.30 (s, 3H). Ammonia Cl mass spectrum m / z (relative intensity) 238 (M + H, 100).

Part D: Preparation of 1- (3-cyanophenyl) -3-ethyl-5 - ((2'-fluoro-4 '- (2-methylsulfonylimidazol-1-yl) phenyl) aminocarbonyl) pyrazole

A solution of 4- (2'-methylsulfonylimidazol-1-yl) aniline (0.37 g, 1.58 mmol) and 1- (3-cyanophenyl) -3-ethylpyrazole-5-carboxylic acid chloro anhydride (1.58 mmol) in 15 mL dichloromethane was added dimethylaminopyridine (0.42 g, 3.48 mmol). The reaction mixture was stirred at room temperature for 15 hours, concentrated under reduced pressure and purified by flash chromatography to give 0.37 g of 1- (3-cyanophenyl) -3-ethyl-5 - ((2'-fluoro-4 '(2-methylsulfonylimidazole). 1-yl) -phenyl) aminocarbonyl) pyrazole. ESI mass spectrum m / z (relative intensity) 460.9 (M + H, 100), 482.9 (M + Na).

Part E: Preparation of 1- (3-Aminomethylphenyl) -3-ethyl-5-r (2'-fluoro-4 '- (2-methylsulfonylimidazol-1-yl) phenyl) aminocarbonyl) pyrazole

Standard catalytic reduction of 1- (3-cyanophenyl) -3-ethyl-5 - [(2'-fluoro-4 '- (2-methylsulfonylimidazol-1-yl) phenyl)] aminocarbonyl) pyrazole with carbon (10%) ) in methanol, purified by HPLC to give 0.10 g of 1- (3-aminomethylphenyl) -3-ethyl-5 - [(2'-fluoro-4 '- (2-methylsulfonylimidazol-1-yl) phenyl)] aminocarbonyl) pyrazole trifluoroacetate . ¹ H NMR (CDCl ₃ , 300 MHz) δ: 10.78 (s, 1H), 7.76 (d, 2H, J = 8.8 Hz) 7.63 (d, 2H, J = 4.1 Hz) ), 7.49-7.35 (m, 5H), 7.26 (d, 1H, J = 1.1 Hz), 6.98 (s, 1H), 4.08 (s, 2H), 3 , 35 (s, 3H), 2.67 (s, 2H, J = 7.7 Hz), 1.24 (t, 3H), J = 7.7 Hz). ESI mass spectrum m / z (rel

237 intensity) 464.9 (M + H, 100). DSGMS: Calcd. For C23H25N6O3S 465.170886, found 465.172332.

Example 236

1 - [(6-Aminomethyl) pyrid-2-yl)] - 3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole trifluoroacetic acid salt

Part A: Preparation of Ethyl 1- (pyrid-2-yl) -3-methylpyrazole-5-carboxylate To a solution of 2-hydrazinopyridine (0.68 g, 6.24 mmol) in 15 mL of glacial acetic acid was added ethyl 2-methoxyimino-4. -oxopentanoate (0.90 g, 4.80 mmol). The reaction mixture was stirred at 100 ° C for 2 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with ethyl acetate, washed with saturated aqueous sodium carbonate and brine, dried (MgSO ₄ ), and concentrated in vacuo. Purification of the residue by flash chromatography (eluting with 3: 1 hexanes / ethyl acetate) afforded 0.4 g (36%) of the title compound. ¹ H NMR (CDCl 3) δ: 8.45 (dd, 1H), 7.82 (td, 1H), 7.61 (d, 1H), 7.29 (dd, 1H), 6.70 (s, 1 H), 4.25 (kv, 2H), 2.38 (s, 3H), 1.23 (t, 3H). Ammonia Cl mass spectrum m / z (relative intensity) 232 (M + H, 100).

Part B: Preparation of ethyl 1- (6-cyanopyrid-2-yl) -3-methylpyrazole-5-carboxylate from ethyl 1- (pyrid-2-yl) -3-methylpyrazole-5-carboxylate (1.4 g, 6 g). , 05 mmol) in 10 ml of glacial acetic acid was added 6 ml (significant excess) of 30% H ₂ O ₂ . The reaction mixture was stirred at 100 ° C for 3 hours, then allowed to cool to room temperature and added to saturated aqueous sodium carbonate. The resulting mixture was extracted with ethyl acetate, the combined organic extracts washed with saturated NaCl solution, dried (MgSO 4) and concentrated in vacuo. The resulting crude N-oxide was dissolved in 20 mL of tetrahydrofuran, trimethylsilyl cyanide (2.4 mL, 18.2 mmol) was added followed by dimethylcarbamoyl chloride (11.7 mL, 18.2 mmol). The reaction mixture was stirred at 65 ° C for 18 h. The reaction mixture was allowed to cool, diluted with ethyl acetate, washed with saturated aqueous sodium hydroxide

238 carbonate and saturated NaCl solution, dried (MgSO ₄ ) and concentrated in vacuo. Purification of the residue by flash chromatography (eluting with 3: 1 hexanes / ethyl acetate) afforded 0.66 g (43%) of the title compound as a white solid. ¹ H NMR (CDCl ₃ ) δ: 7.98 (m, 2H), 7.61 (td, 1H), 6.67 (s, 1H), 4.38 (kv, 2H), 2.38 (s , 3H), 1.32 (t, 3H). Ammonia Cl mass spectrum m / z (relative intensity) 257 (M + H, 100).

Part C: Preparation of 1-Γ (6-θ3ηορί ^ -2-ιΊ) 1-3-ηΐ6ΐίΙ-5-Γ (2 '+ /' βί ^ υΐίΐ3Γηΐηο3υΚοηιΊ- | Ί, 1Ίbiphen-4-yl) -aminocarbonylpyrazole.

To a solution of (2'-tert-butylaminosulfonyl- [1,1 '] -biphen-4-yl) -amine (0.24 g, 0.78 mmol) was added dropwise trimethylaluminum (1.2 mL) at 20 ° C in methylene chloride at 25 ° C. Of a 2.0 M solution in toluene, 2.34 mmol). The resulting solution was stirred until gas evolution ceased (~ 15 min). To this solution was added a solution of ethyl 1- (6-cyanopyrid-2-yl) -3-methylpyrazole-5-carboxylate (0.20 g, 0.78 mmol) in methylene chloride. The resulting solution was stirred at 40 ° C for 3 h, then cooled to 25 ° C and quenched by addition of saturated aqueous NH ₄ Cl. After dilution with ethyl acetate, the layers were separated, the organic layer washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. Purification of the residue by flash chromatography (eluting with 1: 1 hexanes / ethyl acetate) afforded 0.15 g (38%) of the title compound as a solid. 1 H NMR (CDCl ₃ ) δ: 10.63 (s, 1H), 8.20 (t, 1H), 8.08 (d, 1H), 7.98 (m, 2H), 7.64 (d , 2H), 7.59 (td, 1H), 7.51 (td, 1H), 7.34 (d, 2H), 7.28 (d, 1H), 6.80 (s, 1H), 6 , 46 (s, 1H), 2.31 (s, 3H), 0.97 (s, 9H). ESI mass spectrum m / z (rel intensity) 515.1 (M + H, 100).

Part D: Preparation of the trifluoroacetic acid salt of 1 - [(6-Aminomethyl) pyrid-2-yl] -3-methyl-5 - [(2'-aminosulfonyl-1,1'-biphen-4-yl) aminocarbonylpyrazole] cyanopyrid-2-yl)] - 3-methyl-5 - [(2'-tert-butylaminosulfonyl- [1,1'J-biphen4-yl) aminocarbonyl] pyrazole (0.14 g, 0.27 mmol) 12 mL HCl (0.023 mL, 0.27 mmol) and 10% Pd / C catalyst (30 mg) were added in absolute ethanol. The resulting mixture was stirred at 1 atm. H ₂ pressure 18 h The mixture is then filtered through a pad of celite and concentrated

239 in a vacuum. The residue was dissolved in 3 ml of trifluoroacetic acid and stirred at 80 ° C for 20 min. The solution was cooled and concentrated in vacuo. Purification of the residue by preparative HPLC (C18 reverse phase column, eluting with H ₂ O / CH ₃ CN with a gradient of 0.5% TFA) and lyophilization gave 70 mg (45%) of the title compound as a white powder. 1 H NMR (DMSO-d ₆ ) δ: 10.56 (s, 1H), 8.18 (m.s, 3H), 8.02 (m, 2H), 7.64 (m, 4H), 7 , 58 (m, 2H), 7.45 (d, 1H), 7.33 (d, 2H), 7.27 (d, 2H), 6.84 (s, 1H), 6.46 (s, 1H), 4.02 (e.g. kv, 2H),

2.30 (s, 3H). ESI mass spectrum m / z (relative intensity) 462.9 (M + H, 100).

Example 237

1 - [(6 - (N-hydroxyamidino) pyrid-2-yl)] - 3-methyl-5 - [(2'-tert-butylaminosulfonyl · [1,1 T] -biphen-4-yl) aminocarbonyl] pyrazole

1-r (6- (A / -hidroksiamidino) pyrid-2-yl) 1-3-methyl-5-f ^{(2--ffefbutilaminosulfonil} i1.1'1 biphen-4-yl) To a solution of 1 -aminokarboniHpirazolo - [(6-cyanopyrid-2-yl)] - 3-methyl-5 - [(2'-tert-butylaminosulfonyl- [1,1 '] - biphen4-yl) aminocarbonyl] pyrazole (0.11 g, 0, To a solution of 21 mmol) in 5 ml of absolute ethanol was added hydroxylamine hydrochloride (0.054 g, 0.77 mmol) and sodium carbonate (0.039 g, 0.36 mmol). The mixture was stirred at 80 ° C for 1 h. then leave to cool. The mixture was diluted with ethyl acetate, washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The solid residue is triturated with ether to give 80 mg (68%) of the title compound as a white solid. 1 H NMR (CDCl ₃ ) δ: 10.79 (s, 1H), 9.95 (s, 1H), 8.0 (dd, 1H), 7.95 (t, 1H), 7.80 (d) , 1H), 7.68 (m, 3H), 7.59 (td, 1H), 7.51 (td, 1H), 7.35 (m, 3H), 6.68 (s, 1H), 6.65 (s, 1H), 5.43 (s, 2H), 2.31 (s, 3H), 0.96 (s, 9H). ESI mass spectrum m / z (relative intensity) 548.1 (M + H, 100).

Example 238

1 - [(6- (Amidinopyrid-2-yl)] - 3-methyl-5 - [(2'-aminosulfonyl- [1,1 ']' - biphen-4-yl) aminocarbonyl] pyrazole trifluoroacetic acid salt

240

Preparation of 1- (6- (Amidinopyrid-2-yl) 1-3-methyl-5 - [(2'-aminosulfonyl-1,1,1'-biphen-4-yl) aminocarbonyl] pyrazole trifluoroacetic acid salt into 1 - [( 6-cyanopyrid-2-yl)] - 3-methyl-5 - [(2'-freibutylaminosulfonyl- [1,1'] -biphen-4-yl) aminocarbonyl] pyrazole (0.28 g, 0.54 mmol) Triethylamine (0.38 mL g, 2.7 mmol) was added to 20 mL of absolute ethanol and the solution was bubbled through a slow bubbling stream of hydrogen sulfide (excess H ₂ S was bubbled through Chlorox bleach) for 20 min, sealed and allowed to stand at room temperature. The solution was concentrated in vacuo, the crude thioamide residue was dissolved in 10 mL of acetone and then 2 ml (high excess) of methyl iodide was added, the resulting mixture was stirred at 60 ° C for 2 h, then cooled and concentrated in vacuo. ammonium acetate (1.8 mL of a 1.5 M solution in methanol, 2.7 mmol) was added and the resulting mixture was stirred at 60 ° C for 2 h, then cooled. sinam and concentrated in vacuo. The residue was dissolved in trifluoroacetic acid, stirred at 80 ° C for 20 min, then cooled and concentrated in vacuo. This residue was purified by preparative HPLC (C18 reverse phase column, eluting with H ₂ O / CH ₃ CN with a gradient of 0.5% TFA) and lyophilization to afford 78 mg (24%) of the title compound as a white powder. ¹ H NMR (DMSO-d ₆ ) δ: 10.70 (s, 1H), 9.36 (pl.s, 2H), 9.04 (pl.s, 2H), 8.31 (t, 1H ), 8.13 (m, 2H), 8.00 (d, 1H), 7.63 (d, 2H), 7.58 (m, 2H), 7.34 (d, 2H), 7.28 (d, 1H), 7.23 (s, 2H), 6.87 (s, 1H), 2.33 (s, 3H). ESI mass spectrum m / z (relative intensity) 476.2 (M + H, 100). DSGMS: Calcd. For C ₂₃ H ₂₂ N ₇ O ₃ S: 476.150485, found: 476.152830.

Example 239

1 - [( ⁶ - (Amidinopyrid-2-yl)] - 3-methyl-5- [3-fluoro- (2'-methylsulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole trifluoroacetic acid salt

Part A: Preparation of ethyl 1 - [(6-thiocarbonylamino) pyrid-2-yl] -3-methylpyrazole-5-carboxylate

241

To a solution of ethyl 1 - [(6-cyanopyrid-2-yl)] - 3-methyl-5-carboxylate was added triethylamine (2.7 mL, 19.4 mmol) in 100 mL of absolute ethanol. This solution was bubbled through a stream of hydrogen sulfide gas (excess H ₂ S was bubbled through Chiorox bleach) for 20 min. Stopper the flask and allow to stand at room temperature overnight. The solution is concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with 10% aqueous HCl and saturated NaCl solution, dried (MgSO ₄ ) and concentrated in vacuo to give 1.1 g (97%) of the title compound which is sufficiently pure and can be used without further purification. 1 H NMR (CDCl ₃ ) δ: 9.01 (m.s, 1H), 8.55 (dd, 1H), 7.92 (t, 1H), 7.82 (dd, 1H), 7.58 (e.g. s, 1H), 6.66 (s, 1H), 4.22 (s, 2H), 2.33 (s, 3H), 1.18 (t, 3H). ESI (m) mass spectrum m / z (relative intensity) 288.9 (MH, 100).

Part B: Preparation of 1 - [(6-Thiocarbonylamino) pyrid-2-yl] -3-methyl-5 - [(1-bromo-3-fluorophenyl-4-yl) aminocarbonyl] pyrazole with 4-brpm-2-fluoroaniline (2.17 g) (11.4 mmol) in 150 mL of methylene chloride was added dropwise to trimethylaluminium (11.4 mL of a 2M solution in toluene, 22.8 mmol). This solution was stirred until gas evolution ceased (15-20 min), followed by addition of ethyl 1 - [(6-thiocarbonylamino) pyrid-2-yl] -3-methylpyrazole-5-carboxylate (1.1 g, 3 g). 8 mmol) in methylene chloride. The resulting solution was stirred and refluxed for 18 hours, then cooled and quenched with saturated aqueous ammonium chloride. The mixture was diluted with ethyl acetate, the layers separated, the organic layer washed with water and saturated NaCl solution, dried (MgSO ₄ ) and concentrated in vacuo. The solid residue is purified by trituration with ether and the remaining solid is dried under vacuum; 1.26 g (76%) of the title compound are obtained. H NMR (DMSO-d _s) δ: 10.62 (br s, 1H), 10.20 (br s, 1H), 8.84 (br s, 1H), 8.33 (dd, 1H), 8.12 (t, 1H), 7.98 (d, 1H), 7.72 (t, 1H), 7.58 (dd, 1H), 7.39 (d, 1H), 6, 75 (s, 1H), 2.30 (s, 3H) md

Part C: Preparation of 1- [6- (N-tert-butyloxycarbonyl) aminoiminomethyl) pyrid-2-yl] -3-methyl-5 - [(1-bromo-3-fluorophenyl-4-yl) aminocarboninpyrazole

242 | A solution of 1 - [(6-thiocarbonylamino) pyrid-2-yl] -3-methyl-5 - [(1-bromo-3-fluorophenyl-4-yl) aminocarbonyl] pyrazole (1.09 g, 2.51 mmol) in 100 mL of acetone is added 12 ml (large excess) of methyl iodide. The resulting solution was stirred at 60 ° C for 2 hours, then cooled and concentrated in vacuo. The residue was dissolved in methanol and ammonium acetate (8.3 mL of a 1.5 M solution in methanol, 12.5 mmol) was added. The resulting mixture was stirred at 60 ° C for 2 h, then cooled and concentrated in vacuo to give 1.0 g of crude amidine. To this residue was added di-tert-butyl dicarbonate (0.52 g, 2.4 mmol) and 4-dimethylaminopyridine (0.29 g, 2.4 mmol) in 10 g of pyridine (0.5 g, 1.2 mmol). The mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water, 10% aqueous HCl and brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by flash chromatography (1: 1 hexanes / ethyl acetate) to give 0.15 g of the title compound. ¹ H NMR (CDCl 3) δ: 9.08 (m.p., 1H), 8.22 (m, 3H), 7.95 (d, 1H), 7.85 (t, 1H), 7.25 ( m, 2H), 6.53 (s, 1H), 2.33 (s, 3H), 1.49 (s, 9H) md ESI mass spectrum m / z 516.9 / 518.9 (M + H) ⁺ .

Part D: 1 - [(6- (N-tert-Butyloxycarbonyl) aminoiminomethyl) pyrid-2-yl] -3-methyl-5-F3-fluoro- (2'-thiomethoxy-1,1,1'-biphen-4-yl) preparation of aminocarboninpyrazole

J 1 - [(6- (N-tert-Butyloxycarbonyl) aminoiminomethyl) pyrid-2-yl] -3-methyl-5 - [(1-bromo-3-fluorophenyl-4-yl) aminocarbonyl] pyrazole (0.15 g, 0 A solution of 29 mmol) in 15 mL of benzene was added 2-thiomethoxyphenylboronic acid (0.07 g, 0.42 mmol), tetrabutylammonium bromide (0.01 g, 0.03 mmol), sodium carbonate (0.09 g, 0.85 mmol). mmol) and 0.80 mL of water. ' The mixture is degassed with a stream of nitrogen followed by the addition of tetrakis-triphenophosphine palladium (0.06 g, 0.05 mmol). The mixture was stirred at 80 ° C for 24 hours. The reaction mixture was allowed to cool and then diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and brine, dried (MgSO _4), filtered through celite and concentrated under vacuum to give 0.157 g (95%) of the title compound. This material is reasonably pure and can be used

243 without additional purification. ¹ H NMR (CDCl ₃ ) δ: 8.40 (t, 1H), 8.02 (m.s, 2H), 7.607.20 (m, 10H), 6.56 (s, 1H), 2.34 (s, 3H), 2.33 (s, 3H), 1.46 (s, 9H) md ESI mass spectrum m / z (relative intensity) 560.9 (M + H, 100).

Part E: Preparation of the trifluoroacetic acid salt of 1- [6- (Amidinopyrid-2-yl) 1-3-methyl-5- [3-fluoro- (2'-methylsulfonyl] -1'-biphen-4-yl) aminocarbonyl] -irazole

To 1 - [(6- (N-tert-Butyloxycarbonyl) aminoiminomethyl) pyrid-2-yl] -3-methyl-5- [3-fluoro- (2'-thiomethoxy- [1,1 '] - biphen-4-yl) ) A solution of aminocarbonyl] pyrazole (0.157 g, 0.28 mmol) in 20 mL of methylene chloride was added with 3-chloroperoxybenzoic acid (0.17 g, 0.99 mmol). The resulting mixture was stirred at room temperature for 24 h. And then diluted with ethyl acetate, washed with saturated aqueous sodium metabisulphite solution, saturated aqueous sodium bicarbonate solution and brine, dried (MgSO ₄₎ and concentrated in vacuo. The residue was dissolved in 5 ml of trifluoroacetic acid and stirred at 80 ° C for 20 min. The reaction mixture was cooled and concentrated in vacuo. This residue was purified by preparative HPLC (C18 reverse phase column, eluting with H ₂ O / CH ₃ CN with a gradient of 0.5% TFA) and lyophilization to afford 80 mg (47%) of the title compound as a white powder. ¹ H NMR (DMSO-d ₆ ) δ: 10.52 (s, 1H), 9.42 (pl.s, 2H), 9.08 (pl.s, 2H), 8.31 (t, 1H) , 8.12 (m, 3H), 7.78-7.73 (m, 3H), 7.42 (d, 1H), 7.32 (d, 1H), 7.20 (d, 1H), 6.89 (s, 1H), 2.89 (s, 3H), 2.33 (s, 3H). ESI mass spectrum m / z (relative intensity) 493.9 (M + H, 100). '

Example 240

1- (3-Aminomethylphenyl) -3-methyl-5 - ((2-methoxy-4- (N-morpholino) phenyl) aminocarbonyl) pyrazole trifluoroacetate

Part A: Preparation of 1- (3-N- (benzyloxycarbonyl) aminophenyl) -3-methyl-5 - ((2-methoxy-4- (N-morpholino) phenyl) aminocarbonyl) pyrazole: 1- (3-N- (Benzyloxycarbonyl) ) a solution of aminophenyl) -3-methylpyrazole-5-carboxylic acid (183 mg, 0.5 mmol) in DMF (10 mL) was added PyBrop (bromo-tris-pyrrolidine-phosphonium hexafluorophosphate, 280 mg, 0.6 mmol) to give a solution

244 was stirred at room temperature for 10 min. N, Ndiisopropylethylamine (1 mL) was added and stirring was continued for 10 min. This solution is then added

2-methoxy-4-N-morpholinaniline (125 mg, 0.6 mmol) and the resulting mixture was stirred at 60 ° C for 3 h. When the mixture has cooled to room temperature, DOWEX (50WX8-100 ion exchange resin, 0.5 g) is added and the mixture is stirred for another 0.5 h. The mixture was filtered and the residue was washed with EtOAc (50 mL). The filtrate was washed with brine (5 x 10 mL), dried over MgSO ₄ , and purified by column chromatography eluting with EtOAc to give the product (261 mg, 95%). ¹ H NMR (CDCl 3) δ: 7.42-7.31 (m, 10H), 7.03 (s, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.50 ( d, J = 2.6 Hz, 2H), 6.42 (dd, J = 8.4 Hz, J = 2.6 Hz, 1H), 4.70 (s, 1H), 4.41 (d, J = 3.9 Hz, 2H), 3.84 (t, J = 4.8 Hz, 4H), 3.78 (s, 3H), 3.09 (t, J = 4.8 Hz, 4H) , 2.35 (s, 3H) md ESI mass spectrum m / z (relative intensity) 556 (M + H, 100).

Part B: Preparation of 1- (3-Aminomethylphenyl) -3-methyl-5 - ((2-methoxy-4- (N-morpholino) phenyl) aminocarbonylpyrazole trifluoroacetate from 1- (3-N- (benzyloxycarbonyl) aminophenyl) -3 Trifluoroacetic acid (5 mL) was added to methyl-5 - ((2-methoxy-4- (Nmorpholino) phenyl) aminocarbonyl) pyrazole (100 mg, 0.18 mmol) and the resulting solution was refluxed for 4 h. and purification by thin layer chromatography (ethyl acetate) to give a viscous liquid (60 mg, 80%). ¹ H NMR (CD ₃ OD) δ: 7.58 (s, 1H), 7.53-7.48 (m, 3H). ), 7.06 (s, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 2.6 Hz, 1H), 6.47 (dd, J) = 8.8 Hz, J = 2.6 Hz, 1H), 4.15 (s, 2H), 3.79 (t, J = 4.8 Hz, 4H), 3.76 (s, 3H), 3.09 (t, J = 4.8 Hz, 4H), 2.35 (s, 3H) md ESI mass spectrum m / z (relative intensity) 422 (M + H, 100).

Example 241

1- (3-Aminomethylphenyl) -3-methyl-5- [4 '- (3 "-methyl-5" -oxo-3 "-pyrazolin-2" -yl) phenyl) aminocarbonyl) pyrazole trifluoroacetate

Part A: Preparation of 1- (3-N- (Benzyloxycarbonylaminophenyl-3-methyl-5 - ((4 '- (3'L ^, -methyl-5' ^, oxo-pyrazoline-2 ') -phenylaminocarbonyl) pyrazole

To a solution of 1- (3-N- (benzyloxycarbonyl) aminophenyl) -3-methylpyrazole-5-carboxylic acid (150 mg, 0.41 mmol) in DMF (5 mL) was added PyBrop (bromo-tris-pyrrolidine-phosphonium hexafluorophosphate, 233 mg). 0.5 mmol) and the resulting solution was stirred at room temperature for 10 min. To this solution was added N, N-dimethylpyridine (70 mg, 0.57 mmol) and stirred for a further 10 min. 2- (4-Aminophenyl) -3-methyl-3-pyrazol-5-one (125 mg, 0.6 mmol) was then added and the resulting mixture was stirred at 60 ° C for 24 h. The mixture was diluted with EtOAc (100 mL), washed with 1N HCl (10 mL), brine (5 x 10 mL), dried over MgSO ₄ , and purified by column chromatography eluting with EtOAc to give the product (260 mg). ESI mass spectrum m / z (relative intensity) 537.2 (M + 1, 100).

Part B: Preparation of 1- (3-Aminomethylphenyl) -3-methyl-5-f '- (3-methyl-5-oxo-3' pyrazolin-2-yl) phenyl) aminocarbonyl) pyrazole trifluoroacetate. -N- (Benzyloxycarbonyl) aminophenyl) -3-methyl-5 - ((4 '- (3' -methyl-5 '-oxopyrazolin-2' -yl) phenyl) aminocarbonyl) pyrazole (260 mg) was added trifluoroacetic acid (5 ml), and the resulting solution was refluxed for 2 hours). Concentration of the solution and purification by thin layer chromatography (ethyl acetate) gave a viscous liquid (120 mg, 74.6% over two steps). ¹ H NMR (CD ₃ OD) δ: 7.69 (d, J = 8.8 Hz, 2H), 7.55 (m.s, 1H), 7.527.46 (m, 3H), 7.35 ( d, J = 8.8 Hz, 2H), 6.87 (s, 1H), 5.57 (s, 1H), 4.14 (s, 2H), 2.35 (s, 3H), 2, 21 (s, 3H) md ESI mass spectrum m / z (relative intensity) 403.1 (M + H, 100).

Example 242

1- (3-Aminomethyl) phenyl] -5 - [(2'-methylsulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] 3- (methylthio) pyrazole trifluoroacetic acid salt

A d ai s: Preparation of 1,1-Di (methylthio) ethylene

In a I-flask with a mechanical stirrer and reflux, dilute methylmagnesium bromide (3.0 M Et ₂ O, 84 mL, 252 mmol) to 1.0 M THF (168 mL) under argon, maintaining the bath temperature below

246 ° C. Within 30 minutes a solution of carbon disulfide (22.6 mL, 376 mmol) in THF (23 mL) was added and the reaction mixture was stored at 40 ° C for 135 min. The heating is stopped and the reaction mixture is cooled to -72 ° C. Lithium diisopropylamide (2.0 M in heptane, THF and ethylbenzene, 126 mL, 252 mmol) was added over 35 min, keeping the internal temperature below -60 ° C. The resulting thick, dark red-orange mass was stored at about -60 ° C for 160 min. Within 45 minutes dimethyl sulfate (48 mL, 504 mmol) was added and the reaction mixture was allowed to warm to room temperature over 70 min. The mechanical stirrer is turned off and the reaction mixture is kept at room temperature for 17 hours. The resulting mixture was diluted with Et ₂ O (300 mL) and added to aqueous sodium bicarbonate solution (20%, 500 mL). All operations are performed under argon atmosphere. The layers were separated, the organic layer was extracted with aqueous sodium bicarbonate solution (25%, 200 mL), dried over MgSO ₄ , filtered and concentrated to about 100 mL. The resulting oil is distilled in vacuo (vapor temperature 70 ° C, 10 mm Hg) to give 25.37 g of product contaminated with ethylbenzene (15.59 g, 52% pure product). 1 H NMR (CDCl 3) δ: 5.24 (s, 2H), 2.36 (s, 6H) md

Part B: Preparation of methyl 4,4-di (methylthio) -2-oxo-but-3-enoate

A solution of 1,1'-Di (methylthio) ethylene (19.73 g, containing 9.95 g of pure compound, 83 mmol) in Et ₂ O (125 mL) was cooled to -60 ° C under argon. Within 3 minutes oxalyl chloride (5.6 mL, 64 mmol) was added allowing the internal temperature to reach -55 ° C. Within 20 minutes the reaction mixture was warmed to -15 ° C and within 2 min. dry methanol (20 mL, 494 mmol) was added. The reaction mixture was allowed to warm further and stirred at room temperature for 2 hours. The resulting mixture was diluted with Et ₂ O and filtered under argon to give a yellow solid (8.28 g, 63%). ¹ H NMR (CDCl 3) δ: 6.84 (s, 1H), 3.87 (s, 3H), 2.57 (s, 3H), 2.55 (s, 3H) md

Part C:

Preparation of methyl 1- (3-cyanophenyl) -3- (methylthio) pyrazole-5-carboxylate

247

Methyl 4,4-di (methylthio) -2-oxo-but-3-enoate (2.0 g, 9.7 mmol), triethylamine (1.5 mL, 10.7 mmol) and cyanophenylhydrazine are mixed in dry methanol (20 mL) hydrochloride (1.81 g, 10.7 mmol), and the mixture was refluxed for 47 hours. The reaction mixture was evaporated, chromatographed over silica gel (CH 2 Cl 2 followed by 40% EtOAc / hexanes); Partially purified intermediate (1.91 g) is obtained, which is dissolved in acetonitrile (85 ml) and refluxed for 23 hours. The crude reaction mixture was chromatographed over silica gel (CH ₂ Cl ₂ ) to give the desired pyrazole (780 mg, 29%). ¹ H NMR (CDCl ₃ ) δ: 7.78 (s, 1H), 7.70 (m, 2H), 7.57 (m, 1H), 6.95 (s, 1H), 3.83 (s) , 3H), 2.57 (s, 3H) md

Part D: Preparation of methyl 1- [3-aminomethyl) phenyl] -3- (methylthio) pyrazole-5-carboxylate to methyl 1- (3-cyanophenyl) -3- (methylthio) pyrazole-5-carboxylate (777 mg, 2.8) mmol) in dry DMF (50 mL) was added CoCl ₂ (39 mg, 0.30 mmol) and NaBH ₄ (158 mg, 4.2 mmol). The stock solution is an emerald green, then turns black. After stirring for 2 h, more NaBH ₄ (145 mg, 3.8 mmol) was added. 3 more hours. CoCl ₂ (330 mg, 2.5 mmol) was added again. The reaction mixture was stirred at room temperature for 17 hours. Methanol (10 mL) was added to quench the reaction and stir for 40 min. The reaction mixture was concentrated to 30 mL, chromatographed over silica gel (0% -100% EtOAc / hexanes followed by 10-30% MeOH / CHCl 3) to give the desired product (198 mg, 25%). ¹ H NMR (CDCl ₃ ) δ: 7.41 (m, 3H), 7.30 (d, 1H, J = 7.3 Hz), 6.90 (s, 1H), 4.02 (m.p. , 1H), 3.78 (s, 3H), 3.49 (s, 2H), 2.54 (s, 3H) md

Part E: Preparation of methyl 1- [3- (t-butoxycarbonylaminomethyl) phenine-3- (methylthio) pyrazole-5-carboxylate

To a suspension of methyl 1- [3-aminomethyl) phenyl] -3- (methylthio) pyrazole-5-carboxylate (195 mg, 0.70 mmol) in dry THF (8 mL) was added di-butyl dicarbonate (184 mg, 0.84 mmol) ). After stirring for 3 hours, additional THF (5 mL) was added to aid in dissolution. The reaction mixture was stirred for another 16 h, and more

Di-t-butyl dicarbonate (54 mg, 0.25 mmol) was added. After 5 more hours. triethylamine (100 μΙ, 0.72 mmol) was added and stirred for 2 h. The reaction mixture was diluted with EtOAc and extracted twice with H ₂ O. The aqueous layers were mixed and extracted with EtOAc. The organic layers were combined, dried over Na ₂ SO _4l was filtered, evaporated and chromatographed on silica gel (30% EtOAc) to afford the title product (228 mg, 86%)? H NMR (CDCl ₃₎ δ: 7.37 (m, 4H); 6.91 (s, 1H), 4.87 (s, 1H), 4.38 (d, 2H, J = 5.8 Hz), 3.79 (s, 3H), 2.56 (s) , 3H), 1.46 (s, 9H) md

F inches: Preparation of 1- [3- (t-Butoxycarbonylaminomethyl) phenyl] -3- (methylthio) pyrazole-5-carboxylic acid

To a solution of methyl 1- [3- (t-butoxycarbonylaminomethyl) phenyl] -3- (methylthio) pyrazole-5-carboxylate (50 mg, 0.13 mmol) in THF (2 mL) was added aqueous LiOH (1.0 M, 160 μΙ). , 0.16 mmol). The resulting solution was stirred for 19 h. More LiOH (30 μΙ, 0.03 mmol) was added and stirred for 3 h. The reaction mixture is partitioned between H ₂ O and Et ₂ O / EtOAc. The aqueous extracts were neutralized with HCl (0.1 M, 1.0 mL) by addition of ice. This aqueous solution is extracted once with Et ₂ O / EtOAc. HCl (0.1 M, 0.5 mL) was added and extracted with Et ₂ O / EtOAc again. A final pH of 3.5 is achieved by the addition of HCl (0.1 M, 0.4 mL). This solution was again extracted with EtOAc. The organic extracts obtained after acidification were mixed, dried over MgSO ₄ , filtered and evaporated to give the desired product (54 mg, 100%). ¹ H NMR (CDCl ₃ ) δ: 7.33 (m, 4H), 6.97 (S, 1H), 4.35 (pi.d, 2H, J = 4.4 Hz), 4.27 (m.p. s, 1H), 2.55 (s, 3H), 1.45 (s, 9H) md

Part G: Preparation of 1- [3- (t-Butoxycarbonylaminomethyl) phenyl] -5-i (2'-methylsulfonyl-1,1'-biphen-4-yl) aminocarbonyl-3- (methylthio) pyrazole

A mixture of 1- [3- (t-butoxycarbonylaminomethyl) phenyl] -3- (methylthio) pyrazole-5-carboxylic acid (94 mg, 0.26 mmol) and oxalyl chloride (35 μΙ, 0.40 mmol) in dry CH ₂ Cl ₂ DMF (3 or 4 drops) was added to ₂ (3 mL). The resulting solution was stirred for 55 min. and is suppressed. After standing for a few minutes in a deep vacuum,

Compound 249 is redissolved in CH ₂ Cl ₂ (3 mL), 4-amino-2'-methylsulfonyl [1,1'J-biphenyl hydrochloride (85 mg, 0.30 mmol) and 4-dimethylaminopyridine (85 mg, 0, 70 mmol) and stirred for 20 h. The reaction mixture was diluted with H ₂ O and extracted twice with EtOAc. The combined organic phases were extracted with aqueous NaHCO ₃ followed by aqueous HCl (0.1 M, ice-cooled). Solid NaCl is added to improve the separation of the layers. The organic layer was removed and the aqueous solution was extracted twice more with EtOAc. The organic extracts were combined, dried over Na ₂ SO _4l filtered and evaporated. The crude product is chromatographed on silica gel (50% EtOAc / hexanes) to give the desired product (65 mg, 43%). ESI mass spectrum mz = 615 (M + Na) ⁺ .

Part H: 1-Aminomethyl-F3) feniH-5-F ^(2-a -metilsulfonil i1,1'l biphen-4-yl) aminocarbonyl] -3- (methylthio) pyrazole Trifluoroacetic acid salt The

- [3- (t-Butoxycarbonylaminoethyl) phenyl] -5 - [(2'-methylsulfonyl- [1,1 '] - biphen4-yl) aminocarbonyl] -3- (methylthio) pyrazole (65 mg, 0, 11 mmol) was dissolved in CH ₂ Cl ₂ (3 mL) and TFA (1 mL) and stirred for 17 h. The reaction mixture was evaporated and purified by preparative HPLC (10-90%

MeCN / H ₂ O / 0.5% TFA) to give the desired product (37 mg, 55%). ¹ H NMR (DMSO) δ: 10.78 (s, 1H), 8.21 (m.s, 2H), 8.08 (d, 1H, J = 7.7 Hz), 7.70 (m, 5H), 7.45 (m, 6H), 7.16 (s, 1H), 4.13 (pi.d, 2H, J = 4.8 Hz), 2.84 (s, 3H), 2, 57 (s, 3H) md ESI mass spectrum m / z = 493 (M + H, 100).

Example 243

1- (3-Aminomethyl-4-fluorophenyl) -3-trifluoromethyl-5 - [(3-fluoro-2'-methylsulfonyl [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole trifluoroacetic acid salt

Part A: Preparation of 1- (3-cyano-4-fluorophenyl) -3-trifluoromethyl-5-methylpyrazole by adding 3-cyano-4-fluorophenylhydrazine lead chloride (10 g, 26.6 mmol) in acetic acid (150 mL). 1,1,1-Trifluoro-2,4-pentandione (4.09 g, 26.6 mmol). The reaction mixture was refluxed overnight. The acetic acid is evaporated off under a rotary evaporator under reduced pressure. Remain

250 was partitioned between ethyl acetate (200 mL) and water (150 mL). The organic phase was separated, washed with water (3 x 100 mL), dried over sodium sulfate, filtered, concentrated, and purified by flash chromatography on silica gel (ethyl acetate: hexane, 1:10) to give 1- (3-cyano-4-fluorophenyl) -3-. trifluoromethyl-5-methylpyrazole (4.0 g). CI mass spectrum m / z (relative intensity) 270 (M + H, 100).

Example b: Preparation of 1- (3-cyano-4-fluorophenyl) -3-trifluoromethyl-5-bromomethylpyrazole with 1- (3-cyano-4-fluorophenyl) -3-trifluoromethyl-5-methylpyrazole (4.0 g) , A solution of 14.87 mmol) in carbon tetrachloride (50 mL) was added NBS (2.65 g, 14.87 mmol) and benzoyl peroxide (0.36 g, 1.48 mmol). The reaction mixture was refluxed overnight. The solvent is removed by rotary evaporation under reduced pressure. The residue was partitioned between ethyl acetate (80 mL) and acid sodium carbonate (saturated, 80 mL). The organic phase was separated, washed with water (60 mL), dried over sodium sulfate, filtered, concentrated, and purified by silica gel flash chromatography (ethyl acetate: hexane, 1:10) to give 1- (3-cyano-4-fluorophenyl) -3-trifluoromethyl-. 5-Bromomethylpyrazole (2.5 g). CI mass spectrum m / z (relative intensity) 348 (M + H, 100).

Part C: Preparation of 1- (3-Cyano-4-fluorophenyl) -3-trifluoromethyl-5-hydroxymethylpyrazole

To 1- (3-cyano-4-fluorophenyl) -3-trifluoromethyl-5-bromomethylpyrazole (2.5 g,

To a solution of 7.18 mmol) in DMSO (40 mL) was added copper (I) oxide (2.16 g, 15.08 mmol) and water (12 mL). The reaction mixture was stirred at 60 ^c C for 2 h., Then was cooled to room temperature and stirred overnight. The next day, the mixture is filtered through celite, the filtrate is washed with ethyl acetate (20 mL), the filtrate is partitioned between ethyl acetate (50 mL) and water (50 mL), the organic phase is separated, washed with water (3 x 30 mL), dried over sodium sulfate, concentrated and purified by flash chromatography (ethyl acetate: hexane, 1: 6) to give 1- (3-cyano

4-fluorophenyl) -3-trifluoromethyl-5-hydroxymethylpyrazole (1.7 g). CI mass spectrum m / z (relative intensity) 286 (M + H, 100).

Part D: Preparation of 1- (3-Cyano-4-fluorophenyl) -3-trifluoromethyl-5-hydroxycarbonylmethylpyrazole

To a solution of 1- (3-cyano-4-fluorophenyl) -3-trifluoromethyl-5-hydroxymethylpyrazole (1.5 g, 5.26 mmol) in acetonitrile at 0 ° C (30 mL) was added NalO ₄ (2.65 g, 11.05 mmol), catalytic amount of RuCl ₃ and water (30 mL). The reaction mixture was stirred at 0 ° C to room temperature overnight. The acetonitrile is evaporated off under a rotary evaporator under reduced pressure. The residue was partitioned between ethyl acetate (60 mL) and HCl (10%, 25 mL). The organic phase was separated, dried over sodium sulfate, filtered and concentrated to give 1- (3-cyano-4-fluorophenyl) -3-trifluoromethyl-5-hydroxycarbonylmethylpyrazole (1.4 g). ESI mass spectrum m / z (rel intensity) 298 (M + H, 100).

Part E: Preparation of 1- (3-cyano-4-fluorophenyl) -3-trifluoromethyl-5 - [(3-fluoro-2'-methylsulfonyl] -1, 1-biphen-4-yl) aminocarboninpyrazole into 1- (3-cyano) To a solution of 4-fluorophenyl) -3-trifluoromethyl-5-hydroxycarbonylmethylpyrazole (0.20 g, 0.67 mmol) in methylene chloride (20 mL) was added CICOCOCI (0.84 g, 6.7 mmol) and a drop of DMF. The reaction mixture was stirred at room temperature overnight. The methylene chloride and excess CiCOCOCI are evaporated off on a rotary evaporator. The residue was redissolved in methylene chloride (20 mL) and 2'-methylsulfonyl- [1,1 T] -3-fluoro-4-aminobiphenyl (0.20 g, 0.67 mmol) and DMAP (0.25) were added to the solution. g, 2.01 mmol). The mixture was stirred at room temperature overnight. The next day, methylene chloride was removed by rotary evaporation under reduced pressure. The residue was partitioned between ethyl acetate (30 mL) and HCl (10%, 20 mL). The organic phase was separated, washed with water (2 x 20 mL), dried over sodium sulfate, filtered, and concentrated to give 1- (3-cyano-4-fluorophenyl) -3-trifluoromethyl-5 - [(3-fluoro) 2'-Methylsulfonyl - [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole (0.32 g). ESI mass spectrum m / z (relative intensity) 569 (M + Na, 100).

252

Part F: Preparation of the trifluoroacetic acid salt of 1- (3-Aminomethyl-4-fluorophenyl) -3-trifluoromethyl-5 - [(3-fluoro-2'-methylsulfonyl-1,1,1'-biphen-4-yl) aminocarboninpyrazole] 1- (3-Cyano-4-fluorophenyl) -3-trifluoromethyl-5 - [(3-fluoro-2'-methylsulfonyl- [1,1 '] biphen-4-yl) aminocarbonyl] pyrazole (50 mg) a solution of ethanol (20 ml) was added palladium (10% on activated carbon, 40 mg). The mixture was hydrogenated at 310 kPa overnight. The next day, the reaction mixture was filtered through celite, the filtrate concentrated, and the residue purified by HPLC (reverse phase gradient) to give 1- (3-aminomethyl-4-fluorophenyl) -3-trifluoromethyl-5 [(3-fluoro-2'-methyl- sulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole (40 mg) as the trifluoroacetic acid salt. ESI mass spectrum m / z (rel intensity) 551 (M + H, 100).

Example 244

Ethyl 1- [3- (aminomethyl) phenyl] -5 - [(3-fluoro-2'-methylsulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole-3-carboxylate trifluoroacetic acid salt

Part A: Preparation of ethyl 4- (2-furyl) -2,4-dioxobutanoate in sodium ethoxide (75 mL of a 21% solution in ethanol, 0.20 mol) in 300 mL of ethanol over 30 min. a mixture of 2-acetylfuran (20.0 g, 0.18 mol) and diethyloxalate (26.5 g, 0.18 mol) in 200 mL of tetrahydrofuran was added. The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered and the solids were washed with ether. The solids are dissolved in water and the solution is acidified with 10% HCl. The aqueous solution was extracted with ethyl acetate, the ethyl acetate layer was washed with saturated NaCl solution, dried (MgSO ₄ ), concentrated in vacuo to give 21.9 g (57%) of the title compound. ¹ H NMR (CDCl 3) δ: 7.68 (d, 1H), 7.35 (d, 1H), 6.93 (s, 1H), 6.62 (dd, 1H), 4.39 (kv, 2H), 1.40 (t, 3H) md

Part B: Preparation of ethyl 1-f (3-cyano) phenylH-5- (2-fur-2-yl) -pyrazole-3-carboxylate

253

To a solution of ethyl 4- (2-furyl) -2,4-dioxobutanoate (3.00 g, 14.3 mmol) in 50 mL of absolute ethanol was added 3-hydrazinobenzonitrile (2.09 g, 15.7 mmol) and p-toluenesulfonic acid (2.45 g, 14.3 mmol). This mixture was stirred at 80 ° C for 2 hours. The reaction mixture is concentrated in vacuo, the residue is dissolved in ethyl acetate, filtered through a pad of silica gel and concentrated in vacuo. Recrystallization of the residue from hexane gave 3.1 g (70%) of the title compound. ¹ H NMR (CDCl 3) δ: 7.80-7.70 (m, 4H), 7.58 (t, 1H), 7.42 (d, 1H), 7.16 (s, 1H), δ 42 (dd, 1H), 6.24 (d, 1H), 4.45 (kv, 2H), 1.42 (t, 3H) md ESI mass spectrum m / z 308.1 (M + H) ⁺ .

Part C: Preparation of ethyl 1 - [(3-cyano) phenyl] -5- (carboxy) pyrazole-3-carboxylate from ethyl 1 - [(3-cyano) phenyl] -5- (2-fur-2-yl) - To a solution of pyrazole-3-carboxylate (1.00 g, 3.25 mmol) in 50 mL of a mixture of acetonitrile / water / carbon tetrachloride (2: 3: 2) was added sodium periodate (3.13 g, 14.64 mmol) and ruthenium trichloride hydrate (0.015 g, 0.071 mmol). The mixture was stirred at room temperature for 1 h, then concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with brine, dried (MgSO ₄₎ and concentrated in vacuo. The residue was triturated with ether to give 0.9 g (96%) of the title compound. 1 H NMR (DMSO d ₆ ) δ: 8.15 (m, 1H), 7.99 (m, 1H), 7.91 (m, 1H), 7.87 (t, 1H), 7.38 (s , 1H), 4.30 (kv, 2H), 1.27 (t, 3H) md ESI mass spectrum: (AP +) m / z 286.1 (M + H) ⁺ .

D ai i s: Preparation of ethyl 1- (3-cyanophenyl) -5- [(3-fluoro-2'-methylsulfonyl-1,1,1'-biphen-4-yl) aminocarbonyl] pyrazole-3-carboxylate

To a solution of ethyl 1 - [(3-cyano) phenyl] -5- (carboxy) pyrazole-3-carboxylate (0.49 g, 1.72 mmol) in 10 mL of benzene was added oxalyl chloride (0.22 mL, 2.58 mmol) and about 3 drops of dimethylformamide. This solution was stirred at room temperature for 6 hours, then concentrated in vacuo. The residue was dissolved in methylene chloride and (3-fluoro-2'-methylsulfonyl- [1,1 '] -biphen-4-yl) amino (0.52 g, 1.72 mmol) and 4-dimethylaminopyridine (0.63 g) were added. , 5.17 mmol). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate, washed with 10% aqueous HCl, saturated with acid

254 sodium carbonate solution and saturated NaCl solution, dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by flash chromatography (eluting with 2: 1 hexanes: ethyl acetate) to give 0.70 g (76%) of the title compound. ¹ H NMR (CDCl ₃ ) δ: 8.32 (t, 1H), 8.22 (dd, 1H), 8.07 (ppm, 1H), 7.87 (m, 1H), 7.79 (m, 2H), 7.70-7.58 (m, 3H), 7.45 (s, 1H), 7.36 (m, 2H), 7.20 (d, 1H), 4.49 ( kv, 2H), 2.73 (s, 3H), 1.45 (t, 3H) md ESI mass spectrum m / z 533.2 (M + H) ⁺ .

Part E: Preparation of the trifluoroacetic acid salt of ethyl 1- [3- (aminomethyl) phenyl] -5- (3-fluoro-2'-methylsulfonyl-1,1'-biphen-4-yl) aminocarboninoirazole-3-carboxylate

To ethyl 1- (3-cyanophenyl) -5 - [(3-fluoro-2'-methyl isulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole-3-carboxylate (0.20 g) , 0.38 mmol) in 100 mL of absolute ethanol was added 2 mL of trifluoroacetic acid and 50 mg of 10% palladium on carbon catalyst. This mixture was stirred at 344.7 kPa hydrogen pressure for 24 hours on a Parr apparatus. The mixture is filtered through a pad of celite and concentrated in vacuo. The residue was purified by preparative HPLC (C18 reverse phase column, eluting with H ₂ O / CH ₃ CN with a gradient of 0.5% TFA) to give, after lyophilization, 130 mg (53%) of the title compound as a white powder. ¹ H NMR (DMSO-d ₆ ) δ: 9.76 (s, 1H), 8.64 (m.s, 3H), 7.94 (d, 1H), 7.67 (m, 1H), 7.50-7.37 (m, 5H), 7.28 (m, 2H), 7.12 (d, 1H), 7.05 (dd, 1H), 6.94 (d, 1H), 4 , 21 (ss, 2H), 3.88 (ss, 2H), 2.51 (s, 3H), 1.19 (t, 3H) md ESI mass spectrum m / z 537.2 (M + H) ) ⁺ .

Example 245

1- [3- (Aminomethyl) phenyl] -5 - [(3-fluoro-2'-methylsulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole-3-carboxylic acid trifluoroacetic acid salt

J Ethyl 1- [3- (aminomethyl) phenyl] -5 - [(3-fluoro-2'-methylsulfonyl- [1,1 '] - biphen-4yl) aminocarbonyl] pyrazole-3-carboxylate trifluoroacetic acid salt (0, Potassium hydroxide (0.013 g, 0.23 mmol) was added to a solution of 03 g, 0.05 mmol) in 5 mL of 1: 1 ethanol / water. This mixture is stirred at room temperature for 3 hours,

255 is then acidified by the addition of a few drops of trifluoroacetic acid. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (C18 reverse phase column, eluting with H ₂ O / CH ₃ CN with 0.5% TFA gradient) to give, after lyophilization, 15 mg (52%) of the title compound as a white powder. 1 H NMR (DMSO-d 6) δ 10.60 (s, 1H), 8.19 (ss, 3H), 8.06 (d, 1H), 7.75 (m, 1H), 7 69-7.51 (m, 5H), 7.50 (m, 2H), 7.39 (d, 1H), 7.34 (dd, 1H), 7.21 (d, 1H), 4.11 (pl.s, 2H), 2.90 (s, 3H) md ESI mass spectrum m / z 509.2 (M + H) ⁺ .

Example 246

1- [3- (Aminomethyl) phenyl] -3- [aminocarbonyl] -5- [3-fluoro- (2'-methylsulfonyl [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole trifluoroacetic acid salt

Part A: Ethyl 1- | '3- (N- (tert-butyloxycarbonyl) aminomethyl) -phenyl-5 l'3-fluoro (2'-methylsulfonyl-H, ^1, 1-biphen-4-yl) 3-aminokarbonilloirazol Preparation of -carboxylate from the ethyl 1- [3- (aminomethyl) phenyl] -5- [3-fluoro- (2 ^: methylsulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole-3- obtained in Example 244. of a solution of carboxylate (0.26 g, 0.40 mmol) in 10 mL of methylene chloride was added di-tert-butyl dicarbonate (0.09 g, 0.40 mmol) and 4-dimethylaminopyridine (0.15 g, 1.20 mmol). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate, washed with 10% aqueous HCl, saturated sodium bicarbonate solution and saturated NaCl solution, dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by flash chromatography (eluting with 2: 1 hexanes / ethyl acetate) to give 0.24 g (80%) of the title compound. Ή NMR (CDCl ₃₎ δ: 8.28 (t ,, 1H), 8.14 (d, 1H), 7.89 (br s, 1H), 7.56 (m, 2H), 7, 45-7.35 (m, 4H), 7.30-7.20 (m, 3H), 7.11 (d, 1H), 4.86 (s, 1H), 4.40 (s, 2H), 4.33 (m, 2H), 2.65 (s, 3H), 1.40 (t, 3H), 1.37 (s, 9H) md ESI (-) mass spectrum m / z ( relative intensity) 635.2 (MH, 100).

Part B: Preparation of 1-β- (Aminomethyl) phenyl-3-aminocarbonin-5-β-fluoro- (2'-methylsulfonyl-1,1'-biphen-4-iaminocarbonyl) pyrazole trifluoroacetic acid salt

256 to Ethyl 1- [3- (N- (tert-butyloxycarbonyl) aminomethyl) phenyl] -5- [3-fluoro- (2'-methylsulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole- To a solution of 3-carboxylate (0.24 g, 0.38 mmol) in 20 mL of 1: 1 tetrahydrofuran / water was added potassium hydroxide (0.08 g, 1.5 mmol). The resulting mixture was stirred at 60 ° C for 1 h, then cooled and concentrated in vacuo. The residue was diluted with water and extracted with 1: 1 hexane / ethyl acetate. The organic extract is separated. The aqueous layer was acidified with aqueous HCl and extracted with ethyl acetate. The extracts were washed with saturated NaCl solution, dried (MgSO ₄ ), and concentrated in vacuo. The residue was dissolved in 10 mL of acetonitrile, cooled to 0 ° C, and triethylamine (0.10 mL, 0.71 mmol) and tert-butyl chloroformate (0.067 mL, 0.52 mmol) were added. This mixture was stirred for 30 min, then ammonia (0.95 mL of a 2M solution in methanol, 1.88 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred for 18 h. The reaction mixture was diluted with ethyl acetate, washed with 10% aqueous HCl, saturated aqueous sodium bicarbonate solution and brine, dried (MgSO ₄₎ and concentrated in vacuo. The residue is dissolved in 5 ml of trifluoroacetic acid and stirred at room temperature for 2 hours. and concentrated in vacuo. Purification of the residue by preparative HPLC (C18 reverse phase column, elution with a H ₂ O / CH ₃ CN with 0.5% TFA) and after lyophilization give 115 mg (40%) of the title compound as a white powder, ¹ H NMR ( DMSO-d6) δ: 9.53 (s, 1H), 8.78 (ss, 3H), 8.04 (d, 1H), 7.86 (m, 1H), 7.64 (s, 1H), 7.52 (m, 1H), 7.42 (m, 2H), 7.37 (m, 3H), 7.20 (d, 1H), 7.17 (m, 2H), 7, 04 (d, 1H), 6.15 (ppm, 1H), 3.99 (ppm, 2H), 2.60 (s, 3H) md ESI (+ mass) mass spectrum m / z (rel. intensity) (ESI) m / z 508.2 (M + H, 100).

Example 247

Ethyl 1- [3- (aminomethyl) phenyl] -3-trifluoromethyl-5- [3-fluoro- (2'-methylsulfonyl [1,1] -biphen-4-yl) aminocarbonyl] pyrazole-4-carboxylate trifluoroacetic acid salt

Part A:

Preparation of N- (3-cyanophenyl) trifluoroacetohydrazonoyl bromide

257

To a solution of 3-hydrazinobenzonitrile HCl salt (1.3 g, 7.66 mmol) in 20 mL of absolute ethanol was added trifluoroacetaldehyde ethyl hemiacetal (1.33 g, 9.19 mmol). The resulting mixture was stirred at 80 ° C for 18 h, then cooled and concentrated in vacuo. The residue was dissolved in 10 ml of dimethylformamide and N-bromosuccinimide (1.36 g, 7.66 mmol) was added. The solution was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate, washed with water, a saturated aqueous sodium bicarbonate solution and a saturated NaCl solution, dried (MgSO ₄ ), and concentrated in vacuo to give 2.1 g (95%) of the title compound which was sufficiently pure and crude. 1 H NMR (CDCl ₃ ) δ: 8.16 (m.p., 1H), 7.47-7.30 (m, 4H) md

B d i s: Preparation of ethyl 3- (2-furyl) -3-oxopropanoate

To a suspension of hexane-washed sodium hydride (3.5 g of 60% dispersion in mineral oil, 90.8 mmol) in 200 ml of tetrahydrofuran was added diethyl carbonate (10.7 g, 90.8 mmol) and 2-acetylfuran (5.0 g, 45, 4 mmol). The resulting mixture was stirred at 70 ° C for 1 h, then cooled to room temperature and quenched by the slow addition of 10% aqueous HCl. The tetrahydrofuran was evaporated in vacuo and the aqueous solution was extracted with ethyl acetate. The organic layer was washed with water and saturated NaCl solution, dried (MgSO ₄ ) and concentrated in vacuo to give 6.9 g (83%) of the title compound which is sufficiently pure and can be used without purification. 1 H NMR (CDCl ₃ ) δ: 7.61 (t, 1H), 7.27 (dd, 1H), 6.57 (dd, 1H), 4.20 (kv, 2H), 3.84 (s , 2H), 1.25 (t, 3H) md

Part C: Preparation of ethyl 1 - [(3-cyano) phenyl] -3-trifluoromethyl-5-furfuryl-2-ylpyrazole-4-carboxylate from ethyl 3- (2-furyl) -3-oxopropanoate (1.87 g, 10, To a solution of 26 mmol) in 20 ml of absolute ethanol was added sodium ethoxide (2.6 mt in a 21% solution in ethanol, 6.84 mmol). A solution of N- (3-cyanophenyl) trifluoroacetohydrazonoyl bromide (1.0 g, 3.42 mmol) in absolute ethanol was then added. The resulting mixture was stirred at room temperature for 3 hours, then diluted with ether. Separated

258 layers, the organic layer was washed with water, saturated sodium carbonate, and saturated NaCl solution, dried (MgSO ₄ ), and concentrated in vacuo. Purification of the residue by flash chromatography (eluting with 4: 1 hexanes / ethyl acetate) afforded 0.80 g (63%) of the title compound. Δ NMR (CDCl3) δ: 7.71 (m, 1H), 7.60 (m, 1H), 7.53 (m, 2H), 7.44 (d, 1H), 6.95 (d, 1H) ), 6.55 (dd, 1H), 4.33 (kv, 2H), 1.32 (t, 3H) md

Part D: Preparation of ethyl 1 - [(3-cyano) phenyl] -3-trifluoromethyl-5-carboxylyrazole-4-carboxylate from ethyl 1 - [(3-cyano) phenyl] -3-trifluoromethyl-5 - [furyl] -2-yl] pyrazole-4 carboxylate (0.75 g, 2.0 mmol) in 30 mL of acetonitrile / water / carbon tetrachloride (2: 3: 2) was added sodium periodate (1.92 g, 9.0 mmol). ) and ruthenium trichloride hydrate (0.008 g, 0.04 mmol). The mixture was stirred at room temperature for 18 hours. and then concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with brine, dried (MgSO ₄₎ and concentrated in vacuo. This residue was dissolved in 1: 1 hexanes / ethyl acetate and extracted with saturated aqueous sodium carbonate. The aqueous layer was acidified with HCl and then extracted with ethyl acetate. The ethyl acetate extracts are washed with saturated NaCl solution, dried (MgSO ₄ ), and concentrated in vacuo to give 0.40 g (56%) of the title compound which is sufficiently pure and can be used crude. 1 H NMR (CDCl 3) δ: 7.82 (m, 1H), 7.71 (d, 1H), 7.64 (m, 2H), 4.55 (kv, 2H), 1.47 (t, 3H) md ESI (s) mass spectrum m / z (relative intensity) 352.1 (MH, 100).

Et al: Preparation of ethyl 1- [3- (cyano) phenyl] -3-trifluoromethyl-5- [3- (trifluoromethylsulfonyl) -1'-biphen-4-yl] aminocarbonine pyrazole-4-carboxylate. - A solution of [(3-cyano) phenyl] -3-trifluoromethyl-5- [carboxy] pyrazole-4-carboxylate (0.33 g, 0.93 mmol) in 10 mL! of methylene chloride was added oxalyl chloride (0.12 mL, 1.4 mmol) and about 3 drops of dimethylformamide. This solution was stirred at room temperature for 6 hours, then concentrated in vacuo. The residue was dissolved in methylene chloride and 4-dimethylaminopyridine (0.34 g, 2.79 mmol) and (2-fluoro-2'-methylsulfonyl- [1,1 '] - biphen-4-yl) amino were added.

259 hydrochloride (0.28 g, 0.93 mmol). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate, washed with 10% aqueous HCl, saturated sodium bicarbonate solution and saturated NaCl solution, dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by flash chromatography (eluting with 2: 1 hexanes: ethyl acetate) to give 0.25 g (45%) of the title compound. 1 H NMR (CDCl ₃ ) δ: 11.27 (s, 1H), 8.29 (t, 1H), 8.21 (d, 1H), 7.79 (m, 2H), 7.67-7 , 52 (m, 4H), 7.40-7.30 (m, 2H), 7.18 (d, 1H), 4.51 (sq, 2H), 2.73 (s, 3H), 1, 45 (t, 3H) md ESI (+ mass) mass spectrum m / z (relative intensity) 623.1 (M + Na, 100).

Part F: Preparation of the trifluoroacetic acid salt of ethyl 1- [3- (aminomethyl) phenin-3-trifluoromethyl-5-β-fluoro- (2'-methylsulfonyl-H, 1'1-biphen-4-yl) aminocarbonine pyrazole-4-carboxylate] ethyl 1- [3- (cyano) phenyl] -3-trifluoromethyl-5- [3-fluoro- (2'-methylsulfonyl- [1,1 '] biphen-4-yl) aminocarbonyl] pyrazole-4-carboxylate (0 , 13 g, 0.22 mmol) in 20 ml of absolute ethanol was added almost. HCl (0.018 mL, 0.22 mmol) and 20 mg 10% palladium on carbon catalyst. This mixture was stirred at 1 atm. hydrogen pressure, 18 hrs. The mixture is filtered through a pad of celite and concentrated in vacuo. Purification of the residue by preparative HPLC (C18 reverse phase column, eluting with H ₂ O / CH ₃ CN with a gradient of 0.5% TFA) gave after lyophilization 35 mg (21%) of the title compound as a white powder. 1 H NMR (DMSO-d 6) δ: 11.22 (s, 1H), 8.21 (p.s. 3H), 8.06 (dd, 1H), 7.87 (t, 1H), 7. 80-7.40 (m, 6H), 7.38 (m, 2H), 7.22 (dd, 1H), 4.26 (sq, 2H), 4.13 (ppm, 2H), 2 , 91 (s, 3H), 1.14 (t, 3H) md ESI (+ mass) mass spectrum m / z (relative intensity) (AP +) m / z 605.2 (M + H, 100).

Example 248

-13- (aminomethyl) phenyl] -5- [3-fluoro- (2'-methylsulfonyl- [1,1 '] -biphen-4-yl) aminocarbonyl] -3- (methylthio) pyrazole trifluoroacetic acid salt

260

Part A: Preparation of 1- [3- (t-Butoxycarbonylaminomethyl) phenyl] -5- [3-flupr- (2'-methylsulfonyl-1,1 '- 1-biphen-4-yl) aminocarbonyl] -3- (methylthio) pyrazole

A solution of 1- [3- (F-butoxycarbonylaminomethyl) phenyl] -3- (methylthio) pyrazole-5-carboxylic acid (553 mg, 1.5 mmol) and oxalyl chloride (260 μΙ, 3.0 mmol) in dry CH ₂ Cl ₂ (30 mi) DMF (3 drops) was added and the resulting solution was stirred at room temperature for 1 h and evaporated to give a solid which was redissolved in dry CH ₂ Cl ₂ (30 mL) and 4-dimethylaminopyridine (585 mg, 4.8 mmol). 4 min, 4-amino-3-fluoro-2'-methylsulfonyl- [1,1 '] - biphenyl hydrochloride (530 mg, 1.8 mmol) was added portionwise over 5 min and stirred for 22 h. NaHCCb followed by once cooled with 0.1 M HCl, the organic layer was dried over MgSO ₄ , filtered and evaporated The crude product was chromatographed on silica gel (40-50% EtOAc / hexanes) to give the desired product (378 mg, 41%). ¹ H NMR (CDCl 3) δ: 8.38 (e.g. t, 1H), 8.21 (dd, 1H, J = 7.7, J '= 1.1 Hz), 7.81 (m.p. , 1H), 7.65 (td, 1H, J = 7.4, J '= 1.4 Hz), 7.58 (td, J = 7.7, J '= 1.5 Hz), 7.43 (m, 4H), 7.32 (m, 2H), 7.17 (d, 1H, J = 8.8 Hz), 6, 84 (s, 1H), 4.90 (ss, 1H), 4.39 (d, 2H, J = 6.3 Hz), 2.72 (s, 3H), 2.60 (s, 3H) ), 1.45 (s, 9H) md

Part B: Preparation of 1- [3- (Aminomethyl) phenin-5-i-fluoro- (2'-methylsulfonyl-1,1'-biphen-4-yl) aminocarbonine-3- (methylthio) oirazole

- [3- (t-Butoxycarbonylaminomethyl) phenyl] -5- [3-fluoro- (2'-methylsulfonyl [1,1 '] - biphen-4-yl) aminocarbonyl] -3- (methylthio) pyrazole (287 mg, 0.47 mmol) was dissolved in CH ₂ Cl ₂ (5 mL) and TFA (5 mL) and stirred at room temperature for 16 h. Evaporation of the reaction mixture and purification of the residue by preparative HPLC (10-70% MeCN / H ₂ O / 0.05% TFA) gave the desired product (271 mg, 92%). ¹ H NMR (DMSO-d ₆ ) δ: 10.60 (s, 1H), 8.25 (m.s, 2H), 8.13 (d, 1H, J = 8.1 Hz), 7.82 (td, 1H, J = 7.3, J '= 1.5 Hz), 7.74 (m, 3H), 7.48 (m, 5H), 7.28 (d, 1H, J = 8, 4Hz), 7.23 (s, 1H), 4.16 (d, 2H, J = 5.8Hz), 2.97 (s, 3H), 2.61 (s, 3H) md APcl mass spectrum m / z 511 (M + H, 100).

Example 249

261

1- [3- (Aminomethyl) phenyl] -5- [3-fluoro- (2'-methylsulfonyl- [1,1]] -biphen-4-yl) aminocarbonyl] -3- (methylsulfonyl) pyrazole trifluoroacetic acid salt

To 1- [3- (L-Butoxycarbonylaminomethyl) phenyl] -5- [3-fluoro- (2'-methylsulfonyl [1,1 '] -biphen-4-yl) aminocarbonyl] -3- (methylthio) pyrazole (89 mg) , 0.15 mmol) of CH ₂ Cl ₂ (5 mL) was added to MCPBA (110 mg, 57-86%) and stirred at room temperature for 6 h. The reaction mixture is extracted once with saturated Na ₂ SO ₃ , then once with saturated NaHCO ₃ . The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was redissolved in CH ₂ Cl ₂ (1.5 mL) and TFA (1.5 mL) and stirred at room temperature for 5 h. Evaporation of the resulting solution and purification of the residue by preparative HPLC (1070% MeCN / H ₂ O / 0.05% TFA) affords the desired product. ¹ H NMR (DMSO-d ₆ ) δ: 10.75 (s, 1H), 8.20 (m.s, 2H), 8.06 (dd, 1H, J = 8.0, J '= 1, 5 Hz), 7.70 (m, 5H), 7.56 (m, 3H), 7.38 (m, 2H), 7.20 (dd, 1H, J = 8.1, J '= 1, 7 Hz), 4.11 (d, 2H, J = 5.5 Hz), 3.36 (s, 3H), 2.91 (s, 3H) md ESI mass spectrum m / z (relative intensity) 543 ( M + H, 100).

Example 250

1- [3- (Aminomethyl) phenyl] -5 - [(4- (5- (methoxyaminocarbonyl) imidazol-1-yl) phenyl] aminocarbonyl] -3-trifluoromethylpyrazole trifluoroacetic acid salt

Part A: A solution of 4-aminonitrobenzene (5.3 g, 38.4 mmol) in ethyl alcohol (50 mL) was treated with n-butylglyoxate (10.0 g, 76.9 mmol). After refluxing for 18 hours, the reaction mixture is concentrated under reduced pressure. The crude residue is used in the next step. To a solution of imine (10.0 g, 40.0 mmol) in methyl alcohol (50 mL) was added potassium carbonate (11.0 g, 80.0 mmol) and tosylmethyl isocyanate (11.7 g, 60.0 mmol). The solution is stirred for 1 hour. at room temperature followed by evaporation of the solvent under reduced pressure. The residue is treated with a saturated sodium chloride solution and the mixture is extracted with methylene chloride. The organic extract is concentrated and the residue is triturated with methyl alcohol. The precipitate was filtered off and dried to give imidazole (5.9 g, 59% over 2 steps). Reduction to aniline

262 was performed in MeOH with 10% Pd / C at 344.7 kPa for 18 h. MS (ESI) m / z (relative intensity) 216 (M + H, 100).

Part B: The product of Part A is then coupled with 1- (3-cyanophenyl) -3-trifluoromethylpyrazole carboxylic acid according to the method described above for the choric anhydride. Purification by chromatography on a silica gel column (hexane: ethyl acetate = 4: 3) gives a pure, copolished product. ESI mass spectrum m / z (relative intensity) 481 (M + H, 100).

Part C: The product from Part B (200 mg, 0.4 mmol) in THF (3 mL) was treated

1N NaOH (0.8 mL, 0.8 mmol). The resulting reaction mixture was stirred for 18 hours. at room temperature, then acidified with 1N HCl to pH 7, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated. The resulting acid (100 mg, 0.2 mmol) was dissolved in THF (5 mL), treated with DIEA (0.001 mL, 0.6 mmol), methoxylamine hydrochloride (0.030 g, 0.36 mmol) and TBTU (83 mg, 0.2 mmol). mmol), is stirred for 18 h. at room temperature. The residue is taken up in water, the mixture is extracted with ethyl acetate, the extract is dried over sodium sulfate and concentrated. Purification by flash column chromatography on silica gel (methanol / methylene chloride, 1: 9) affords the intermediate methoxyhydroxamate (60 mg, 56%). ESI mass spectrum m / z (relative intensity) 496 (M + H, 100). The nitrile reduction to benzylamine is then carried out under standard conditions. ¹ H NMR (CD 3 OD) δ: 3.74 (s, 3H), 4.21 (s, 2H), 7.43 (s, 1H), 7.46 (m, 2H), 7.60 (m, 3 H), 7.78 (m, 2 H), 7.80 (m, 3 H) md ESI mass spectrum m / z (relative intensity) 442 (M + H, 100).

Example 251

1- [3- (Aminomethyl) phenyl] -5 - [(4- (5- (methyl-1,2,3-triazol-1-yl) phen-1-yl) aminocarbonyl] -3-trifluoromethylpyrazole trifluoroacetic acid salt

263

Part A: Solution of 4-tert-Butyl- [1- (4-nitrophenyl)] - 5-methyl-1,2,3-triazol-1-ylcarboxylate (Maybridge Chemical Company, 0.5 g, 1.6 mmol) TFA (10 mL) was refluxed for 18 h. The reaction mixture is concentrated under reduced pressure. The residue is reduced to aniline under standard conditions and not purified. ¹ H NMR (CDCl ₃ ) δ: 2.36 (s, 3H), 6.83 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H), 7.80 (s, 1H) md ESI mass spectrum m / z (relative intensity) 175 (M + H, 100).

Part B: This intermediate is then coupled with 1- (3-cyanophenyl) -3-trifluoromethylpyrazolecarboxylic acid according to the chloro-anhydride methodology described above to reduce the nitrile to benzylamine, and the product is purified by reverse phase HPLC to give the title compound as a colorless solid. ¹ H NMR (CD ₃ OD) δ: 2.35 (s, 3H), 4.22 (s, 2H), 7.51 (d, J = 9.5 Hz, 2H), 7.55 (s, 1H), 7.60 (m, 3H), 7.65 (s, 1H), 7.71 (s, 1H), 7.89 (d, J = 9.2 Hz, 2H) md ESI mass spectrum m / z (relative intensity) 500 (M + H, 100).

Table 1a

For example, Ring M Z _R ia A ' A " B MS 1 pyrrole-a CONH H CH CH 2-H ₂ NSO ₂ -C ₆ H ₄ 460.3 2 pyrrole-a CONH H CH CH 2-t-Bu-HNSO ₂ - C ₆ H ₄ 516.4 3 pyrrole-a CONH Br CH CH 2-H ₂ NSO ₂ -C ₆ H ₄ 538.2 4 pyrrole-a CONH H N CH 2-H ₂ NSO ₂ -C ₆ H ₄ 461.3

264

5 pyrrole-b CONH ben- blue CH CH 2-H ₂ NSO ₂ -C ₆ H ₄ 550.3 6th pyrrole-b CONH ben- blue CH CH 2-t-Bu-HNSO ₂ - C ₆ H ₄ 606.5 7th imidazole-b CONH H CH CH 2-H ₂ NSO ₂ -C ₆ H ₄ 461.1 8th imidazole-b CONH H CH CH 2-t-Bu-HNSO ₂ - C ₆ H ₄ 517.2 9th imidazole-a CONH H CH CH 2-H ₂ NSO ₂ -C ₆ H ₄ 461.3 10th pyrazole CONH CH ₃ CH CH 2-H ₂ NSO ₂ -C _s H ₄ 475.2 11th pyrazole NHCO ch ₃ CH CH 2-H ₂ NSO ₂ -C ₆ H ₄ 475.2 12th pyrazole CONH ch ₃ CH CH 2- (5'-CF ₃ - tetrazoI-T-yl), - C ₆ H ₄ 532.4 13th 4-CI-pyrazole CONH ch ₃ CH CH 2-t-Bu-NHSO ₂ - C ₆ H ₄ 509.1 14th pyrazole CONH cf ₃ CH CH 2-H ₂ NSO ₂ -C ₆ H ₄ 529.0 15th 4-CH3O- pyrazole CONH cf ₃ CH CH 2-H ₂ NSO ₂ -C _s H ₄ 559.4 16th pyrazole CONH ch ₃ CH CH 1-imidazolyl 386.2 17th pyrazole CONH ch ₃ CH CH -O-2'-CH ₃ SO ₂ - c ₆ h ₄ 490.3 18th pyrazole COCHs ch ₃ CH CH 2-H ₂ NSO ₂ -C ₆ H ₄ 474.2 19th 1,2,3- triazole CONH H CH CH 2-H ₂ NSO ₂ -C ₆ H ₄ 463.1 20th tetrazole CONH - CH CH 2-CF ₃ -C ₆ H ₄ 452.2 21st tetrazole SCH ₂ - C-CI CH 2-H ₂ NSO ₂ -C ₆ H ₄ 500.2 22nd tetrazole soch ₂ - C-CI CH 2-H ₂ NSO ₂ -C ₆ H ₄ 516.2 23rd tetrazole so ₂ ch ₂ - C-CI CH 2-H ₂ NSO ₂ -C ₆ H ₄ 532.2 24th tetrazole CONH - CH CH 2-H ₂ NSO ₂ -C ₆ H ₄ 463.3 25th pyrazole CONH ch ₃ N CH 2-H ₂ NSO ₂ -CsH ₄ 476.3 26th pyrazole CONH ch ₃ N N 2-H ₂ NSO ₂ -C ₆ H ₄ 477.2 27th pyrazole CONH ch ₃ C-CI CH 2-H ₂ NSO ₂ -C ₆ H ₄ 509.3 28th pyrazole CONH ch ₃ C-F CH 2-H ₂ NSO ₂ -CsH ₄ 493.2 29th pyrazole CONH ch ₃ CH CH 2-H ₂ NSO ₂ -4-F- c ₆ h ₃ 493.3 30th pyrazole CONH ch ₃ CH CH 2-CF ₃ -C _s H ₄ 464.3 31st pyrazole CONH ch ₃ C-CI CH 2-CF ₃ -C ₆ H ₄ 498.3 32 pyrazole CONH ch ₃ C-F CH 2-CF ₃ -C ₆ H ₄ 482.2 33 pyrazole CONH ch ₃ N CH 2-CF ₃ -C ₆ H ₄ 465.3 34 pyrazole CONH ch ₃ CH CH 2-FC ₆ H ₄ 414.3 35 pyrazole CONH ch ₃ C-CI CH 2-FC ₆ H ₄ 448.0 36 pyrazole CONH ch ₃ CH CH 2-CH ₃ SO ₂ -C ₆ H ₄ 474.3 37 pyrazole CONCH3 ch ₃ CH CH 2-H ₂ NSO ₂ -C ₆ H ₄ 489.3 38 pyrazole CONH c ₄ h ₉ CH CH 2-H ₂ NSO ₂ -C ₆ H ₄ 517.4 39 pyrazole CONH c ₄ h ₉ N CH 2-H ₂ NSO ₂ -C ₆ H ₄ 518.2

265

40 pyrazole CONH C4H9 N CH 2-CF ₃ -CgH ₄ 506.3 41 pyrazole CONH cf ₃ CH CH 2-CH ₃ SO ₂ -CgH ₄ 528.2 42 pyrazole CONH cf ₃ CH CH 2-CF ₃ -CgH ₄ 518.2 43 4-CH3O- pyrazole CONH cf ₃ CH CH 2-CF ₃ -C ₆ H ₄ 548.3 44 pyrazole CONH ch ₃ CH CH cf ₃ 388.2 45 imidazole-a CONH 4- ch ₃ CH CH 2-H ₂ NSO2-C ₆ H ₄ 475.3 46th 1,2,3- triazole CONH H N CH 2-H ₂ NSO ₂ -C ₆ H ₄ 463.3 47 1,2,3- triazole CONH H CH CH 2-CF ₃ -C ₆ H ₄ 451.3 48 1,2,4- triazole CONH cf ₃ CH CH 2-H ₂ NSO ₂ -CsH ₄ 530.3

Table 1b

1,2,3-Triazoph

R ^1a

Imidazole-d

N-N

R ^1a

Pyrazole

N-N U V N. 'N

1,2,4-Triazole

1,3,4-Triazole

Tetrazole

Unless otherwise stated, D is in the meta-position and is an amidino group (AM) and R is not,

For example, M Z R ^1a A-B MS 49 pyrazole CONH methyl 4- (4'-chlorophenyl) - thiazol-2-yl 437.1 50 pyrazole CONH methyl 2'-CF ₃ S-biphenyl 496.1 51 pyrazole CONH .methyl 2'-CF ₃ S (O) -biphenyl 512 52 pyrazole CONH methyl 2'-CF ₃ S (O) _2- Biphenyl 528.1 53 pyrazole CONH methyl 4-Carboxymethyl-C ₆ H ₄ 378.2 54 pyrazole CONH methyl 4-N, N- (CH ₃ ) ₂ NC (O) - c ₆ h ₄ 391 55 pyrazole CONH methyl 4-N, N- (CH ₃ ) ₂ NS (O) ₂ - c ₆ h ₄ 426 56 pyrazole CONH methyl 4-t-Bu-HNSO ₂ -C ₆ H ₄ 455 57 pyrazole CONH methyl 4-H ₂ NSO ₂ -C ₆ H 4 381.3 58 pyrazole CONH methyl 4-CF ₃ -C ₆ H ₄ 388.1

266

59 pyrazole CONH methyl 4-Benzylsulfonyl- piperidyl 481.2 60 pyrazole CONCH3 methyl 2'-H ₂ NSO ₂ -biphenyl 489.2 61 pyrazole CONH methyl 4'-F-biphenyl 493.1 62 pyrazole CONH methyl 5- (2'-H ₂ NSO ₂ -C ₅ H ₄ ) -pyridin-2-yl 476.1 63 pyrazole (D = -CN) CONH methyl 5- (2'-H ₂ NSO ₂ -C _s H ₄ ) -pyridin-2-yl 459.1 64 pyrazole CONH methyl 2'-CF ₃ -biphenyl 464.2 65 pyrazole (D = CONH ₂ ) CONH methyl 2'-H ₂ NSO ₂ -biphenyl 476.1 66 pyrazole CONH methyl 2'-H ₂ NSO ₂ -3-chlorobiphenyl 509.1 67 pyrazole CONH methyl 2'-CF ₃ -3-chlorobiphenyl 498.1 68 pyrazole CONH C ₄ H ₉ 2'-H ₂ NSO ₂ -biphenyl 517.2 69 pyrazole CONH C ₄ H _s 2'-CF ₃ -biphenyl 507.2 70 pyrazole CONH C ₄ H _s 5- (2'-H ₂ NSO ₂ -C ₆ H ₄ ) -pyridin-2-yl 518.2 71 4-CH3O- pyrazole CONH CF ₃ 2'-CF ₃ -biphenyl 548.2 72 pyrazole CONH CF ₃ 2'-CF ₃ -biphenyl 518.1 73 pyrazole CONH CF ₃ 2'-SO ₂ CH ₃ -biphenyl 528.1 74 pyrazole CONH methyl 2'-H ₂ NSO ₂ -3-Br- biphenyl 553.1 75 pyrazole (D = CONH ₂ ) CONH methyl 2'-H ₂ NSO ₂ -3-Br- biphenyl 554.1 76 pyrazole COCH ₂ methyl 2'-H ₂ NSO ₂ -biphenyl 474.2 77 pyrazole (D = CONH ₂ ) CONH methyl 5- ^(2! H ₂ NSO ₂ -C ₆ H ₄₎ - pyridin-2-yl 477.1 78 pyrazole CONH cf ₃ 5- (2'-t-Bu-HNSO ₂ -C ₆ H ₄ ) -pyrimidin-2-yl 587.2 79 pyrazole CONH cf ₃ 5- (2'-H ₂ NSO ₂ -C _s H ₄ ) -pyrimidin-2-yl 531.1 80 pyrazole (D = CONH ₂ ) CONH cf ₃ 5- (2'-H ₂ NSO ₂ -C ₆ H ₄ ) - pyrimidin-2-yl 532.1 81 pyrazole (D = -CN) CONH ' cf ₃ 4'-imidazol-1-yl- C _S H ₄ 440.1 82 pyrazole CONH cf ₃ 4'-Morpholin-1-yl-C ₆ H ₄ 459.2 83 pyrazole (D = CONH ₂ ) CONH cf ₃ 4'-Morpholin-1-yl-C ₆ H ₄ 460.1 84 pyrazole CONH cf ₃ 5- (2'-H ₂ NSO ₂ -C _s H ₄ ) -pyridin-2-yl 530.1 85 pyrazole (D = CONH ₂ ) CONH cf ₃ 5- (2'-H ₂ NSO ₂ -C ₆ H ₄ ) -pyridin-2-yl 531.1

267

86 pyrazole CONH cf ₃ 4 '- (3-methyltetrazol-1-yl) C ₆ H ₄ 456.2 87 pyrazole nhso ₂ methyl 2'-naphthyl 406.1 88 pyrazole nhso ₂ methyl 2 '- (4-bromo-C6H ₄₎ 434.0 89 pyrazole (D = CH ₂ NH ₂ ) CONH methyl 2'-H ₂ NSO ₂ -biphenyl 462.2 90 pyrazole (D = CH ₂ NH ₂ ) CONH cf ₃ 2'-H ₂ NSO ₂ -biphenyl 516.1 91 pyrazole CONH methyl 5- (2'-CF ₃ -C ₆ H ₄ ) -pyrid-2-yl 465.2 92 pyrazole CONH methyl 5- (2'-H ₂ NSO ₂ -C _s H ₄ ) -pyrimidin-2-yl 477.2 93 pyrazole CONH methyl 2'-F-biphenyl 414.2 94 pyrazole CONH methyl 3-CI-2′-F-biphenyl 448.1 95 pyrazole CONH methyl 3-F-2 ^: -F-Biphenyl 482.2 96 pyrazole CONH methyl 3-F-2'-H ₂ NSO ₂ - Biphenyl 493.1 97 pyrazole CONH methyl 5- (2'-FC ₆ H ₄ ) -pyrid-2- type 415.2 98 pyrazole CONH methyl 5- (2'-t-Bu-NHSO ₂ - phenyl) pyrimidin-2-yl 533.2 99 pyrazole CONH methyl 5- (2'-H ₂ NSO ₂ -C ₆ H ₄ ) ([1,6] -dihydropyrimidin-2-yl) 579.2 100 pyrazole CONH methyl 4-Pyrid-3'-yl-C ₆ H ₄ 379.2 101 pyrazole CONH methyl 2- (2'-pyridyl) ethyl 349.2 102 pyrazole CONH methyl 3- ₍₄ C6H) propyl- 362.2 103 pyrazole CONH methyl 4- (pyrid-2'-yl) C ₆ H 4 397.2 104 pyrazole CONH methyl 4- (i-Propoxyl) C ₆ H ₄ 378.2 105 pyrazole CONH methyl 5- (2'-CF ₃ -phenyl) pyrimidin-2-yl) 466.2 106 pyrazole CONH methyl 4- (piperidine-SO ₂ ) C ₆ H ₄ ) 467.2 107 pyrazole CONH methyl 4- (piperidine-CO) C ₆ H ₄ ) 431.1 108 pyrazole (R = F) CONH methyl 2'-H ₂ NSO ₂ -biphenyl 493 109 pyrazole (D = CONH ₂ ) (R = F) CONH methyl 2'-H ₂ NSO ₂ -biphenyl 494.1 110 3-pyrazole CONH 1-methyl 2'-H ₂ NSO ₂ -biphenyl 475.3 111 pyrazole CONH methyl 4- (pyrazol-4'-yl) C ₆ H ₄ 386.3 112 pyrazole CONH methyl 5- (2'-SO ₂ CH ₃ -C ₆ H ₄ ) pyrid-2-yl 475.2 113 pyrazole CONH methyl 5- (2'-SO ₂ CH ₃ - 476.2

268

C ₆ H ₄ ) pyrimidin-2-yl 114 pyrazole (D = -CN) CONH methyl 5- (2'-SO ₂ CH ₃ -C ₆ H ₄ ) pyrimidin-2-yl 459.0 115 pyrazole (D = CONH ₂ ) CONH methyl 5- (2'-SO ₂ CH ₃ -C ₆ H ₄ ) pyrimidin-2-yl 477.1 116 pyrazole (D = N-NH ₂ - AM) CONH methyl 2'-t-Bu-NHSO ₂ - Biphenyl 490.2 117 pyrazole (D = N-NH ₂ - AM) CONH methyl 2'-H ₂ NSO ₂ -biphenyl 546.2 118 pyrazole (D = N-Me-N- HO-AM) CONH methyl 2'-t-Bu-NHSO ₂ - Biphenyl 561.2 119 pyrazole (D = N-Me-AM) CONH methyl 2'-t-Bu-NHSO ₂ - Biphenyl 545.2 120 pyrazole (D = N-Me-AM) CONH methyl 2'-H ₂ NSO ₂ -biphenyl 489.2 121 tetrazole CONH - 5- (2'-H ₂ NSO ₂ -C ₆ H ₄ ) - pyridin-2-i (as) 464.2 122 tetrazole (D = CONH ₂ ) CONH - 5- (2'-H ₂ NSO ₂ -C ₆ H 4) - pyridin-2-yl) 465.1 123 tetrazole CONH - 5- (2'-CF ₃ -C ₆ H ₄ ) - pyridin-2-yl) 453.2 124 tetrazole CONH - 4-Br-C ₆ H ₄ 386.0 125 tetrazole (D = CONH ₂ ) CONH - 5- (2'-CF ₃ -CgH ₄ ) - pyridin-2-yl) 454.1 126 tetrazole ch ₂ - 2'-CF ₃ -biphenyl 423.2 127 1- (3-AM- phenyl) methyl pyrazole CONH methyl 2'-H ₂ NSO ₂ -biphenyl 489 128 1- (4-AM- phenyl) methyl pyrazole CONH methyl 2'-H ₂ NSO ₂ -biphenyl 489 129 imidazole-a CONH - 2'-H ₂ NSO ₂ -biphenyl 461 130 imidazole-a CONH 4-methyl 2'-H ₂ NSO ₂ -biphenyl 475.2 131 imidazole-a CONH 5-Cl, 4-Me 2'-H ₂ NSO ₂ -biphenyl 509.1 132 imidazole-c CONH 2-methyl 2'-H ₂ NSO ₂ -biphenyl 475.1 133 pyrazole CONH methyl 4 '- (N-benzimidazol-1-yl) C ₆ H ₄ 436.2 134 pyrazole (D = CONH ₂ ) CONH methyl 4 '- (N-benzimidazol-1-yl) C ₆ H ₄ 437.2 135 pyrazole CONH methyl 4- (2'-methylimidazol-1-yl) C ₆ H ₄ 400.2 136 pyrazole (D = CONH ₂ ) CONH methyl 4- (2'-methylimidazol-1-yl) C ₆ H ₄ 401.2

269

137 pyrazole CONH methyl 4 '- (1,2,4-triazol-2-yl) CsH ₄ 387.2 138 pyrazole CONH methyl 4'-Cyclohexyl-C ₆ H ₄ 402.2 139 pyrazole CONH methyl biphenyl 396.2 140 pyrazole CONH methyl 4′-Morpholine-CsH ₄ 405.2 141 pyrazole CONH methyl 4 '- (2-CF ₃ -tetrazol-1-yl) C ₆ H ₄ 456.2 142 pyrazole (D = CH ₂ NH ₂ ) CONH methyl 4 '- (2-CF ₃ -tetrazol-1-yl) C _g H ₄ 443.2 143 pyrazole pyrazole methyl 4- (CH _{3) 2} NC (O) NH-, C ₆ H ₄ 406.2 144 pyrazole CONH methyl 4- (CH ₃ ) ₂ NC _s H ₄ 391.2 145 pyrazole (D = CONH ₂ ) CONH methyl 4- (CH ₃ ) ₂ NC _s H ₄ 392.2 146 pyrazole CONH methyl 4-Tetrazol-1-yl-C ₆ H ₄ 388.2 147 pyrazole (D = CONH ₂ ) CONH methyl 4-Tetrazol-1-yl-C ₆ H ₄ 389.2 148 pyrazole CONH methyl 4- (N-acetylpiperazin-1-yl) C ₆ H ₄ 446.2 149 pyrazole CONH methyl 4- (Nt-butoxycarbonylpiperazin-1-yl) C ₆ H ₄ 504.3 150 pyrazole CONH methyl 4- (piperazin-1-yl) C ₆ H ₄ 404.2 151 pyrazole CONH cf ₃ 4-Cyclohexylphenyl 456.2 152 pyrazole CONH methyl 4- (N-morpholino) -3-chloro-C ₆ H ₄ 439.2 153 pyrazole CONH CH ₃ S. 2'-H ₂ NSO ₂ -biphenyl 507.1 154 pyrazole CONH ch ₃ so 2'-H ₂ NSO ₂ -biphenyl 523.1 155 pyrazole CONH ch ₃ so ₂ 2'-H ₂ NSO ₂ -biphenyl 539.1 156 tetrazole (D = CONH ₂ ) CH ₂ - 2'-CF ₃ -biphenyl) 424.1 157 tetrazole (D = CONH ₂ ) ch ₂ - 2'-H ₂ NSO ₂ -biphenyl 435.1 158 pyrazole CONH methyl 4- cyclopentyloxyphenyl 404.2 159 pyrazole CONH • methyl 3- (pyrid-2-yl-NHCH ₂ ) C ₆ H ₄ 426.2 160 pyrazole CONH methyl 4- (N- imidazolyl) phenyl 386.2 161 pyrazole CONH cf ₃ 4- (N-morpholine) -3-CI-C ₅ H ₄ 493.1 162 pyrazole CONH methyl 4- (N-pyrrolidino karbinilas) -3-Cl-C6H ₄ 451.2 163 pyrazole CONH methyl 4- (N-morpholinocarbinyl) -3-Cl-C ₆ H ₄ 433.2

270

164 pyrazole D = -CN CONH cf ₃ 4- (N- imidazolyl) phenyl 423.2 165 pyrazole CONH cf ₃ 4- (N- imidazolyl) phenyl 440.2 166 pyrazole CONH cf ₃ 4- (N-methyltetrazolon-1-yl) phenyl 472.1 167 pyrazole (D = CONH ₂ ) coch ₂ methyl 2'-H ₂ NSO ₂ -biphenyl 433.2 168 pyrazole CONH methyl 4-N-pyrrolidino- methylienyl 403.2 169 pyrazole (D = NH ₂ ) CONH methyl 2'-H ₂ NSO ₂ -biphenyl 448.1 170 pyrazole (D = 2-NH ₂ ) CONH methyl 2'-H ₂ NSO ₂ -biphenyl 448.1 171 pyrazole (D = NH ₂ ) (R = 4-Cl) CONH methyl 2'-H ₂ NSO ₂ -biphenyl 482.0 172 pyrazole (D = NH ₂ ) (R = 4-F) CONH methyl 2'-H ₂ NSO ₂ -biphenyl 466.0 173 pyrazole (D = NH ₂ ) (R = 4-OMe) CONH methyl 2'-H ₂ NSO ₂ -biphenyl 478.1 174 tetrazole (D = NH ₂ ) (R = 4-Cl) CONH 2'-H ₂ NSO ₂ -biphenyl 470.0 175 tetrazole (D = NH ₂ ) (R = 4-Cl) CONH 5- (2'-H ₂ NSO ₂ -C ₆ H ₄ ) pyridin-2-yl 471.2 176 tetrazole (D = NH ₂ ) (R = 4-OMe) CONH 2'-H ₂ NSO ₂ -biphenyl 466.0 177 pyrazole (D = CH ₂ NH ₂ ) CONH methyl 5- (2'-H ₂ NSO _2. C ₆ H ₄ ) pyridin-2-yl 463.3 178 pyrazole (D = CH ₂ NH ₂ ) (R = 4-CH ₃ ) CONH methyl 2'-H ₂ NSO ₂ -biphenyl 476 179 pyrazole (D = CH ₂ NH ₂ ) (R = 4-F) CONH methyl 2'-H ₂ NSO ₂ -biphenyl 480 180 pyrazole (D = CH ₂ NH ₂ ) CONH cf ₃ 4- (N-pyrrolidinocarbonyl) C _s H ₄ 458.2 181 pyrazole (D = *) CONH methyl 2'-H ₂ NSO ₂ -biphenyl! 547.2 182 pyrazole (D = **) CONH methyl 2'-t-Bu-NHSO ₂ - Biphenyl 603.2

271

183 pyrazole (D = **) CONH methyl 2'-H ₂ NSO ₂ -biphenyl 547.2 184 ω ' Λ * Oh i CL CONH methyl 2'-H ₂ NSO ₂ -biphenyl 631.2 185 1- (pyrid-2-yl) - pyrazole CONH methyl 3-F-2'-H ₂ NSO ₂ - Biphenyl 452 186 1- (6-Br-pyrid2-yl) -pyrazole CONH methyl 3-F-2'-H ₂ NSO ₂ - Biphenyl 530 187 tetrazole (D = 3-NH ₂ ) (R = 4-Cl) CONH 3-CI-2'-H ₂ NSO ₂ - Biphenyl 504.0 188 tetrazole (D = 3-NH ₂ ) (R = 4-Cl) CONH 4- (N-pyrrolidinocarbonyl) C ₆ H ₄ 430 189 tetrazole (D = CH ₂ NH ₂ ) CONH - 2'-H ₂ NSO ₂ -biphenyl 450.2 190 1,3,4-Triazole (D = CH ₂ NH ₂ ) CONH H 3-F-2'-H ₂ NSO ₂ - Biphenyl 467.9 191 imidazole-d (D = CH ₂ NH ₂ ) CONH - 2'-H ₂ NSO ₂ -biphenyl 448.2 192 imidazole-d (D = CH ₂ NH ₂ ) CONH - 2'-H ₃ CSO ₂ -biphenyl 447 193 imidazole-d CONH - 2'-H ₂ NSO ₂ -biphenyl 461.2 194 pyrazole (D = CH ₂ NHCH ₃ ) CONH methyl 3-F-2'-H ₂ NSO ₂ - Biphenyl 494.1 195 pyrazole (D = CH ₂ NHCH ₃ ) CONH methyl 3-F-2'-H ₃ CSO ₂ - Biphenyl 492.2 196 pyrazole (D = CH ₂ NH ₂ ) CONH 3-CF ₃ 4-OCH ₃ 2'-H ₃ CSO ₂ -biphenyl 545.1 197 pyrazole (D = CH ₂ NH ₂ ) CONH cf ₃ 2-F-4- (N-pyrrolidinocarbonyl) C ₆ H ₄ 476.2 198 pyrazole (D = CH ₂ NH ₂ ) CONH cf ₃ 3-F-4- (N-Pyrrolidinocarbonyl) C _s H ₄ 476.2 199 pyrazole (D = CH ₂ NH ₂ ) CONH cf ₃ 2'-H ₃ CSO ₂ -biphenyl 515.1 200 pyrazole (D = CH ₂ NH ₂ ) CONH . cf ₃ 3-F-2'-H ₂ NSO ₂ - Biphenyl 534.1 201 pyrazole (D = CH ₂ NH ₂ ) CONH cf ₃ 5- (2'-H ₂ NSO _2. C _s H ₄ ) [1,6-dihiro] pyrimidin-2-yl 520.1 202 pyrazole (D = CH ₂ NH ₂ ) CONH cf ₃ 5- (2'-H ₂ NSO _2. C ₆ H ₄ ) pyrimidin-2-yl 518.1 203 pyrazole (D = CH (CH ₃ ) - NH ₂ ) CONH cf ₃ 2'-H ₂ NSO ₂ -biphenyl 530.1

272

204 pyrazole (D = C (= NH) - N-morpholine CONH cf ₃ 3-F-2'-H ₂ NSO ₂ - Biphenyl 616.9 205 pyrazole (D = CH ₂ NH ₂ ) CH (OH) CH ₂ cf ₃ 2'-H ₂ NSO ₂ -biphenyl 517.2 206 pyrazole (D = CH ₂ NH ₂ ) CONH cf ₃ 3-F-2'-H ₃ CSO ₂ - Biphenyl 532.9 207 pyrazole (D = CH ₂ NH ₂ ) CONH cf ₃ 5- (2'-H ₃ CSO _2. C ₆ H ₄ ) pyrimidin-2-yl 517.1 208 pyrazole CONH cf ₃ 3-F-2'-H ₂ NSO ₂ - Biphenyl 546 209 pyrazole CONH cf ₃ 3-F-2'-H ₃ CSO ₂ - Biphenyl 547.1 210 pyrazole (D = CH ₂ NH ₂ ) COCH ₂ cf ₃ 2'-H ₂ NSO ₂ -biphenyl 514.8 211 pyrazole (D = CH ₂ NH ₂ ) CONH ch ₂ so ₂ - ch ₃ 2'-H ₂ NSO ₂ -biphenyl 540.1 212 pyrazole CONH ch ₂ nh- SO ₂ CH 3 2'-H ₂ NSO ₂ -biphenyl 568.1 213 pyrazole (D = CH ₂ NH ₂ ) CONH ch ₂ nh- so ₂ ch ₃ 3-F-2'-H ₃ CSO ₂ - Biphenyl 572.1 214 pyrazole (D = CH (= NH) NHCO2CH3) CONH methyl 5- (2'-H ₂ NSO _2. C _s H ₄ ) pyrimidin-2-yl 535.1 215 pyrazole (D = CH ₂ NH ₂ ) CONH methyl 2'-H ₃ CSO ₂ -biphenyl 461.2 216 pyrazole (D = CH ₂ NH ₂ ) CONH cf ₃ 3-CH ₃ -2'-H ₃ CSO ₂ - Biphenyl 530.2 217 1,2,3-Triazole (D = CH ₂ NH ₂ ) CONH 3-F-2'-H ₃ CSO ₂ - Biphenyl 466.1 218 pyrazole (D = CH ₂ NH ₂ ) (R = 4-CH ₃ ) CONH methyl 2'-H ₂ NSO ₂ -biphenyl 476.2 219 pyrazole (D = CH ₂ NH ₂ ) (R = 4-F) CONH methyl 2'-H ₂ NSO ₂ -biphenyl 480.2 220 pyrazole (D = CH ₂ NH ₂ ) (R = 4-Cl) CONH methyl 2'-H ₂ NSO ₂ -biphenyl 479.1 221 pyrazole (D = CH ₂ NH ₂ ) (R = 4-F) CONH cf ₃ 3-F-2'-H ₂ NSO ₂ - Biphenyl 551.9 222 pyrazole (D = CH ₂ NH ₂ ) CONH methyl 3-F-2'-H ₂ NSO ₂ - Biphenyl 480 223 pyrazole CONH methyl 3-F-2'-H ₃ CSO ₂ - 479

273

(D = CH ₂ NH ₂ ) biphenyl 224 pyrazole CONH methyl 3-F-4- (N- morpholino) phenyl 423.2 225 pyrazole (D = CH ₂ NH ₂ ) CONH methyl 3-F-4- (N- morpholino) phenyl 410.2 226 pyrazole (D = CH ₂ NH ₂ ) CONH CF ₃ 3-F-4- (2'-CH ₃ -imidazol-1-yl) phenyl 459.2 227 pyrazole (D = CN) CH ₂ O methyl biphenyl 420 228 pyrazole ch ₂ o methyl biphenyl 437.2 229 pyrazole (D = CONH ₂ ) ch ₂ o methyl biphenyl 438.2 230 pyrazole CONH cf ₃ 2-F-4- (N- morpholino) phenyl 477.2 231 pyrazole (D = CONH ₂ ) CONH cf ₃ 2-F-4- (N- morpholino) phenyl 478.1 232 pyrazole (D = CH ₂ NH ₂ ) CONH cf ₃ 3-CF ₃ -4- (N-morpholino) phenyl 514 233 pyrazole (D = CH ₂ NH ₂ ) CONH ethyl 3-F-2'-H ₂ NSO ₂ - Biphenyl 493.9 234 pyrazole (D = CH ₂ NH ₂ ) CONH ethyl 3-F-2'-H ₃ CSO ₂ - Biphenyl 493 235 pyrazole (D = CH ₂ NH ₂ ) CONH ethyl 2-F-4- (2'-H ₃ CSO ₂ - imidazolyl) phenyl 465.2 236 1- (6-NH ₂ CH ₂ - pyrid-2-yl) - pyrazole CONH methyl 2'-H ₂ NSO ₂ -biphenyl 462.9 237 1- (6-C (= NH ₂ ) NOH-pyrid-2-yl) - pyrazole CONH methyl 2'-t-BuHNSO ₂ - Biphenyl 548.1 238 1- (6-AM-pyrid2-yl) -pyrazole CONH methyl 2'-H ₂ NSO ₂ -biphenyl 476.2 239 1- (6-AM-pyrid2-yl) -pyrazole CONH methyl 3-F-2'-H ₃ CSO ₂ - Biphenyl 493.9 ' 240 pyrazole (D = CH ₂ NH ₂ ) CONH methyl 2-CH ₃ O-4- (N-morpholino) phenyl 422.2 241 pyrazole (D = CH ₂ NH ₂ ) CONH methyl 4- (3'-CH ₃ ^-5'-oxo-3! Pyrazol-2'-yl) phenyl To 403.1 242 pyrazole (D = CH ₂ NH ₂ ) CONH sch ₃ 2'-H ₃ CSO ₂ -biphenyl 493 243 pyrazole (D = CH ₂ NH ₂ ) (R = 4-F) CONH cf ₃ 2'-H ₃ CSO ₂ -biphenyl 551 244 pyrazole (D = CH ₂ NH ₂ ) CONH CO ₂ Et 3-F-2'-H ₃ CSO ₂ - Biphenyl 537.2

274

245 pyrazole (D = CH ₂ NH ₂ ) CONH COOH 3-F-2'-H ₃ CSO ₂ - Biphenyl 509.2 246 pyrazole (D = CH ₂ NH ₂ ) CONH conh ₂ 2-F-2'-H ₃ CSO ₂ - Biphenyl 537.2 247 pyrazole (D = CH ₂ NH ₂ ) CONH 3-CF ₃ 4-CO ₂ Et 3-F-2 ^: -H ₃ CSO ₂ - Biphenyl 605.2 248 pyrazole (D = CH ₂ NH ₂ ) CONH sch ₃ 3-F-2'-H ₃ CSO ₂ - Biphenyl 511 249 pyrazole (D = CH ₂ NH ₂ ) CONH so ₂ ch ₃ 3-F-2'-H ₃ CSO ₂ - Biphenyl 543 250 pyrazole (D = CH ₂ NH ₂ ) CONH cf ₃ 4 - ((5-CH ₃ ONHC (O)) imidazol-1-yl phenyl 442 251 pyrazole (D = CH ₂ NH ₂ ) CONH cf ₃ 4- (5-CH ₃ -1,2,3-triazol-1-yl) phenyl 500

* D = Ethylcarboxamidine group ** D = 1 ”-imino-1” - (N-morphoHno) methyl *** D = N - ((5-methyl-2-oxo-1,3-dioxol-4-yl) methoxycarbonyl) amidine group.

The following tables are representative examples of compounds of the present invention. The example given in each column of the table is considered to include all compounds of the formulas given at the beginning of the table. For example, Example 1 in Table 2 includes all compounds of formulas a-nn, and Example 1 in Table 3 includes all compounds of formulas a-nn.

The following tables in Group A read:

5-pyrim idyll

2-pyrim idyll

3-Pyridine Las Cl

2,6-diF-phenyl

Table 275

k m

n

276

s t

u V w X

277

ee

ff

gg

hh

R?

nh ₂ ss

For example, R ^1a

CH ₃

CH ₃ phenyl 2- (aminosulfonyl) phenyl phenyl 2- (methylaminosulfonyl) phenyl

278

3 ch ₃ phenyl 1-Pyrrolidinocarbonyl 4 ch ₃ phenyl 2- (methylsulfonyl) phenyl 5 ch ₃ phenyl 4-Morpholine 6th ch ₃ phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 7th ch ₃ phenyl 4-morpholinocarbonyl 8th ch ₃ phenyl 2-methyl-1-imidazolyl 9th ch ₃ phenyl 5-methyl-1-imidazolyl 10th ch ₃ phenyl 2-methylsulfonyl-1-imidazolyl 11th ch ₃ 2-pyridyl 2- (aminosulfonyl) phenyl 12th ch ₃ 2-pyridyl 2- (methylaminosulfonyl) phenyl 13th ch ₃ 2-pyridyl 1-Pyrrolidinocarbonyl 14th ch ₃ 2-pyridyl 2- (methylsulfonyl) phenyl 15th ch ₃ 2-pyridyl 4-Morpholine 16th ch ₃ 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 17th ch ₃ 2-pyridyl 4-morpholinocarbonyl 18th ch ₃ 2-pyridyl 2-methyl-1-imidazolyl 19th ch ₃ 2-pyridyl 5-methyl-1-imidazolyl ' 20th ch ₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 21st ch ₃ 3-pyridyl 2- (aminosulfonyl) phenyl 22nd ch ₃ 3-pyridyl 2- (methylaminosulfonyl) phenyl 23rd ch ₃ 3-pyridyl 1-Pyrrolidinocarbonyl 24th ch ₃ 3-pyridyl 2- (methylsulfonyl) phenyl 25th ch ₃ 3-pyridyl 4-Morpholine 26th ch ₃ 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 27th ch ₃ 3-pyridyl 4-morpholinocarbonyl 28th ch ₃ 3-pyridyl 2-methyl-1-imidazolyl 29th ch ₃ 3-pyridyl 5-methyl-1-imidazolyl 30th ch ₃ 3-pyridyl 2-Methylsulfone I -1 -imidazolyl 31st ch ₃ 2-pyrimidyl 2- (aminosulfonyl) phenyl 32 ch ₃ 2-pyrimidif 2- (methylaminosulfonyl) phenyl 33 ch ₃ 2-pyrimidyl 1-Pyrrolidinocarbonyl 34 ch ₃ 2-pyrimidyl 2- (methylsulfonyl) phenyl 35 ch ₃ 2-pyrimidyl 4-Morpholine 36 ch ₃ 2-pyrimidyl 2- (1'-CF ₃ -tetrazol-2-yl) phenyl 37 ch ₃ 2-pyrimidyl 4-morpholinocarbonyl 38 ch ₃ 2-pyrimidyl 2-methyl-1-imidazolyl 39 ch ₃ 2-pyrimidyl 5-methyl-1-imidazolyl 40 ch ₃ : 2-Pyrimidyl 2-methylsulfonyl-1-imidazolyl 41 ch ₃ 5-pyrimidyl 2- (Aminosulfonyl) phenyl 42 ch ₃ 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 43 ch ₃ 5-pyrimidyl 1-Pyrrolidinocarbonyl 44 ch ₃ 5-pyrimidyl 2- (methylsulfonyl) phenyl 45 ch ₃ 5-pyrimidyl 4-Morpholine 46th ch ₃ 5-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 47 ch ₃ 5-pyrimidyl 4-morpholinocarbonyl 48 ch ₃ 5-pyrimidyl 2-methyl-1-imidazolyl 49 ch ₃ 5-pyrimidyl 5-methyl-1-imidazolyl 50 ch ₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl

279

51 ch ₃ 2-Cl-phenyl 2- (aminosulfonyl) phenyl 52 ch ₃ 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 53 ch ₃ 2-Cl-phenyl 1-Pyrrolidinocarbonyl 54 CHa 2-Cl-phenyl 2- (methylsulfonyl) phenyl 55 CHa 2-Cl-phenyl 4-Morpholine 56 CHa 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 57 CHa 2-Cl-phenyl 4-morpholinocarbonyl 58 CHa 2-Cl-phenyl 2-methyl-1-imidazolyl 59 CHa 2-Cl-phenyl 5-methyl-1-imidazolyl 60 CHa 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 61 CHa 2-F-phenyl 2- (aminosulfonyl) phenyl 62 CHa 2-F-phenyl 2- (methylaminosulfonyl) phenyl 63 CHa 2-F-phenyl 1-Pyrrolidinocarbonyl 64 CHa 2-F-phenyl 2- (methylsulfonyl) phenyl 65 CHa 2-F-phenyl 4-Morpholine 66 CHa 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 67 CHa 2-F-phenyl 4-morpholinocarbonyl 68 CHa 2-F-phenyl 2-methyl-1-imidazolyl 69 CHa 2-F-phenyl 5-methyl-1-imidazolyl 70 CHa 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 71 CHa 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 72 CHa 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 73 CHa 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 74 CHa 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 75 CHa 2,6-diF-phenyl 4-Morpholine 76 CHa 2,6-diF-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 77 CHa 2,6-diF-phenyl 4-morpholinocarbonyl 78 CHa 2,6-diF-phenyl 2-methyl-1-imidazolyl 79 CHa 2,6-diF-phenyl 5-methyl-1-imidazolyl 80 CHa 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 81 CH ₂ CH ₃ phenyl 2- (Aminosulfonyl) phenyl 82 CH ₂ CH ₃ phenyl 2- (methylaminosulfonyl) phenyl 83 CH2CH3 phenyl 1-Pyrrolidinocarbonyl 84 CH2CH3 phenyl 2- (methylsulfonyl) phenyl 85 CH ₂ CH ₃ phenyl 4-Morpholine 86 CH ₂ CH ₃ phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 87 CH ₂ CH ₃ phenyl 4-morpholinocarbonyl 88 CH2CH3 phenyl 2-methyl-1-imidazolyl 89 CH ₂ CH ₃ phenyl 5-methyl-1-imidazolyl 90 CH ₂ CH ₃ phenyl 2-m ethyl sulfonyl-1-imidazolyl 91 ch ₂ ch ₃ 2-pyridyl 2- (aminosulfonyl) phenyl 92 CH ₂ CH ₃ 2-pyridyl 2- (methylaminosulfonyl) phenyl 93 CH ₂ CH ₃ 2-pyridyl 1-Pyrrolidinocarbonyl 94 ch ₂ ch ₃ 2-pyridyl 2- (methylsulfonyl) phenyl 95 CH ₂ CH ₃ 2-pyridyl 4-Morpholine 96 CH ₂ CH ₃ 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 97 CH ₂ CH ₃ 2-pyridyl 4-morpholinocarbonyl 98 CH ₂ CH ₃ 2-pyridyl 2-methyl-1-imidazolyl

280

99 CH2CH3 2-Pyricyl 5-methyl-1-imidazolyl 100 ch ₂ ch ₃ 2-Pyrictyl 2-m ethyl sulfonyl-1-imidazolyl 101 ch ₂ ch ₃ 3-pyridyl 2- (aminosulfonyl) phenyl 102 ch ₂ ch ₃ 3-pyridyl 2- (methylaminosulfonyl) phenyl 103 ch ₂ ch ₃ 3-pyridyl 1-Pyrrolidinocarbonyl 104 ch ₂ ch ₃ 3-pyridyl 2- (methylsulfonyl) phenyl 105 ch ₂ ch ₃ 3-pyridyl 4-Morpholine 106 ch ₂ ch ₃ 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 107 ch ₂ ch ₃ 3-pyridyl 4-morpholinocarbonyl 108 ch ₂ ch ₃ 3-pyridyl 2-methyl-1-imidazolyl 109 ch ₂ ch ₃ 3-pyridyl 5-methyl-1-imidazolyl 110 ch ₂ ch ₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 111 ch ₂ ch ₃ 2-pyrimidyl 2- (aminosulfonyl) phenyl 112 ch ₂ ch ₃ 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 113 ch ₂ ch ₃ 2-pyrimidyl 1-Pyrrolidinocarbonyl 114 ch ₂ ch ₃ 2-pyrimidyl 2- (methylsulfonyl) phenyl 115 ch ₂ ch ₃ 2-pyrimidyl 4-Morpholine 116 ch ₂ ch ₃ 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 117 ch ₂ ch ₃ 2-pyrimidyl 4-morpholinocarbonyl 118 ch ₂ ch ₃ 2-pyrimidyl 2-methyl-1-imidazolyl 119 ch ₂ ch ₃ 2-pyrimidyl 5-methyl-1-imidazolyl 120 ch ₂ ch ₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 121 ch ₂ ch ₃ 5-pyrimidyl 2- (aminosulfonyl) phenyl 122 ch ₂ ch ₃ 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 123 ch ₂ ch ₃ 5-pyrimidyl 1-Pyrrolidinocarbonyl 124 ch ₂ ch ₃ 5-pyrimidyl 2- (methylsulfonyl) phenyl 125 ch ₂ ch ₃ 5-pyrimidyl 4-Morpholine 126 ch ₂ ch ₃ 5-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 127 ch ₂ ch ₃ 5-pyrimidyl 4-morpholinocarbonyl 128 ch ₂ ch ₃ 5-pyrimidyl 2-methyl-1-imidazolyl 129 ch ₂ ch ₃ 5-pyrimidyl 5-methyl-1-imidazolyl 130 ch ₂ ch ₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 131 ch ₂ ch ₃ 2-Cl-phenyl 2- (aminosulfonyl) phenyl 132 ch ₂ ch ₃ 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 133 ch ₂ ch ₃ 2-Cl-phenyl 1-Pyrrolidinocarbonyl 134 ch ₂ ch ₃ 2-Cl-phenyl 2- (methylsulfonyl) phenyl 135 ch ₂ ch ₃ .2-Cl-Phenyl 4-Morpholine 136 ch ₂ ch ₃ ; 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 137 ch ₂ ch ₃ 2-Cl-phenyl 4-morpholinocarbonyl 138 ch ₂ ch ₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 139 ch ₂ ch ₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 140 ch ₂ ch ₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 141 ch ₂ ch ₃ 2-F-phenyl 2- (aminosulfonyl) phenyl 142 ch ₂ ch ₃ 2-F-phenyl 2- (methylaminosulfonyl) phenyl 143 ch ₂ ch ₃ 2-F-phenyl 1-Pyrrolidinocarbonyl 144 ch ₂ ch ₃ 2-F-phenyl 2- (methylsulfonyl) phenyl 145 ch ₂ ch ₃ 2-F-phenyl 4-Morpholine 146 ch ₂ ch ₃ 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl

281

147 CH2CH3 2-F-phenyl 4-morpholinocarbonyl 148 CH ₂ CH ₃ 2-F-phenyl 2-methyl-1-imidazolyl 149 ch ₂ ch ₃ 2-F-phenyl 5-methyl-1-imidazolyl 150 ch ₂ ch ₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 151 ch ₂ ch ₃ 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 152 ch ₂ ch ₃ 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 153 ch ₂ ch ₃ 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 154 ch ₂ ch ₃ 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 155 ch ₂ ch ₃ 2,6-diF-phenyl 4-Morpholine 156 ch ₂ ch ₃ 2,6-diF-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 157 ch ₂ ch ₃ 2,6-diF-phenyl 4-morpholinocarbonyl 158 ch ₂ ch ₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 159 ch ₂ ch ₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 160 ch ₂ ch ₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 161 cf ₃ phenyl 2- (aminosulfonyl) phenyl 162 cf ₃ phenyl 2- (Mephilaminosulphonyl) phenyl 163 cf ₃ phenyl 1-Pyrrolidinocarbonyl 164 cf ₃ phenyl 2- (methylsulfonyl) phenyl 165 cf ₃ phenyl 4-Morpholine 166 cf ₃ phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 167 cf ₃ phenyl 4-morpholinocarbonyl 168 cf ₃ phenyl 2-methyl-1-imidazolyl 169 cf ₃ phenyl 5-methyl-1-imidazolyl 170 cf ₃ phenyl 2-Methyl Isulfonyl-1-imidazolyl 171 cf ₃ 2-pyridyl 2- (aminosulfonyl) phenyl 172 cf ₃ 2-pyridyl 2- (methylaminosulfonyl) phenyl 173 cf ₃ 2-pyridyl 1-Pyrrolidinocarbonyl 174 cf ₃ 2-pyridyl 2- (methylsulfonyl) phenyl 175 cf ₃ 2-pyridyl 4-Morpholine 176 cf ₃ 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 177 cf ₃ 2-pyridyl 4-morpholinocarbonyl 178 cf ₃ 2-pyridyl 2-methyl-1-imidazolyl 179 cf ₃ 2-pyridyl 5-methyl-1-imidazolyl 180 cf ₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 181 cf ₃ 3-pyridyl 2- (aminosulfonyl) phenyl 182 cf ₃ 3-pyridyl 2- (methylaminosulfonyl) phenyl 183 cf ₃ 3-pyridyl 1-Pyrrolidinocarbonyl 184 cf ₃ 3-pyridyl 2- (methylsulfonyl) phenyl 185 cf ₃ 3-pyridyl 4-Morpholine 186 cf ₃ 3-pyridyl 2- (1'-CF ₃ -tetrazol-2-yl) phenyl 187 cf ₃ 3-pyridyl 4-morpholinocarbonyl 188 cf ₃ 3-pyridyl 2-methyl-1-imidazolyl 189 cf ₃ 3-pyridyl 5-methyl-1-imidazolyl 190 cf ₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 191 cf ₃ 2-pyrimidyl 2- (aminosulfonyl) phenyl 192 cf ₃ 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 193 cf ₃ 2-pyrimidyl 1-Pyrrolidinocarbonyl 194 cf ₃ 2-pyrimidyl 2- (methylsulfonyl) phenyl

282

195 cf ₃ 2-pyrimidyl 4-Morpholine 196 cf ₃ 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 197 cf ₃ 2-pyrimidyl 4-morpholinocarbonyl 198 cf ₃ 2-pyrimidyl 2-methyl-1-imidazolyl 199 cf ₃ 2-pyrimidyl 5-methyl-1-imidazolyl 200 cf ₃ 2-pyrimidyl 2-M ethyl sulfone I -1-imidazole glass 201 cf ₃ 5-pyrimidyl 2- (aminosulfonyl) phenyl 202 cf ₃ 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 203 cf ₃ 5-pyrimidyl 1-Pyrrolidinocarbonyl 204 cf ₃ 5-pyrimidyl 2- (methylsulfonyl) phenyl 205 cf ₃ 5-pyrimidyl 4-Morpholine 206 cf ₃ 5-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 207 cf ₃ 5-pyrimidyl 4-morpholinocarbonyl 208 cf ₃ 5-pyrimidyl 2-methyl-1-imidazolyl 209 cf ₃ 5-pyrimidyl 5-methyl-1-imidazolyl 210 cf ₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 211 cf ₃ 2-CI Phenyl 2- (aminosulfonyl) phenyl ' 212 cf ₃ 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 213 cf ₃ 2-Cl-phenyl 1-Pyrrolidinocarbonyl 214 cf ₃ 2-Cl-phenyl 2- (methylsulfonyl) phenyl 215 cf ₃ 2-Cl-phenyl 4-Morpholine 216 cf ₃ 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 217 cf ₃ 2-C 1 -phenyl 4-morpholinocarbonyl 218 cf ₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 219 cf ₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 220 cf ₃ 2-Cl-phenyl 2-Methylsulfonyl-1-imidazolyl 221 cf ₃ 2-F-phenyl 2- (aminosulfonyl) phenyl 222 cf ₃ 2-F-phenyl 2- (methylaminosulfonyl) phenyl 223 cf ₃ 2-F-phenyl 1-Pyrrolidinocarbonyl 224 cf ₃ 2-F-phenyl 2- (methylsulfonyl) phenyl 225 cf ₃ 2-F-phenyl 4-Morpholine 226 cf ₃ 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 227 cf ₃ 2-F-phenyl 4-morpholinocarbonyl 228 cf ₃ 2-F-phenyl 2-methyl-1-imidazolyl 229 cf ₃ 2-F-phenyl 5-methyl-1-imidazolyl 230 cf ₃ 2-F-phenyl 2-Methylsulfone I-1-imidazolyl 231 cf ₃ 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 232 cf ₃ 2, '6-diF-phenyl 2- (methylaminosulfonyl) phenyl 233 cf ₃ 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 234 cf ₃ 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 235 cf ₃ 2,6-diF-phenyl 4-Morpholine 236 cf ₃ 2,6-diF-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 237 cf ₃ 2,6-diF-phenyl 4-morpholinocarbonyl 238 cf ₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 239 cf ₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 240 cf ₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 241 sch ₃ phenyl 2- (aminosulfonyl) phenyl 242 sch ₃ phenyl 2- (methylaminosulfonyl) phenyl

283

243 sch ₃ phenyl 1-Pyrrolidinocarbonyl 244 sch ₃ phenyl 2- (methylsulfonyl) phenyl 245 sch ₃ phenyl 4-Morpholine 246 sch ₃ phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 247 sch ₃ phenyl 4-morpholinocarbonyl 248 sch ₃ phenyl 2-methyl-1-imidazolyl 249 sch ₃ phenyl 5-methyl-1-imidazolyl 250 sch ₃ phenyl 2-methylsulfonyl-1-imidazolyl 251 sch ₃ 2-pyridyl 2- (aminosulfonyl) phenyl 252 sch ₃ 2-pyridyl 2- (methylaminosulfonyl) phenyl 253 sch ₃ 2-pyridyl 1-Pyrrolidinocarbonyl 254 sch ₃ 2-pyridyl 2- (methylsulfonyl) phenyl 255 sch ₃ 2-pyridyl 4-Morpholine 256 sch ₃ 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 257 sch ₃ 2-pyridyl 4-morpholinocarbonyl 258 sch ₃ 2-pyridyl 2-methyl-1-imidazolyl 259 sch ₃ 2-pyridyl 5-methyl-1-imidazolyl 260 sch ₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 261 sch ₃ 3-pyridyl 2- (aminosulfonyl) phenyl 262 sch ₃ 3-pyridyl 2- (methylaminosulfonyl) phenyl 263 SCH ₃ 3-pyridyl 1-Pyrrolidinocarbonyl 264 sch ₃ 3-pyridyl 2- (methylsulfonyl) phenyl 265 sch ₃ 3-pyridyl 4-Morpholine 266 sch ₃ 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 267 sch ₃ 3-pyridyl 4-morpholinocarbonyl 268 sch ₃ 3-pyridyl 2-methyl-1-imidazolyl 269 sch ₃ 3-pyridyl 5-methyl-1-imidazolyl 270 SCHa 3-pyridyl 2-methylsulfonyl-1-imidazolyl 271 SCHa 2-pyrimidyl 2- (aminosulfonyl) phenyl 272 sch ₃ 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 273 sch ₃ 2-pyrimidyl 1-Pyrrolidinocarbonyl 274 sch ₃ 2-pyrimidyl 2- (methylsulfonyl) phenyl 275 sch ₃ 2-pyrimidyl 4-Morpholine 276 sch ₃ 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 277 sch ₃ 2-pyrimidyl 4-morpho.linocarbonyl 278 sch ₃ 2-pyrimidyl 2-mephyl-1-imidazolyl 279 SCHa 2-pyrimidyl 5-methyl-1-imidazolyl 280 SCH ₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 281 SCH ₃ 5-pyrimidyl 2- (aminosulfonyl) phenyl 282 SCH ₃ 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 283 sch ₃ 5-pyrimidyl 1-Pyrrolidinocarbonyl 284 sch ₃ 5-pyrimidyl 2- (methylsulfonyl) phenyl 285 sch ₃ 5-pyrimidyl 4-Morpholine 286 sch ₃ 5-pyrimidyl 2- (1'-CF ₃ -tetrazol-2-yl) phenyl 287 SCH ₃ 5-pyrimidyl 4-morpholinocarbonyl 288 SCHa 5-pyrimidyl 2-methyl-1-imidazolyl 289 SCHa 5-pyrimidyl 5-methyl-1-imidazolyl 290 SCHa 5-pyrimidyl 2-Methylsulfonyl-1-imidazolyl

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291 sch ₃ 2-Cf-phenyl 2- (aminosulfonyl) phenyl 292 sch ₃ 2-ΟΙ-ίθηΐΐΒ3 2- (methylaminosulfonyl) phenyl 293 sch ₃ 2-Cl-phenyl 1-Pyrrolidinocarbonyl 294 sch ₃ 2-Cl-phenyl 2- (methylsulfonyl) phenyl 295 sch ₃ 2-Cl-phenyl 4-Morpholine 296 sch ₃ 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 297 sch ₃ 2-C 1 -phenyl 4-morpholinocarbonyl 298 sch ₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 299 sch ₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 300 sch ₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 301 sch ₃ 2-F-phenyl 2- (aminosulfonyl) phenyl 302 sch ₃ 2-F-phenyl 2- (methylaminosulfonyl) phenyl 303 sch ₃ 2-F-phenyl 1-Pyrrolidinocarbonyl 304 sch ₃ 2-F-phenyl 2- (methylsulfonyl) phenyl 305 sch ₃ 2-F-phenyl 4-Morpholine 306 sch ₃ 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 307 sch ₃ 2-F-phenyl 4-morpholinocarbonyl. 308 sch ₃ 2-F-phenyl 2-methyl-1-imidazolyl 309 sch ₃ 2-F-phenyl 5-methyl-1-imidazolyl 310 sch ₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 311 sch ₃ 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 312 sch ₃ 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 313 sch ₃ 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 314 sch ₃ 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 315 sch ₃ 2,6-diF-phenyl 4-Morpholine 316 sch ₃ 2,6-diF-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 317 sch ₃ 2,6-diF-phenyl 4-morpholinocarbonyl 318 sch ₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 319 sch ₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 320 sch ₃ 2,6-diF-phenyl 2-methylsulfone 1-1 -imidazolyl 321 soch ₃ phenyl 2- (aminosulfonyl) phenyl 322 soch ₃ phenyl 2- (methylaminosulfonyl) phenyl 323 soch ₃ phenyl 1-Pyrrolidinocarbonyl 324 soch ₃ phenyl 2- (methylsulfonyl) phenyl 325 soch ₃ phenyl 4-Morpholine 326 soch ₃ phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 327 soch ₃ phenyl 4-morpholinocarbonyl 328 soch ₃ phenyl 2-methyl-1-imidazolyl 329 soch ₃ phenyl 5-methyl-1-imidazolyl 330 soch ₃ phenyl 2-methylsulfonyl-1-imidazolyl 331 soch ₃ 2-pyridyl 2- (aminosulfonyl) phenyl 332 soch ₃ 2-pyridyl 2- (methylaminosulfonyl) phenyl 333 soch ₃ 2-pyridyl 1-Pyrrolidinocarbonyl 334 soch ₃ 2-pyridyl 2- (methylsulfonyl) phenyl 335 soch ₃ 2-pyridyl 4-Morpholine 336 soch ₃ 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 337 soch ₃ 2-pyridyl 4-morpholinocarbonyl 338 soch ₃ 2-pyridyl 2-methyl-1-imidazolyl

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339 SOCH ₃ 2-pyridyl 5-methyl-1-imidazolyl 340 SOCH3 2-pyridyl 2-methylsulfonyl-1-imidazolyl 341 SOCH3 3-pyridyl 2- (aminosulfonyl) phenyl 342 SOCH3 3-pyridyl 2- (methylaminosulfonyl) phenyl 343 SOCH3 3-pyridyl 1-Pyrrolidinocarbonyl 344 SOCH3 3-pyridyl 2- (methylsulfonyl) phenyl 345 SOCH3 3-pyridyl 4-Morpholine 346 SOCH3 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 347 SOCH3 3-pyridyl 4-morpholinocarbonyl 348 SOCH3 3-pyridyl 2-methyl-1-imidazolyl 349 SOCH3 3-pyridyl 5-methyl-1-imidazolyl 350 SOCH3 3-pyridyl 2-Methyl Isulfonyl-1-imidazolyl 351 SOCH3 2-pyrimidyl 2- (aminosulfonyl) phenyl 352 SOCH3 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 353 SOCH3 2-pyrimidyl 1-Pyrrolidinocarbonyl 354 SOCH3 2-pyrimidyl 2- (methylsulfonyl) phenyl 355 SOCH3 2-pyrimidyl 4-Morpholine 356 SOCH3 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 357 SOCH3 2-pyrimidyl 4-morpholinocarbonyl 358 SOCH3 2-pyrimidyl 2-methyl-1-imidazolyl 359 SOCH3 2-pyrimidyl 5-methyl-1-imidazolyl 360 SOCH3 2-pyrimidyl 2-Methylsulfonyl-1-imidazolyl 361 SOCH3 5-pyrimidyl 2- (aminosulfonyl) phenyl 362 SOCH3 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 363 SOCH3 5-pyrimidyl 1-Pyrrolidinocarbonyl 364 SOCH3 5-pyrimidyl 2- (methylsulfonyl) phenyl 365 SOCH3 5-pyrimidyl 4-Morpholine 366 SOCH3 5-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl as 367 SOCH3 5-pyrimidyl 4-morpholinocarbonyl 368 SOCH3 5-pyrimidyl 2-methyl-1-imidazolyl 369 SOCH3 5-pyrimidyl 5-methyl-1-imidazolyl 370 SOCH3 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 371 SOCH3 2-CI-Phenyl 2- (aminosulfonyl) phenyl 372 SOCH3 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 373 SOCH3 2-Cl-phenyl 1-Pyrrolidinocarbonyl 374 SOCH3 2-Cl-phenyl 2- (methylsulfonyl) phenyl 375 SOCH3 2-Cl-phenyl 4-Morpholine 376 SOCH3 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 377 SOCH3 2-Cl-phenyl 4-morpholinocarbonyl 378 SOCH3 2-Cl-phenyl 2-methyl-1-imidazolyl 379 SOCH3 2-Cl-phenyl 5-methyl-1-imidazolyl 380 SOCH3 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 381 SOCH3 2-F-phenyl 2- (aminosulfonyl) phenyl 382 SOCH3 2-F-phenyl 2- (methylaminosulfonyl) phenyl 383 SOCH3 2-F-phenyl 1-Pyrrolidinocarbonyl 384 SOCH3 2-F-phenyl 2- (methylsulfonyl) phenyl 385 SOCH3 2-F-phenyl 4-Morpholine 386 SOCH3 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl

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387 SOCH ₃ 2-F-phenyl 4-morpholinocarbonyl 388 SOCH3 2-F-phenyl 2-methyl-1-imidazolyl 389 SOCH3 2-F-phenyl 5-methyl-1-imidazolyl 390 SOCH3 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 391 SOCH3 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 392 SOCH3 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 393 SOCH3 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 394 SOCH3 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 395 SOCH3 2,6-diF-phenyl 4-Morpholine 396 SOCH3 2,6-diF-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 397 SOCH3 2,6-diF-phenyl 4-morpholinocarbonyl 398 SOCHa 2,6-diF-phenyl 2-methyl-1-imidazolyl 399 SOCH3 2,6-diF-phenyl 5-methyl-1-imidazolyl 400 SOCH3 2,6-diF-phenyl 2-Methyl Isulfonyl-1-imidazolyl 401 SO ₂ CH ₃ phenyl 2- (aminosulfonyl) phenyl 402 so ₂ ch ₃ phenyl 2- (methylaminosulfonyl) phenyl 403 so ₂ ch ₃ phenyl 1-Pyrrolidinocarbonyl 404 so ₂ ch ₃ phenyl 2- (methylsulfonyl) phenyl 405 so ₂ ch ₃ phenyl 4-Morpholine 406 so ₂ ch ₃ phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 407 so ₂ ch ₃ phenyl 4-morpholinocarbonyl 408 so ₂ ch ₃ phenyl 2-methyl-1-imidazolyl 409 so ₂ ch ₃ phenyl 5-methyl-1-imidazolyl 410 so ₂ ch ₃ phenyl 2-methylsulfonyl-1-imidazolyl 411 so ₂ ch ₃ 2-pyridyl 2- (aminosulfonyl) phenyl 412 so ₂ ch ₃ 2-pyridyl 2- (methylaminosulfonyl) phenyl 413 so ₂ ch ₃ 2-pyridyl 1-Pyrrolidinocarbonyl 414 so ₂ ch ₃ 2-pyridyl 2- (methylsulfonyl) phenyl 415 so ₂ ch ₃ 2-pyridyl 4-Morpholine 416 so ₂ ch ₃ 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 417 so ₂ ch ₃ 2-pyridyl 4-morpholinocarbonyl 418 so ₂ ch ₃ 2-pyridyl 2-methyl-1-imidazolyl 419 so ₂ ch ₃ 2-pyridyl. 5-methyl-1-imidazolyl 420 so ₂ ch ₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 421 so ₂ ch ₃ 3-piri dil 2- (aminosulfonyl) phenyl 422 so ₂ ch ₃ 3-pyridyl 2- (methylaminosulfonyl) phenyl 423 so ₂ ch ₃ 3-pyridyl 1-Pyrrolidinocarbonyl 424 SO2CH3 3-Pyridyl 2- (methylsulfonyl) phenyl 425 so ₂ ch ₃ 3-pyridyl 4-Morpholine 426 so ₂ ch ₃ 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 427 so ₂ ch ₃ 3-pyridyl 4-morpholinocarbonyl 428 so ₂ ch ₃ 3-pyridyl 2-methyl-1-imidazolyl 429 so ₂ ch ₃ 3-pyridyl 5-methyl-1-imidazolyl 430 so ₂ ch ₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 431 so ₂ ch ₃ 2-pyrimidyl 2- (aminosulfonyl) phenyl 432 so ₂ ch ₃ 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 433 so ₂ ch ₃ 2-pyrimidyl 1-Pyrrolidinocarbonyl 434 so ₂ ch ₃ 2-pyrimidyl 2- (methylsulfonyl) phenyl

287

435 SO ₂ CH ₃ 2-pyrimidyl 4-Morpholine 436 SO ₂ CH ₃ 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 437 so ₂ ch ₃ 2-pyrimidyl 4-morpholinocarbonyl 438 so ₂ ch ₃ 2-pyrimidyl 2-methyl-1-imidazolyl 439 so ₂ ch ₃ 2-pyrimidyl 5-methyl-1-imidazolyl 440 so ₂ ch ₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 441 so ₂ ch ₃ 5-pyrimidyl 2- (aminosulfonyl) phenyl 442 so ₂ ch ₃ 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 443 so ₂ ch ₃ 5-pyrimidyl 1-Pyrrolidinocarbonyl 444 so ₂ ch ₃ 5-pyrimidyl 2- (methylsulfonyl) phenyl 445 so ₂ ch ₃ 5-pyrimidyl 4-Morpholine 446 so ₂ ch ₃ 5-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 447 so ₂ ch ₃ 5-pyrimidyl 4-morpholinocarbonyl 448 so ₂ ch ₃ 5-pyrimidyl 2-methyl-1-imidazolyl 449 so ₂ ch ₃ 5-pyrimidyl 5-methyl-1-imidazolyl 450 so ₂ ch ₃ 5-pyrimidyl 2-Methylsulfone I-1-imidazolyl 451 so ₂ ch ₃ 2-Cl-phenyl 2- (aminosulfonyl) phenyl 452 so ₂ ch ₃ 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 453 so ₂ ch ₃ 2-Cl-phenyl 1-Pyrrolidinocarbonyl 454 so ₂ ch ₃ 2-Cl-phenyl 2- (methylsulfonyl) phenyl 455 so ₂ ch ₃ 2-Cl-phenyl 4-Morpholine 456 so ₂ ch ₃ 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 457 so ₂ ch ₃ 2-Cl-phenyl 4-morpholinocarbonyl 458 so ₂ ch ₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 459 so ₂ ch ₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 460 so ₂ ch ₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 461 so ₂ ch ₃ 2-F-phenyl 2- (aminosulfonyl) phenyl 462 so ₂ ch ₃ 2-F-phenyl 2- (methylaminosulfonyl) phenyl 463 so ₂ ch ₃ 2-F-phenyl 1-Pyrrolidinocarbonyl 464 so ₂ ch ₃ 2-F-phenyl 2- (methylsulfonyl) phenyl 465 so ₂ ch ₃ 2-F-phenyl 4-Morpholine 466 so ₂ ch ₃ 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 467 so ₂ ch ₃ 2-F-phenyl 4-morpholinocarbonyl 468 so ₂ ch ₃ 2-F-phenyl 2-methyl-1-imidazolyl 469 so ₂ ch ₃ 2-F-phenyl 5-methyl-1-imidazolyl 470 so ₂ ch ₃ 2-F-phenyl 2-Methyl Isulfonyl-1-imidazolyl 471 so ₂ ch ₃ 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 472 so ₂ ch ₃ 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 473 so ₂ ch ₃ 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 474 so ₂ ch ₃ 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 475 so ₂ ch ₃ 2,6-diF-phenyl 4-Morpholine 476 so ₂ ch ₃ 2,6-diF-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 477 so ₂ ch ₃ 2,6-diF-phenyl 4-morpholinocarbonyl 478 so ₂ ch ₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 479 so ₂ ch ₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 480 so ₂ ch ₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 481 ch ₂ nh-so ₂ ch ₃ phenyl 2- (aminosulfonyl) phenyl 482 ch ₂ nh-so ₂ ch ₃ phenyl 2- (methylaminosulfonyl) phenyl

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483 CH ₂ NH-SO ₂ CH ₃ phenyl 1-Pyrrolidinocarbonyl 484 ch ₂ nh-so ₂ ch ₃ phenyl 2- (methylsulfonyl) phenyl 485 ch ₂ nh-so ₂ ch ₃ phenyl 4-Morpholine 486 ch ₂ nh-so ₂ ch ₃ phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 487 ch ₂ nh-so ₂ ch ₃ phenyl 4-morpholinocarbonyl 488 ch ₂ nh-so ₂ ch ₃ phenyl 2-methyl-1-imidazolyl 489 ch ₂ nh-so ₂ ch ₃ phenyl 5-methyl-1-imidazolyl 490 ch ₂ nh-so ₂ ch ₃ phenyl 2-methylsulfonyl-1-imidazolyl 491 ch ₂ nh-so ₂ ch ₃ 2-pyridyl 2- (aminosulfonyl) phenyl 492 ch ₂ nh-so ₂ ch ₃ 2-pyridyl 2- (methylaminosulfonyl) phenyl 493 ch ₂ nh-so ₂ ch ₃ 2-pyridyl 1-Pyrrolidinocarbonyl 494 ch ₂ nh-so ₂ ch ₃ 2-pyridyl 2- (methylsulfonyl) phenyl 495 ch ₂ nh-so ₂ ch ₃ 2-pyridyl 4-Morpholine 496 ch ₂ nh-so ₂ ch ₃ 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 497 ch ₂ nh-so ₂ ch ₃ 2-pyridyl 4-morpholinocarbonyl 498 ch ₂ nh-so ₂ ch ₃ 2-pyridyl 2-methyl-1-imidazolyl 499 ch ₂ nh-so ₂ ch ₃ 2-pyridyl 5-methyl-1-imidazolyl 500 ch ₂ nh-so ₂ ch ₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 501 ch ₂ nh-so ₂ ch ₃ 3-pyridyl 2- (aminosulfonyl) phenyl 502 ch ₂ nh-so ₂ ch ₃ 3-pyridyl 2- (methylaminosulfonyl) phenyl 503 ch ₂ nh-so ₂ ch ₃ 3-pyridyl 1-Pyrrolidinocarbonyl 504 ch ₂ nh-so ₂ ch ₃ 3-pyridyl 2- (methylsulfonyl) phenyl 505 ch ₂ nh-so ₂ ch ₃ 3-pyridyl 4-Morpholine 506 ch ₂ nh-so ₂ ch ₃ 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 507 ch ₂ nh-so ₂ ch ₃ 3-pyridyl 4-morpholinocarbonyl 508 ch ₂ nh-so ₂ ch ₃ 3-pyridyl 2-methyl-1-imidazolyl 509 ch ₂ nh-so ₂ ch ₃ 3-pyridyl 5-methyl-1-imidazolyl 510 ch ₂ nh-so ₂ ch ₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 511 ch ₂ nh-so ₂ ch ₃ 2-pyrimidyl 2- (aminosulfonyl) phenyl 512 ch ₂ nh-so ₂ ch ₃ 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 513 ch ₂ nh-so ₂ ch ₃ 2-pyrimidyl 1-Pyrrolidinocarbonyl 514 ch ₂ nh-so ₂ ch ₃ 2-pyrimidyl 2- (methylsulfonyl) phenyl 515 ch ₂ nh-so ₂ ch ₃ 2-pyrimidyl 4-Morpholine 516 ch ₂ nh-so ₂ ch ₃ 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 517 ch ₂ nh-so ₂ ch ₃ 2-pyrimidyl 4-morpholinocarbonyl 518 ch ₂ nh-so ₂ ch ₃ 2-pyrimidyl 2-methyl-1-imidazolyl 519 ch ₂ nh-so ₂ ch ₃ 2-pyrimidyl 5-methyl-1-imidazolyl 520 ch ₂ nh-so ₂ ch ₃ 2-pyrimidyl 2-Methylsulfone I-1-imidazolyl 521 ch ₂ nh-so ₂ ch ₃ 5-pyrimidyl 2- (aminosulfonyl) phenyl 522 ch ₂ nh-so ₂ ch ₃ 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 523 ch ₂ nh-so ₂ ch ₃ 5-pyrimidyl 1-Pyrrolidinocarbonyl 524 ch ₂ nh-so ₂ ch ₃ 5-pyrimidyl 2- (methylsulfonyl) phenyl 525 ch ₂ nh-so ₂ ch ₃ 5-pyrimidyl 4-Morpholine 526 ch ₂ nh-so ₂ ch ₃ 5-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 527 ch ₂ nh-so ₂ ch ₃ 5-pyrimidyl 4-morpholinocarbonyl 528 ch ₂ nh-so ₂ ch ₃ 5-pyrimidyl 2-methyl-1-imidazolyl 529 ch ₂ nh-so ₂ ch ₃ 5-pyrimidyl 5-methyl-1-imidazolyl 530 ch ₂ nh-so ₂ ch ₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl

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531 CH 2 NH-SO 2 CH 3 2-Cl-phenyl 2- (aminosulfonyl) phenyl 532 CH 2 NH-SO 2 CH 3 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 533 CH 2 NH-SO 2 CH 3 2-Cl-phenyl 1-Pyrrolidinocarbonyl 534 CH 2 NH-SO 2 CH 3 2-Cl-phenyl 2- (methylsulfonyl) phenyl 535 CH 2 NH-SO 2 CH 3 2-Cl-phenyl 4-Morpholine 536 CH 2 NH-SO 2 CH 3 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 537 CH 2 NH-SO 2 CH 3 2-Cl-phenyl 4-morpholinocarbonyl 538 CH 2 NH-SO 2 CH 3 2-Cl-phenyl 2-methyl-1-imidazolyl 539 CH 2 NH-SO 2 CH 3 2-Cl-phenyl 5-methyl-1-imidazolyl 540 CH 2 NH-SO 2 CH 3 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 541 CH 2 NH-SO 2 CH 3 2-F-phenyl 2- (aminosulfonyl) phenyl 542 CH 2 NH-SO 2 CH 3 2-F-phenyl 2- (methylaminosulfonyl) phenyl 543 ch ₂ nh-so ₂ ch ₃ 2-F-phenyl 1-Pyrrolidinocarbonyl 544 ch ₂ nh-so ₂ ch ₃ 2-F-phenyl 2- (methylsulfonyl) phenyl 545 ch ₂ nh-so ₂ ch ₃ 2-F-phenyl 4-Morpholine 546 ch ₂ nh-so ₂ ch ₃ 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 547 ch ₂ nh-so ₂ ch ₃ 2-F-phenyl 4-morpholinocarbonyl 548 ch ₂ nh-so ₂ ch ₃ 2-F-phenyl 2-methyl-1-imidazolyl 549 ch ₂ nh-so ₂ ch ₃ 2-F-phenyl 5-methyl-1-imidazolyl 550 ch ₂ nh-so ₂ ch ₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 551 ch ₂ nh-so ₂ ch ₃ 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 552 ch ₂ nh-so ₂ ch ₃ 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 553 ch ₂ nh-so ₂ ch ₃ 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 554 ch ₂ nh-so ₂ ch ₃ 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 555 ch ₂ nh-so ₂ ch ₃ 2,6-diF-phenyl 4-Morpholine 556 ch ₂ nh-so ₂ ch ₃ 2,6-diF-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 557 ch ₂ nh-so ₂ ch ₃ 2,6-diF-phenyl 4-morpholinocarbonyl 558 ch ₂ nh-so ₂ ch ₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 559 ch ₂ nh-so ₂ ch ₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 560 ch ₂ nh-so ₂ ch ₃ 2,6-diF-phenyl 2-Methylsulfonyl-1-imidazolyl 561 Cl phenyl 2- (aminosulfonyl) phenyl 562 Cl phenyl 2- (methylaminosulfonyl) phenyl 563 Cl phenyl 1-Pyrrolidinocarbonyl 564 Cl phenyl 2- (methylsulfonyl) phenyl 565 Cl phenyl 4-Morpholine 566 Cl phenyl 2- (1'-CF ₃ -tetrazol-2-yl) phenyl 567 Cl phenyl 4-morpholinocarbonyl 568 Cl phenyl 2-methyl-1-imidazolyl 569 Cl phenyl 5-methyl-1-imidazolyl 570 Cl phenyl 2-methylsulfonyl-1-imidazolyl 571 Cl 2-pyridyl 2- (aminosulfonyl) phenyl 572 Cl 2-PyridHas 2- (methylaminosulfonyl) phenyl 573 Cl 2-pyridyl 1-Pyrrolidinocarbonyl 574 Cl 2-pyridyl 2- (methylsulfonyl) phenyl 575 Cl 2-pyridyl 4-Morpholine 576 Cl 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 577 Cl 2-pyridyl 4-morpholinocarbonyl 578 Cl 2-pyridyl 2-methyl-1-imidazolyl

290

579 Cl 2-pyridyl 5-methyl-1-imidazolyl 580 Cl 2-pyridyl 2-methylsulfonyl-1-imidazolyl 581 Cl 3-pyridyl 2- (aminosulfonyl) phenyl 582 Cl 3-pyridyl 2- (methylamino-phenyl) -phenyl 583 Cl 3-pyridyl 1-Pyrrolidinocarbonyl 584 Cl 3-pyridyl 2- (methylsulfonyl) phenyl 585 Cl 3-pyridyl 4-Morpholine 586 Cl 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 587 Cl 3-pyridyl 4-morpholinocarbonyl 588 Cl 3-pyridyl 2-methyl-1-imidazolyl 589 Cl 3-pyridyl 5-methyl-1-imidazolyl 590 Cl 3-pyridyl 2-methylsulfonyl-1-imidazolyl 591 Cl 2-pyrimidyl 2- (aminosulfonyl) phenyl 592 Cl 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 593 Cl 2-pyrimidyl 1-Pyrrolidinocarbonyl 594 Cl 2-pyrimidyl 2- (methylsulfonyl) phenyl 595 Cl 2-pyrimidyl 4-Morpholine 596 Cl 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 597 Cl 2-pyrimidyl 4-morpholinocarbonyl 598 Cl 2-pyrimidyl 2-methyl-1-imidazolyl 599 Cl 2-pyrimidyl 5-methyl-1-imidazolyl 600 Cl 2-pyrimidyl 2-Methylsulfone I-1-imidazolyl 601 Cl 5-pyrimidyl 2- (aminosulfonyl) phenyl 602 Cl 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 603 Cl 5-pyrimidyl 1-Pyrrolidinocarbonyl 604 Cl 5-pyrimidyl 2- (methylsulfonyl) phenyl 605 Cl 5-pyrimidyl 4-Morpholine 606 Cl 5-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 607 Cl 5-pyrimidyl 4-morpholinocarbonyl 608 Cl 5-pyrimidyl 2-methyl-1-imidazolyl 609 Cl 5-pyrimidyl 5-methyl-1-imidazolyl 610 Cl 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 611 Cl 2-Cl-phenyl 2- (aminosulfonyl) phenyl 612 Cl 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 613 Cl 2-Cl-phenyl 1-Pyrrolidinocarbonyl 614 Cl 2-Cl-phenyl 2- (methylsulfonyl) phenyl 615 Cl . 2-Cl-phenyl 4-Morpholine 616 Cl  2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl as 617 Cl 2-Cl-phenyl 4-morpholinocarbonyl 618 Cl 2-Cl-phenyl 2-methyl-1-imidazolyl 619 Cl 2-Cl-phenyl 5-methyl-1-imidazolyl 620 Cl 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 621 Cl 2-F-phenyl 2- (Aminosulfonyl) phenyl 622 Cl 2-F-phenyl 2- (methylaminosulfonyl) phenyl 623 Cl 2-F-phenyl 1-Pyrrolidinocarbonyl 624 Cl 2-F-phenyl 2- (methylsulfonyl) phenyl 625 Cl 2-F-phenyl 4-Morpholine 626 Ci 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl

291

627 Cl 2-F-phenyl 4-morpholinocarbonyl 628 Cl 2-F-phenyl 2-methyl-1-imidazolyl 629 Cl 2-F-phenyl 5-methyl-1-imidazolyl 630 Cl 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 631 Cl 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 632 Cl 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 633 Cl 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 634 Cl 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 635 Cl 2,6-diF-phenyl 4-Morpholine 636 Cl 2,6-diF-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 637 Cl 2,6-diF-phenyl 4-morpholinocarbonyl 638 Cl 2,6-diF-phenyl 2-methyl-1-imidazolyl 639 Cl 2,6-diF-phenyl 5-methyl-1-imidazolyl 640 Cl 2,6-diF-phenyl 2-Methylsulfone I-1-imidazolyl 641 F phenyl 2- (aminosulfonyl) phenyl 642 F phenyl 2- (methylaminosulfonyl) phenyl 643 F phenyl 1-Pyrrolidinocarbonyl 644 F phenyl 2- (methylsulfonyl) phenyl 645 F phenyl 4-Morpholine 646 F phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 647 F phenyl 4-morpholinocarbonyl 648 F phenyl 2-methyl-1-imidazolyl 649 F phenyl 5-methyl-1-imidazolyl 650 F phenyl 2-Methyl Isulfone 1-1 -imidazolyl 651 F 2-pyridyl 2- (aminosulfonyl) phenyl 652 F 2-pyridyl 2- (methylaminosulfonyl) phenyl 653 F 2-pyridyl 1-Pyrrolidinocarbonyl 654 F 2-pyridyl 2- (methylsulfonyl) phenyl 655 F 2-pyridyl 4-Morpholine 656 F 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 657 F 2-pyridyl 4-morpholinocarbonyl 658 F 2-pyridyl 2-methyl-1-imidazolyl 659 F 2-pyridyl 5-methyl-1-imidazolyl 660 F 2-pyridyl 2-methylsulfonyl-1-imidazolyl 661 F 3-pyridyl 2- (aminosulfonyl) phenyl 662 F 3-pyridyl 2- (methylaminosulfonyl) phenyl 663 F 3-pyridyl 1-Pyrrolidinocarbonyl 664 F 3-pyridyl 2- (methylsulfonyl) phenyl 665 F 3-pyridyl 4-Morpholine 666 F 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 667 F 3-pyridyl 4-morpholinocarbonyl 668 F 3-pyridyl 2-methyl-1-imidazolyl 669 F 3-pyridyl 5-methyl-1-imidazolyl 670 F 3-pyridyl 2-Methyl Isulfonyl-1-imidazolyl 671 F 2-pyrimidine 2- (aminosulfonyl) phenyl 672 F 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 673 F 2-pyrimidyl 1-Pyrrolidinocarbonyl 674 F 2-pyrimidyl 2- (methylsulfonyl) phenyl

675 F 2-pyrimidyl 4-Morpholine 676 F 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl as 677 F 2-pyrimidyl 4-morpholinocarbonyl 678 F 2-pyrimidyl 2-methyl-1-imidazolyl 679 F 2-pyrimidyl 5-methyl-1-imidazolyl 680 F 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 681 F 5-pyrimidyl 2- (aminosulfonyl) phenyl 682 F 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 683 F 5-pyrimidyl 1-Pyrrolidinocarbonyl 684 F 5-pyrimidyl 2- (methylsulfonyl) phenyl 685 F 5-pyrimidyl 4-Morpholine 686 F 5-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 687 F 5-pyrimidyl 4-morpholinocarbonyl 688 F 5-pyrimidyl 2-methyl-1-imidazolyl 689 F 5-pyrimidyl 5-methyl-1-imidazolyl 690 F 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 691 F 2-Cl-phenyl 2- (aminosulfonyl) phenyl 692 F 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 693 F 2-Cl-phenyl 1-Pyrrolidinocarbonyl 694 F 2-Cl-phenyl 2- (methylsulfonyl) phenyl 695 F 2-Cl-phenyl 4-Morpholine 696 F 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl as 697 F 2-Cl-phenyl 4-morpholinocarbonyl 698 F 2-Cl-phenyl 2-methyl-1-imidazolyl 699 F 2-Cl-phenyl 5-methyl-1-imidazolyl 700 F 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 701 F 2-F-phenyl 2- (aminosulfonyl) phenyl 702 F 2-F-phenyl 2- (methylaminosulfonyl) phenyl 703 F 2-F-phenyl 1-Pyrrolidinocarbonyl 704 F 2-F-phenyl 2- (methylsulfonyl) phenyl 705 F 2-F-phenyl 4-Morpholine 706 F 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 707 F 2-F-phenyl 4-morpholinocarbonyl 708 F 2-F-phenyl 2-methyl-1-imidazolyl 709 F 2-F-phenyl 5-methyl-1-imidazolyl 710 F 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 711 F 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 712 F 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 713 F 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 714 F 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 715 F 2,6-diF-phenyl 4-Morpholine 716 F 2,6-diF-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 717 F 2,6-diF-phenyl 4-morpholinocarbonyl 718 F 2,6-diF-phenyl 2-methyl-1-imidazolyl 719 F 2,6-diF-phenyl 5-methyl-1-imidazolyl 720 F 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 721 CO ₂ CH ₃ phenyl 2- (aminosulfonyl) phenyl 722 co ₂ ch ₃ phenyl 2- (methylaminosulfonyl) phenyl

293

723 CO ₂ CH ₃ phenyl 1-Pyrrolidinocarbonyl 724 co ₂ ch ₃ phenyl 2- (methylsulfonyl) phenyl 725 co ₂ ch ₃ phenyl 4-Morpholine 726 co ₂ ch ₃ phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 727 co ₂ ch ₃ phenyl 4-morpholinocarbonyl 728 CO ₂ CH ₃ phenyl 2-methyl-1-imidazolyl 729 CO ₂ CH ₃ phenyl 5-methyl-1-imidazolyl 730 co ₂ ch ₃ phenyl 2-Methylsulfonyl-1-imidazolyl 731 CO2CH3 2-pyridyl 2- (aminosulfonyl) phenyl 732 CO ₂ CH ₃ 2-pyridyl 2- (methylaminosulfonyl) phenyl 733 co ₂ ch ₃ 2-pyridyl 1-Pyrrolidinocarbonyl 734 co ₂ ch ₃ 2-pyridyl 2- (methylsilylphenyl) phenyl 735 co ₂ ch ₃ 2-pyridyl 4-Morpholine 736 co ₂ ch ₃ 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 737 co ₂ ch ₃ 2-pyridyl 4-morpholinocarbonyl 738 CO2CH3 2-pyridyl 2-methyl-1-imidazolyl 739 CO ₂ CH ₃ 2-pyridyl 5-methyl-1-imidazolyl 740 co ₂ ch ₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 741 co ₂ ch ₃ 3-pyridyl 2- (aminosulfonyl) phenyl 742 co ₂ ch ₃ 3-pyridyl 2- (methylaminosulfonyl) phenyl 743 co ₂ ch ₃ 3-pyridyl 1-Pyrrolidinocarbonyl 744 co ₂ ch ₃ 3-pyridyl 2- (methylsulfonyl) phenyl 745 co ₂ ch ₃ 3-pyridyl 4-morpholine 746 CO2CH3 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 747 CO ₂ CH ₃ 3-pyridif 4-morpholinocarbonyl 748 co ₂ ch ₃ 3-pyridia 2-methyl-1-imidazolyl 749 co ₂ ch ₃ 3-pyridyl 5-methyl-1-imidazolyl 750 co ₂ ch ₃ 3-pyridia 2-Methylsulfonyl-1-imidazolyl 751 co ₂ ch ₃ 2-pyrimidyl 2- (aminosulfonyl) phenyl 752 co ₂ ch ₃ 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 753 co ₂ ch ₃ 2-pyrimidyl 1-Pyrrolidinocarbonyl 754 co ₂ ch ₃ 2-pyrimidyl 2- (methylsulfonyl) phenyl 755 co ₂ ch ₃ 2-pyrimidyl 4-morpholine 756 co ₂ ch ₃ 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 757 co ₂ ch ₃ 2-pyrimidyl 4-morpholinocarbonyl 758 co ₂ ch ₃ 2-pyrimidyl 2-methyl-1-imidazolyl 759 co ₂ ch ₃ 2-pyrimidyl 5-methyl-1-imidazolyl 760 CO2CH3 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 761 CO ₂ CH ₃ 5-pyrimidyl 2- (aminosulfonyl) phenyl 762 CO ₂ CH ₃ 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 763 CO ₂ CH ₃ 5-pyrimidyl 1-Pyrrolidinocarbonyl 764 co ₂ ch ₃ 5-pyrimidyl 2- (methylsulfonyl) phenyl 765 co ₂ ch ₃ 5-pyrimidyl 4-Morpholine 766 co ₂ ch ₃ 5-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 767 co ₂ ch ₃ 5-pyrimidyl 4-morpholinocarbonyl 768 co ₂ ch ₃ 5-pyrimidyl 2-methyl-1-imidazolyl 769 co ₂ ch ₃ 5-pyrimidyl 5-methyl-1-imidazolyl 770 co ₂ ch ₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl

294

771 CO ₂ CH ₃ 2-Cl-phenyl 2- (aminosulfonyl) phenyl 772 co ₂ ch ₃ 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 773 co ₂ ch ₃ 2-Cl-phenyl 1-Pyrrolidinocarbonyl 774 co ₂ ch ₃ 2-Cl-phenyl 2- (methylsulfonyl) phenyl 775 co ₂ ch ₃ 2-Cl-phenyl 4-Morpholine 776 co ₂ ch ₃ 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl HERE co ₂ ch ₃ 2-Cl-phenyl 4-morpholinocarbonyl TT8 co ₂ ch ₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 779 co ₂ ch ₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 780 co ₂ ch ₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 781 co ₂ ch ₃ 2-F-phenyl 2- (aminosulfonyl) phenyl 782 co ₂ ch ₃ 2-F-phenyl 2- (methylaminosulfonyl) phenyl 783 co ₂ ch ₃ 2-F-phenyl 1-Pyrrolidinocarbonyl 784 co ₂ ch ₃ 2-F-phenyl 2- (methylsulfonyl) phenyl 785 co ₂ ch ₃ 2-F-phenyl 4-Morpholine 786 co ₂ ch ₃ 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 787 co ₂ ch ₃ 2-F-phenyl 4-morpholinocarbonyl 788 co ₂ ch ₃ 2-F-phenyl 2-methyl-1-imidazolyl 789 co ₂ ch ₃ 2-F-phenyl 5-methyl-1-imidazolyl 790 co ₂ ch ₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 791 co ₂ ch ₃ 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 792 co ₂ ch ₃ 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 793 co ₂ ch ₃ 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 794 co ₂ ch ₃ 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 795 co ₂ ch ₃ 2,6-diF-phenyl 4-Morpholine 796 co ₂ ch ₃ 2,6-diF-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 797 co ₂ ch ₃ 2,6-diF-phenyl 4-morpholinocarbonyl 798 co ₂ ch ₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 799 co ₂ ch ₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 800 co ₂ ch ₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 801 ch ₂ and ₃ phenyl 2- (aminosulfonyl) phenyl 802 ch ₂ and ₃ phenyl 2- (methylaminosulfonyl) phenyl 803 ch ₂ and ₃ phenyl 1-Pyrrolidinocarbonyl 804 ch ₂ and ₃ phenyl 2- (methylsulfonyl) phenyl 805 ch ₂ and ₃ phenyl 4-Morpholine 806 ch ₂ and ₃ phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 807 ch ₂ and ₃ phenyl 4-morpholinocarbonyl 808 ch ₂ and ₃  phenyl 2-methyl-1-imidazolyl 809 ch ₂ and ₃ phenyl 5-methyl-1-imidazolyl 810 ch ₂ and ₃ phenyl 2-Methylsulfonyl-1-imidazolyl 811 ch ₂ and ₃ 2-pyridyl 2- (aminosulfonyl) phenyl 812 ch ₂ and ₃ 2-pyridyl 2- (methylaminosulfonyl) phenyl 813 CH2OCH3 2-pyridyl 1-Pyrrolidinocarbonyl 814 ch ₂ and ₃ 2-pyridyl 2- (methylsulfonyl) phenyl 815 ch ₂ and ₃ 2-pyridyl 4-Morpholine 816 ch ₂ and ₃ 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl as 817 ch ₂ and ₃ 2-pyridyl 4-morpholinocarbonyl 818 ch ₂ and ₃ 2-pyridyl 2-methyl-1-imidazolyl

295

819 CH ₂ OCH ₃ 2-pyridyl 5-methyl-1-imidazolyl 820 ch ₂ and ₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 821 ch ₂ and ₃ 3-pyridyl 2- (aminosulfonyl) phenyl 822 ch ₂ and ₃ 3-pyridyl 2- (methylaminosulfonyl) phenyl 823 ch ₂ and ₃ 3-pyridyl 1-Pyrrolidinocarbonyl 824 ch ₂ and ₃ 3-pyridyl 2- (methylsulfonyl) phenyl 825 ch ₂ and ₃ 3-pyridyl 4-Morpholine 826 ch ₂ and ₃ 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl as 827 ch ₂ and ₃ 3-pyridyl 4-morpholinocarbonyl 828 ch ₂ and ₃ 3-pyridyl 2-methyl-1-imidazolyl 829 ch ₂ and ₃ 3-pyridyl 5-methyl-1-imidazolyl 830 ch ₂ and ₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 831 ch ₂ and ₃ 2-pyrimidyl 2- (aminosulfonyl) phenyl 832 ch ₂ and ₃ 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 833 ch ₂ and ₃ 2-pyrimidyl 1-Pyrrolidinocarbonyl 834 ch ₂ and ₃ 2-pyrimidyl 2- (methylsulfonyl) phenyl 835 ch ₂ and ₃ 2-pyrimidyl 4-Morpholine 836 ch ₂ and ₃ 2-pyrimidyl 2- (T-CF ₃ -tetrazol-2-yl) phenyl 837 ch ₂ and ₃ 2-pyrimidyl 4-morpholinocarbonyl 838 ch ₂ and ₃ 2-pyrimidyl 2-methyl-1-imidazolyl 839 ch ₂ and ₃ 2-pyrimidyl 5-methyl-1-imidazolyl 840 ch ₂ and ₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 841 ch ₂ and ₃ 5-pyrimidyl 2- (aminosulfonyl) phenyl 842 ch ₂ and ₃ 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 843 ch ₂ and ₃ 5-pyrimidyl 1-Pyrrolidinocarbonyl 844 ch ₂ and ₃ 5-pyrimidyl 2- (methylsulfonyl) phenyl 845 ch ₂ and ₃ 5-pyrimidyl 4-Morpholine 846 ch ₂ and ₃ 5-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-ii) phenyl 847 ch ₂ and ₃ 5-pyrimidyl 4-morpholinocarbonyl 848 ch ₂ and ₃ 5-pyrimidyl 2-methyl-1-imidazolyl 849 ch ₂ and ₃ 5-pyrimidyl 5-methyl-1-imidazolyl 850 ch ₂ and ₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 851 ch ₂ and ₃ 2-Cl-phenyl 2- (aminosulfonyl) phenyl 852 ch ₂ and ₃ 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 853 ch ₂ and ₃ 2-Cl-phenyl 1-Pyrrolidinocarbonyl 854 ch ₂ and ₃ 2-Cl-phenyl 2- (methylsulfonyl) phenyl 855 ch ₂ and ₃ 2-Cl-phenyl 4-Morpholine 856 ch ₂ and ₃ 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl as 857 ch ₂ and ₃ 2-Cl-phenyl 4-morpholinocarbonyl 858 ch ₂ and ₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 859 ch ₂ and ₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 860 ch ₂ and ₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 861 ch ₂ and ₃ 2-F-phenyl 2- (aminosulfonyl) phenyl 862 ch ₂ and ₃ 2-F-phenyl 2- (methylaminosulfonyl) phenyl 863 ch ₂ and ₃ 2-F-phenyl 1-Pyrrolidinocarbonyl 864 ch ₂ and ₃ 2-F-phenyl 2- (methylsulfonyl) phenyl 865 ch ₂ and ₃ 2-F-phenyl 4-Morpholine 866 ch ₂ and ₃ 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl

296

867 CH2OCH3 2-F-phenyl 4-morpholinocarbonyl 868 CH2OCH3 2-F-phenyl 2-methyl-1-imidazolyl 869 CH2OCH3 2-F-phenyl 5-methyl-1-imidazolyl 870 CH ₂ OCH ₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 871 ch ₂ and ₃ 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 872 CH ₂ OCH ₃ 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 873 ch ₂ and ₃ 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 874 ch ₂ and ₃ 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 875 ch ₂ and ₃ 2,6-diF-phenyl 4-Morpholine 876 ch ₂ and ₃ 2,6-diF-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 877 ch ₂ and ₃ 2,6-diF-phenyl 4-morpholinocarbonyl 878 ch ₂ and ₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 879 ch ₂ and ₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 880 ch ₂ and ₃ 2,6-diF-phenyl 2-Methylsulfonyl-1-imidazolyl 881 conh ₂ phenyl 2- (aminosulfonyl) phenyl 882 conh ₂ phenyl 2- (methylaminosulfonyl) phenyl 883 CONH2 phenyl 1-Pyrrolidinocarbonyl · 884 CONH2 phenyl 2- (methylsulfonyl) phenyl 885 conh ₂ phenyl 4-Morpholine 886 conh ₂ phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 887 conh ₂ phenyl 4-morpholinocarbonyl 888 conh ₂ phenyl 2-methyl-1-imidazolyl 889 conh ₂ phenyl 5-methyl-1-imidazolyl 890 conh ₂ phenyl 2-methylsulfonyl-1-imidazolyl 891 conh ₂ 2-pyridyl 2- (aminosulfonyl) phenyl 892 conh ₂ 2-pyridyl 2- (methylaminosulfonyl) phenyl 893 conh ₂ 2-pyridyl 1-Pyrrolidinocarbonyl 894 conh ₂ 2-pyridyl 2- (methylsulfonyl) phenyl 895 conh ₂ 2-pyridyl 4-Morpholine 896 conh ₂ 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 897 conh ₂ 2-pyridyl 4-morpholinocarbonyl 898 conh ₂ 2-pyridyl 2-methyl-1-imidazolyl 899 conh ₂ 2-pyridyl 5-methyl-1-imidazolyl 900 conh ₂ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 901 conh ₂ 3-pyridyl 2- (aminosulfonyl) phenyl 902 conh ₂ 3-pyridyl 2- (methylaminosulfonyl) phenyl 903 conh ₂ 3-pyridyl 1-Pyrrolidinocarbonyl 904 conh ₂ : 3-Pyridyl 2- (methylsulfonyl) phenyl 905 conh ₂ 3-pyridyl 4-Morpholine 906 conh ₂ 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 907 conh ₂ 3-pyridyl 4-morpholinocarbonyl 908 conh ₂ 3-pyridyl 2-methyl-1-imidazolyl 909 conh ₂ 3-pyridyl 5-methyl-1-imidazolyl 910 conh ₂ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 911 conh ₂ 2-pyrimidyl 2- (aminosulfonyl) phenyl 912 conh ₂ 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 913 conh ₂ 2-pyrimidyl 1-Pyrrolidinocarbonyl 914 conh ₂ 2-pyrimidyl 2- (methylsulfonyl) phenyl

297

915 conh ₂ 2-pyrimidyl 4-Morpholine 916 conh ₂ 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 917 CONH ₂ 2-pyrimidyl 4-morpholinocarbonyl 918 conh ₂ 2-pyrimidyl 2-methyl-1-imidazolyl 919 CONH2 2-pyrimidine 5-methyl-1-imidazolyl 920 conh ₂ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 921 CONH2 5-pyrimidyl 2- (aminosulfonyl) phenyl 922 CONH2 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 923 CONH2 5-pyrimidyl 1-Pyrrolidinocarbonyl 924 CONH2 5-pyrimidyl 2- (methylsulfonyl) phenyl 925 CONH2 5-pyrimidyl 4-Morpholine 926 CONH2 5-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 927 CONH2 5-pyrimidyl 4-morpholinocarbonyl 928 CONH2 5-pyrimidyl 2-methyl-1-imidazolyl 929 conh ₂ 5-pyrimidyl 5-methyl-1-imidazolyl 930 CONH2 5-pyrimidyl 2-Methylsulfonyl-1-imidazolyl 931 CONH2 2-Cl-phenyl 2- (aminosulfonyl) phenyl 932 CONH2 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 933 CONH2 2-Cl-phenyl 1-Pyrrolidinocarbonyl 934 CONH2 2-Cl-phenyl 2- (methylsulfonyl) phenyl 935 CONH2 2-Cl-phenyl 4-Morpholine 936 conh ₂ 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 937 CONH2 2-Cl-phenyl 4-morpholinocarbonyl 938 CONH2 2-Cl-phenyl 2-methyl-1-imidazolyl 939 CONH2 2-Cl-phenyl 5-methyl-1-imidazolyl 940 CONH2 2-Cl-phenyl 2-Methyl Isulfone 1-1 -imidazolyl 941 CONH2 2-F-phenyl 2- (aminosulfonyl) phenyl 942 CONH2 2-F-phenyl 2- (methylaminosulfonyl) phenyl 943 conh ₂ 2-F-phenyl 1-Pyrrolidinocarbonyl 944 CONH2 2-F-phenyl 2- (methylsulfonyl) phenyl 945 CONH2 2-F-phenyl 4-Morpholine 946 CONH2 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 947 CONH2 2-F-phenyl 4-morpholinocarbonyl 948 CONH2 2-F-phenyl 2-methyl-1-imidazolyl 949 CONH2 2-F-phenyl 5-methyl-1-imidazolyl 950 CONH2 2-F-phenyl 2-Methyl Isulfonyl-1-imidazolyl 951 CONH2 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 952 CONH2 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 953 CONH2 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 954 CONH2 2,6-diF-phenyl 2- (methylsulfonyl) phenif 955 CONH2 2,6-diF-phenyl 4-Morpholine 956 CONH2 2,6-diF-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl as 957 CONH2 2,6-diF-phenyl 4-morpholinocarbonyl 958 CONH2 2,6-diF-phenyl 2-methyl-1-imidazolyl 959 CONH2 2,6-diF-phenyl 5-methyl-1-imidazolyl 960 CONH2 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl

Table 298

o

P q

299

y z aa

bb cc dd

ee ff gg

300

nn

For example, A B 1 phenyl 2- (aminosulfonyl) phenyl 2 phenyl 2 - '(methylaminosulfonyl) phenyl 3 phenyl 1-Pyrrolidinocarbonyl 4 phenyl 2- (methylsulfonyl) phenyl 5 phenyl 4-Morpholine 6th phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 7th phenyl 4-morpholinocarbonyl 8th phenyl 2-methyl-1-imidazolyl 9th phenyl 5-methyl-1-imidazolyl 10th phenyl 2-methylsulfonyl-1-imidazolyl 11th 2-pyridyl 2- (aminosulfonyl) phenyl 12th 2-pyridyl 2- (methylaminosulfonyl) phenyl 13th 2-pyridyl 1-Pyrrolidinocarbonyl 14th 2-pyridyl 2- (methylsulfonyl) phenyl 15th 2-pyridyl 4-Morpholine 16th 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl

301

17th 2-pyridyl 4-morpholinocarbonyl 18th 2-pyridyl 2-methyl-1-imidazolyl 19th 2-pyridyl 5-methyl-1-imidazolyl 20th 2-pyridyl 2-methylsulfonyl-1-imidazolyl 21st 3-pyridyl 2- (aminosulfonyl) phenyl 22nd 3-pyridyl 2- (methylaminosulfonyl) phenyl 23rd 3-pyridyl 1-Pyrrolidinocarbonyl 24th 3-pyridyl 2- (methylsulfonyl) phenyl 25th 3-pyridyl 4-Morpholine 26th 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 27th 3-pyridyl 4-morpholinocarbonyl 28th 3-pyridyl 2-methyl-1-imidazolyl 29th 3-pyridyl 5-methyl-1-imidazolyl 30th 3-pyridyl 2-Methylsulfonyl-1-imidazolyl 31 · 2-pyrimidyl 2- (aminosulfonyl) phenyl 32 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 33 2-pyrimidyl 1-Pyrrolidinocarbonyl 34 2-pyrimidyl 2- (methylsulfonyl) phenyl 35 2-pyrimidyl 4-Morpholine 36 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 37 2-pyrimidyl 4-morpholinocarbonyl 38 2-pyrimidyl 2-methyl-1-imidazolyl 39 2-pyrimidyl 5-methyl-1-imidazolyl 40 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 41 5-pyrimidyl 2- (aminosulfonyl) phenyl 42 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 43 5-pyrimidyl 1-Pyrrolidinocarbonyl 44 5-pyrimidyl 2- (methylsulfonyl) phenyl 45 5-pyrimidyl 4-Morpholine 46th 5-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 47 5-pyrimidyl 4-morpholinocarbonyl 48 5-pyrimidyl 2-methyl-1-imidazolyl 49 5-pyrimidyl 5-methyl-1-imidazolyl 50 5-pyrimidyl 2-Methylsulfonyl-1-imidazolyl 51 2-Cl-phenyl 2- (aminosulfonyl) phenyl 52 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 53 2-Cl-phenyl 1-Pyrrolidinocarbonyl 54 2-Cl-phenyl 2- (methylsulfonyl) phenyl 55 2-Cl-phenyl 4-Morpholine 56 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl as 57 2-Cl-phenyl 4-morpholinocarbonyl 58 2-Cl-phenyl 2-methyl-1-imidazolyl 59 2-Cl-phenyl 5-methyl-1-imidazolyl 60 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 61 2-F-phenyl 2- (aminosulfonyl) phenyl 62 2-F-phenyl 2- (methylaminosulfonyl) phenyl 63 2-F-phenyl 1-Pyrrolidinocarbonyl 64 2-F-phenyl 2- (methylsulfonyl) phenyl

302

2-F-phenyl 4-Morpholine 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 2-F-phenyl 4-morpholinocarbonyl 2-F-phenyl 2-methyl-1-imidazolyl 2-F-phenyl 5-methyl-1-imidazolyl 2-F-phenyl 2-Methylsulfone I-1-imidazolyl 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 2,6-diF-phenyl 4-Morpholine 2,6-diF-phenyl 2- (1'-CF ₃ -tetrazol-2-yl) phenyl 2,6-diF-phenyl 4-morpholinocarbonyl 2,6-diF-phenyl 2-methyl-1-imidazolyl 2,6-diF-phenyl 5-methyl-1-imidazolyl 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl

Table 303

304

305

306

For example, R ^1a A B 1 ch ₃ phenyl 2- (aminosulfonyl) phenyl 2 ch ₃ phenyl 2- (methylaminosulfonyl) phenyl 3 ch ₃ phenyl 1-Pyrrolidinocarbonyl 4 CHa phenyl 2- (methylsulfonyl) phenyl 5 CHa phenyl 4-moriolin 6th CH ₃ phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 7th CH ₃ phenyl 4-morpholinocarbonyl 8th CHa phenyl 2-methyl-1-imidazolyl 9th CHa phenyl 5-methyl-1-imidazolyl 10th CHa phenyl 2-methylsulfonyl-1-imidazolyl 11th CHa 2-pyridyl 2- (aminosulfonyl) phenyl 12th CHa 2-pyridyl 2- (methylaminosulfonyl) phenyl 13th CH ₃ 2-pyridyl 1-Pyrrolidinocarbonyl

307

14th ch ₃ 2-pyridyl 2- (methylsulfonyl) phenyl 15th ch ₃ 2-pyridyl 4-Morpholine 16th ch ₃ 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 17th ch ₃ 2-pyridyl 4-morpholinocarbonyl 18th ch ₃ 2-pyridyl 2-methyl-1-imidazolyl 19th ch ₃ 2-pyridyl 5-methyl-1-imidazolyl 20th ch ₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 21st ch ₃ 3-pyridyl 2- (aminosulfonyl) phenyl 22nd ch ₃ 3-pyridyl 2- (methylaminosulfonyl) phenyl 23rd ch ₃ 3-pyridyl 1-Pyrrolidinocarbonyl 24th ch ₃ 3-pyridyl 2- (methylsulfonyl) phenyl 25th ch ₃ 3-pyridyl 4-Morpholine 26th ch ₃ 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 27th ch ₃ 3-pyridyl 4-morpholinocarbonyl 28th ch ₃ 3-pyridyl 2-methyl-1-imidazolyl 29th ch ₃ 3-pyridyl 5-methyl-1-imidazolyl 30th ch ₃ 3-pyridyl 2-Methylsulfonyl-1-imidazolyl 31st ch ₃ 2-pyrimidyl 2- (aminosulfonyl) phenyl 32 ch ₃ 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 33 ch ₃ 2-pyrimidyl 1-Pyrrolidinocarbonyl 34 ch ₃ 2-pyrimidyl 2- (methylsulfonyl) phenyl 35 ch ₃ 2-pyrimidyl 4-Morpholine 36 ch ₃ 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 37 ch ₃ 2-pyrimidyl 4-morpholinocarbonyl 38 ch ₃ 2-pyrimidyl 2-methyl-1-imidazolyl 39 ch ₃ 2-pyrimidyl 5-methyl-1-imidazolyl 40 ch ₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 41 ch ₃ 5-pyrimidyl 2- (aminosulfonyl) phenyl 42 ch ₃ 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 43 ch ₃ 5-pyrimidyl 1-Pyrrolidinocarbonyl 44 ch ₃ 5-pyrimidyl 2- (methylsulfonyl) phenyl 45 ch ₃ 5-pyrimidyl 4-Morpholine 46th ch ₃ 5-pyrimidyl 2- (1'-CF ₃ -tetrazol-2-yl) phenyl 47 ch ₃ 5-pyrimidyl 4-morpholinocarbonyl 48 ch ₃ 5-pyrimidyl 2-methyl-1-imidazolyl 49 ch ₃ 5-pyrimidyl 5-methyl-1-imidazolyl 50 ch ₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 51 ch ₃ 2-Cl-phenyl 2- (aminosulfonyl) phenyl 52 ch ₃ 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 53 ch ₃ 2-Cl-phenyl 1-Pyrrolidinocarbonyl 54 ch ₃ 2-Cl-phenyl 2- (methylsulfonyl) phenyl 55 ch ₃ 2-Cl-phenyl 4-Morpholine 56 ch ₃ 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 57 ch ₃ 2-Cl-phenyl 4-morpholinocarbonyl 58 ch ₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 59 ch ₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 60 ch ₃ 2-Cl-phenyl 2-Methylsulfone 1-1 -imidazolyl 61 ch ₃ 2-F-phenyl 2- (aminosulfonyl) phenyl

308

62 ch ₃ 2-F-phenyl 2- (methylaminosulfonyl) phenyl 63 ch ₃ 2-F-phenyl 1-Pyrrolidinocarbonyl 64 ch ₃ 2-F-phenyl 2- (methylsulfonyl) phenyl 65 ch ₃ 2-F-phenyl 4-Morpholine 66 ch ₃ 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 67 ch ₃ 2-F-phenyl 4-morpholinocarbonyl 68 ch ₃ 2-F-phenyl 2-methyl-1-imidazolyl 69 ch ₃ 2-F-phenyl 5-methyl-1-imidazolyl 70 ch ₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 71 ch ₃ 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 72 ch ₃ 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 73 ch ₃ 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 74 ch ₃ 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 75 ch ₃ 2,6-diF-phenyl 4-Morpholine 76 ch ₃ 2,6-diF-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 77 ch ₃ 2,6-diF-phenyl 4-morpholinocarbonyl 78 ch ₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 79 ch ₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 80 ch ₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 81 ch ₂ ch ₃ phenyl 2- (aminosulfonyl) phenyl 82 ch ₂ ch ₃ phenyl 2- (methylaminosulfonyl) phenyl 83 ch ₂ ch ₃ phenyl 1-Pyrrolidinocarbonyl 84 ch ₂ ch ₃ phenyl 2- (methylsulfonyl) phenyl 85 ch ₂ ch ₃ phenyl 4-Morpholine 86 ch ₂ ch ₃ phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 87 ch ₂ ch ₃ phenyl 4-morpholinocarbonyl 88 ch ₂ ch ₃ phenyl 2-methyl-1-imidazolyl 89 ch ₂ ch ₃ phenyl 5-methyl-1-imidazolyl 90 ch ₂ ch ₃ phenyl 2-methylsulfonyl-1-imidazolyl 91 ch ₂ ch ₃ 2-pyridyl 2- (aminosulfonyl) phenyl 92 ch ₂ ch ₃ 2-pyridyl 2- (methylamino-phenyl) -phenyl 93 ch ₂ ch ₃ 2-pyridyl 1-Pyrrolidinocarbonyl 94 ch ₂ ch ₃ 2-pyridyl 2- (methylsulfonyl) phenyl 95 ch ₂ ch ₃ 2-pyridyl 4-Morpholine 96 ch ₂ ch ₃ 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 97 ch ₂ ch ₃ 2-pyridyl 4-morpholinocarbonyl 98 ch ₂ ch ₃ 2-pyridyl 2-methyl-1-imidazolyl 99 ch ₂ ch ₃ 2-pyridyl 5-methyl-1-imidazolyl 100 ch ₂ ch ₃ '2-Pyridyl 2-methylsulfonyl-1-imidazolyl 101 ch ₂ ch ₃ 3-pyridyl 2- (aminosulfonyl) phenyl 102 ch ₂ ch ₃ 3-pyridyl 2- (methylaminosulfonyl) phenyl 103 ch ₂ ch ₃ 3-pyridyl 1-Pyrrolidinocarbonyl 104 ch ₂ ch ₃ 3-pyridyl 2- (methylsulfonyl) phenyl 105 ch ₂ ch ₃ 3-pyridyl 4-Morpholine 106 ch ₂ ch ₃ 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 107 ch ₂ ch ₃ 3-pyridyl 4-morpholinocarbonyl 108 ch ₂ ch ₃ 3-pyridyl 2-methyl-1-imidazolyl 109 ch ₂ ch ₃ 3-pyridyl 5-methyl-1-imidazolyl

309

110 CH ₂ CH ₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 111 CH ₂ CH ₃ 2-pyrimidyl 2- (aminosulfonyl) phenyl 112 ch ₂ ch ₃ 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 113 ch ₂ ch ₃ 2-pyrimidyl 1-Pyrrolidinocarbonyl 114 ch ₂ ch ₃ 2-pyrimidyl 2- (methylsulfonyl) phenyl 115 ch ₂ ch ₃ 2-pyrimidyl 4-Morpholine 116 ch ₂ ch ₃ 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 117 ch ₂ ch ₃ 2-pyrimidyl 4-morpholinocarbonyl 118 ch ₂ ch ₃ 2-pyrimidyl 2-methyl-1-imidazolyl 119 ch ₂ ch ₃ 2-pyrimidyl 5-methyl-1-imidazolyl 120 ch ₂ ch ₃ 2-pyrimidyl 2-year-old Ifoni I-1-imidazolyl 121 ch ₂ ch ₃ 5-pyrimidyl 2- (aminosulfonyl) phenyl 122 ch ₂ ch ₃ 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 123 ch ₂ ch ₃ 5-pyrimidyl 1-Pyrrolidinocarbonyl 124 ch ₂ ch ₃ 5-pyrimidyl 2- (methylsulfonyl) phenyl 125 ch ₂ ch ₃ 5-pyrimidyl 4-Morpholine 126 ch ₂ ch ₃ 5-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 127 ch ₂ ch ₃ 5-pyrimidyl 4-morpholinocarbonyl 128 ch ₂ ch ₃ 5-pyrimidyl 2-methyl-1-imidazolyl 129 ch ₂ ch ₃ 5-pyrimidyl 5-methyl-1-imidazolyl 130 ch ₂ ch ₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 131 ch ₂ ch ₃ 2-Cl-phenyl 2- (aminosulfonyl) phenyl 132 ch ₂ ch ₃ 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 133 ch ₂ ch ₃ 2-Cl-phenyl 1-Pyrrolidinocarbonyl 134 ch ₂ ch ₃ 2-Cl-phenyl 2- (methylsulfonyl) phenyl 135 ch ₂ ch ₃ 2-Cl-phenyl 4-Morpholine 136 ch ₂ ch ₃ 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 137 ch ₂ ch ₃ 2-Cl-phenyl 4-morpholinocarbonyl 138 ch ₂ ch ₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 139 ch ₂ ch ₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 140 ch ₂ ch ₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 141 ch ₂ ch ₃ 2-F-phenyl 2- (aminosulfonyl) phenyl 142 ch ₂ ch ₃ 2-F-Phenyl 2- (methylaminosulfonyl) phenyl 143 CH2CH3 2-F-phenyl 1-Pyrrolidinocarbonyl 144 ch ₂ ch ₃ 2-F-phenyl 2- (methylsulfonyl) phenyl 145 ch ₂ ch ₃ 2-F-phenyl 4-Morpholine 146 ch ₂ ch ₃ 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 147 ch ₂ ch ₃ 2-F-phenyl 4-morpholinocarbonyl 148 ch ₂ ch ₃ 2-F-phenyl 2-methyl-1-imidazolyl 149 ch ₂ ch ₃ 2-F-phenyl 5-methyl-1-imidazolyl 150 ch ₂ ch ₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 151 ch ₂ ch ₃ 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 152 ch ₂ ch ₃ 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 153 ch ₂ ch ₃ 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 154 ch ₂ ch ₃ 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 155 ch ₂ ch ₃ 2,6-diF-phenyl 4-Morpholine 156 ch ₂ ch ₃ 2,6-diF-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 157 CH2CH3 2,6-diF-phenyl 4-morpholinocarbonyl

310

158 CH2CH3 2,6-diF-phenyl 2-methyl-1-imidazolyl 159 CH2CH3 2,6-diF-phenyl 5-methyl-1-imidazolyl 160 CH2CH3 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 161 cf ₃ phenyl 2- (aminosulfonyl) phenyl 162 cf ₃ phenyl 2- (methylaminosulfonyl) phenyl 163 cf ₃ phenyl 1-Pyrrolidinocarbonyl 164 C Fa phenyl 2- (methylsulfonyl) phenyl 165 CF ₃ phenyl 4-Morpholine 166 cf ₃ phenyl 2- (T-CF ₃ -tetrazol-2-yl) phenyl 167 cf ₃ phenyl 4-morpholinocarbonyl 168 cf ₃ phenyl 2-methyl-1-imidazolyl 169 cf ₃ phenyl 5-methyl-1-imidazolyl 170 cf ₃ . phenyl 2-methylsulfonyl-1-imidazolyl 171 cf ₃ 2-pyridyl 2- (aminosulfonyl) phenyl 172 cf ₃ 2-pyridyl 2- (methylaminosulfonyl) phenyl 173 cf ₃ 2-pyridyl 1-Pyrrolidinocarbonyl 174 cf ₃ 2-pyridyl 2- (methylsulfonyl) phenyl · 175 cf ₃ 2-pyridyl 4-Morpholine 176 cf ₃ 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 177 cf ₃ 2-pyridyl 4-morpholinocarbonyl 178 cf ₃ 2-pyridyl 2-methyl-1-imidazolyl 179 cf ₃ 2-pyridyl 5-methyl-1-imidazolyl 180 cf ₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 181 cf ₃ 3-pyridyl 2- (aminosulfonyl) phenyl 182 cf ₃ 3-pyridyl 2- (methylaminosu [phenyl] phenyl) 183 cf ₃ 3-pyridyl 1-Pyrrolidinocarbonyl 184 cf ₃ 3-pyridyl 2- (methylsulfonyl) phenyl 185 cf ₃ 3-pyridyl 4-Morpholine 186 cf ₃ 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 187 cf ₃ 3-pyridyl 4-morpholinocarbonyl 188 cf ₃ 3-pyridyl 2-methyl-1-imidazolyl 189 cf ₃ 3-pyridyl 5-methyl-1-imidazolyl 190 cf ₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 191 cf ₃ 2-pyrimidyl 2- (aminosulfonyl) phenyl 192 cf ₃ 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 193 cf ₃ 2-pyrimidyl 1-Pyrrolidinocarbonyl 194 cf ₃ 2-pyrimidyl 2- (mephylsulfonyl) phenyl 195 cf ₃ .2-Pyrimidyl 4-Morpholine 196 cf ₃  2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 197 cf ₃ 2-pyrimidyl 4-morpholinocarbonyl 198 cf ₃ 2-pyrimidyl 2-methyl-1-imidazolyl 199 cf ₃ 2-pyrimidyl 5-methyl-1-imidazolyl 200 cf ₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 201 cf ₃ 5-pyrimidyl 2- (aminosulfonyl) phenyl 202 cf ₃ 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 203 cf ₃ 5-pyrimidyl 1-Pyrrolidinocarbonyl 204 cf ₃ 5-pyrimidyl 2- (methyl (sulfonyl) phenyl) 205 cf ₃ 5-pyrimidyl 4-Morpholine

206 cf ₃ 5-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 207 cf ₃ 5-pyrimidyl 4-morpholinocarbonyl 208 cf ₃ 5-pyrimidyl 2-methyl-1-imidazolyl 209 cf ₃ 5-pyrimidyl 5-methyl-1-imidazolyl 210 cf ₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 211 cf ₃ 2-Cl-phenyl 2- (aminosulfonyl) phenyl 212 cf ₃ 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 213 cf ₃ 2-Cl-phenyl 1-Pyrrolidinocarbonyl 214 cf ₃ 2-Cl-phenyl 2- (methylsulfonyl) phenyl 215 cf ₃ 2-C 1 -phenyl 4-Morpholine 216 cf ₃ 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 217 cf ₃ 2-Cl-phenyl 4-morpholinocarbonyl 218 cf ₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 219 cf ₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 220 cf ₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 221 cf ₃ 2-F-phenyl 2- (aminosulfonyl) phenyl 222 cf ₃ 2-F-phenyl 2- (methylaminosulfonyl) phenyl 223 cf ₃ 2-F-phenyl 1-Pyrrolidinocarbonyl 224 cf ₃ 2-F-phenyl 2- (methylsulfonyl) phenyl 225 cf ₃ 2-F-phenyl 4-Morpholine 226 cf ₃ 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 227 cf ₃ 2-F-phenyl 4-morpholinocarbonyl 228 cf ₃ 2-F-phenyl 2-methyl-1-imidazolyl 229 cf ₃ 2-F-phenyl 5-methyl-1-imidazolyl 230 cf ₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 231 cf ₃ 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 232 cf ₃ 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 233 cf ₃ 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 234 cf ₃ 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 235 cf ₃ 2,6-diF-phenyl 4-Morpholine 236 cf ₃ 2,6-diF-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl as 237 cf ₃ 2,6-diF-phenyl 4-morpholinocarbonyl 238 cf ₃ 2,6-diF-phenyl - 2-methyl-1-imidazolyl 239 cf ₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 240 cf ₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 241 sch ₃ phenyl 2- (aminosulfonyl) phenyl 242 sch ₃ phenyl 2- (methylaminosulfonyl) phenyl 243 sch ₃ phenyl 1-Pyrrolidinocarbonyl 244 sch ₃ phenyl 2- (methylsulfonyl) phenyl 245 sch ₃ phenyl 4-Morpholine 246 sch ₃ phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 247 sch ₃ phenyl 4-morpholinocarbonyl 248 sch ₃ phenyl 2-methyl-1-imidazolyl 249 sch ₃ phenyl 5-methyl-1-imidazolyl 250 sch ₃ phenyl 2-methylsulfonyl-1-imidazolyl 251 sch ₃ 2-pyridyl 2- (aminosulfonyl) phenyl 252 sch ₃ 2-pyridyl 2- (methylaminosulfonyl) phenyl 253 sch ₃ 2-pyridyl 1-Pyrrolidinocarbonyl

312

254 sch ₃ 2-pyridyl 2- (methylsulfonyl) phenyl 255 sch ₃ 2-pyridyl 4-Morpholine 256 sch ₃ 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 257 sch ₃ 2-pyridyl 4-morpholinocarbonyl 258 sch ₃ 2-pyridyl 2-methyl-1-imidazolyl 259 sch ₃ 2-pyridyl 5-methyl-1-imidazolyl 260 sch ₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 261 sch ₃ 3-pyridyl 2- (aminosulfonyl) phenyl 262 sch ₃ 3-pyridyl 2- (methylaminosulfonyl) phenyl 263 sch ₃ 3-pyridyl 1-Pyrrolidinocarbonyl 264 sch ₃ 3-pyridyl 2- (methylsulfonyl) phenyl 265 sch ₃ 3-pyridyl 4-Morpholine 266 sch ₃ 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 267 sch ₃ 3-pyridyl 4-morpholinocarbonyl 268 sch ₃ 3-pyridyl 2-methyl-1-imidazolyl 269 sch ₃ 3-pyridyl 5-methyl-1-imidazolyl 270 sch ₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 271 sch ₃ 2-pyrimidyl 2- (aminosulfonyl) phenyl 272 sch ₃ 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 273 sch ₃ 2-pyrimidyl 1-Pyrrolidinocarbonyl 274 sch ₃ 2-pyrimidyl 2- (methylsulfonyl) phenyl 275 sch ₃ 2-pyrimidyl 4-Morpholine 276 sch ₃ 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 277 sch ₃ 2-pyrimidyl 4-morpholinocarbonyl 278 sch ₃ 2-pyrimidyl 2-methyl-1-imidazolyl 279 sch ₃ 2-pyrimidyl 5-methyl-1-imidazolyl 280 sch ₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 281 sch ₃ 5-pyrimidyl 2- (aminosulfonyl) phenyl 282 sch ₃ 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 283 sch ₃ 5-pyrimidyl 1-Pyrrolidinocarbonyl 284 sch ₃ 5-pyrimidyl 2- (methylsulfonyl) phenyl 285 sch ₃ 5-pyrimidyl 4-Morpholine 286 sch ₃ 5-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 287 sch ₃ 5-pyrimidyl 4-morpholinocarbonyl 288 sch ₃ 5-pyrimidyl 2-methyl-1-imidazolyl 289 sch ₃ 5-pyrimidyl 5-methyl-1-imidazolyl 290 sch ₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 291 sch ₃ .. 2-Cl-phenyl 2- (aminosulfonyl) phenyl 292 sch ₃ 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 293 sch ₃ 2-Cl-phenyl 1-Pyrrolidinocarbonyl 294 sch ₃ 2-Cl-phenyl 2- (methylsulfonyl) phenyl 295 sch ₃ 2-Cl-phenyl 4-Morpholine 296 sch ₃ 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl as 297 sch ₃ 2-Cl-phenyl 4-morpholinocarbonyl 298 sch ₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 299 sch ₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 300 sch ₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 301 sch ₃ 2-F-phenyl 2- (aminosulfonyl) phenyl

313

302 sch ₃ 2-F-phenyl 2- (methylaminosulfonyl) phenyl 303 sch ₃ 2-F-phenyl 1-Pyrrolidinocarbonyl 304 sch ₃ 2-F-phenyl 2- (methylsulfonyl) phenyl 305 sch ₃ 2-F-phenyl 4-Morpholine 306 sch ₃ 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 307 sch ₃ 2-F-phenyl 4-morpholinocarbonyl 308 sch ₃ 2-F-phenyl 2-methyl-1-imidazolyl 309 sch ₃ 2-F-phenyl 5-methyl-1-imidazolyl 310 sch ₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 311 sch ₃ 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 312 sch ₃ 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 313 sch ₃ 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 314 sch ₃ 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 315 sch ₃ 2,6-diF-phenyl 4-Morpholine 316 sch ₃ 2,6-diF-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 317 sch ₃ 2,6-diF-phenyl 4-morpholinocarbonyl 318 sch ₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 319 sch ₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 320 sch ₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 321 soch ₃ phenyl 2- (aminosulfonyl) phenyl 322 soch ₃ phenyl 2- (methylaminosulfonyl) phenyl 323 soch ₃ phenyl 1-Pyrrolidinocarbonyl 324 soch ₃ phenyl 2- (methylsulfonyl) phenyl 325 soch ₃ phenyl 4-Morpholine 326 soch ₃ phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 327 soch ₃ phenyl 4-morpholinocarbonyl 328 soch ₃ phenyl 2-methyl-1-imidazolyl 329 soch ₃ phenyl 5-methyl-1-imidazolyl 330 soch ₃ phenyl 2-methylsulfonyl-1-imidazolyl 331 soch ₃ 2-pyridyl 2- (aminosulfonyl) phenyl 332 soch ₃ 2-pyridyl 2- (methylaminosulfonyl) phenyl 333 soch ₃ 2-pyridyl 1-Pyrrolidinocarbonyl 334 soch ₃ 2-pyridyl 2- (methylsulfonyl) phenyl 335 soch ₃ 2-pyridyl 4-Morpholine 336 soch ₃ 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 337 soch ₃ 2-pyridyl 4-morpholinocarbonyl 338 soch ₃ 2-pyridyl 2-methyl-1-imidazolyl 339 soch ₃ 2-pyridyl 5-methyl-1-imidazolyl 340 soch ₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 341 soch ₃ 3-p irid 2- (aminosulfonyl) phenyl 342 soch ₃ 3-pyridyl 2- (methylaminosylphonyl) phenyl 343 soch ₃ 3-pyridyl 1-Pyrrolidinocarbonyl 344 soch ₃ 3-pyridyl 2- (methylsulfonyl) phenyl 345 soch ₃ 3-pyridyl 4-Morpholine 346 soch ₃ 3-pyridyl 2- (1'-CF ₃ -tetrazol-2-yl) phenyl 347 soch ₃ 3-pyridyl 4-morpholinocarbonyl 348 soch ₃ 3-pyridyl 2-methyl-1-imidazolyl 349 soch ₃ 3-pyridyl 5-methyl-1-imidazolyl

314

350 SOCH ₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 351 soch ₃ 2-pyrimidyl 2- (aminosulfonyl) phenyl 352 soch ₃ 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 353 soch ₃ 2-pyrimidyl 1-Pyrrolidinocarbonyl 354 soch ₃ 2-pyrimidyl 2- (methylsulfonyl) phenyl 355 soch ₃ 2-pyrimidyl 4-Morpholine 356 soch ₃ 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 357 soch ₃ 2-pyrimidyl 4-morpholinocarbonyl 358 soch ₃ 2-pyrimidyl 2-methyl-1-imidazolyl 359 soch ₃ 2-pyrimidyl 5-methyl-1-imidazolyl 360 soch ₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 361 soch ₃ 5-pyrimidyl 2- (aminosulfonyl) phenyl 362 soch ₃ 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 363 soch ₃ 5-pyrimidyl 1-Pyrrolidinocarbonyl 364 soch ₃ 5-pyrimidyl 2- (methylsulfonyl) phenyl 365 soch ₃ 5-pyrimidyl 4-Morpholine 366 soch ₃ 5-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 367 SOCHs 5-pyrimidyl 4-morpholinocarbonyl 368 soch ₃ 5-pyrimidyl 2-methyl-1-imidazolyl 369 SOCH3 5-pyrimidyl 5-methyl-1-imidazolyl 370 soch ₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 371 SOCH3 2-Cl-phenyl 2- (aminosulfonyl) phenyl 372 SOCH3 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 373 soch ₃ 2-Cl-phenyl 1-Pyrrolidinocarbonyl 374 soch ₃ 2-CI Phenyl 2- (methylsulfonyl) phenyl 375 SOCHs 2-Cl-phenyl 4-Morpholine 376 SOCH3 2-C 1 -phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 377 soch ₃ 2-Cl-phenyl 4-morpholinocarbonyl 378 SOCH3 2-Cl-phenyl 2-methyl-1-imidazolyl 379 soch ₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 380 soch ₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 381 SOCH ₃ 2-F-phenyl 2- (aminosulfonyl) phenyl 382 soch ₃ 2-F-phenyl 2- (methylaminosulfonyl) phenyl 383 soch ₃ 2-F-phenyl 1-Pyrrolidinocarbonyl 384 soch ₃ 2-F-phenyl 2- (methylsulfonyl) phenyl 385 soch ₃ 2-F-phenyl 4-Morpholine 386 soch ₃ 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 387 SOCH3 2-F-phenyl 4-morpholinocarbonyl 388 soch ₃ 2-F-phenyl 2-methyl-1-imidazolyl 389 soch ₃ 2-F-phenyl 5-methyl-1-imidazolyl 390 soch ₃ 2-F-phenyl 2-Methyl Isulfonyl-1-imidazolyl 391 soch ₃ 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 392 soch ₃ 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 393 soch ₃ 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 394 soch ₃ 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 395 soch ₃ 2,6-diF-phenyl 4-Morpholine 396 soch ₃ 2,6-diF-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 397 soch ₃ 2,6-diF-phenyl 4-morpholinocarbonyl

398 SOCH ₃ 315 2,6-diF-phenyl LT 4673 2-methyl-1-imidazolyl 399 SOCH ₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 400 SOCH3 2,6-diF-phenyl 2-Methyl Isulfonyl-1-imidazolyl 401 SO ₂ CH ₃ phenyl 2- (aminosulfonyl) phenyl 402 so ₂ ch ₃ phenyl 2- (methylaminosulfonyl) phenyl 403 so ₂ ch ₃ phenyl 1-Pyrrolidinocarbonyl 404 so ₂ ch ₃ phenyl 2- (methylsulfonyl) phenyl 405 so ₂ ch ₃ phenyl 4-Morpholine 406 so ₂ ch ₃ phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 407 so ₂ ch ₃ phenyl 4-morpholinocarbonyl 408 so ₂ ch ₃ phenyl 2-methyl-1-imidazolyl 409 so ₂ ch ₃ phenyl 5-methyl-1-imidazolyl 410 so ₂ ch ₃ phenyl 2-methylsulfonyl-1-imidazolyl 411 so ₂ ch ₃ 2-pyridyl 2- (aminosulfonyl) phenyl 412 so ₂ ch ₃ 2-pyridyl 2- (methylaminosulfonyl) phenyl 413 so ₂ ch ₃ 2-pyridyl 1-Pyrrolidinocarbonyl 414 so ₂ ch ₃ 2-pyridyl 2- (methylsulfonyl) phenyl 415 so ₂ ch ₃ 2-pyridyl 4-Morpholine 416 so ₂ ch ₃ 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 417 so ₂ ch ₃ 2-pyridyl 4-morpholinocarbonyl 418 so ₂ ch ₃ 2-pyridyl 2-methyl-1-imidazolyl 419 so ₂ ch ₃ 2-pyridyl 5-methyl-1-imidazolyl 420 so ₂ ch ₃ 2-pyridyl 2-Methylsulfonyl-1-imidazolyl 421 so ₂ ch ₃ 3-pyridyl 2- (aminosulfonyl) phenyl 422 so ₂ ch ₃ 3-pyridyl 2- (methylaminosulfonyl) phenyl 423 so ₂ ch ₃ 3-pyridyl 1-Pyrrolidinocarbonyl 424 so ₂ ch ₃ 3-pyridyl 2- (methylsulfonyl) phenyl 425 so ₂ ch ₃ 3-pyridyl 4-Morpholine 426 so ₂ ch ₃ 3-pyridia 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 427 so ₂ ch ₃ 3-pyridyl 4-morpholinocarbonyl 428 so ₂ ch ₃ 3-pyridyl 2-methyl-1-imidazolyl 429 so ₂ ch ₃ 3-pyridyl 5-methyl-1-imidazolyl 430 so ₂ ch ₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 431 so ₂ ch ₃ 2-pyrimidyl 2- (aminosulfonyl) phenyl 432 so ₂ ch ₃ 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 433 so ₂ ch ₃ 2-pyrimidyl 1-Pyrrolidinocarbonyl 434 so ₂ ch ₃ 2-pyrimidyl 2- (methylsulfonyl) phenyl 435 so ₂ ch ₃ 2-pyrimidyl 4-Morpholine 436 so ₂ ch ₃ 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 437 so ₂ ch ₃ 2-pyrimidyl 4-morpholinocarbonyl 438 so ₂ ch ₃ 2-pyrimidyl 2-methyl-1-imidazolyl 439 so ₂ ch ₃ 2-pyrimidyl 5-methyl-1-imidazolyl 440 so ₂ ch ₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 441 so ₂ ch ₃ 5-pyrimidyl 2- (Aminosulfonyl) phenyl 442 so ₂ ch ₃ 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 443 so ₂ ch ₃ 5-pyrimidyl 1-Pyrrolidinocarbonyl 444 so ₂ ch ₃ 5-pyrimidyl 2- (methylsulfonyl) phenyl 445 so ₂ ch ₃ 5-pyrimidyl 4-Morpholine

316

446 SO2CH3 5-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 447 SO ₂ CH ₃ 5-pyrimidyl 4-morpholinocarbonyl 448 SO2CH3 5-pyrimidyl 2-methyl-1-imidazolyl 449 SO2CH3 5-pyrimidyl 5-methyl-1-imidazolyl 450 so ₂ ch ₃ 5-pyrimidyl 2-Methylsulfonyl-1-imidazolyl 451 SO2CH3 2-Cl-phenyl 2- (Aminosulfonyl) phenyl 452 SO2CH3 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 453 SO ₂ CH ₃ 2-Cl-phenyl 1-Pyrrolidinocarbonyl 454 so ₂ ch ₃ 2-Cl-phenyl 2- (methylsulfonyl) phenyl 455 so ₂ ch ₃ 2-Cl-phenyl 4-Morpholine 456 so ₂ ch ₃ 2-Cl-phenyl 2- (1'-CF ₃ -tetrazol-2-yl) phenyl 457 so ₂ ch ₃ 2-Cl-phenyl 4-morpholinocarbonyl 458 so ₂ ch ₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 459 so ₂ ch ₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 460 so ₂ ch ₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 461 so ₂ ch ₃ 2-F-phenyl 2- (aminosulfonyl) phenyl 462 so ₂ ch ₃ 2-F-phenyl 2- (methylaminosulfonyl) phenyl 463 so ₂ ch ₃ 2-F-phenyl 1-Pyrrolidinocarbonyl 464 so ₂ ch ₃ 2-F-phenyl 2- (methylsulfonyl) phenyl 465 so ₂ ch ₃ 2-F-phenyl 4-Morpholine 466 so ₂ ch ₃ 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 467 so ₂ ch ₃ 2-F-phenyl 4-morpholinocarbonyl 468 so ₂ ch ₃ 2-F-phenyl 2-methyl-1-imidazolyl 469 so ₂ ch ₃ 2-F-phenyl 5-methyl-1-imidazolyl 470 so ₂ ch ₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 471 so ₂ ch ₃ 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 472 so ₂ ch ₃ 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 473 so ₂ ch ₃ 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 474 so ₂ ch ₃ 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 475 so ₂ ch ₃ 2,6-diF-phenyl 4-Morpholine 476 so ₂ ch ₃ 2,6-diF-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 477 so ₂ ch ₃ 2,6-diF-phenyl 4-morpholinocarbonyl 478 so ₂ ch ₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 479 so ₂ ch ₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 480 so ₂ ch ₃ 2,6-diF-phenyl . 2-methylsulfonyl-1-imidazolyl 481 ch ₂ nh-so ₂ ch ₃ phenyl 2- (aminosulfonyl) phenyl 482 ch ₂ nh-so ₂ ch ₃ phenyl 2- (methylaminosulfonyl) phenyl 483 ch ₂ nh-so ₂ ch ₃ phenyl 1-Pyrrolidinocarbonyl 484 ch ₂ nh-so ₂ ch ₃ phenyl 2- (methylsulfonyl) phenyl 485 ch ₂ nh-so ₂ ch ₃ phenyl 4-Morpholine 486 ch ₂ nh-so ₂ ch ₃ phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 487 ch ₂ nh-so ₂ ch ₃ phenyl 4-morpholinocarbonyl 488 ch ₂ nh-so ₂ ch ₃ phenyl 2-methyl-1-imidazolyl 489 ch ₂ nh-so ₂ ch ₃ phenyl 5-methyl-1-imidazolyl 490 ch ₂ nh-so ₂ ch ₃ phenyl 2-methylsulfonyl-1-imidazolyl 491 ch ₂ nh-so ₂ ch ₃ 2-pyridyl 2- (aminosulfonyl) phenyl 492 ch ₂ nh-so ₂ ch ₃ 2-pyridyl 2- (methylaminosulfonyl) phenyl 493 ch ₂ nh-so ₂ ch ₃ 2-pyridyl 1-Pyrrolidinocarbonyl

317

494 CH 2 NH-SO 2 CH 3 2-pyridyl 2- (methylsulfonyl) phenyl 495 ch ₂ nh-so ₂ ch ₃ 2-pyridyl 4-Morpholine 496 ch ₂ nh-so ₂ ch ₃ 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 497 ch ₂ nh-so ₂ ch ₃ 2-pyridyl 4-morpholinocarbonyl 498 ch ₂ nh-so ₂ ch ₃ 2-pyridyl 2-methyl-1-imidazolyl 499 ch ₂ nh-so ₂ ch ₃ 2-pyridyl 5-methyl-1-imidazolyl 500 ch ₂ nh-so ₂ ch ₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 501 ch ₂ nh-so ₂ ch ₃ 3-pyridyl 2- (aminosulfonyl) phenyl 502 ch ₂ nh-so ₂ ch ₃ 3-pyridyl 2- (methylaminosulfonyl) phenyl 503 ch ₂ nh-so ₂ ch ₃ 3-pyridyl 1-Pyrrolidinocarbonyl 504 ch ₂ nh-so ₂ ch ₃ 3-pyridyl 2- (methylsulfonyl) phenyl 505 ch ₂ nh-so ₂ ch ₃ 3-pyridyl 4-Morpholine 506 ch ₂ nh-so ₂ ch ₃ 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 507 ch ₂ nh-so ₂ ch ₃ 3-pyridyl 4-morpholinocarbonyl 508 ch ₂ nh-so ₂ ch ₃ 3-pyridyl 2-methyl-1-imidazolyl 509 ch ₂ nh-so ₂ ch ₃ 3-pyridyl 5-methyl-1-imidazolyl 510 ch ₂ nh-so ₂ ch ₃ 3-pyridyl 2-Methylsulfonyl-1-imidazolyl 511 ch ₂ nh-so ₂ ch ₃ 2-pyrimidyl 2- (aminosulfonyl) phenyl 512 ch ₂ nh-so ₂ ch ₃ 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 513 ch ₂ nh-so ₂ ch ₃ 2-pyrimidyl 1-Pyrrolidinocarbonyl 514 ch ₂ nh-so ₂ ch ₃ 2-pyrimidyl 2- (methylsulfonyl) phenyl 515 ch ₂ nh-so ₂ ch ₃ 2-pyrimidyl 4-Morpholine 516 ch ₂ nh-so ₂ ch ₃ 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 517 ch ₂ nh-so ₂ ch ₃ 2-pyrimidyl 4-morpholinocarbonyl 518 ch ₂ nh-so ₂ ch ₃ 2-pyrimidyl 2-methyl-1-imidazolyl 519 ch ₂ nh-so ₂ ch ₃ 2-pyrimidyl 5-methyl-1-imidazolyl 520 ch ₂ nh-so ₂ ch ₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 521 ch ₂ nh-so ₂ ch ₃ 5-pyrimidyl 2- (aminosulfonyl) phenyl 522 ch ₂ nh-so ₂ ch ₃ 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 523 ch ₂ nh-so ₂ ch ₃ 5-pyrimidyl 1-Pyrrolidinocarbonyl 524 ch ₂ nh-so ₂ ch ₃ 5-pyrimidyl 2- (methylsulfonyl) phenyl 525 ch ₂ nh-so ₂ ch ₃ 5-pyrimidyl 4-Morpholine 526 ch ₂ nh-so ₂ ch ₃ 5-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 527 ch ₂ nh-so ₂ ch ₃ 5-pyrimidyl 4-morpholinocarbonyl 528 ch ₂ nh-so ₂ ch ₃ 5-pyrimidyl 2-methyl-1-imidazolyl 529 ch ₂ nh-so ₂ ch ₃ 5-pyrimidyl 5-methyl-1-imidazolyl 530 ch ₂ nh-so ₂ ch ₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 531 ch ₂ nh-so ₂ ch ₃ 2-G'1-Phenyl 2- (aminosulfonyl) phenyl 532 ch ₂ nh-so ₂ ch ₃ 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 533 ch ₂ nh-so ₂ ch ₃ 2-Cl-phenyl 1-Pyrrolidinocarbonyl 534 ch ₂ nh-so ₂ ch ₃ 2-Cl-phenyl 2- (methylsulfonyl) phenyl 535 ch ₂ nh-so ₂ ch ₃ 2-Cl-phenyl 4-Morpholine 536 ch ₂ nh-so ₂ ch ₃ 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 537 ch ₂ nh-so ₂ ch ₃ 2-Cl-phenyl 4-morpholinocarbonyl 538 ch ₂ nh-so ₂ ch ₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 539 ch ₂ nh-so ₂ ch ₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 540 ch ₂ nh-so ₂ ch ₃ 2-Cl-phenyl 2-Methylsulfonyl-1-imidazolyl 541 ch ₂ nh-so ₂ ch ₃ 2-F-phenyl 2- (aminosulfonyl) phenyl

318

542 CH ₂ NH-SO ₂ CH ₃ 2-F-phenyl 2- (methylaminosulfonyl) phenyl 543 ch ₂ nh-so ₂ ch ₃ 2-F-phenyl 1-Pyrrolidinocarbonyl 544 ch ₂ nh-so ₂ ch ₃ 2-F-phenyl 2- (methylsulfonyl) phenyl 545 ch ₂ nh-so ₂ ch ₃ 2-F-phenyl 4-Morpholine 546 ch ₂ nh-so ₂ ch ₃ 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 547 ch ₂ nh-so ₂ ch ₃ 2-F-phenyl 4-morpholinocarbonyl 548 ch ₂ nh-so ₂ ch ₃ 2-F-phenyl 2-methyl-1-imidazolyl 549 ch ₂ nh-so ₂ ch ₃ 2-F-phenyl 5-methyl-1-imidazolyl 550 ch ₂ nh-so ₂ ch ₃ 2-F-phenyl 2-Methylsulfonyl-1-imidazolyl 551 ch ₂ nh-so ₂ ch ₃ 2,6-diF-phenyl 2- (Aminosulfonyl) phenyl 552 ch ₂ nh-so ₂ ch ₃ 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 553 ch ₂ nh-so ₂ ch ₃ 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 554 ch ₂ nh-so ₂ ch ₃ 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 555 ch ₂ nh-so ₂ ch ₃ 2,6-diF-phenyl 4-Morpholine 556 ch ₂ nh-so ₂ ch ₃ 2,6-diF-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 557 ch ₂ nh-so ₂ ch ₃ 2,6-diF-phenyl 4-morpholinocarbonyl 558 ch ₂ nh-so ₂ ch ₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 559 ch ₂ nh-so ₂ ch ₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 560 ch ₂ nh-so ₂ ch ₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 561 Cl phenyl 2- (aminosulfonyl) phenyl 562 Cl phenyl 2- (methylaminosulfonyl) phenyl 563 Cl phenyl 1-Pyrrolidinocarbonyl 564 Cl phenyl 2- (methylsulfonyl) phenyl 565 Cl phenyl 4-Morpholine 566 Cl phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 567 Cl phenyl 4-morpholinocarbonyl 568 Cl phenyl 2-methyl-1-imidazolyl 569 Cl phenyl 5-methyl-1-imidazolyl 570 Cl phenyl 2-Methylsulfone 1-1 -imidazolyl 571 Cl 2-pyridyl 2- (aminosulfonyl) phenyl 572 Cl 2-pyridyl 2- (methylamino) phenyl) phenyl 573 Cl 2-pyridyl 1-Pyrrolidinocarbonyl 574 Cl 2-pyridyl 2- (methylsulfonyl) phenyl 575 Cl 2-pyridyl 4-Morpholine 576 Cl 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 577 Cl 2-pyridyl 4-morpholinocarbonyl 578 Cl 2-pyridyl 2-methyl-1-imidazolyl 579 Cl 2-pyridyl 5-methyl-1-imidazolyl 580 Cl 2-pyridyl 2-methylsulfonyl-1-imidazolyl 581 Cl 3-pyridyl 2- (Aminosulfonyl) phenyl 582 Cl 3-pyridyl 2- (methylaminosulfonyl) phenyl 583 Cl 3-pyridyl 1-Pyrrolidinocarbonyl 584 Cl 3-pyridyl 2- (methylsulfonyl) phenyl 585 Cl 3-pyridyl 4-Morpholine 586 Cl 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 587 Cl 3-pyridyl 4-morpholinocarbonyl 588 Cl 3-pyridyl 2-methyl-1-imidazolyl 589 Cl 3-pyridyl 5-methyl-1-imidazolyl

319

590 Cl 3-pyridyl 2-Methylsulfonyl-1-imidazolyl 591 Cl 2-pyrimidyl 2- (aminosulfonyl) phenyl 592 Cl 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 593 Cl 2-pyrimidyl 1-Pyrrolidinocarbonyl 594 Cl 2-pyrimidyl 2- (methylsulfonyl) phenyl 595 Cl 2-pyrimidyl 4-Morpholine 596 Cl 2-pyrimidyl 2- (T-CF ₃ -tetrazol-2-yl) phenyl 597 Cl 2-pyrimidine 4-morpholinocarbonyl 598 Cl 2-pyrimidyl 2-methyl-1-imidazolyl 599 Cl 2-pyrimidyl 5-methyl-1-imidazolyl 600 Cl 2-pyrimidine 2-Ethylsulfonyl-1-imidazolyl 601 Cl 5-pyrimidyl 2- (aminosulfonyl) phenyl 602 Cl 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 603 Cl 5-pyrimidyl 1-Pyrrolidinocarbonyl 604 Cl 5-pyrimidyl 2- (methylsulfonyl) phenyl 605 Cl 5-pyrimidyl 4-Morpholine 606 Cl 5-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 607 Cl 5-pyrimidyl 4-morpholinocarbonyl 608 Cl 5-pyrimidyl 2-methyl-1-imidazolyl 609 Cl 5-pyrimidyl 5-methyl-1-imidazolyl 610 Cl 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 611 Cl 2-Cl-phenyl 2- (aminosulfonyl) phenyl 612 Cl 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 613 Cl 2-Cl-phenyl 1-Pyrrolidinocarbonyl 614 Cl 2-Cl-phenyl 2- (methylsulfonyl) phenyl 615 Cl 2-Cl-phenyl 4-Morpholine 616 Cl 2-Cl-phenyl 2- (1 ^l -CF ₃ tetrazolo-2-yl) phenyl 617 Cl 2-Cl-phenyl 4-morpholinocarbonyl 618 Cl 2-Cl-phenyl 2-methyl-1-imidazolyl 619 Cl 2-Cl-phenyl 5-methyl-1-imidazolyl 620 Cl 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 621 Cl 2-F-Phenif 2- (aminosulfonyl) phenyl 622 Cl 2-F-phenyl 2- (methylaminosulfonyl) phenyl 623 Cl 2-F-phenyl 1-Pyrrolidinocarbonyl 624 Cl 2-F-phenyl 2- (methylsulfonyl) phenyl 625 Cl 2-F-Phenyl 4-Morpholine 626 Cl 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 627 Cl 2-F-phenyl 4-morpholinocarbonyl 628 Cl 2-F-phenyl 2-methyl-1-imidazolyl 629 Cl 2-F-phenyl 5-methyl-1-imidazolyl 630 Cl 2-F-phenyl 2-Methylsulfonyl-1-imidazolyl 631 Cl 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 632 Cl 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 633 Cl 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 634 Cl 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 635 Cl 2,6-diF-phenyl 4-Morpholine 636 Cl 2,6-diF-phenyl 2- (1 '-CF 3 -tetrazol-2-yl) phenyl 637 Cl 2,6-diF-phenyl 4-morpholinocarbonyl

320

638 Cl 2,6-diF-phenyl 2-methyl-1-imidazolyl 639 Cl 2,6-diF-phenyl 5-methyl-1-imidazolyl 640 Cl 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 641 F phenyl 2- (aminosulfone!) Phenyl 642 F phenyl 2- (methylaminosulfonyl) phenyl 643 F phenyl 1-Pyrrolidinocarbonyl 644 F phenyl 2- (Methylsulfonyl) phenyl 645 F phenyl 4-Morpholine 646 F phenyl 2- (1'-CF ₃ -tetrazol-2-yl) phenyl 647 F phenyl 4-morpholinocarbonyl 648 F phenyl 2-methyl-1-imidazolyl 649 F phenyl 5-methyl-1-imidazolyl 650 F phenyl 2-Methyl Isulfone 1-1 -imidazolyl 651 F 2-pyridyl 2- (aminosulfonyl) phenyl 652 F 2-pyridyl 2- (methylaminosulfonyl) phenyl 653 F 2-pyridyl 1-Pyrrolidinocarbonyl 654 F 2-pyridyl 2- (methylsulfonyl) phenyl 655 F 2-pyridyl 4-Morpholine 656 F 2-pyridyl 2- (1'-CF ₃ -tetrazol-2-yl) phenyl 657 F 2-pyridyl 4-morpholinocarbonyl 658 F 2-pyridyl 2-methyl-1-imidazolyl 659 F 2-pyridyl 5-methyl-1-imidazolyl 660 F 2-pyridyl 2-methylsulfonyl-1-imidazolyl 661 F 3-pyridyl 2- (aminosulfonyl) phenyl 662 F 3-pyridyl 2- (methylaminosulfonyl) phenyl 663 F 3-pyridyl 1-Pyrrolidinocarbonyl 664 F 3-pyridyl 2- (methylsulfonyl) phenyl 665 F 3-pyridyl 4-Morpholine 666 F 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 667 F 3-pyridyl 4-morpholinocarbonyl 668 F 3-pyridyl 2-methyl-1-imidazolite 669 F 3-pyridyl 5-methyl-1-imidazolyl 670 F 3-pyridyl 2-methylsulfonyl-1-imidazolyl 671 F 2-pyrimidyl 2- (aminosulfonyl) phenyl 672 F 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 673 F 2-pyrimidyl 1-Pyrrolidinocarbonyl 674 F 2-pyrimidyl 2- (methylsulfonyl) phenyl 675 F 2-pyrimidyl 4-Morpholine 676 F 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 677 F 2-pyrimidyl 4-morpholinocarbonyl 678 F 2-pyrimidyl 2-methyl-1-imidazolyl 679 F 2-pyrimidyl 5-methyl-1-imidazolyl 680 F 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 681 F 5-pyrimidyl 2- (aminosulfonyl) phenyl 682 F 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 683 F 5-pyrimidyl 1-Pyrrolidinocarbonyl 684 F 5-pyrimidyl 2- (methylsulfonyl) phenyl 685 F 5-pyrimidyl 4-Morpholine

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686 F 5-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 687 F 5-pyrimidyl 4-morpholinocarbonyl 688 F 5-pyrimidyl 2-methyl-1-imidazolyl 689 F 5-pyrimidyl 5-methyl-1-imidazolyl 690 F 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 691 F 2-Cl-phenyl 2- (aminosulfonyl) phenyl 692 F 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 693 F 2-CI Phenyl 1-Pyrrolidinocarbonyl 694 F 2-Cl-phenyl 2- (methylsulfonyl) phenyl 695 F 2-Cl-phenyl 4-Morpholine 696 F 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 697 F 2-Cl-phenyl 4-morpholinocarbonyl 698 F 2-Cl-phenyl 2-methyl-1-imidazolyl 699 F 2-Cl-phenyl 5-methyl-1-imidazolyl 700 F 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 701 F 2-F-phenyl 2- (aminosulfonyl) phenyl 702 F 2-F-phenyl 2- (methyl, minosulfonyl) phenyl 703 F 2-F-phenyl 1-Pyrrolidinocarbonyl 704 F 2-F-phenyl 2- (methylsulfonyl) phenyl 705 F 2-F-phenyl 4-Morpholine 706 F 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 707 F 2-F-phenyl 4-morpholinocarbonyl 708 F 2-F-phenyl 2-methyl-1-imidazolyl 709 F 2-F-phenyl 5-methyl-1-imidazolyl 710 F 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 711 F 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 712 F 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 713 F 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 714 F 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 715 F 2,6-diF-phenyl 4-Morpholine 716 F 2,6-diF-phenyl 2- (1'-CF ₃ -tetrazol-2-yl) phenyl 717 F 2,6-diF-phenyl 4-morpholinocarbonyl 718 F 2,6-diF-phenyl 2-methyl-1-imidazolyl 719 F - 2,6-diF-phenyl 5-methyl-1-imidazolyl 720 F 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 721 CO ₂ CH ₃ phenyl 2- (aminosulfonyl) phenyl 722 co ₂ ch ₃ phenyl 2- (methylaminosulfonyl) phenyl 723 co ₂ ch ₃ phenyl 1-Pyrrolidinocarbonyl 724 co ₂ ch ₃ phenyl 2- (methylsulfonyl) phenyl 725 co ₂ ch ₃ phenyl 4-Morpholine 726 co ₂ ch ₃ phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 727 co ₂ ch ₃ phenyl 4-morpholinocarbonyl 728 co ₂ ch ₃ phenyl 2-methyl-1-imidazolyl 729 co ₂ ch ₃ phenyl 5-methyl-1-imidazolyl 730 co ₂ ch ₃ phenyl 2-Methyl Isulfone 1-1 -imidazolyl 731 co ₂ ch ₃ 2-pyridyl 2- (aminosulfonyl) phenyl 732 co ₂ ch ₃ 2-pyridyl 2- (methylaminosulfonyl) phenyl 733 co ₂ ch ₃ 2-pyridyl 1-Pyrrolidinocarbonyl

322

734 CO2CH3 2-pyridyl 2- (methylsulfonyl) phenyl 735 CO2CH3 2-pyridyl 4-Morpholine 736 CO2CH3 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 737 CO ₂ CH ₃ 2-pyridyl 4-morpholinocarbonyl 738 co ₂ ch ₃ 2-pyridyl 2-methyl-1-imidazolyl 739 co ₂ ch ₃ 2-pyridyl 5-methyl-1-imidazolyl 740 co ₂ ch ₃ 2-pyridia 2-methylsulfonyl-1-imidazolyl 741 co ₂ ch ₃ 3-pyridyl 2- (aminosulfonyl) phenyl 742 CO2CH3 3-pyridyl 2- (methylaminosulfonyl) phenyl 743 CO2CH3 3-pyridyl 1-Pyrrolidinocarbonyl 744 co ₂ ch ₃ 3-pyridyl 2- (methylsulfonyl) phenyl 745 co ₂ ch ₃ 3-pyridyl 4-Morpholine 746 co ₂ ch ₃ 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 747 co ₂ ch ₃ 3-pyridyl 4-morpholinocarbonyl 748 CO2CH3 3-pyridyl 2-methyl-1-imidazolyl 749 CO ₂ CH ₃ 3-pyridyl 5-methyl-1-imidazolyl 750 co ₂ ch ₃ 3-pyridia 2-methylsulfonyl-1-imidazolyl 751 co ₂ ch ₃ 2-pyrimidine 2- (aminosulfonyl) phenyl 752 co ₂ ch ₃ 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 753 co ₂ ch ₃ 2-pyrimidyl 1-Pyrrolidinocarbonyl 754 co ₂ ch ₃ 2-pyrimidyl 2- (methylsulfonyl) phenyl 755 co ₂ ch ₃ 2-pyrimidyl 4-Morpholine 756 co ₂ ch ₃ 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 757 co ₂ ch ₃ 2-pyrimidyl 4-morpholinocarbonyl 758 co ₂ ch ₃ 2-pyrimidyl 2-methyl-1-imidazolyl 759 co ₂ ch ₃ 2-pyrimidyl 5-methyl-1-imidazolyl 760 co ₂ ch ₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 761 CO2CH3 5-pyrimidyl 2- (aminosulfonyl!) Phenyl 762 CO ₂ CH ₃ 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 763 co ₂ ch ₃ 5-pyrimidyl 1-Pyrrolidinocarbonyl 764 co ₂ ch ₃ 5-pyrimidyl 2- (methylsulfonyl) phenyl 765 co ₂ ch ₃ 5-pyrimidyl 4-Morpholine 766 co ₂ ch ₃ 5-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 767 co ₂ ch ₃ 5-pyrimidyl 4-morpholinocarbonyl 768 co ₂ ch ₃ 5-pyrimidyl 2-methyl-1-imidazolyl 769 co ₂ ch ₃ 5-pyrimidyl 5-methyl-1-imidazolyl 770 co ₂ ch ₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 771 CO2CH3 .. 2-Cl-phenyl 2- (aminosulfonyl) phenyl 772 co ₂ ch ₃ 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 773 co ₂ ch ₃ 2-Cl-phenyl 1-Pyrrolidinocarbonyl 774 co ₂ ch ₃ 2-Cl-phenyl 2- (methylsulfonyl) phenyl 775 co ₂ ch ₃ 2-Cl-phenyl 4-Morpholine 776 co ₂ ch ₃ 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 777 co ₂ ch ₃ 2-Cl-phenyl 4-morpholinocarbonyl 778 co ₂ ch ₃ 2-CI Phenyl 2-methyl-1-imidazolyl 779 co ₂ ch ₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 780 co ₂ ch ₃ 2-Cl-phenyl 2-m ethyl sulfonyl-1-imidazolyl 781 co ₂ ch ₃ 2-F-phenyl 2- (aminosulfonyl) phenyl

323

782 CO2CH3 2-F-phenyl 2- (methylaminosulfonyl) phenyl 783 CO ₂ CH ₃ 2-F-phenyl 1-Pyrrolidinocarbonyl 784 co ₂ ch ₃ 2-F-phenyl 2- (methylsulfonyl) phenyl 785 co ₂ ch ₃ 2-F-phenyl 4-Morpholine 786 co ₂ ch ₃ 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 787 co ₂ ch ₃ 2-F-phenyl 4-morpholinocarbonyl 788 co ₂ ch ₃ 2-F-phenyl 2-methyl-1-imidazolyl 789 co ₂ ch ₃ 2-F-phenyl 5-methyl-1-imidazolyl 790 co ₂ ch ₃ 2-F-phenyl 2-Methyl Isulfonyl-1-imidazolyl 791 co ₂ ch ₃ 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 792 co ₂ ch ₃ 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 793 co ₂ ch ₃ 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 794 co ₂ ch ₃ 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 795 co ₂ ch ₃ 2,6-diF-phenyl 4-Morpholine 796 co ₂ ch ₃ 2,6-diF-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 797 co ₂ ch ₃ 2,6-diF-phenyl 4-morpholinocarbonyl 798 co ₂ ch ₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 799 co ₂ ch ₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 800 co ₂ ch ₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 801 ch ₂ and ₃ phenyl 2- (aminosulfonyl) phenyl 802 ch ₂ and ₃ phenyl 2- (methylaminosulfonyl) phenyl 803 ch ₂ and ₃ phenyl 1-Pyrrolidinocarbonyl 804 ch ₂ and ₃ phenyl 2- (methylsulfonyl) phenyl 805 ch ₂ and ₃ phenyl 4-Morpholine 806 ch ₂ and ₃ phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 807 ch ₂ and ₃ phenyl 4-morpholinocarbonyl 808 ch ₂ and ₃ phenyl 2-methyl-1-imidazolyl 809 ch ₂ and ₃ phenyl 5-methyl-1-imidazolyl 810 ch ₂ and ₃ phenyl 2-methylsulfonyl-1-imidazolyl 811 ch ₂ and ₃ 2-pyridyl 2- (aminosulfonyl) phenyl 812 ch ₂ and ₃ 2-pyridyl 2- (methylaminosulfonyl) phenyl 813 ch ₂ and ₃ 2-pyridyl 1-Pyrrolidinocarbonyl 814 ch ₂ and ₃ 2-pyridyl 2- (methylsulfonyl) phenyl 815 ch ₂ and ₃ 2-pyridyl 4-Morpholine 816 ch ₂ and ₃ 2-pyridyl 2- (1'-CF ₃ -tetrazol-2-yl) phenyl · 817 ch ₂ and ₃ 2-pyridyl 4-morpholinocarbonyl 818 ch ₂ and ₃ 2-pyridyl 2-methyl-1-imidazolyl 819 ch ₂ and ₃ 2-pyridyl 5-methyl-1-imidazolyl 820 ch ₂ and ₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 821 ch ₂ and ₃ 3-pyridyl 2- (aminosulfonyl) phenyl 822 ch ₂ and ₃ 3-pyridyl 2- (methylaminosulfonyl) phenyl 823 ch ₂ and ₃ 3-pyridyl 1-Pyrrolidinocarbonyl 824 ch ₂ and ₃ 3-pyridyl 2- (methylsulfonyl) phenyl 825 ch ₂ and ₃ 3-pyridyl 4-Morpholine 826 ch ₂ and ₃ 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 827 ch ₂ and ₃ 3-pyridyl 4-morpholinocarbonyl 828 ch ₂ and ₃ 3-pyridyl 2-methyl-1-imidazolyl 829 ch ₂ and ₃ 3-pyridyl 5-methyl-1-imidazolyl

324

830 CH2OCH3 3-pyridyl 2-methylsulfonyl-1-imidazolyl 831 CH ₂ OCH ₃ 2-pyrimidyl 2- (aminosulfonyl) phenyl 832 ch ₂ and ₃ 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 833 ch ₂ and ₃ 2-pyrimidyl 1-Pyrrolidinocarbonyl 834 ch ₂ and ₃ 2-pyrimidyl 2- (methylsulfonyl) phenyl 835 ch ₂ and ₃ 2-pyrimidyl 4-Morpholine 836 ch ₂ and ₃ 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 837 ch ₂ and ₃ 2-pyrimidyl 4-morpholinocarbonyl 838 ch ₂ and ₃ 2-pyrimidyl 2-methyl-1-imidazolyl 839 ch ₂ and ₃ 2-pyrimidyl 5-methyl-1-imidazolyl 840 ch ₂ and ₃ 2-pyrimidyl 2-Methylsulfonyl-1-imidazolyl 841 ch ₂ and ₃ 5-pyrimidyl 2- (aminosulfonyl) phenyl 842 ch ₂ and ₃ 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 843 ch ₂ and ₃ 5-pyrimidyl 1-Pyrrolidinocarbonyl 844 ch ₂ and ₃ 5-pyrimidyl 2- (methylsulfonyl) phenyl 845 ch ₂ and ₃ 5-pyrimidyl 4-Morpholine 846 ch ₂ and ₃ 5-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 847 ch ₂ and ₃ 5-pyrimidyl 4-morpholinocarbonyl 848 ch ₂ and ₃ 5-pyrimidyl 2-methyl-1-imidazolyl 849 ch ₂ and ₃ 5-pyrimidyl 5-methyl-1-imidazolyl 850 ch ₂ and ₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 851 ch ₂ and ₃ 2-Cl-phenyl 2- (aminosulfonyl) phenyl 852 ch ₂ and ₃ 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 853 ch ₂ and ₃ 2-CI-phenyl 1-Pyrrolidinocarbonyl 854 ch ₂ and ₃ 2-Cl-phenyl 2- (methylsulfonyl) phenyl 855 ch ₂ and ₃ 2-Cl-phenyl 4-Morpholine 856 ch ₂ and ₃ 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 857 ch ₂ and ₃ 2-Cl-phenyl 4-morpholinocarbonyl 858 ch ₂ and ₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 859 ch ₂ and ₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 860 ch ₂ and ₃ 2-C 1 -phenyl 2-methylsulfonyl-1-imidazolyl 861 ch ₂ and ₃ 2-F-phenyl 2- (aminosulfonyl) phenyl 862 ch ₂ and ₃ 2-F-phenyl 2- (methylaminosulfonyl) phenyl 863 ch ₂ and ₃ 2-F-phenyl 1-Pyrrolidinocarbonyl 864 ch ₂ and ₃ 2-F-phenyl 2- (methylsulfonyl) phenyl 865 ch ₂ and ₃ 2-F-phenyl 4-Morpholine 866 ch ₂ and ₃ 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl; as 867 ch ₂ and ₃ · '·' 2-F-phenyl 4-morpholinocarbonyl 868 ch ₂ and ₃ 2-F-phenyl 2-methyl-1-imidazolyl 869 ch ₂ and ₃ 2-F-phenyl 5-methyl-1-imidazolyl 870 ch ₂ and ₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 871 ch ₂ and ₃ 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 872 ch ₂ and ₃ 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 873 ch ₂ and ₃ 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 874 ch ₂ and ₃ 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 875 ch ₂ and ₃ 2,6-diF-phenyl 4-Morpholine 876 ch ₂ and ₃ 2,6-diF-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 877 ch ₂ and ₃ 2,6-diF-phenyl 4-morpholinocarbonyl

325

878 CH2OCH3 2,6-diF-phenyl 2-methyl-1-imidazolyl 879 CH2OCH3 2,6-diF-phenyl 5-methyl-1-imidazolyl 880 CH2OCH3 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 881 CONH2 phenyl 2- (aminosulfonyl) phenyl (as 882 CONH2 phenyl 2- (methylaminosulfonyl) phenyl 883 CONH2 phenyl 1-Pyrrolidinocarbonyl 884 CONH2 phenyl 2- (methylsulfonyl) phenyl 885 CONH2 phenyl 4-Morpholine 886 conh ₂ phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 887 conh ₂ phenyl 4-morpholinocarbonyl 888 conh ₂ phenyl 2-methyl-1-imidazolyl 889 conh ₂ phenyl 5-methyl-1-imidazolyl 890 conh ₂ phenyl 2-methylsulfonyl-1-imidazolyl 891 conh ₂ 2-pyridyl 2- (aminosulfonyl) phenyl 892 conh ₂ 2-pyridyl 2- (methylaminosulfonyl) phenyl 893 conh ₂ 2-pyridyl 1-Pyrrolidinocarbonyl 894 conh ₂ 2-pyridyl 2- (methylsulfonyl) phenyl 895 conh ₂ 2-pyridyl 4-Morpholine 896 conh ₂ 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 897 conh ₂ 2-pyridyl 4-morpholinocarbonyl 898 conh ₂ 2-pyridyl 2-methyl-1-imidazolyl 899 conh ₂ 2-pyridyl 5-methyl-1-imidazolyl 900 conh ₂ 2-pyridyl 2-m ethyl sulfonyl-1-imidazolyl 901 conh ₂ 3-pyridyl 2- (aminosulfonyl) phenyl 902 conh ₂ 3-pyridyl 2- (methylaminosulfonyl) phenyl 903 CONH2 3-pyridyl 1-Pyrrolidinocarbonyl 904 conh ₂ 3-pyridyl 2- (methylsulfonyl) phenyl 905 CONH2 3-pyridyl 4-Morpholine 906 conh ₂ 3-pyridyl 2- (1'-CF ₃ -tetrazol-2-yl) phenyl 907 conh ₂ 3-pyridyl 4-morpholinocarbonyl 908 conh ₂ 3-pyridyl 2-methyl-1-imidazolyl 909 conh ₂ 3-pyridyl 5-methyl-1-imidazolyl 910 conh ₂ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 911 conh ₂ 2-pyrimidyl 2- (aminosulfonyl) phenyl 912 conh ₂ 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 913 CONH2 2-pyrimidyl 1-Pyrrolidinocarbonyl 914 conh ₂ 2-pyrimidyl 2- (methylsulfonyl) phenyl 915 conh ₂ 2-pyrimidyl 4-Morpholine 916 conh ₂ 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 917 conh ₂ 2-pyrimidyl 4-morpholinocarbonyl 918 conh ₂ 2-pyrimidine 2-methyl-1-imidazolyl 919 conh ₂ 2-pyrimidyl 5-methyl-1-imidazolyl 920 conh ₂ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 921 conh ₂ 5-pyrimidyl 2- (aminosulfonyl) phenyl 922 conh ₂ 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 923 conh ₂ 5-pyrimidyl 1-Pyrrolidinocarbonyl 924 conh ₂ 5-pyrimidyl 2- (methylsulfonyl) phenyl 925 conh ₂ 5-pyrimidyl 4-Morpholine

326

926 conh ₂ 5-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 927 conh ₂ 5-pyrimidyl 4-morpholinocarbonyl 928 conh ₂ 5-pyrimidyl 2-methyl-1-imidazolyl 929 conh ₂ 5-pyrimidyl 5-methyl-1-imidazolyl 930 conh ₂ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 931 conh ₂ 2-Cl-phenyl 2- (aminosulfonyl) phenyl 932 conh ₂ 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 933 conh ₂ 2-Cl-phenyl 1-Pyrrolidinocarbonyl 934 conh ₂ 2-Cl-phenyl 2- (methylsulfonyl) phenyl 935 conh ₂ 2-Cl-phenyl 4-Morpholine 936 conh ₂ 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 937 conh ₂ 2-Cl-phenyl 4-morpholinocarbonyl 938 conh ₂ 2-Cl-phenyl 2-methyl-1-imidazolyl 939 conh ₂ 2-Cl-phenyl 5-methyl-1-imidazolyl 940 conh ₂ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 941 conh ₂ 2-F-phenyl 2- (aminosulfonyl) phenyl 942 conh ₂ 2-F-phenyl 2- (methylaminosulfonyl) phenyl 943 conh ₂ 2-F-phenyl 1-Pyrrolidinocarbonyl 944 conh ₂ 2-F-phenyl 2- (methylsulfonyl) phenyl 945 conh ₂ 2-F-phenyl 4-Morpholine 946 conh ₂ 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 947 conh ₂ 2-F-phenyl 4-morpholinocarbonyl 948 conh ₂ 2-F-phenyl 2-methyl-1-imidazolyl 949 conh ₂ 2-F-phenyl 5-methyl-1-imidazolyl 950 conh ₂ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 951 conh ₂ 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 952 conh ₂ 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 953 conh ₂ 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 954 conh ₂ 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 955 conh ₂ 2,6-diF-phenyl 4-Morpholine 956 conh ₂ 2,6-diF-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 957 conh ₂ 2,6-diF-phenyl 4-morpholinocarbonyl 958 conh ₂ 2,6-diF-phenyl 2-methyl-1-imidazolyl 959 conh ₂ 2,6-diF-phenyl 5-methyl-1-imidazolyl 960 conh ₂ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl

table

327

1 phenyl 2- (aminosulfonyl) phenyl 2 phenyl 2- (methylaminosulfonyl) phenyl 3 phenyl 1-Pyrrolidinocarbonyl 4 phenyl 2- (methylsulfonyl) phenyl 5 phenyl 4-Morpholine 6th phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 7th phenyl 4-morpholinocarbonyl 8th phenyl 2-methyl-1-imidazolyl 9th phenyl 5-methyl-1-imidazolyl 10th phenyl 2-methylsulfonyl-1-imidazolyl 11th 2-pyridyl 2- (aminosulfonyl) phenyl 12th 2-pyridyl 2- (methylaminosulfonyl) phenyl 13th 2-pyridyl 1-Pyrrolidinocarbonyl 14th 2-pyridyl 2- (methylsulfonyl) phenyl 15th 2-pyridyl 4-Morpholine 16th 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 17th 2-pyridyl 4-morpholinocarbonyl 18th 2-pyridyl 2-methyl-1-imidazolyl 19th 2-pyridyl 5-methyl-1-imidazolyl 20th 2-pyridyl 2-methylsulfonyl-1-imidazolyl 21st 3-pyridyl 2- (aminosulfonyl!) Phenyl 22nd 3-pyridyl 2- (methylaminosulfonyl) phenyl 23rd 3-pyridyl 1-Pyrrolidinocarbonyl 24th 3-pyridyl 2- (methylsulfonyl) phenyl 25th 3-pyridyl 4-Morpholine 26th 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 27th 3-pyridyl 4-morpholinocarbonyl 28th 3-pyridyl 2-methyl-1-imidazolyl 29th 3-pyridyl 5-methyl-1-imidazolyl 30th 3-pyridyl 2-methylsulfonyl-1-imidazolyl 31st 2-pyrimidyl 2- (aminosulfonyl) phenyl 32 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 33 2-pyrimidyl 1-Pyrrolidinocarbonyl 34 2-pyrimidyl 2- (methylsulfonyl) phenyl 35 2-pyrimidyl 4-Morpholine 36 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 37 2-pyrimidyl 4-morpholinocarbonyl 38 2-pyrimidyl 2-methyl-1-imidazolyl 39 2-pyrimidyl 5-methyl-1-imidazolyl 40 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 41 5-pyrimidyl 2- (aminosulfonyl) phenyl 42 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 43 5-pyrimidyl 1-Pyrrolidinocarbonyl 44 5-pyrimidyl 2- (methylsulfonyl) phenyl 45 5-pyrimidyl 4-Morpholine 46th 5-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 47 5-pyrimidyl 4-morpholinocarbonyl 48 5-pyrimidyl 2-methyl-1-imidazolyl

328

49 5-pyrimidyl 5-methyl-1-imidazolyl 50 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 51 2-Cl-phenyl 2- (aminosulfonyl) phenyl 52 2-CI Phenyl 2- (methylaminosulfonyl) phenyl 53 2-Cl-phenyl 1-Pyrrolidinocarbonyl 54 2-Cl-phenyl 2- (methylsulfonyl) phenyl 55 2-Cl-phenyl 4-Morpholine 56 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 57 2-Cl-phenyl 4-morpholinocarbonyl 58 2-Cl-phenyl 2-methyl-1-imidazolyl 59 2-Cl-phenyl 5-methyl-1-imidazolyl 60 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 61 2-F-phenyl 2- (aminosulfonyl) phenyl 62 2-F-phenyl 2- (methylaminosulfonyl) phenyl 63 2-F-phenyl 1-Pyrrolidinocarbonyl 64 2-F-phenyl 2- (methylsulfonyl) phenyl 65 2-F-phenyl 4-Morpholine 66 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 67 2-F-phenyl 4-morpholinocarbonyl 68 2-F-phenyl 2-methyl-1-imidazolyl 69 2-F-phenyl 5-methyl-1-imidazolyl 70 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 71 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 72 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 73 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 74 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 75 2,6-diF-phenyl 4-Morpholine 76 2,6-diF-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 77 2,6-diF-phenyl 4-morpholinocarbonyl 78 2,6-diF-phenyl 2-methyl-1-imidazolyl 79 2,6-diF-phenyl 5-methyl-1-imidazolyl 80 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl

table

d e

f

329

330

o

331

For each example, DE has:

(A) pyridin-4-yl-CH _{2 I} (B) 2-amino-pyrimidin-4-yl, (C) 6-amino-pyridin-2-yl, (D) 3-amidin-4-F-phenyl, or (E) N-amidino-3-piperidinyl.

For example, _R1a A  B 1 ch ₃ phenyl 2- (aminosulfonyl) phenyl 2 ch ₃ phenyl 2- (methylaminosulfonyl) phenyl 3 ch ₃ phenyl 1-Pyrrolidinocarbonyl 4 ch ₃ phenyl 2- (methylsulfonyl) phenyl 5 ch ₃ phenyl 4-Morpholine 6th ch ₃ phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 7th ch ₃ phenyl 4-morpholinocarbonyl 8th ch ₃ phenyl 2-methyl-1-imidazolyl 9th ch ₃ phenyl 5-methyl-1-imidazolyl 10th ch ₃ phenyl 2-methylsulfonyl-1-imidazolyl 11th ch ₃ 2-pyridyl 2- (aminosulfonyl) phenyl

332

12th ch ₃ 2-pyridyl 2- (methylaminosulfonyl) phenyl 13th ch ₃ 2-pyridyl 1-Pyrrolidinocarbonyl 14th ch ₃ 2-pyridyl 2- (methylsulfonyl) phenyl 15th ch ₃ 2-pyridyl 4-Morpholine 16th ch ₃ 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 17th ch ₃ 2-pyridyl 4-morpholinocarbonyl 18th ch ₃ 2-pyridyl 2-methyl-1-imidazolyl 19th ch ₃ 2-pyridyl 5-methyl-1-imidazolyl 20th ch ₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 21st ch ₃ 3-pyridyl 2- (aminosulfonyl) phenyl 22nd ch ₃ 3-pyridyl 2- (methylaminosulfonyl) phenyl 23rd ch ₃ 3-pyridyl 1-Pyrrolidinocarbonyl 24th ch ₃ 3-pyridyl 2- (methylsulfonyl) phenyl 25th ch ₃ 3-pyridyl 4-Morpholine 26th ch ₃ 3-pyridyl 2- (1 '-CF ₃ -theirazol-2-yl) phenyl 27th ch ₃ 3-pyridyl 4-morpholinocarbonyl 28th ch ₃ 3-pyridyl 2-methyl-1-imidazolyl 29th ch ₃ 3-pyridyl 5-methyl-1-imidazolyl 30th ch ₃ 3-pyridyl 2-Methyl Isulfonyl-1-imidazolyl 31st ch ₃ 2-pyrimidyl 2- (aminosulfonyl) phenyl 32 ch ₃ 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 33 ch ₃ 2-pyrimidyl 1-Pyrrolidinocarbonyl 34 ch ₃ 2-pyrimidyl 2- (methylsulfonyl) phenyl 35 ch ₃ 2-pyrimidyl 4-Morpholine 36 ch ₃ 2-pyrimidyl 2- {1 '-CF ₃ -tetrazol-2-yl) phenyl 37 ch ₃ 2-pyrimidyl 4-morpholinocarbonyl 38 ch ₃ 2-pyrimidyl 2-methyl-1-imidazolyl 39 ch ₃ 2-pyrimidyl 5-methyl-1-imidazolyl 40 ch ₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 41 ch ₃ 5-pyrimidyl 2- (aminosulfonyl) phenyl 42 ch ₃ 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 43 CHa 5-pyrimidyl 1-Pyrrolidinocarbonyl 44 ch ₃ 5-pyrimidyl 2- (methylsulfonyl) phenyl 45 ch ₃ 5-pyrimidyl 4-Morpholine 46th ch ₃ 5-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 47 ch ₃ 5-pyrimidyl 4-morpholinocarbonyl 48 ch ₃ 5-pyrimidyl 2-methyl-1-imidazolyl 49 ch ₃ .5-Pyrimidyl 5-methyl-1-imidazolyl 50 ch ₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 51 CHa 2-Cl-phenyl 2- (aminosulfonyl!) Phenyl 52 CH ₃ 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 53 ch ₃ 2-Cl-phenyl 1-Pyrrolidinocarbonyl 54 ch ₃ 2-Cl-phenyl 2- (methylsulfonyl) phenyl 55 ch ₃ 2-Cl-phenyl 4-Morpholine 56 ch ₃ 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl as 57 CHa 2-Cl-phenyl 4-morpholinocarbonyl 58 CH ₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 59 ch ₃ 2-Cl-phenyl 5-methyl-1-imidazolyl

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CH ₃ 2 -Cl-phenyl 2-methylsulfonyl-1-imidazolyl

61 ch ₃ 2-F-phenyl 2- (aminosulfonyl) phenyl 62 ch ₃ 2-F-phenyl 2- (methylaminosulfonyl) phenyl 63 ch ₃ 2-F-phenyl 1-Pyrrolidinocarbonyl 64 ch ₃ 2-F-phenyl 2- (methylsulfonyl) phenyl 65 ch ₃ 2-F-phenyl 4-Morpholine 66 ch ₃ 2-F-phenyl 2- (T-CF ₃ -tetrazol-2-yl) phenyl 67 ch ₃ 2-F-phenyl 4-morpholinocarbonyl 68 ch ₃ 2-F-phenyl 2-methyl-1-imidazolyl 69 ch ₃ 2-F-phenyl 5-methyl-1-imidazolyl 70 ch ₃ 2-F-phenyl 2-m ethyl sulfonyl-1-imidazolyl 71 ch ₃ 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 72 ch ₃ 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 73 ch ₃ 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 74 ch ₃ 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 75 ch ₃ 2,6-diF-phenyl 4-Morpholine 76 ch ₃ 2,6-diF-phenyl 2- (T-CF ₃ -tetrazol-2-yl) phenyl 77 ch ₃ 2,6-diF-phenyl 4-morpholinocarbonyl 78 ch ₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 79 ch ₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 80 ch ₃ 2,6-diF-phenyl 2-Methyl Isulfonyl-1-imidazolyl 81 ch ₂ ch ₃ phenyl 2- (aminosulfonyl) phenyl 82 ch ₂ ch ₃ phenyl 2- (methylaminosulfonyl) phenyl 83 ch ₂ ch ₃ phenyl 1-Pyrrolidinocarbonyl 84 ch ₂ ch ₃ phenyl 2- (methylsulfonyl) phenyl 85 ch ₂ ch ₃ phenyl 4-Morpholine 86 ch ₂ ch ₃ phenyl 2- (1'-CF ₃ -tetrazol-2-yl) phenyl 87 ch ₂ ch ₃ phenyl 4-morpholinocarbonyl 88 ch ₂ ch ₃ phenyl 2-methyl-1-imidazolyl 89 CH2CH3 phenyl 5-methyl-1-imidazolyl 90 ch ₂ ch ₃ phenyl 2-methylsulfonyl-1-imidazolyl 91 ch ₂ ch ₃ 2-pyridyl 2- (aminosulfonyl) phenyl 92 ch ₂ ch ₃ 2-pyridyl 2- (methylaminosulfonyl) phenyl 93 ch ₂ ch ₃ 2-pyridyl 1-Pyrrolidinocarbonyl 94 ch ₂ ch ₃ 2-pyridyl 2- (methylsulfonyl) phenyl 95 ch ₂ ch ₃ 2-pyridyl 4-Morpholine 96 ch ₂ ch ₃ 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 97 ch ₂ ch ₃ 2-pyridyl 4-morpholinocarbonyl 98 ch ₂ ch ₃ 2-pyridyl 2-methyl-1-imidazolyl 99 ch ₂ ch ₃ 2-pyridyl 5-methyl-1-imidazolyl 100 ch ₂ ch ₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 101 ch ₂ ch ₃ 3-pyridyl 2- (aminosulfonyl) phenyl 102 ch ₂ ch ₃ 3-pyridyl 2- (methylaminosulfonyl) phenyl 103 ch ₂ ch ₃ 3-pyridyl 1-Pyrrolidinocarbonyl 104 ch ₂ ch ₃ 3-pyridyl 2- (methylsulfonyl) phenyl 105 ch ₂ ch ₃ 3-pyridyl 4-Morpholine 106 CH2CH3 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 107 ch ₂ ch ₃ 3-pyridyl 4-morpholinocarbonyl

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108 CH2CH3 3-pyridyl 2-methyl-1-imidazolyl 109 CH ₂ CH ₃ 3-pyridyl 5-methyl-1-imidazolyl 110 ch ₂ ch ₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 111 ch ₂ ch ₃ 2-pyrimidyl 2- (aminosulfonyl) phenyl 112 ch ₂ ch ₃ 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 113 ch ₂ ch ₃ 2-pyrimidyl 1-Pyrrolidinocarbonyl 114 ch ₂ ch ₃ 2-pyrimidyl 2- (methylsulfonyl) phenyl 115 ch ₂ ch ₃ 2-pyrimidyl 4-Morpholine 116 ch ₂ ch ₃ 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 117 ch ₂ ch ₃ 2-pyrimidyl 4-morpholinocarbonyl 118 ch ₂ ch ₃ 2-pyrimidyl 2-methyl-1-imidazolyl 119 ch ₂ ch ₃ 2-pyrimidyl 5-methyl-1-imidazolyl 120 ch ₂ ch ₃ 2-pyrimidyl 2-Methyl Isulfonyl-1-imidazolyl 121 ch ₂ ch ₃ 5-pyrimidyl 2- (aminosulfonyl) phenyl 122 ch ₂ ch ₃ 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 123 ch ₂ ch ₃ 5-pyrimidyl 1-Pyrrolidinocarbonyl 124 ch ₂ ch ₃ 5-pyrimidyl 2- (methylsulfonyl) phenyl. 125 ch ₂ ch ₃ 5-pyrimidyl 4-Morpholine 126 ch ₂ ch ₃ 5-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 127 ch ₂ ch ₃ 5-pyrimidyl 4-morpholinocarbonyl 128 ch ₂ ch ₃ 5-pyrimidyl 2-methyl-1-imidazolyl 129 ch ₂ ch ₃ 5-pyrimidyl 5-methyl-1-imidazolyl 130 ch ₂ ch ₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 131 ch ₂ ch ₃ 2-Cl-phenyl 2- (aminosulfonyl) phenyl 132 ch ₂ ch ₃ 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 133 ch ₂ ch ₃ 2-Cl-phenyl 1-Pyrrolidinocarbonyl 134 ch ₂ ch ₃ 2-Cl-phenyl 2- (methylsulfonyl) phenyl 135 ch ₂ ch ₃ 2-Cl-phenyl 4-Morpholine 136 ch ₂ ch ₃ 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 137 ch ₂ ch ₃ 2-Cl-phenyl 4-morpholinocarbonyl 138 ch ₂ ch ₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 139 ch ₂ ch ₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 140 ch ₂ ch ₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 141 ch ₂ ch ₃ 2-F-phenyl 2- (aminosulfonyl) phenyl 142 ch ₂ ch ₃ 2-F-phenyl 2- (methylaminosulfonyl) phenyl 143 ch ₂ ch ₃ 2-F-phenyl 1-Pyrrolidinocarbonyl 144 ch ₂ ch ₃ 2-F-phenyl 2- (methylsulfonyl) phenyl 145 ch ₂ ch ₃ , 2-F-phenyl 4-Morpholine 146 ch ₂ ch ₃ 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 147 ch ₂ ch ₃ 2-F-phenyl 4-morpholinocarbonyl 148 ch ₂ ch ₃ 2-F-phenyl 2-methyl-1-imidazolyl 149 ch ₂ ch ₃ 2-F-phenyl 5-methyl-1-imidazolyl 150 ch ₂ ch ₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 151 ch ₂ ch ₃ 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 152 ch ₂ ch ₃ 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 153 ch ₂ ch ₃ 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 154 ch ₂ ch ₃ 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 155 ch ₂ ch ₃ 2,6-diF-phenyl 4-Morpholine

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156 CH ₂ CH ₃ 2,6-diF-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 157 CH2CH3 2,6-diF-phenyl 4-morpholinocarbonyl 158 CH2CH3 2,6-diF-phenyl 2-methyl-1-imidazolyl 159 CH2CH3 2,6-diF-phenyl 5-methyl-1-imidazolyl 160 CH2CH3 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 161 cf ₃ phenyl 2- (aminosulfonyl) phenyl 162 cf ₃ phenyl 2- (methylaminosulfonyl) phenyl 163 cf ₃ phenyl 1-Pyrrolidinocarbonyl 164 cf ₃ phenyl 2- (methylsulfonyl) phenyl 165 cf ₃ phenyl 4-Morpholine 166 cf ₃ phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 167 cf ₃ phenyl 4-morpholinocarbonyl 168 cf ₃ phenyl 2-methyl-1-imidazolyl 169 cf ₃ phenyl 5-methyl-1-imidazolyl 170 cf ₃ phenyl 2-methylsulfonyl-1-imidazolyl 171 cf ₃ 2-pyridyl 2- (aminosulfonyl) phenyl 172 cf ₃ 2-pyridyl 2- (methylaminosulfonyl) phenyl 173 cf ₃ 2-pyridyl 1-Pyrrolidinocarbonyl 174 cf ₃ 2-pyridyl 2- (methylsulfonyl) phenyl 175 cf ₃ 2-pyridyl 4-Morpholine 176 cf ₃ 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 177 cf ₃ 2-pyridyl 4-morpholinocarbonyl 178 cf ₃ 2-pyridyl 2-methyl-1-imidazolyl 179 cf ₃ 2-pyridyl 5-methyl-1-imidazolyl 180 cf ₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 181 cf ₃ 3-pyridyl 2- (Aminosulfonyl) phenyl 182 cf ₃ 3-pyridyl 2- (methylaminosulfonyl) phenyl 183 cf ₃ 3-pyridyl 1-Pyrrolidinocarbonyl 184 cf ₃ 3-pyridyl 2- (methylsulfonyl) phenyl 185 cf ₃ 3-pyridyl 4-Morpholine 186 cf ₃ 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 187 cf ₃ 3-pyridyl 4-morpholinocarbonyl 188 cf ₃ 3-pyridyl 2-methyl-1-imidazolyl 189 cf ₃ 3-pyridyl 5-methyl-1-imidazolyl 190 cf ₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl · 191 cf ₃ 2-pyrimidyl 2- (aminosulfonyl) phenyl 192 cf ₃ 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 193 cf ₃ 2-pyrimidyl 1-Pyrrolidinocarbonyl 194 cf ₃ 2-pi'rimidyl 2- (methylsulfonyl) phenyl 195 cf ₃ 2-pyrimidyl 4-Morpholine 196 cf ₃ 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 197 cf ₃ 2-pyrimidyl 4-morpholinocarbonyl 198 cf ₃ 2-pyrimidyl 2-methyl-1-imidazolyl 199 cf ₃ 2-pyrimidyl 5-methyl-1-imidazolyl 200 cf ₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 201 cf ₃ 5-pyrimidyl 2- (aminosulfonyl) phenyl 202 cf ₃ 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 203 cf ₃ 5-pyrimidyl 1-Pyrrolidinocarbonyl

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204 cf ₃ 5-pyrimidyl 2- (methylsulfonyl) phenyl 205 cf ₃ 5-pyrimidyl 4-Morpholine 206 cf ₃ 5-pyrimidyl 2- (T-CF ₃ -tetrazol-2-yl) phenyl 207 cf ₃ 5-pyrimidyl 4-morpholinocarbonyl 208 cf ₃ 5-pyrimidyl 2-methyl-1-imidazolyl 209 cf ₃ 5-pyrimidyl 5-methyl-1-imidazolyl 210 cf ₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 211 cf ₃ 2-Cl-phenyl 2- (aminosulfonyl) phenyl 212 cf ₃ 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 213 cf ₃ 2-Cl-phenyl 1-Pyrrolidinocarbonyl 214 cf ₃ 2-Cl-phenyl 2- (methylsulfonyl) phenyl 215 cf ₃ 2-Cl-phenyl 4-Morpholine 216 cf ₃ 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 217 cf ₃ 2-Cl-phenyl 4-morpholinocarbonyl 218 cf ₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 219 cf ₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 220 cf ₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 221 cf ₃ 2-F-Phenyl 2- (aminosulfonyl) phenyl 222 cf ₃ 2-F-phenyl 2- (methylaminosulfonyl) phenyl 223 cf ₃ 2-F-phenyl 1-Pyrrolidinocarbonyl 224 cf ₃ 2-F-phenyl 2- (methylsulfonyl) phenyl 225 cf ₃ 2-F-phenyl 4-morpholine 226 cf ₃ 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 227 cf ₃ 2-F-phenyl 4-morpholinocarbonyl 228 cf ₃ 2-F-phenyl 2-methyl-1-imidazolyl 229 cf ₃ 2-F-phenyl 5-methyl-1-imidazolyl 230 cf ₃ 2-F-phenyl 2-Methylsulfonyl-1-imidazolyl 231 cf ₃ 2,6-diF-phenyl 2- (aminosulfonyl!) Phenyl 232 cf ₃ 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 233 cf ₃ 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 234 cf ₃ 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 235 cf ₃ 2,6-diF-phenyl 4-Morpholine 236 cf ₃ 2,6-diF-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 237 cf ₃ 2,6-diF-phenyl 4-morpholinocarbonyl 238 cf ₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 239 cf ₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 240 cf ₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 241 sch ₃ · / Phenyl 2- (aminosulfonyl) phenyl 242 sch ₃ phenyl 2- (methylaminosulfonyl) phenyl 243 sch ₃ phenyl 1-Pyrrolidinocarbonyl 244 sch ₃ phenyl 2- (methylsulfonyl) phenyl 245 sch ₃ phenyl 4-Morpholine 246 sch ₃ phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 247 sch ₃ phenyl 4-morpholinocarbonyl 248 sch ₃ phenyl 2-methyl-1-imidazolyl 249 sch ₃ phenyl 5-methyl-1-imidazolyl 250 sch ₃ phenyl 2-Methylsulfonyl-1-imidazolyl 251 sch ₃ 2-pyridyl 2- (aminosulfonyl!) Phenyl

337

252 sch ₃ 2-pyridyl 2- (methylaminosulfonyl) phenyl 253 sch ₃ 2-pyridyl 1-Pyrrolidinocarbonyl 254 sch ₃ 2-pyridyl 2- (methylsulfonyl) phenyl 255 sch ₃ 2-pyridyl 4-Morpholine 256 sch ₃ 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 257 sch ₃ 2-pyridyl 4-morpholinocarbonyl 258 sch ₃ 2-pyridyl 2-methyl-1-imidazolyl 259 sch ₃ 2-pyridyl 5-methyl-1-imidazolyl 260 sch ₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 261 sch ₃ 3-pyridyl 2- (aminosulfonyl) phenyl 262 sch ₃ 3-pyridyl 2- (methylaminosulfonyl) phenyl 263 sch ₃ 3-pyridyl 1-Pyrrolidinocarbonyl 264 sch ₃ 3-pyridyl 2- (methylsulfonyl) phenyl 265 sch ₃ 3-pyridyl 4-Morpholine 266 sch ₃ 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 267 sch ₃ 3-pyridyl 4-morpholinocarbonyl 268 sch ₃ 3-pyridyl 2-methyl-1-imidazolyl 269 sch ₃ 3-pyridyl 5-methyl-1-imidazolyl 270 sch ₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 271 sch ₃ 2-pyrimidyl 2- (aminosulfonyl) phenyl 272 sch ₃ 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 273 sch ₃ 2-pyrimidyl 1-Pyrrolidinocarbonyl 274 sch ₃ 2-pyrimidyl 2- (methylsulfonyl) phenyl 275 sch ₃ 2-pyrimidyl 4-Morpholine 276 sch ₃ 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl as 277 sch ₃ 2-pyrimidyl 4-morpholinocarbonyl 278 sch ₃ 2-pyrimidyl 2-methyl-1-imidazolyl 279 sch ₃ 2-pyrimidyl 5-methyl-1-imidazolyl 280 sch ₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 281 sch ₃ 5-pyrimidyl 2- (aminosulfonyl) phenyl 282 sch ₃ 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 283 sch ₃ 5-pyrimidyl 1-Pyrrolidinocarbonyl 284 sch ₃ 5-pyrimidyl 2- (methylsulfonyl) phenyl 285 sch ₃ 5-pyrimidyl 4-Morpholine 286 sch ₃ 5-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 287 SCHa 5-pyrimidyl 4-morpholinocarbonyl 288 SCHa 5-pyrimidyl 2-methyl-1-imidazolyl 289 sch ₃ 5-prrimidyl 5-methyl-1-imidazolyl 290 sch ₃ 5-pyrimidyl 2-Methylsulfonyl-1-imidazolyl 291 sch ₃ 2-Cl-phenyl 2- (aminosulfonyl) phenyl 292 sch ₃ 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 293 SCHa 2-Cl-phenyl 1-Pyrrolidinocarbonyl 294 sch ₃ 2-Cl-phenyl 2- (methylsulfonyl) phenyl 295 SCHa 2-Cl-phenyl 4-Morpholine 296 sch ₃ 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 297 sch ₃ 2-Cl-phenyl 4-morpholinocarbonyl 298 sch ₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 299 sch ₃ 2-CI Phenyl 5-methyl-1-imidazolyl

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300 sch ₃ 2-Cl-phenyl 2-Methyl Isulfonyl-1-imidazolyl 301 sch ₃ 2-F-phenyl 2- (aminosulfonyl) phenyl 302 sch ₃ 2-F-phenyl 2- (methylaminosulfonyl) phenyl 303 sch ₃ 2-F-phenyl 1-Pyrrolidinocarbonyl 304 sch ₃ 2-F-phenyl 2- (methylsulfonyl) phenyl 305 sch ₃ 2-F-phenyl 4-Morpholine 306 sch ₃ 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 307 sch ₃ 2-F-phenyl 4-morpholinocarbonyl 308 sch ₃ 2-F-phenyl 2-methyl-1-imidazolyl 309 sch ₃ 2-F-phenyl 5-methyl-1-imidazolyl 310 sch ₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 311 sch ₃ 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 312 sch ₃ 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 313 sch ₃ 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 314 sch ₃ 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 315 sch ₃ 2,6-diF-phenyl 4-Morpholine 316 sch ₃ 2,6-diF-phenyl 2- (1'-CF ₃ -tetrazol-2-yl) phenyl 317 sch ₃ 2,6-diF-phenyl 4-morpholinocarbonyl 318 sch ₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 319 sch ₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 320 sch ₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 321 soch ₃ phenyl 2- (aminosulfonyl) phenyl 322 soch ₃ phenyl 2- (methylaminosulfonyl) phenyl 323 soch ₃ phenyl 1-Pyrrolidinocarbonyl 324 soch ₃ phenyl 2- (methylsulfonyl) phenyl 325 soch ₃ phenyl 4-Morpholine 326 soch ₃ phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 327 soch ₃ phenyl 4-morpholinocarbonyl 328 SOCHa phenyl 2-methyl-1-imidazolyl 329 soch ₃ phenyl 5-methyl) -1-imidazolyl 330 soch ₃ phenyl 2-methylsulfonyl-1-imidazolyl 331 soch ₃ 2-pyridyl 2- (aminosulfonyl) phenyl 332 soch ₃ 2-pyridyl 2- (methylaminosulfonyl) phenyl 333 soch ₃ 2-pyridyl 1-Pyrrolidinocarbonyl 334 soch ₃ 2-pyridyl 2- (methylsulfonyl) phenyl 335 soch ₃ 2-pyridyl 4-Morpholine 336 soch ₃ 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 337 soch ₃ .. 2-Pyridyl 4-morpholinocarbonyl 338 soch ₃ 2-pyridyl 2-methyl-1-imidazolyl 339 soch ₃ 2-pyridyl 5-methyl-1-imidazolyl 340 soch ₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 341 soch ₃ 3-pyridyl 2- (aminosulfonyl) phenyl 342 soch ₃ 3-pyridyl 2- (methylaminosulfonyl) phenyl 343 SOCH3 3-pyridyl 1-Pyrrolidinocarbonyl 344 soch ₃ 3-pyridyl 2- (methylsulfonyl) phenyl 345 soch ₃ 3-pyridyl 4-Morpholine 346 soch ₃ 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 347 soch ₃ 3-pyridyl 4-morpholinocarbonyl

339

348 SOCH ₃ 3-pyridyl 2-methyl-1-imidazolyl 349 SOCH3 3-pyridyl 5-methyl-1-imidazolyl 350 SOCH3 3-pyridyl 2-methylsulfonyl-1-imidazolyl 351 SOCH3 2-pyrimidyl 2- (aminosulfonyl) phenyl 352 SOCH3 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 353 SOCH3 2-pyrimidyl 1-Pyrrolidinocarbonyl 354 SOCH3 2-pyrimidyl 2- (methylsulfonyl) phenyl 355 SOCH3 2-pyrimidyl 4-Morpholine 356 SOCH3 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 357 SOCH3 2-pyrimidyl 4-morpholinocarbonyl 358 SOCH3 2-pyrimidyl 2-methyl-1-imidazolyl 359 SOCH3 2-pyrimidyl 5-methyl-1-imidazolyl 360 SOCH3 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 361 SOCH3 5-pyrimidyl 2- (aminosulfonyl) phenyl 362 SOCH3 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 363 soch ₃ 5-pyrimidyl 1-Pyrrolidinocarbonyl 364 soch ₃ 5-pyrimidyl 2- (methylsulfonyl) phenyl 365 soch ₃ 5-pyrimidyl 4-Morpholine 366 soch ₃ 5-pyrimidyl 2- (1 ^: -CF ₃ -etrazol-2-yl) phenyl 367 soch ₃ 5-pyrimidyl 4-morpholinocarbonyl 368 soch ₃ 5-pyrimidyl 2-methyl-1-imidazolyl 369 soch ₃ 5-pyrimidyl 5-methyl-1-imidazolyl 370 soch ₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 371 soch ₃ 2-Cl-phenyl 2- (aminosulfonyl) phenyl 372 soch ₃ 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 373 soch ₃ 2-Cl-phenyl 1-Pyrrolidinocarbonyl 374 soch ₃ 2-Cl-phenyl 2- (methylsulfonyl) phenyl 375 soch ₃ 2-Cl-phenyl 4-Morpholine 376 soch ₃ 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 377 SOCH3 2-Cl-phenyl 4-morpholinocarbonyl 378 soch ₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 379 soch ₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 380 soch ₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 381 soch ₃ 2-F-phenyl 2- (aminosulfonyl) phenyl 382 soch ₃ 2-F-phenyl 2- (methylaminosulfonyl) phenyl 383 soch ₃ 2-F-phenyl 1-Pyrrolidinocarbonyl 384 soch ₃ 2-F-phenyl 2- (methylsulfonyl) phenyl 385 soch ₃ 2-F-phenyl 4-Morpholine 386 soch ₃ 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 387 soch ₃ 2-F-phenyl 4-morpholinocarbonyl 388 soch ₃ 2-F-phenyl 2-methyl-1-imidazolyl 389 soch ₃ 2-F-phenyl 5-methyl-1-imidazolyl 390 soch ₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 391 soch ₃ 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 392 soch ₃ 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 393 SOCH ₃ 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 394 soch ₃ 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 395 soch ₃ 2,6-diF-phenyl 4-Morpholine

340

396 SOCH ₃ 2,6-diF-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 397 SOCH3 2,6-diF-phenyl 4-morpholinocarbonyl 398 SOCH3 2,6-diF-phenyl 2-methyl-1-imidazolyl 399 SOCH3 2,6-diF-phenyl 5-methyl-1-imidazolyl 400 SOCH3 2,6-diF-phenyl 2-Methylsulfonyl-1-imidazolyl 401 SO ₂ CH ₃ phenyl 2- (aminosulfonyl) phenyl 402 so ₂ ch ₃ phenyl 2- (methylaminosulfonyl) phenyl 403 so ₂ ch ₃ phenyl 1-Pyrrolidinocarbonyl 404 so ₂ ch ₃ phenyl 2- (methylsulfonyl) phenyl 405 so ₂ ch ₃ phenyl 4-Morpholine 406 so ₂ ch ₃ phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 407 so ₂ ch ₃ phenyl 4-morpholinocarbonyl 408 so ₂ ch ₃ • phenyl 2-methyl-1-imidazolyl 409 so ₂ ch ₃ phenyl 5-methyl-1-imidazolyl 410 so ₂ ch ₃ phenyl 2-Methyl Isulfonyl-1-imidazolyl 411 so ₂ ch ₃ 2-pyridyl 2- (aminosulfonyl) phenyl 412 so ₂ ch ₃ 2-pyridyl 2- (methylaminosulfonyl) phenyl 413 so ₂ ch ₃ 2-pyridyl 1-Pyrrolidinocarbonyl 414 so ₂ ch ₃ 2-pyridyl 2- (methylsulfonyl) phenyl 415 so ₂ ch ₃ 2-pyridyl 4-Morpholine 416 so ₂ ch ₃ 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 417 so ₂ ch ₃ 2-pyridyl 4-morpholinocarbonyl 418 so ₂ ch ₃ 2-pyridyl 2-methyl-1-imidazolyl 419 so ₂ ch ₃ 2-pyridyl 5-methyl-1-imidazolyl 420 so ₂ ch ₃ 2-pyridyl 2-methylsulfonyl 1-1-imidazolyl 421 so ₂ ch ₃ 3-pyridyl 2- (aminosulfonyl) phenyl 422 so ₂ ch ₃ 3-pyridyl 2- (methylaminosulfonyl) phenyl 423 so ₂ ch ₃ 3-pyridyl 1-Pyrrolidinocarbonyl 424 so ₂ ch ₃ 3-pyridyl 2- (methylsulfonyl) phenyl 425 so ₂ ch ₃ 3-pyridyl 4-Morpholine 426 so ₂ ch ₃ 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 427 so ₂ ch ₃ 3-pyridyl 4-morpholinocarbonyl 428 so ₂ ch ₃ 3-pyridyl 2-methyl-1-imidazolyl 429 so ₂ ch ₃ 3-pyridyl 5-methyl-1-imidazolyl 430 so ₂ ch ₃ 3-pyridyl 2-Methylsulfone-1-imidazolyl 431 so ₂ ch ₃ 2-pyrimidine 2- (aminosulfonyl) phenyl 432 so ₂ ch ₃ 2-pyrimidine 2- (methylaminosulfonyl) phenyl 433 so ₂ ch ₃ 2-pyrimidyl 1-Pyrrolidinocarbonyl 434 so ₂ ch ₃ 2-pyrimidyl 2- (methylsulfonyl) phenyl 435 so ₂ ch ₃ 2-pyrimidyl 4-Morpholine 436 so ₂ ch ₃ 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 437 so ₂ ch ₃ 2-pyrimidyl 4-morpholinocarbonyl 438 so ₂ ch ₃ 2-pyrimidyl 2-methyl-1-imidazolyl 439 so ₂ ch ₃ 2-pyrimidyl 5-methyl-1-imidazolyl 440 so ₂ ch ₃ 2-pyrimidyl 2-Methylsulfonyl-1-imidazolyl 441 so ₂ ch ₃ 5-pyrimidyl 2- (aminosulfonyl) phenyl 442 so ₂ ch ₃ 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 443 so ₂ ch ₃ 5-pyrimidyl 1-Pyrrolidinocarbonyl

341

444 so ₂ ch ₃ 5-pyrimidyl 2- (methylsulfonyl) phenyl 445 so ₂ ch ₃ 5-pyrimidyl 4-Morpholine 446 so ₂ ch ₃ 5-pyrimidyl 2- (1 ¹ -CF ₃ tetrazolo-2-yl) phenyl 447 so ₂ ch ₃ 5-pyrimidyl 4-morpholinocarbonyl 448 so ₂ ch ₃ 5-pyrimidyl 2-methyl-1-imidazolyl 449 so ₂ ch ₃ 5-pyrimidyl 5-methyl-1-imidazolyl 450 so ₂ ch ₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 451 so ₂ ch ₃ 2-Cl-phenyl 2- (aminosulfonyl) phenyl 452 so ₂ ch ₃ 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 453 so ₂ ch ₃ 2-Cl-phenyl 1-Pyrrolidinocarbonyl 454 so ₂ ch ₃ 2-Cl-phenyl 2- (methylsulfonyl) phenyl 455 so ₂ ch ₃ 2-Cl-phenyl 4-Morpholine 456 so ₂ ch ₃ 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 457 so ₂ ch ₃ 2-Cl-phenyl 4-morpholinocarbonyl 458 so ₂ ch ₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 459 so ₂ ch ₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 460 so ₂ ch ₃ 2-Cl-phenyl 2-Methyl Isulfonyl -1-imidazolyl 461 so ₂ ch ₃ 2-F-phenyl 2- (aminosulfonyl) phenyl 462 so ₂ ch ₃ 2-F-phenyl 2- (methylaminosulfonyl) phenyl 463 so ₂ ch ₃ 2-F-phenyl 1-Pyrrolidinocarbonyl 464 so ₂ ch ₃ 2-F-phenyl 2- (methylsulfonyl) phenyl 465 so ₂ ch ₃ 2-F-phenyl 4-Morpholine 466 so ₂ ch ₃ 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 467 so ₂ ch ₃ 2-F-phenyl 4-morpholinocarbonyl 468 so ₂ ch ₃ 2-F-phenyl 2-methyl-1-imidazolyl 469 so ₂ ch ₃ 2-F-phenyl 5-methyl-1-imidazolyl 470 so ₂ ch ₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 471 so ₂ ch ₃ 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 472 so ₂ ch ₃ 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 473 so ₂ ch ₃ 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 474 so ₂ ch ₃ 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 475 so ₂ ch ₃ 2,6-diF-phenyl 4-Morpholine 476 so ₂ ch ₃ 2,6-diF-phenyl. 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 477 so ₂ ch ₃ 2,6-diF-phenyl 4-morpholinocarbonyl 478 so ₂ ch ₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 479 so ₂ ch ₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl '480 so ₂ ch ₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 481 ch ₂ nh-so ₂ ch ₃ phenyl 2- (aminosulfonyl) phenyl 482 ch ₂ nh-so ₂ ch ₃ phenyl 2- (methylaminosulfonyl) phenyl 483 ch ₂ nh-so ₂ ch ₃ phenyl 1-Pyrrolidinocarbonyl 484 ch ₂ nh-so ₂ ch ₃ phenyl 2- (methylsulfonyl) phenyl 485 ch ₂ nh-so ₂ ch ₃ phenyl 4-Morpholine 486 ch ₂ nh-so ₂ ch ₃ phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 487 ch ₂ nh-so ₂ ch ₃ phenyl 4-morpholinocarbonyl 488 ch ₂ nh-so ₂ ch ₃ phenyl 2-methyl-1-imidazolyl 489 ch ₂ nh-so ₂ ch ₃ phenyl 5-methyl-1-imidazolyl 490 ch ₂ nh-so ₂ ch ₃ phenyl 2 years! sulfonyl-1-imidazolyl 491 ch ₂ nh-so ₂ ch ₃ 2-pyridyl 2- (aminosulfonyl) phenyl

342

492 CH 2 NH-SO 2 CH 3 2-pyridyl 2- (methylaminosulfonyl) phenyl 493 CH ₂ NH-SO ₂ CH ₃ 2-pyridyl 1-Pyrrolidinocarbonyl 494 ch ₂ nh-so ₂ ch ₃ 2-pyridyl 2- (methylsulfonyl) phenyl 495 ch ₂ nh-so ₂ ch ₃ 2-pyridyl 4-Morpholine 496 ch ₂ nh-so ₂ ch ₃ 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 497 ch ₂ nh-so ₂ ch ₃ 2-pyridyl 4-morpholinocarbonyl 498 ch ₂ nh-so ₂ ch ₃ 2-pyridyl 2-methyl-1-imidazolyl 499 ch ₂ nh-so ₂ ch ₃ 2-pyridyl 5-methyl-1-imidazolyl 500 ch ₂ nh-so ₂ ch ₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 501 ch ₂ nh-so ₂ ch ₃ 3-pyridyl 2- (Aminosu! Background) phenyl 502 ch ₂ nh-so ₂ ch ₃ 3-pyridyl 2- (methylaminosulfonyl) phenyl 503 ch ₂ nh-so ₂ ch ₃ 3-pyridyl 1-Pyrrolidinocarbonyl 504 ch ₂ nh-so ₂ ch ₃ 3-pyridyl 2- (methylsulfonyl) phenyl 505 ch ₂ nh-so ₂ ch ₃ 3-pyridyl 4-Morpholine 506 ch ₂ nh-so ₂ ch ₃ 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 507 ch ₂ nh-so ₂ ch ₃ 3-pyridyl 4-morpholinocarbonyl 508 ch ₂ nh-so ₂ ch ₃ 3-pyridyl 2-methyl-1-imidazolyl 509 ch ₂ nh-so ₂ ch ₃ 3-pyridyl 5-methyl-1-imidazolyl 510 ch ₂ nh-so ₂ ch ₃ 3-pyridyl 2-Methylsulfonyl-1-imidazolyl 511 ch ₂ nh-so ₂ ch ₃ 2-pyrimidyl 2- (aminosulfonyl!) Phenyl 512 ch ₂ nh-so ₂ ch ₃ 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 513 ch ₂ nh-so ₂ ch ₃ 2-pyrimidyl 1-Pyrrolidinocarbonyl 514 ch ₂ nh-so ₂ ch ₃ 2-pyrimidyl 2- (methylsulfonyl) phenyl 515 ch ₂ nh-so ₂ ch ₃ 2-pyrimidyl 4-Morpholine 516 ch ₂ nh-so ₂ ch ₃ 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 517 ch ₂ nh-so ₂ ch ₃ 2-pyrimidyl 4-morpholinocarbonyl 518 ch ₂ nh-so ₂ ch ₃ 2-pyrimidyl 2-methyl-1-imidazolyl 519 CH 2 NH-SO 2 CH 3 2-pyrimidyl 5-methyl-1-imidazolyl 520 CH ₂ NH-SO ₂ CH ₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 521 ch ₂ nh-so ₂ ch ₃ 5-pyrimidyl 2- (aminosulfonyl) phenyl 522 ch ₂ nh-so ₂ ch ₃ 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 523 ch ₂ nh-so ₂ ch ₃ 5-pyrimidyl 1-Pyrrolidinocarbonyl 524 ch ₂ nh-so ₂ ch ₃ 5-pyrimidyl 2- (methylsulfonyl) phenyl 525 ch ₂ nh-so ₂ ch ₃ 5-pyrimidyl 4-Morpholine 526 ch ₂ nh-so ₂ ch ₃ 5-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 527 ch ₂ nh-so ₂ ch ₃ 5-pyrimidyl 4-morpholinocarbonyl 528 ch ₂ nh-so ₂ ch ₃ 5-pyrimidyl 2-methyl-1-imidazolyl 529 ch ₂ nh-so ₂ ch ₃ • 5-pyrimidyl 5-methyl-1-imidazolyl 530 ch ₂ nh-so ₂ ch ₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 531 ch ₂ nh-so ₂ ch ₃ 2-Cl-phenyl 2- (aminosulfonyl) phenyl 532 ch ₂ nh-so ₂ ch ₃ 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 533 ch ₂ nh-so ₂ ch ₃ 2-Cl-phenyl 1-Pyrrolidinocarbonyl 534 ch ₂ nh-so ₂ ch ₃ 2-Cl-phenyl 2- (methylsulfonyl) phenyl 535 ch ₂ nh-so ₂ ch ₃ 2-Cl-phenyl 4-Morpholine 536 ch ₂ nh-so ₂ ch ₃ 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 537 ch ₂ nh-so ₂ ch ₃ 2-Cl-phenyl 4-morpholinocarbonyl 538 ch ₂ nh-so ₂ ch ₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 539 ch ₂ nh-so ₂ ch ₃ 2-Cl-phenyl 5-methyl-1-imidazolyl

343

540 CH2NH-SO2CH3 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl

541 CH 2 NH-SO 2 CH 3 2-F-phenyl 2- (aminosulfonyl) phenyl 542 CH 2 NH-SO 2 CH 3 2-F-phenyl 2- (methylaminosulfonyl) phenyl 543 CH ₂ NH-SO ₂ CH ₃ 2-F-phenyl 1-Pyrrolidinocarbonyl 544 ch ₂ nh-so ₂ ch ₃ 2-F-phenyl 2- (methylsulfonyl) phenyl 545 ch ₂ nh-so ₂ ch ₃ 2-F-phenyl 4-Morpholine 546 ch ₂ nh-so ₂ ch ₃ 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 547 ch ₂ nh-so ₂ ch ₃ 2-F-phenyl 4-morpholinocarbonyl 548 ch ₂ nh-so ₂ ch ₃ 2-F-phenyl 2-methyl-1-imidazolyl 549 ch ₂ nh-so ₂ ch ₃ 2-F-phenyl 5-methyl-1-imidazolyl 550 ch ₂ nh-so ₂ ch ₃ 2-F-phenyl 2-Methyl Isuifonyl-1-imidazolyl 551 ch ₂ nh-so ₂ ch ₃ 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 552 ch ₂ nh-so ₂ ch ₃ 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 553 ch ₂ nh-so ₂ ch ₃ 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 554 ch ₂ nh-so ₂ ch ₃ 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 555 ch ₂ nh-so ₂ ch ₃ 2,6-diF-phenyl 4-Morpholine 556 ch ₂ nh-so ₂ ch ₃ 2,6-diF-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 557 ch ₂ nh-so ₂ ch ₃ 2,6-diF-phenyl 4-morpholinocarbonyl 558 ch ₂ nh-so ₂ ch ₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 559 ch ₂ nh-so ₂ ch ₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 560 ch ₂ nh-so ₂ ch ₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 561 Cl phenyl 2- (aminosulfonyl) phenyl 562 Cl phenyl 2- (methylaminosulfonyl) phenyl 563 Cl phenyl 1-Pyrrolidinocarbonyl 564 Cl phenyl 2- (methylsulfonyl) phenyl 565 Cl phenyl 4-Morpholine 566 Cl phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 567 Cl phenyl 4-morpholinocarbonyl 568 Cl phenyl 2-methyl-1-imidazolyl 569 Cl phenyl 5-methyl-1-imidazolyl 570 Cl phenyl 2-Methylsulfonyl-1-imidazolyl 571 Cl 2-pyridyl 2- (aminosulfonyl) phenyl 572 Cl 2-pyridyl 2- (methylaminosulfonyl) phenyl 573 Cl 2-pyridyl 1-Pyrrolidinocarbonyl 574 Cl 2-pyridyl 2- (methylsulfonyl) phenyl 575 Cl 2-pyridyl 4-Morpholine 576 Cl 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 577 Cl 2-pyridyl 4-morpholinocarbonyl 578 Cl 2-pyridyl 2-methyl-1-imidazolyl 579 Cl 2-pyridyl 5-methyl-1-imidazolyl 580 Cl 2-pyridyl 2-methylsulfonyl-1-imidazolyl 581 Cl 3-pyridyl 2- (aminosulfonyl) phenyl 582 Cl 3-pyridyl 2- (methylaminosulfonyl) phenyl 583 Cl 3-pyridyl 1-Pyrrolidinocarbonyl 584 Cl 3-pyridyl 2- (methylsulfonyl) phenyl 585 Cl 3-pyridyl 4-Morpholine 586 Cl 3-pyridyl 2- (1'-CF ₃ -tetrazol-2-yl) phenyl 587 Cl 3-pyridyl 4-morpholinocarbonyl

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588 Cl 3-pyridyl 2-methyl-1-imidazolyl 589 Cl 3-pyridyl 5-methyl-1-imidazolyl 590 Cl 3-pyridyl 2-methylsulfonyl-1-imidazolyl 591 Cl 2-pyrimidyl 2- (aminosulfonyl) phenyl 592 Cl 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 593 Cl 2-pyrimidyl 1-Pyrrolidinocarbonyl 594 Cl 2-Pyrimidyl 2- (methylsulfonyl) phenyl 595 Cl 2-pyrimidyl 4-Morpholine 596 Cl 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 597 Cl 2-pyrimidyl 4-morpholinocarbonyl 598 Cl 2-pyrimidyl 2-methyl-1-imidazolyl 599 Cl 2-pyrimidyl 5-methyl-1-imidazolyl 600 Cl 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 601 Cl 5-pyrimidyl 2- (aminosulfonyl) phenyl 602 Cl 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 603 Cl 5-pyrimidyl 1-Pyrrolidinocarbonyl 604 Cl 5-pyrimidyl 2- (methylsulfonyl) phenyl · 605 Cl 5-pyrimidyl 4-Morpholine 606 Cl 5-pyrimidyl 2- (1 ¹ -CF ₃ tetrazolo-2-yl) phen II AS 607 Cl 5-pyrimidyl 4-morpholinocarbonyl 608 Cl 5-pyrimidyl 2-methyl-1-imidazolyl 609 Cl 5-pyrimidyl 5-methyl-1-imidazolyl 610 Cl 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 611 Cl 2-Cl-phenyl 2- (aminosulfonyl) phenyl 612 Cl 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 613 Cl 2-Cl-phenyl 1-Pyrrolidinocarbonyl 614 Cl 2-Cl-phenyl 2- (methylsulfonyl) phenyl 615 Cl 2-Cl-phenyl 4-Morpholine 616 Cl 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 617 Cl 2-Cl-phenyl 4-morpholinocarbonyl 618 Cl 2-Cl-phenyl 2-methyl-1-imidazolyl 619 Cl 2-Cl-phenyl 5-methyl-1-imidazolyl 620 Cl 2-Cu-phenyl 2-methylsulfonyl-1-imidazolyl 621 Cl 2-F-phenyl 2- (aminosulfonyl) phenyl 622 Cl 2-F-phenyl 2- (methylaminosulfonyl) phenyl 623 Cl 2-F-phenyl 1-Pyrrolidinocarbonyl 624 Cl 2-F-phenyl 2- (methylsulfonyl) phenyl 625 Cl · 2-F-phenyl 4-Morpholine 626 Cl 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 627 Cl 2-F-phenyl 4-morpholinocarbonyl 628 Cl 2-F-phenyl 2-methyl-1-imidazolyl 629 Cl 2-F-phenyl 5-methyl-1-imidazolyl 630 Cl 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 631 Cl 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 632 Cl 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 633 Cl 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 634 Cl 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 635 Cl 2,6-diF-phenyl 4-Morpholine

³⁴⁵ EN 4673 B

636 Cl 2,6-diF-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 637 Cl 2,6-diF-phenyl 4-morpholinocarbonyl 638 Cl 2,6-diF-phenyl 2-methyl-1-imidazolyl 639 Cl 2,6-diF-phenyl 5-methyl-1-imidazolyl 640 Cl 2,6-diF-phenyl 2-Methyl Isulfonyl-1-imidazolyl 641 F phenyl 2- (aminosulfonyl) phenyl 642 F phenyl 2- (methifaminosulfonyl) phenyl 643 F phenyl 1-Pyrrolidinocarbonyl 644 F phenyl 2- (methylsulfonyl) phenyl 645 F phenyl 4-Morpholine 646 F phenyl 2- (1'-CF ₃ -tetrazol-2-yl) phenyl 647 F phenyl 4-morpholinocarbonyl 648 F phenyl 2-methyl-1-imidazolyl 649 F phenyl 5-methyl-1-imidazolyl 650 F phenyl 2-methylsulfonyl-1-imidazolyl 651 F 2-pyridyl 2- (aminosulfonyl) phenyl 652 F 2-pyridyl 2- (methylaminosulfonyl) phenyl 653 F 2-pyridyl 1-Pyrrolidinocarbonyl 654 F 2-pyridyl 2- (methylsulfonyl) phenyl 655 F 2-pyridyl 4-Morpholine 656 F 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 657 F 2-pyridyl 4-morpholinocarbonyl 658 F 2-pyridyl 2-methyl-1-imidazolyl 659 F 2-pyridyl 5-methyl-1-imidazolyl 660 F 2-pyridyl 2-methylsulfonyl-1-imidazolyl 661 F 3-pyridyl 2- (aminosulfonyl) phenyl 662 F 3-pyridyl 2- (methylaminosulfonyl) phenyl 663 F 3-pyridyl 1-Pyrrolidinocarbonyl 664 F 3-pyridyl 2- (methylsulfonyl) phenyl 665 F 3-pyridyl 4-Morpholine 666 F 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 667 F 3-pyridyl 4-morpholinocarbonyl 668 F 3-pyridyl 2-methyl-1-imidazolyl 669 F 3-pyridyl 5-methyl-1-imidazolyl 670 F 3-pyridyl 2-methylsulfonyl-1-imidazolyl 671 F 2-pyrimidyl 2- (aminosulfonyl) phenyl 672 F 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 673 F 2-pyrimidyl 1-Pyrrolidinocarbonyl 674 F 2-pyrimidyl 2- (methylsulfonyl) phenyl 675 F 2-pyrimidyl 4-Morpholine 676 F 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 677 F 2-pyrimidyl 4-morpholinocarbonyl 678 F 2-pyrimidyl 2-methyl-1-imidazolyl 679 F 2-pyrimidyl 5-methyl-1-imidazolyl 680 F 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 681 F 5-pyrimidyl 2- (aminosulfonyl) phenyl 682 F 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 683 F 5-pyrimidyl 1-Pyrrolidinocarbonyl

346

684 F 5-pyrimidyl 2- (methylsulfonyl) phenyl 685 F 5-pyrimidyl 4-Morpholine 686 F 5-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 687 F 5-pyrimidyl 4-morpholinocarbonyl 688 F 5-pyrimidyl 2-methyl-1-imidazolyl 689 F 5-pyrimidyl 5-methyl-1-imidazolyl 690 F 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 691 F 2-Cl-phenyl 2- (aminosulfonyl) phenyl 692 F 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 693 F 2-Cl-phenyl 1-Pyrrolidinocarbonyl 694 F 2-Cf-phenyl 2- (methylsulfonyl) phenyl 695 F 2-Cl-phenyl 4-Morpholine 696 F 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl as 697 F 2-Cl-phenyl 4-morpholinocarbonyl 698 F 2-Cl-phenyl 2-methyl-1-imidazolyl 699 F 2-Cl-phenyl 5-methyl-1-imidazolyl 700 F 2-Cl-phenyl 2-Methylsulfonyl-1-imidazolyl 701 F 2-F-phenyl 2- (aminosulfonyl) phenyl 702 F 2-F-phenyl 2- (methylaminosulfonyl) phenyl 703 F 2-F-phenyl 1-Pyrrolidinocarbonyl 704 F 2-F-phenyl 2- (methylsulfonyl) phenyl 705 F 2-F-phenyl 4-Morpholine 706 F 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 707 F 2-F-phenyl 4-morpholinocarbonyl 708 F 2-F-phenyl 2-methyl-1-imidazolyl 709 F 2-F-phenyl 5-methyl-1-imidazolyl 710 F 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 711 F 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 712 F 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 713 F 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 714 F 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 715 F 2,6-diF-phenyl 4-Morpholine 716 F 2,6-diF-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 717 F 2,6-diF-phenyl 4-morpholinocarbonyl 718 F 2,6-diF-phenyl 2-methyl-1-imidazolyl 719 F 2,6-diF-phenyl 5-methyl-1-imidazolyl 720 F 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 721 CO2CH3 phenyl 2- (aminosulfonyl) phenyl 722 CO2CH3 phenyl 2- (methylaminosulfonyl) phenyl 723 CO ₂ CH ₃ phenyl 1-Pyrrolidinocarbonyl 724 co ₂ ch ₃ phenyl 2- (methylsulfonyl) phenyl 725 co ₂ ch ₃ phenyl 4-Morpholine 726 co ₂ ch ₃ phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 727 co ₂ ch ₃ phenyl 4-morpholinocarbonyl 728 co ₂ ch ₃ phenyl 2-methyl-1-imidazolyl 729 co ₂ ch ₃ phenyl 5-methyl-1-imidazolyl 730 co ₂ ch ₃ phenyl 2-methylsulfonyl-1-imidazolyl 731 co ₂ ch ₃ 2-pyridyl 2- (aminosulfonyl) phenyl

347

732 CO ₂ CH ₃ 2-pyridyl 2- (methylaminosulfonyl) phenyl 733 CO2CH3 2-pyridyl 1-Pyrrolidinocarbonyl 734 CO ₂ CH ₃ 2-pyridyl 2- (methylsulfonyl) phenyl 735 co ₂ ch ₃ 2-pyridyl 4-Morpholine 736 co ₂ ch ₃ 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 737 co ₂ ch ₃ 2-pyridyl 4-morpholinocarbonyl 738 co ₂ ch ₃ 2-pyridyl 2-methyl-1-imidazolyl 739 co ₂ ch ₃ 2-pyridyl 5-methyl-1-imidazolyl 740 co ₂ ch ₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 741 co ₂ ch ₃ 3-pyridyl 2- (aminosulfonyl) phenyl 742 co ₂ ch ₃ 3-pyridyl 2- (methylaminosulfonyl) phenyl 743 co ₂ ch ₃ 3-pyridyl 1-Pyrrolidinocarbonyl 744 co ₂ ch ₃ 3-pyridyl 2- (methylsulfonyl) phenyl 745 co ₂ ch ₃ 3-pyridyl 4-Morpholine 746 co ₂ ch ₃ 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 747 co ₂ ch ₃ 3-pyridyl 4-morpholinocarbonyl 748 co ₂ ch ₃ 3-pyridyl 2-methyl-1-imidazolyl 749 co ₂ ch ₃ 3-pyridyl 5-methyl-1-imidazolyl 750 co ₂ ch ₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 751 co ₂ ch ₃ 2-pyrimidyl 2- (aminosulfonyl) phenyl 752 co ₂ ch ₃ 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 753 co ₂ ch ₃ 2-pyrimidyl 1-Pyrrolidinocarbonyl 754 co ₂ ch ₃ 2-pyrimidyl 2- (methylsulfonyl) phenyl 755 co ₂ ch ₃ 2-pyrimidyl 4-Morpholine 756 co ₂ ch ₃ 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 757 co ₂ ch ₃ 2-pyrimidyl 4-morpholinocarbonyl 758 co ₂ ch ₃ 2-pyrimidyl 2-methyl-1-imidazolyl 759 co ₂ ch ₃ 2-pyrimidyl 5-methyl-1-imidazolyl 760 co ₂ ch ₃ 2-pyrimidyl 2-Methylsulfonyl-1-imidazolyl 761 co ₂ ch ₃ 5-pyrimidyl 2- (aminosulfonyl) phenyl 762 co ₂ ch ₃ 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 763 co ₂ ch ₃ 5-pyrimidyl 1-Pyrrolidinocarbonyl 764 co ₂ ch ₃ 5-pyrimidyl 2- (methylsulfonyl) phenyl 765 co ₂ ch ₃ 5-pyrimidyl 4-Morpholine 766 co ₂ ch ₃ 5-pyrimidyl 2- (T-CF ₃ -tetrazol-2-yl) phenyl 767 co ₂ ch ₃ 5-pyrimidyl 4-morpholinocarbonyl 768 co ₂ ch ₃ 5-pyrimidyl 2-methyl-1-imidazolyl 769 co ₂ ch ₃ 5-pyrimidyl 5-methyl-1-imidazolyl 770 co ₂ ch ₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 771 co ₂ ch ₃ 2-Cl-phenyl 2- (aminosulfonyl) phenyl 772 co ₂ ch ₃ 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 773 co ₂ ch ₃ 2-Cl-phenyl 1-Pyrrolidinocarbonyl 774 co ₂ ch ₃ 2-Cl-phenyl 2- (methylsulfonyl) phenyl 775 co ₂ ch ₃ 2-Cl-phenyl 4-Morpholine 776 co ₂ ch ₃ 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 777 co ₂ ch ₃ 2-Cl-phenyl 4-morpholinocarbonyl 778 co ₂ ch ₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 779 co ₂ ch ₃ 2-Cl-phenyl 5-methyl-1-imidazolyl

780 CO ₂ CH ₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 781 CO2CH3 2-F-phenyl 2- (aminosulfonyl) phenyl 782 CO2CH3 2-F-phenyl 2- (methylaminosulfonyl) phenyl 783 CO ₂ CH ₃ 2-F-Phenyl 1-Pyrrolidinocarbonyl 784 co ₂ ch ₃ 2-F-phenyl 2- (methylsulfonyl) phenyl 785 co ₂ ch ₃ 2-F-phenyl 4-Morpholine 786 co ₂ ch ₃ 2-F-Phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 787 co ₂ ch ₃ 2-F-phenyl 4-morpholinocarbonyl 788 co ₂ ch ₃ 2-F-phenyl 2-methyl-1-imidazolyl 789 co ₂ ch ₃ 2-F-phenyl 5-methyl-1-imidazolyl 790 co ₂ ch ₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 791 co ₂ ch ₃ 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 792 co ₂ ch ₃ 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 793 co ₂ ch ₃ 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 794 co ₂ ch ₃ 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 795 co ₂ ch ₃ 2,6-diF-phenyl 4-Morpholine 796 co ₂ ch ₃ 2,6-diF-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 797 co ₂ ch ₃ 2,6-diF-phenyl 4-morpholinocarbonyl 798 co ₂ ch ₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 799 co ₂ ch ₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 800 co ₂ ch ₃ 2,6-diF-phenyl 2-Methyl Isulfonyl-1-imidazolyl 801 ch ₂ and ₃ phenyl 2- (aminosulfonyl) phenyl 802 ch ₂ and ₃ phenyl 2- (methylaminosulfonyl) phenyl 803 ch ₂ and ₃ phenyl 1-Pyrrolidinocarbonyl 804 ch ₂ and ₃ phenyl 2- (methylsulfonyl) phenyl 805 ch ₂ and ₃ phenyl 4-Morpholine 806 ch ₂ and ₃ phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 807 ch ₂ and ₃ phenyl 4-morpholinocarbonyl 808 ch ₂ and ₃ phenyl 2-methyl-1-imidazolyl 809 ch ₂ and ₃ phenyl 5-methyl-1-imidazolyl 810 ch ₂ and ₃ phenyl 2-methylsulfonyl-1-imidazolyl 811 ch ₂ and ₃ 2-pyridyl 2- (aminosulfonyl) phenyl 812 ch ₂ and ₃ 2-pyridyl 2- (methylaminosulfonyl) phenyl 813 ch ₂ and ₃ 2-pyridyl 1-Pyrrolidinocarbonyl 814 ch ₂ and ₃ 2-pyridyl 2- (methylsulfonyl) phenyl 815 ch ₂ and ₃ 2-pyridyl 4-Morpholine 816 ch ₂ and ₃ 2-pyridia 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 817 ch ₂ and ₃ • 2-Pyridyl 4-morpholinocarbonyl 818 ch ₂ and ₃ 2-pyridyl 2-methyl-1-imidazolyl 819 ch ₂ and ₃ 2-pyridyl 5-methyl-1-imidazolyl 820 ch ₂ and ₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 821 ch ₂ and ₃ 3-pyridyl 2- (aminosulfonyl) phenyl 822 ch ₂ and ₃ 3-pyridyl 2- (methylaminosulfonyl) phenyl 823 ch ₂ and ₃ 3-pyridyl 1-Pyrrolidinocarbonyl 824 CH2OCH3 3-pyridyl 2- (methylsulfonyl) phenyl 825 ch ₂ and ₃ 3-pyridyl 4-Morpholine 826 ch ₂ and ₃ 3-pyridyl 2- (1'-CF ₃ -tetrazol-2-yl) phenyl 827 ch ₂ and ₃ 3-pyridyl 4-morpholinocarbonyl

349

828 CH2OCH3 3-pyridyl 2-methyl-1-imidazolyl 829 CH2OCH3 3-pyridyl 5-methyl-t-imidazolyl 830 CH2OCH3 3-pyridyl 2-methylsulfonyl-1-imidazolyl 831 CH2OCH3 2-pyrimidyl 2- (aminosulfonyl) phenyl 832 CH2OCH3 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 833 CH ₂ OCH ₃ 2-pyrimidyl 1-Pyrrolidinocarbonyl 834 ch ₂ and ₃ 2-pyrimidyl 2- (methylsulfonyl) phenyl 835 ch ₂ and ₃ 2-pyrimidyl 4-Morpholine 836 CH2OCH3 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 837 CH ₂ OCH ₃ 2-pyrimidyl 4-morpholinocarbonyl 838 ch ₂ and ₃ 2-pyrimidyl 2-methyl-1-imidazolyl 839 ch ₂ and ₃ 2-pyrimidyl 5-methyl-1-imidazolyl 840 ch ₂ and ₃ 2-pyrimidyl 2-Methyl Isulfonyl-1-imidazolyl 841 ch ₂ and ₃ 5-pyrimidyl 2- (aminosulfonyl) phenyl 842 ch ₂ and ₃ 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 843 ch ₂ and ₃ 5-pyrimidyl 1-Pyrrolidinocarbonyl 844 ch ₂ and ₃ 5-pyrimidyl 2- (methylsulfonyl) phenyl 845 ch ₂ and ₃ 5-pyrimidyl 4-Morpholine 846 ch ₂ and ₃ 5-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 847 ch ₂ and ₃ 5-pyrimidyl 4-morpholinocarbonyl 848 ch ₂ and ₃ 5-pyrimidyl 2-methyl-1-imidazolyl 849 CH2OCH3 5-pyrimidyl 5-methyl-1-imidazolyl 850 ch ₂ and ₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 851 ch ₂ and ₃ 2-Cl-phenyl 2- (aminosulfonyl) phenyl 852 ch ₂ and ₃ 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 853 ch ₂ and ₃ 2-Cl-phenyl 1-Pyrrolidinocarbonyl 854 ch ₂ and ₃ 2-Cl-phenyl 2- (methylsulfonyl) phenyl 855 ch ₂ and ₃ 2-Cl-phenyl 4-Morpholine 856 CH2OCH3 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 857 ch ₂ and ₃ 2-Cl-phenyl 4-morpholinocarbonyl 858 ch ₂ and ₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 859 ch ₂ and ₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 860 ch ₂ and ₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 861 ch ₂ and ₃ 2-F-phenyl 2- (aminosulfonyl) phenyl 862 ch ₂ and ₃ 2-F-phenyl 2- (methylaminosulfonyl) phenyl 863 CH2OCH3 2-F-phenyl 1-Pyrrolidinocarbonyl 864 ch ₂ and ₃ 2-F-phenyl 2- (methylsulfonyl) phenyl 865 ch ₂ and ₃ 2-F-phenyl 4-Morpholine 866 ch ₂ and ₃ 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 867 ch ₂ and ₃ 2-F-phenyl 4-morpholinocarbonyl 868 ch ₂ and ₃ 2-F-phenyl 2-methyl-1-imidazolyl 869 ch ₂ and ₃ 2-F-phenyl 5-methyl-1-imidazolyl 870 ch ₂ and ₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 871 ch ₂ and ₃ 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 872 ch ₂ and ₃ 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 873 ch ₂ and ₃ 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 874 ch ₂ and ₃ 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 875 ch ₂ and ₃ 2,6-diF-phenyl 4-Morpholine

350

876 CH ₂ OCH ₃ 2,6-diF-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 877 ch ₂ and ₃ 2,6-diF-phenyl 4-morpholinocarbonyl 878 ch ₂ and ₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 879 ch ₂ and ₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 880 ch ₂ and ₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 881 conh ₂ phenyl 2- (aminosulfonyl) phenyl 882 conh ₂ phenyl 2- (methylaminosulfonyl) phenyl 883 conh ₂ phenyl 1-Pyrrolidinocarbonyl 884 conh ₂ phenyl 2- (methylsulfonyl) phenyl 885 conh ₂ phenyl 4-Morpholine 886 conh ₂ phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 887 conh ₂ phenyl 4-morpholinocarbonyl 888 conh ₂ phenyl 2-methyl-1-imidazolyl 889 conh ₂ phenyl 5-methyl-1-imidazolyl 890 conh ₂ phenyl 2-methylsulfonyl-1-imidazolyl 891 conh ₂ 2-pyridyl 2- (aminosulfonyl) phenyl 892 conh ₂ 2-pyridyl 2- (methylaminosulfonyl) phenyl 893 conh ₂ 2-pyridyl 1-Pyrrolidinocarbonyl 894 conh ₂ 2-pyridyl 2- (methylsulfonyl) phenyl 895 conh ₂ 2-pyridyl 4-Morpholine 896 conh ₂ 2-pyridia 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 897 conh ₂ 2-pyridyl 4-morpholinocarbonyl 898 conh ₂ 2-pyridyl 2-methyl-1-imidazolyl 899 conh ₂ 2-pyridyl 5-methyl-1-imidazolyl 900 conh ₂ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 901 conh ₂ 3-pyridyl 2- (aminosulfonyl) phenyl 902 conh ₂ 3-pyridyl 2- (methylaminosulfonyl) phenyl 903 conh ₂ 3-pyridia 1-Pyrrolidinocarbonyl 904 conh ₂ 3-pyridyl 2- (methylsulfonyl) phenyl 905 conh ₂ 3-pyridyl 4-Morpholine 906 conh ₂ 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 907 conh ₂ 3-pyridyl 4-morpholinocarbonyl 908 conh ₂ 3-pyridyl 2-methyl-1-imidazolyl 909 conh ₂ 3-pyridyl 5-methyl-1-imidazolyl 910 conh ₂ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 911 conh ₂ 2-pyrimidyl 2- (aminosulfonyl) phenyl 912 conh ₂ 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 913 conh ₂ 2-pyrimidyl 1-Pyrrolidinocarbonyl 914 conh ₂ 2-pyrimidyl 2- (methylsulfonyl) phenyl 915 conh ₂ 2-pyrimidyl 4-Morpholine 916 conh ₂ 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 917 conh ₂ 2-pyrimidyl 4-morpholinocarbonyl 918 conh ₂ 2-pyrimidyl 2-methyl-1-imidazolyl 919 conh ₂ 2-pyrimidyl 5-methyl-1-imidazolyl 920 conh ₂ 2-pyrimidyl 2-Methyl Isulfone I-1-imidazolyl 921 conh ₂ 5-pyrimidyl 2- (aminosulfonyl) phenyl 922 CONHa 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 923 conh ₂ 5-pyrimidyl 1-Pyrrolidinocarbonyl

351

924 conh ₂ 5-pyrimidyl 2- (methylsulfonyl) phenyl 925 conh ₂ 5-pyrimidyl 4-Morpholine 926 conh ₂ 5-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 927 conh ₂ 5-pyrimidyl 4-morpholinocarbonyl 928 conh ₂ 5-pyrimidyl 2-methyl-1-imidazolyl 929 conh ₂ 5-pyrimidyl 5-methyl-1-imidazolyl 930 conh ₂ 5-pyrimidyl 2-methyl with Ifoni I-1-imidazolyl 931 conh ₂ 2-Cl-phenyl 2- (aminosulfonyl) phenyl 932 conh ₂ 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 933 conh ₂ 2-Cl-phenyl 1-Pyrrolidinocarbonyl 934 conh ₂ 2-Cl-phenyl 2- (methylsulfonyl) phenyl 935 conh ₂ 2-Cl-phenyl 4-Morpholine 936 conh ₂ 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 937 conh ₂ 2-Cl-phenyl 4-morpholinocarbonyl 938 conh ₂ 2-Cl-phenyl 2-methyl-1-imidazolyl 939 conh ₂ 2-Cl-phenyl 5-methyl-1-imidazolyl 940 conh ₂ 2-Cl-phenyl 2-Methylsulfonyl-1-imidazolyl 941 conh ₂ 2-F-phenyl 2- (aminosulfonyl) phenyl 942 conh ₂ 2-F-phenyl 2- (methylaminosulfonyl) phenyl 943 conh ₂ 2-F-phenyl 1-Pyrrolidinocarbonyl 944 conh ₂ 2-F-phenyl 2- (methylsulfonyl) phenyl 945 conh ₂ 2-F-phenyl 4-Morpholine 946 conh ₂ 2-F-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 947 conh ₂ 2-F-phenyl 4-morpholinocarbonyl 948 conh ₂ 2-F-phenyl 2-methyl-1-imidazolyl 949 conh ₂ 2-F-phenyl 5-methyl-1-imidazolyl 950 conh ₂ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 951 conh ₂ 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 952 conh ₂ 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 953 conh ₂ 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 954 conh ₂ 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 955 conh ₂ 2,6-diF-phenyl 4-Morpholine 956 conh ₂ 2,6-diF-phenyl 2- (1'-CF ₃ -tetrazol-2-yl) phenyl 957 conh ₂ 2,6-diF-phenyl 4-morpholinocarbonyl 958 conh ₂ 2,6-diF-phenyl 2-methyl-1-imidazolyl 959 conh ₂ 2,6-diF-phenyl 5-methyl-1-imidazolyl 960 conh ₂ 2,6-diF-phenyl 2-Methylsulfonyl-1-imidazolyl

table

For every example DE is

352 (A) Pyridin-4-yl-CH ₂ , (B) 2-Amino-pyrimidin-4-yl, (C) 6-Amino-pyridin-2-yl, (D) 3-Amidin-4-F- phenyl or (E) N-amidino-3-piperidinyl.

For example, A B 1 phenyl 2- (aminosulfonyl) phenyl 2 phenyl 2- (methylaminosulfonyl) phenyl 3 phenyl 1-Pyrrolidinocarbonyl 4 phenyl 2- (methylsulfonyl) phenyl 5 phenyl 4-Morpholine 6th phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 7th phenyl 4-morpholinocarbonyl 8th phenyl 2-methyl-1-imidazolyl 9th phenyl 5-methyl-1-imidazolyl 10th phenyl 2-methylsulfonyl-1-imidazolyl 11th 2-pyridyl 2- (aminosulfonyl) phenyl 12th 2-pyridyl 2- (methylaminosulfonyl) phenyl 13th 2-pyridyl 1-Pyrrolidinocarbonyl 14th 2-pyridyl 2- (methylsulfonyl) phenyl 15th 2-pyridyl 4-Morpholine 16th 2-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 17th 2-pyridyl 4-morpholinocarbonyl 18th 2-pyridyl 2-methyl-1-imidazolyl 19th 2-pyridyl 5-methyl-1-imidazolyl 20th 2-pyridyl 2-methylsulfonyl-1-imidazolyl 21st 3-pyridyl 2- (aminosulfonyl) phenyl 22nd 3-pyridyl 2- (methylaminosulfonyl) phenyl 23rd 3-pyridyl 1-Pyrrolidinocarbonyl 24th 3-pyridyl 2- (methylsulfonyl) phenyl 25th 3-pyridyl 4-Morpholine 26th 3-pyridyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 27th 3-pyridyl 4-morpholinocarbonyl 28th 3-pyridyl 2-methyl-1-imidazolyl 29th 3-pyridyl 5-methyl-1-imidazolyl 30th 3-pyridyl 2-methylsulfonyl-1-imidazolyl 31st 2-pyrimidyl 2- (aminosulfonyl) phenyl 32 2-pyrimidyl 2- (methylaminosulfonyl) phenyl 33 2-pyrimidyl 1-Pyrrolidinocarbonyl 34 2-pyrimidyl 2- (methylsulfonyl) phenyl 35 2-pyrimidyl 4-Morpholine 36 2-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 37 2-pyrimidyl 4-morpholinocarbonyl 38 2-pyrimidyl 2-methyl-1-imidazolyl 39 2-pyrimidine 5-methyl-1-imidazolyl 40 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 41 5-pyrimidyl 2- (aminosulfonyl) phenyl

353

42 5-pyrimidyl 2- (methylaminosulfonyl) phenyl 43 5-pyrimidyl 1-Pyrrolidinocarbonyl 44 5-pyrimidyl 2- (methylsulfonyl) phenyl 45 5-pyrimidyl 4-Morpholine 46th 5-pyrimidyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 47 5-pyrimidyl 4-morpholinocarbonyl 48 5-pyrimidyl 2-methyl-1-imidazolyl 49 5-pyrimidyl 5-methyl-1-imidazolyl 50 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 51 2-Cl-phenyl 2- (aminosulfonyl) phenyl 52 2-Cl-phenyl 2- (methylaminosulfonyl) phenyl 53 2-Cl-phenyl 1-Pyrrolidinocarbonyl 54 2-Cl-phenyl 2- (methylsulfonyl) phenyl 55 2-Cl-phenyl 4-Morpholine 56 2-Cl-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 57 2-Cl-phenyl 4-morpholinocarbonyl 58 2-Cl-phenyl 2-methyl-1-imidazolyl 59 2-Cl-phenyl 5-methyl-1-imidazolyl 60 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 61 2-F-phenyl 2- (aminosulfonyl) phenyl 62 2-F-phenyl 2- (methylaminosulfonyl) phenyl 63 2-F-phenyl 1-Pyrrolidinocarbonyl 64 2-F-phenyl 2- (methylsulfonyl) phenyl 65 2-F-phenyl 4-Morpholine 66 2-F-phenyl 2- (1'-CF ₃ -tetrazol-2-yl) phenyl 67 2-F-phenyl 4-morpholinocarbonyl 68 2-F-phenyl 2-methyl-1-imidazolyl 69 2-F-phenyl 5-methyl-1-imidazolyl 70 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 71 2,6-diF-phenyl 2- (aminosulfonyl) phenyl 72 2,6-diF-phenyl 2- (methylaminosulfonyl) phenyl 73 2,6-diF-phenyl 1-Pyrrolidinocarbonyl 74 2,6-diF-phenyl 2- (methylsulfonyl) phenyl 75 2,6-diF-phenyl 4-Morpholine 76 2,6-diF-phenyl 2- (1 '-CF ₃ -tetrazol-2-yl) phenyl 77 2,6-diF-phenyl 4-morpholinocarbonyl 78 2,6-diF-phenyl 2-me'tyl-1-imidazolyl 79 2,6-diF-phenyl 5-methyl-1-imidazolyl 80 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl

OPPORTUNITIES

The compounds of the present invention may be used as anticoagulants for the treatment or prophylaxis of thromboembolic disorders in mammals. Here

The term "thromboembolic disorders" used herein includes arterial or venous cardiovascular or cerebrovascular disorders, such as persistent angina, first or recurrent myocardial infarction, sudden ischemic death, transient ischemic attack, paralysis, atherosclerosis, venous thrombosis, thrombophlebitis, arterial embolism, cerebral vascular embolism, renal embolism and pulmonary embolism. The anticoagulant effect of the compounds of the present invention is believed to be due to inhibition of factor Xa or thrombin.

The efficacy of the compounds of the present invention as factor Xa inhibitors was determined using purified human factor Xa and a synthetic substrate. The rate of hydrolysis of the chromogenic substrate S2222 (Kabi Pharmacia, Franklin, OH) catalyzed by factor Xa was measured in the absence and presence of the compounds of the present invention. Hydrolysis of the substrate releases pNA, which is controlled spectrophotometrically by measuring the increase in absorbance at 405 nm. The decrease in the rate of change in absorbance at 405 nm in the presence of an inhibitor indicates inhibition of the enzyme. The results of this assay are expressed as the inhibition constant Kj.

Factor Xa assays were performed in 0.10 M sodium phosphate buffer, pH 7.5 containing 0.20 M NaCl and 0.5% PEG 8000. Substrate hydrolysis Michael constant, Km, was determined at 25 ° C using Lineweaver's. and Burk's method. K i values were determined by reacting 0.2-0.5 nM human factor Xa (Enzyme Research Laboratories, South Bend, IN) with substrate (0.20 mM -1 mM) in the presence of an inhibitor. Reactions were run for 30 min. and 25-30 min. velocities (time versus rate of absorption change) were measured over the interval. The following equation was used to derive the kj values:

(V ₀ -Vs) / V _s = 1 / (K (1 + S / Km)) where:

v ₀ is the rate of control reaction in the absence of inhibitor, v _s is the rate of reaction in the presence of inhibitor,

I is the concentration of inhibitor

Kj is the dissociation constant of the enzyme: inhibitor complex,

355

S is the substrate concentration,

Km is Michael's constant.

Using the procedure described above, a number of compounds of the present invention were found to have K <10 μΜ, indicating that these compounds are suitable as effective Xa inhibitors.

The antithrombotic activity of the compounds of the present invention may be demonstrated using a rabbit arterial-venous (AV) shunt thrombosis model. Rabbits of 2-3 kg mass anesthetized with a mixture of xylazine (10 mg / kg, i.m.) and ketamine (50 mg / kg) were used in this model. The saline-filled AV shunt is connected between the femoral artery and femoral vein tubes. The AV shunt consists of a 6 cm connecting tube containing a piece of silk thread. Blood flows from the femoral artery through the AV shunt to the femoral vein. Exposure of the running blood to the silky thread causes the formation of a large thrombus. After 40 minutes the shunt is disconnected and the silk thread covered with a thrombus is weighed. Test agents or vehicle (i.v., i.p., s.c. or orally) are administered prior to the AV shunt opening. The percentage inhibition of thrombus formation is determined for each test group. ID50 values (dose that causes 50% inhibition of thrombus formation) are determined by linear regression.

The compounds of formula (I) may also be used as inhibitors of serine proteases, namely human thrombin, plasma calicrine and plasmin. Due to the inhibitory effect of these compounds, they have been found to be suitable for the prophylaxis or treatment of physiological reactions, blood coagulation and inflammation catalyzed by said class of enzymes. More particularly, these compounds are useful as medicaments for the treatment of diseases resulting from increased thrombin activity such as myocardial infarction, and as reagents used as anticoagulants to convert blood into plasma for diagnostic or other industrial purposes.

Certain compounds of the present invention have been shown to be direct inhibitors of thrombin, a serine protease, due to their ability to inhibit cleavage of low molecular weight substrates catalyzed by thrombin purified system. In vitro inhibition constants were determined by

356

Kettner et al. J. Biol. Chem. 265, 18289-18297 (1990), which is incorporated herein by reference. These experiments involved spectrophotometrically controlled hydrolysis of the chromogenic substrate S2238 (Helena Laboratories, Beaumont, TX), which is mediated by thrombin. Addition of an inhibitor to the test mixture results in a decrease in absorption indicating that thrombin is inhibitory. Human thrombin (Enzyme Research Laboratories, Ine., South Bend, IN) was incubated at 0.2 nM in 0.10 M sodium phosphate buffer, pH 7.5, 0.20 M NaCl, and 0.5% PEG 6000, with various substrate concentrations in the range of 0.20-0.02 mM. After 25-30 min. after incubation, thrombin activity was measured by measuring the increase in absorbance at 405 nm resulting from substrate hydrolysis. Inhibition constants are derived from the inverse dependence of the reaction rate on substrate concentration using the standard Lineweaver and Burk method. Using the procedure described above, some compounds of the present invention were found to have a K less than 10 μ K; this confirms that the compounds of the present invention can be used as effective thrombin inhibitors.

The compounds of the present invention may be used alone or in combination with one or more additional therapeutic agents. Such agents include other anticoagulants or anticoagulants, antiplatelet or platelet inhibitors, thrombin inhibitors, or thrombolytic or fibrinolytic agents.

These compounds may be administered to a mammal in therapeutically effective amounts. The term "therapeutically effective amount" means an amount of a compound of formula (I) that, when administered to a mammal alone or in combination with an additional therapeutic agent, can effectively prevent or ameliorate the thromboembolic disease or arrest the progression of the disease.

The term "in combination" or "combination therapy" means that a compound of formula (I) and one or more additional therapeutic agents are administered to a mammal being treated together. When used in combination, each component can be taken at the same time or one after the other

357 in what order at different times. In this way, each component can be administered separately but close enough over time to achieve the desired therapeutic effect. Other anticoagulants (or coagulation inhibitors) that may be used in combination with the compounds of the present invention include warfarin and heparin, and other factor Xa inhibitors such as those described in the publications of the invention.

As used herein, the term "antiplatelet agents (or platelet inhibiting agents)" refers to agents that inhibit platelet function, such as platelet aggregation, adhesion, or granule secretion. Such agents include, but are not limited to, various known non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and piroxicam, and their pharmaceutically acceptable forms. Of the NSAIDS, aspirin (acetylsalicylic acid or ASA) and piroxicam are the most suitable. Other suitable antiplatelet agents include ticlopidine, including its pharmaceutically acceptable salts or prodrug forms. Ticlopidine is also a desirable compound as it is known to have a mild gastrointestinal effect. Still other suitable platelet inhibiting agents include lib / illa antagonists, thromoxane-A2 receptor antagonists and thromboxane-A2 synthetase inhibitors, and pharmaceutically acceptable salts or prodrug forms thereof,

The term "thrombin inhibitors" is used herein. (or (anti-thrombin agents) "means serine protease thrombin inhibitors. Inhibition of thrombin stops various processes mediated by thrombin, such as thrombin-mediated platelet activation and / or plasminogen activator-1 and / or serotinin granules). secretion), and / or fibrin formation, and many thrombin inhibitors are known to those skilled in the art, and it is to be understood that they can all be used in combination with the compounds of the present invention, including but not limited to borarginine derivatives,

358 borpeptides, heparins, hirudin and argatroban, including their pharmaceutically acceptable salts and their prodrug forms. Borarginine derivatives and borpeptides include the N-acetyl and peptide derivatives of boric acid, such as the C-terminal derivatives of lysine, ornithine, arginine, homoarginine α-aminoboronic acid and their respective isothiuronium analogs. As used herein, the term hirudin includes suitable hirudin analogues, herein referred to as hiruloges, such as disulfatohirudin. Borpeptide thrombin inhibitors include compounds described in Kettner et al. European Patent Application Publication No. 5,187,157; No. 293881 A2, which are incorporated herein by reference. Other suitable borarginine derivatives and borpeptide thrombin inhibitors are described in PCT application publication no. 92/07869 and European Patent Application Publication No. 471,651 A2, which are incorporated herein by reference.

As used herein, the term "thrombolytic (or fibrinolytic) agents (or thrombolytic or fibrinolytic)" means agents that dissolve blood clots (thrombi). Such agents include tissue plasminogen activator, anistreplase, urokinase, or streptokinase, including pharmaceutically acceptable salts thereof, or prodrug forms thereof. As used herein, the term "anistreplase" refers to an anisoylated plasminogen strepotokinase activator complex such as that described in European Patent Application Ser. 028,489, which is given as a reference. As used herein, the term "urokinase" means both double and single chain urokinase; the latter also known as prourokinase.

The use of the compounds of formula (I) of the present invention in combination with such additional therapeutic agent may be more effective than the administration of a single compound or agent since it may permit lower doses of each. Lower doses reduce the chance of side effects and at the same time increase the yield.

The compounds of the present invention are also suitable as standards or reference compounds, for example as quality or control standards, in assays relating to factor Xa inhibition. For example, a compound of the present invention can be used as a standard in a test in which

359 compares its known activity with a compound of unknown activity. This allows the experimenter to ensure that the test has been properly performed and allows comparisons, especially if the test compound is a derivative of the reference compound. In the development of new assays or methodologies, the compounds of the present invention can be used to test their efficacy.

The compounds of the present invention may also be used in diagnostic assays involving factor Xa. For example, the presence of Factor Xa in an unknown sample can be determined by adding a chromogenic substrate S2222 to a series of solutions containing the test sample and optionally one of the compounds of the present invention. If the presence of pNA in the solution containing the test sample is observed but does not occur in the presence of the compound of the invention, it can be concluded that the sample contains factor Xa.

DOSAGE AND PHARMACEUTICAL FORM

The compounds of the present invention may be administered in oral dosage forms such as tablets, capsules (which include sustained release or sustained release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. They can also be administered in forms suitable for intravenous (bolus or infusion), intraperitoneal, subcutaneous or intravenous administration; all such dosage forms are known to those skilled in the pharmaceutical art. The compounds may be administered alone, but will generally be administered in combination with a pharmaceutical carrier selected from the route of administration and usual pharmaceutical practice.

It will be appreciated that the dosage regimen of the compounds of the present invention should depend on known factors such as the pharmacodynamic characteristics of the particular agent, its nature and route of administration; type of recipient, age, sex, health status, medical status and weight, nature and degree of symptoms, overall mode of treatment, frequency of treatment, route of administration, patient's kidney and liver function, and desired effect. The therapist or veterinarian can identify and prescribe the right one

360 effective amount of the drug needed to prevent, eliminate or stop the progression of thromboembolic disease.

According to general principles, the daily dose of each active ingredient, when used for the stated effects, should be about 0.01-1000 mg / kg / day, preferably 0.01-100 mg / kg / day, and most preferably 1-20 mg / kg / day. For intravenous administration, the preferred dosage range will be approximately 1-10 mg / kg / minute at a constant infusion rate. The compounds of the present invention may be administered as a single daily dose or the total daily dose may be divided into separate doses 2 to 4 times daily.

The compounds of the present invention may be administered in the form of intranasal diluents, or by transdermal administration using transdermal patches. In the case of transdermal delivery systems, dosing is preferably continuous throughout the dosing regimen.

The compounds are usually administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to as pharmaceutical carriers) suitably selected according to the desired mode of administration, e.g. tablets, capsules, elixirs, syrups, etc., for oral use, and in accordance with general pharmaceutical practice.

For example, the active ingredient in oral tablets or capsules may be mixed with an oral, non-toxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, mannitol, potassium sulfate, calcium sulfate, mannitol. ; in liquid form for oral administration, the oral components of the drug can be mixed with an oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. In addition, suitable binders, lubricants, disintegrating agents and coloring agents may be incorporated into the mixture if desired or desired. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, sweeteners in corn, natural and synthetic resins such as acacia, tragacanth or sodium alginate,

361 carboxymethylcellulose, polyethylene glycol, waxes and the like. The lubricants used in such dosage forms may include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.

The compounds of the present invention may be administered in the form of liposomal delivery systems, such as small unicellular vesicles, large unicellular vesicles, and multicellular vesicles. Liposomes can be made from various phospholipids such as cholesterol, stearylamine or phosphatidylcholines.

The compounds of the present invention may also be mixed with soluble polymers as drug carriers at appropriate sites. Such polymers may be polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide phenol, polyhydroxyethyl aspartamide-phenol, or polyethylene oxide-polylysine, substituted with palmitoyl residues. In addition, the compounds of the present invention may be mixed with polymers of the biodegradable class suitable for controlled release of the drug, for example, polyphenolic acid, polyglycolic acid, ροϋ-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyridates, hydrogel block copolymers.

Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 mg to about 100 mg of active ingredient per unit dosage form. In these pharmaceutical compositions, the active ingredient is generally present in an amount of 0.5 to 95% by weight, based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and a suitable carrier such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar diluents may also be used to make compressed tablets. Both tablets, capsules and capsules may be manufactured as sustained release products to provide continuous release of the drug over time. Compressed tablets may be sugar coated or film coated to mask the unpleasant taste or to protect the tablet from weathering, or enteric coated to provide selective gastrointestinal disintegration.

362

Liquid oral dosage forms may contain coloring and flavoring agents to make them more acceptable to the patient.

Generally, suitable carriers for parenteral solutions include water, suitable oils, saline, aqueous dextrose (glucose) and related sugars, and glycols such as propylene glycol or polyethylene glycol. Preferably, the parenteral solution contains a water-soluble salt of the active ingredient, a suitable stabilizing agent and, if necessary, buffering agents. Suitable stabilizing agents include antioxidants such as acid sodium sulfite, sodium sulfite, or ascorbic acid, either alone or in admixture. Citric acid and its salts and EDTA are also used. In addition, parenteral solutions may contain safeners such as benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences by Mack Publishing Company, a standard reference in the art.

Pharmaceutical dosage forms suitable for use in the compounds of the present invention are illustrated by the following examples:

Capsules

Many capsule units may be made up of two-part hard gelatin capsules, each containing 100 mg of the active ingredient powder, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

Soft gelatine capsules

A mixture of active ingredient in edible oil such as soybean, cottonseed or olive oil can be prepared and injected in a positive displacement pump into gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried.

Pills

Tablets may be prepared by conventional means so that the unit dose contains 100 mg of the active ingredient, 0.2 mg of colloidal silica, 5

363 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose. The necessary coatings can be applied to give a pleasant taste or delayed adsorption.

Solution for injection

Injectable parenteral compositions may be prepared by mixing 1.5% by weight of the active ingredient in 10% by volume propylene glycol and water. This solution may be rendered isotonic by the addition of sodium chloride and sterilized.

Suspensions

Aqueous suspensions may be formulated for oral administration such that each of 5 ml contains 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethylcellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution (U.S.P.) and 0.025 ml of vanillin.

When the compounds of the present invention are in combination with other anticoagulants, for example, the daily dose of a compound of formula (I) may be from about 0.1 mg to about 100 mg / kg and the second anticoagulant from about 1 mg to about 7.5 mg / kg of patient body weight. In tablet dosage forms, the compounds of the present invention will generally be present in an amount of about 5 to 10 mg per unit dose, and the second anticoagulant may be in the range of 1 to 5 mg per unit dose.

When the compounds of formula (I) are used in combination with an anti-platelet agent, the general principle is that the daily dose of a compound of formula (I) may generally be from about 0.01 to 25 mg and the anti-platelet agent from about 50 to 150 mg, preferably about 0.1 -1 mg of a compound of formula (I) and about 1 to 3 mg of anti-platelet agent per kilogram of patient body weight.

When the compounds of formula (I) are administered in combination with a thrombolytic agent, the daily dose of a compound of formula (I) may generally be from about 0.1 mg to about 1 mg / kg body weight, and the dose of thrombolytic agents may be reduced by about 70-80% dose when a single thrombolytic agent is administered.

When one or more of the above-mentioned second therapeutic agents is administered with a compound of formula (I), the amount of each component in the daily dosage and typical dosage form can generally be reduced relative to the

364 at the usual dose of the agent alone, due to the additive or synergistic effects of the therapeutic agents used in combination.

In the case where they are used in a single dosage unit, there is a possibility that chemical interactions will occur between the components of the combination. For this reason, when the compound of formula (I) and the second therapeutic agent are present in a single dosage unit, they are formulated such that while the active ingredients are formulated in a single dosage unit, physical contact between the active ingredients is minimized (i.e. reduced). For example, one active ingredient may be enteric coated. Not only can one of the active ingredients be enteric coated, it is possible to minimize contact between the active ingredients of the combination, but also to control the release of one of these components into the gastrointestinal tract so that one of these components is not excreted in the stomach but in the intestine. One of the active ingredients may also be coated with a substance that provides sustained release throughout the gastrointestinal tract and also serves to minimize physical contact between the active ingredients in the combination. Additionally, the sustained release component may also be enteric coated so that the release of this component is limited to the intestine. Another strategy could include a product-combination dosage form wherein one component is coated with a sustained release material and / or an enteric release polymer and the second component is also coated with a polymer such as low viscosity hydroxypropylmethylcellulose (HPMC) or other appropriate material known in the art. to further distinguish between the active components. Polymer coating creates an additional barrier to interaction with another component.

These and other ways of minimizing contact between product-combination components, when used as a single dosage form or as separate forms, but at the same time or in the same combination, are readily apparent to those skilled in the art.

It will be understood that various modifications of the present invention are possible based on the above advice. It must therefore be understood that

Within the scope of the following 365, the present invention may be practiced otherwise than as specifically described herein.

366

Claims (25)

DEFINITION OF INVENTION 1. A compound of formula I: (l) In which: in the ring, M is, apart from J, 0-3 N atoms, provided that when M is 2 N atoms, R ^1b is absent and if M is 3 N atoms, then R ^1a and R ^{1b are not present} ; J is N or NH: D is selected from CN, C (= NR ⁸ ) NR ⁷ R ⁹ , NHC (= NR ⁸ ) NR ⁷ R ⁹ , NR ⁸ CH (= NR ⁷ ), C (O) NR ⁷ R ⁸ and (CR ^8). R ⁹ ) _t NR ⁷ R ⁸ with the proviso that in Part E, D is in the meta or para position with respect to G; E is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and piperidinyl substituted with 1 R; otherwise, D-E-G together represent pyridyl substituted with 1 R: R is selected from H, halogen, (CH ₂₎ ³ Tor, Ci- -alkiIo _4, OCF ₃ and CF _3; G is absent or selected from NHCH ₂ , OCH ₂ and SCH ₂ , provided that when s is 0, then G is attached to the ring carbon atom of M; The ring is selected from C _1-4 alkylene, (CH ₂ ) _r O (CH ₂ ) r, (CH ₂ ) _r NR ³ (CH ₂ ) r, (CH ₂ ) _r C (O) (CH ₂ ) r, (CH ₂ ) _r C ( O) OC (CH ₂ ) _r , (CH ₂ ) _r C O (CH ₂ ) _r , (CH ₂ ) _r C (O) NR ³ (CH 2) _r , (CH ₂ ) _r NR ³ C (O) (CH 2) r, (CH 2) r OC (O) O (CH2) r, (CH 2) r OC (O) NR ³ (CH 2) _r, (CH _{2) r} NR ³ C (O) O (CH 2) r, (CH2) RNA ³ C (O) NR ³ (CH 2) _r, (CH _{2) o} S (O) _p (CH _{2) r,} (CH _{2) r} SO ₂ NR ³ (CH 2) r, (CH 2) RNA ³ SO 2 (CH _{2) r,} and (CH _{2) r} NR ³ SO 2 NR ³ (CH 2) _r, provided that z does not NN, NO, NS, NCH ₂ N, NCH ₂ O, or NCH ₂ S bond with ring M or group A; R ^1a and R ^1b, independently of one another, absent or selected from - (CH 2) rr ¹ NCH2R ^1, OCH 2 R ¹ ", SCH 2 R ^1", N (CH2) 2 (CH2) tR = ¹ ', O (CH 2 ) ₂ (CH ₂ ) _t R ¹ and S (CH ₂ ) 2 (CH ₂ ) _t R ¹ , or are linked together to form a 5-8 membered saturated, partially saturated or unsaturated ring 367 for a system having 0-2 substituents on R ⁴ and having 0-2 heteroatoms selected from the group consisting of N, O and S; R ¹ is selected from H, C 1-3 alkyl, halogen, (CF 2) r CF 3, OR ² , NR ² R ^2a , C (O) R ^2c , OC (O) R ² , (CF 2) _r CO ₂ R ^2c , S (O) pR ^2b , NR ² (CH ² ) _r OR ² , NR ² C (O) R ^2b , NR ² C (O) NHR ^2b , NR ² C (O) ² R ^2a , OC (O) NR ^2b , C (O) NR ² R ^2a , SO ² NR ² R ^2a , NR ² SO ² R ^2b , C _3-6 carbocyclic. residues substituted with 0-2 R ⁴ and 510-membered heterocyclic systems containing 1-4 heteroatoms selected from the group consisting of N, O and S substituted with 0-2 R ⁴ ; R ¹ is selected from H, C (O) R ^2b , C (O) NR ² R ^2a , S (O) R ^2b , S (O) ² R ^2b and SO ² NR ² R ^2a ; R ^{2 is in} each case selected from H, CF _3l Ci. _6- alkyl, benzyl, C ₃ . ₆ carbocyclic residues with 0-2 R ^4b and 5-6 membered heterocyclic systems containing 1-4 heteroatoms selected from the group consisting of N, O and S substituted with 0-2 R ^4b ; R ^{2a is in} each case selected from H, CF _3l Ci. _6- alkyl, benzyl, C ₃ . ₆ carbocyclic residues with 0-2 R ^4b and 5-6 membered heterocyclic systems containing 1-4 heteroatoms selected from the group consisting of N, O and S substituted with 0-2 R ^4b ; R ^2b in any event, is selected from CF _3, Ci_ ₄ -alkoxy, Ci-e-alkyl, benzyl, C ₃ .6 carbocyclic residue with 0-2 R ^4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O and S substituted with 0-2 R ^4b ; R ^{2c is in} each case selected from CF ₃ , OH, Ci. _4- alkoxy, C 1-4 alkyl, benzyl, C ₃ . _6- carbocyclic moieties with 0-2 R ^4b and 5-6 membered heterocyclic systems containing 1-4 heteroatoms selected from the group consisting of N, O and S substituted with 0-2 R ^4b ; alternatively, R ² and R ^{2a are} taken together to form a 5- or 6-membered saturated, partially saturated or unsaturated ring substituted with 0-2 R ⁴ and having 0-1 additional heteroatoms selected from the group consisting of N, O and S; R ^{3 is in} each case selected from H, Ci. _4- alkyl and phenyl; R ^{3a is in} each case selected from H, Ci. _4- alkyl and phenyl; 368 A is selected from: C 3-10 -carbocyclic Q2 carbons substituted with 0-2 R ⁴ and 5-10 membered heterocyclic systems having 1-4 heteroatoms selected from the group consisting of N, O and S substituted with 0-2 R ⁴ ; B is selected from: Χ-Y, NR ² R ^2a , C (= NR ² ) NR ² R ^2a , NR ² C (= NR ² ) NR ² R ^2a , Ca 10 carbocyclic residues 0-2 substituents R ^4a and 5-10 -membered heterocyclic systems containing 1-4 heteroatoms selected from the group consisting of N, O and S substituted with 0-2 R ^4a : X is selected from C _1-4 alkylene, -CR ² (CR ² R ^2b ) (CH 2) t -, -C (O) -, -C (= NR) -, -CR ² (NR ¹ R ² ) - , -CR ² (OR ² ) -, -CR ² (SR ² ) -, -C (O) CR ² R ^2a -, -CR ² R ^2a C (O) -, -S (O) p -, - S (O) pCR ² R ^2a -, -CR ² R ^2a S (O) p -, -S (O) ² NR ² -, -NR ² S (O) 2 -, -NR ² S (O) ² CR ^2. R ^2a -, -CR ² R ^2a S (O) ₂ NR ² -, -NR ² S (O) ₂ NR ² -, -C (O) NR ² -, -NR ² C (O) -, -C ( O) NR ² CR ² R ^2a -, -NR ² C (O) CR ² R ^2a -, -CR ² R ^2a C (O) NR ² -, -CR ² R ^2a NR ² C (O) -, - NR ² C (O) O-, -OC (O) NR ² -, -NR ² C (O) NR ² -, -NR ² -, -NR ² CR ² R ^2a -, -CR ² R ^2a NR ² -, -O-, -CR ² R ^2a O-, and -OCR ² R ^2a -; Y is selected from: (CH ₂ ) _r NR ² R _2a , provided that Χ-Y does not form an NN, ON or SN bond, C ₃ -io carbocyclic residue substituted with 0-2 R ^4a, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R ^4a; R ^{4 is} at each occurrence selected from = O, (CH ₂ ) _r OR ² , halogen, C 1-4 alkyl, CN, NO ₂ , (CH ₂ ) _r NR ² R ^2a , (CH ₂ ) _r C (O) R ^2b , NR ² C (O) R ^2a , C (O) NR ² R ^2a , NR ² C (O) NR ² R ^2a , CH (= NR ² ) NR ² R ^2a , NHC (= NR ² ) NR ² R ^2a , SO 2 NR ² R ^2a, NR ² SO 2 NR ² R ^2a, NR ² SO 2 C ,. _4- yl, NR ² SO ² R ⁵ , S (O) PR ⁵ , (CF 2) r CF 3, NCH ² R ¹ , OCH ² R ¹ , SCH ² R ¹ ', N (CH ₂ ) ₂ (CH ₂ ) _t R ¹ , O (CH ₂ ). ) 2 (CH 2), R ¹ 'and S (CH ₂ ) ₂ (CH ₂ ) _t R ¹ , 369 otherwise, one of R ⁴ is a 5-6 membered aromatic heterocycle containing 1-4 heteroatoms selected from the group consisting of N, O and S; R ^{4a is} at each occurrence selected from = O, (CH ₂ ) _r OR ² , halo, C 1-4 alkyl, CN, NO ₂ , (CH ₂ ) _r NR ² R ^2a , (CH ₂ ) _r C (O) R ^2b , NR ² C (O) R ^2b , C (O) NR ² R ^2a , NR ² C (O) NR ² R ^2a , CH (= NR ² ) NR ² R ^2a , NHC (= NR ² ) NR ² R ^2a , SO 2 NR ² R ^2a, NR ² SO 2 NR ² R ^2a, NR ² SO 2 C _{1st 4-} alkyl, NR ² SO ² R ⁵ , S (O) PR ⁵ and (CF ₂ ) _r CF ₃ ; otherwise, one of R ^4a is a 5-6 membered aromatic heterocycle containing 1-4 heteroatoms selected from the group consisting of N, O, and S: R ^{4b is in} each case selected from = O, (CH ₂ ) _r OR ³ , halogen, C 1-4 alkyl, CN, NO ₂ , (CH ₂ ) _r NR ³ R ^3a , (CH ₂ ) _r C (O) R ³ , NR ³ C (O) R ^3a, C (O) NR ³ R ^3a, NR ³ C (O) NR ³ R ^3a, CH (= NR ³⁾ NR ³ R ^3a, NHC (= NR ³⁾ NR ³ R ^3a , SO 2 NR ³ R ^3a, NR ³ SO 2 NR ³ R ^3a, NR ³ SO 2 -C _{first 4} alkyl, NR ³ SO2CF3, NR ³ SO 2 -phenyl, S (O) _p CF _3, S (0) _p lambda-cI-4 alkyl, S (O) _p -phenyl, and (CF _{2) r} CF _3; R ^{5 is in} each case selected from CF ₃ , Ci. ₆ alkyl, phenyl substituted with 0-2 R ^6, and benzyl substituted with 0-2 ^R6; R ^{6 is} at each occurrence selected from H, OH, (CH ² ) r OR ² , halogen, C 1-4 alkyl, CN, NO ² _l (CH ₂ ) _r NR ² R ^2a , (CH ₂ ) _r C (O) R ^2b , NR ² C (O) R ^2b , NR ² C (O) NR ² R ^2a , CH (= NH) NH 2, NHC (= NH) NH ₂ , SO ₂ NR ² R ^2a , NR ² SO ₂ NR ² R ^2a and NR ² SO ² C 1-4 alkyl; R ^{7 is in} each case selected from H, OH, C _1-6 alkyl, Ci. ₆ -alkylcarbonyl, CVE-alkoxy, Ci- ₄ alkoxy carbonyl, (CH _{2) n} -phenyl, C ₆ -io aryloxy-C _{6 io-aryloxycarbonyl,} C6-io arilmetilkarbonilo, Ci_ alkiIkarboniloksi _{4-Ci-4-alkoxycarbonyl} C ₆ .io arylcarbonyloxy-C ,. ₄ alkoxycarbonyl, Ci. _6- alkylaminocarbonyl, phenylaminocarbonyl and phenylC 1-4 alkoxycarbonyl; R ^{8 is} at each occurrence selected from H, Ci. _6- alkyl and (CH ₂ ) _n -phenyl; alternatively, R ⁷ and R ⁸ together form a 5-6 membered saturated ring containing 0-1 additional heteroatoms selected from the group consisting of N, O is S; R ^{9 is} at each occurrence selected from H, C 1-6 alkyl and (CH ₂ ) _n -phenyl; n is in each case selected from O, 1,2 and 3; m is in each case selected from O, 1 and 2; 370p is in any case selected from 0, 1 and 2; r is in each case selected from 0, 1,2 and 3; s is in each case selected from 0, 1 and 2; and t is in each case selected from 0 and 1; provided that DEG- (CH ₂ ) _S - and -ZAB are not both benzamidines; a stereoisomer thereof or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1 having the formula la-lh: , R ^{1b R} ”/ J ^x za ^ _d la xR ^1b / Λ-α. _β , R ^1b la OK E ^JZ - ^A -b Ic ii - Dia N /, \ N ^R BD ^ ^EJZA '' B ld N-N \\ u \\ N-N HV N. ^X Z ^ A \ ^Β \ λ ^ ^ζ | g D ' Ih wherein the D-E- and -Z-A-B groups are attached to neighboring ring atoms; Z is selected from CH ₂ O, OCH ₂ , CH ₂ NH, NHCH _{2 i} C (O), CH ₂ C (O), C (O) CH ₂ , NHC (O), C (O) NH, CH ₂ S (O) ₂ , S (O) ₂ (CH ₂ ), SO ₂ NH and NHSO ₂ , provided that Z does not form NN, NO, NCH ₂ N or NCH ₂ O-rings to ring M or group A; A is selected from one of the following carbocyclic and heterocyclic systems substituted with 0-2 R ⁴ : phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, 1,2-thiazolifo, 4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5371 thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2 , 4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl and isoindazolyl; B is selected from: Y, Χ-Y, NR ² R ^2a , C (= NR ² ) NR ² R ^2a, and NR ² C (= NR ² ) NR ² R ^2a ; X is selected from C _1-4 alkylene, -C (O) -, - C (= NR) -, -CR ² (NR ² R ^2a ) -, -C (O) CR ² R ^2a -, -CR ² R ^2a C (O) -, -C (O) NR ² -, -NR ² C (O) - , -C (O) NR ² CR ² R ^2a -, -NR ² C (O) CR ² R ^2a -, -CR ² R ^2a C (O) NR ² -, -CR ² R ^2a NR ² C (O) ) -, -NR ² C (O) NR ² -, -NR ² -, -NR ² CR ² R ^2a -, -CR ² R ^2a NR ² -, -O-, -CR ² R ^2a O-, and -OCR ² R ^2a -; Y is NR ² R _2a , provided that Χ-Y does not form an NN or ON bond; otherwise, Y is selected from one of the following carbocyclic and heterocyclic systems substituted with 0-2 R ^4a : cyclopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, imidazolyl, imidazolyl, imidazolyl 3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl and isoindazolium; otherwise, Y is selected from the following bicyclic heteroaryl ring systems: K is selected from O, S, NH and N. 372 3. The compound of claim 2 having the formula IIa-IIf: N-N N • A \ D 'lld _R 1a A \ _R 1a Y - N D ' N I .E Iff in which: Z is selected from C (O), CH ₂ C (O), C (O) CH ₂ , NHC (O), C (O) NH, C (O) N (CH ₃ ), CH ₂ S (O) ₂ , S (O) ₂ (CH ₂ ), SO ₂ NH and NHSO ₂ , provided that Z does not form NN or NCH ₂ N bonds with ring M or group A. 4. A compound according to claim 3 wherein: E is phenyl substituted with R or 2-pyridyl substituted with R; D is selected from NH ₂ , C (O) NH ₂ , C (= NH) NH _{2 1} CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH (CH ₃ ) NH ₂ and C (CH ₃ ) ₂ NH ₂ with the proviso that the ring D in the M ring is in the meta or para position with respect to the E group; and R is selected from H, OCH ₃ , Cl and F. 5. A compound according to claim 4 wherein: DE is selected from 3-aminophenyl, 3-amidinophenyl, 3-aminomethylphenyl, 3aminocarbonylphenyl, 3- (methylaminomethyl) phenyl, 3- (1-aminoethyl) phenyl, 3- (2-amino-2-propyl) phenyl, 4-chloro- 3-aminophenyl, 4-chloro-3-amidinophenyl, 4-chloro-3-aminomethylphenyl, 4-chloro-3- (methylaminomethyl) phenyl, 4-fluoro-3aminophenyl, 4-fluoro-3-amidinophenyl, 4-fluoro-3 -aminomethylphenyl, 4-fluoro-3- (methylaminomethyl) phenyl, 6-aminopyrid-2-yl, 6-amidinopyrid-2-yl, 6-aminomethylpyrid-2-yl, 6-aminocarbonylpyrid-2-yl, 6- (methylaminomethyl) pyrid-2-yl, 6- (1-aminoethyl) pyrid-2-yl and 6- (2-amino-2propyl) pyrid-2-yl. 373 6. A compound according to claim 3 wherein: Z is C (O) and CONH, provided that Z does not form an N-N bond with group A; A is selected from phenyl, pyridyl and pyrimidyl, and is substituted with 0-2 R ⁴ ; and B is selected from Χ-Υ, phenyl, pyrrolidine, morpholine, 1,2,3-triazolyl and imidazolyl, and is substituted with 0-1 R ^4a ; R ^{4 is} at each occurrence selected from OH, (CH ₂ ) _r OR ² , halogen, C 1-4 alkyl, (CH ₂ ) _r NR ² R ^2a and (CF ₂ ) _r CF ₃ ; R ^4a is selected from C 1-4 alkyl, CF 3, S (O) PR ⁵ , SO ² NR ² R ^2a and 1-CF ₃ -tetrazol-2-yl; R ^{5 is} at each occurrence selected from CF ₃ , C _1-6 alkyl, phenyl and benzyl; X is CH ₂ or C (O); and Y is selected from pyrrolidine and morpholine. 7. A compound according to claim 6 wherein: A is selected from the group consisting of: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2aminophenyl and 2-methoxyphenyl; and B is selected from the group consisting of: 2-CF ₃ -phenyl, 2- (aminosulfonyl) phenyl, 2- (methylaminosulfonyl) phenyl, 2- (dimethylaminosulfonyl) phenyl, 1-pyrrole dinocarbonyl, 2- (methylsulfonyl) phenyl, 4-morpholine, 2- (1 '-CF ₃ ) -tetrazol-2-yl) phenyl, 4-morpholinocarbonyl, 2-methyl-1-imidazolyl, 5-methyl-1-imidazolyl, 2-methylsulfonyl-1-imidazolyl, 2-methylsulfonyl-1-imidazolyl, and 5-year (-1,2,3-triazolyl. 8. A compound according to claim 3 wherein: E is phenyl substituted with R or 2-pyridyl substituted with R; D is selected from NH ₂ , C (O) NH ₂ , C (= NH) NH ₂ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH (CH ₃ ) NH ₂ and C (CH ₃ ) ₂ NH ₂ with the proviso that the ring D in the M ring is in the meta or para position with respect to the E group; and R is selected from H, OCH ₃ , Cl and F; Z is C (O) CH ₂ and CONH, provided that Z does not form an NN bond to group A; A is selected from phenyl, pyridyl and pyrimidyl, and is substituted with 0-2 R ⁴ ; and 374 B is selected from Χ-Υ, phenyl, pyrrolidine, morpholine, 1,2,3-triazolyl and imidazolyl, and is substituted with 0-1 R ^4a ; R ^{4 is} at each occurrence selected from OH, (CH ² ) r OR ² , halogen, C 1-4 alkyl, (CH ² ) _r NR ² R ^2a and (CF ₂ ) _r CF ₃ ; R ^4a is selected from C 1-4 alkyl, CF 3, S (O) PR ⁵ , SO ² NR ² R ^2a and 1-CF ₃ -tetrazol-2-yl; R ^{5 is} at each occurrence selected from CF ₃ , C 1 -C 6 alkyl, phenyl and benzyl; X is CH ₂ or C (O); and Y is selected from pyrrolidine and morpholine. 9. A compound according to claim 8 wherein: DE is selected from 3-aminophenyl, 3-amidinophenyl, 3-aminomethylphenyl, 3aminocarbonylphenyl, 3- (methylaminomethyl) phenyl, 3- (1-aminoethyl) phenyl, 3- (2-amino-2-propyl) phenyl, 4-chloro-. 3-aminophenyl, 4-chloro-3-amidinophenyl, 4-chloro-3-aminomethylphenyl, 4-chloro-3- (methylaminomethyl) phenyl, 4-fluoro-3aminophenyl, 4-fluoro-3-amidinophenyl, 4-fluoro-3 -aminomethylphenyl, 4-fluoro-3- (methylaminomethyl) phenyl, 6-aminopyrid-2-yl, 6-amidinopyrid-2-yl, 6-aminomethylpyrid-2-yl, 6-aminocarbonylpyrid-2-yl, 6- (methylaminomethyl) pyrid-2-i (o, 6- (1-aminoethyl) pyrid-2-yl, 6- (2-amino-2propyl) pyrid-2-yl; A is selected from the group consisting of: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2aminophenyl and 2-methoxyphenyl; and B is selected from the group consisting of: 2-CF ₃ -phenyl (o, 2- (aminosulfonyl) phenyl, 2- (methylaminosulfonyl) phenyl, 2- (dimethylaminosulfonyl) phenyl, 1-pyrrolidinocarbonyl, 2- (methylsulfonyl) phenyl, 4-morpholine. , 2- (1'-CF ₃ ) -tetrazol-2-yl) phenyl, 4-morpholinocarbonyl, 2-methyl-1-imidazolyl, 5-methyl-1-imidazolyl, 2-methylsulfonyl-1-imidazolyl, and 5-methyl-1 , 2,3-triazolyl. 10. A compound according to claim 9, which is a compound of formula Ha. 11. A compound according to claim 9, which is a compound of formula IIb. 375 12. A compound according to claim 9, which is a compound of formula IIc. 13. A compound according to claim 9, which is a compound of formula IId. 14. A compound according to claim 9, which is a compound of formula Ile. 15. A compound according to claim 9, which is a compound of formula IIf. 16. A compound according to claim 3 wherein: D is selected from C (= NR ⁸ ) NR ⁷ R ⁸ , C (O) NR ⁷ R ⁸ , NR ⁷ R ⁸ and CH ₂ NR ⁷ R ⁸ , provided that the ring D in the M group is meta to E. or in a parapet; E is phenyl substituted with R or pyridyl substituted with R: R is selected from H, Cl, F, OR ³ , CH ₃ , CH ₂ CH ₃ , OCF ₃ and CF ₃ ; Z is selected from C (O), CH ₂ C (O), C (O) CH ₂ , NHC (O) and C (O) NH, provided that Z does not form an NN bond to ring M or a group A; R ^1a and R ^1b, independently of one another, absent or selected from - (CH _{2) r} -R ¹ 'NCH2R ^1, OCH 2 R ¹ ", SCH 2 R ^1", N (CH _{2) 2} (CH ₂₎ tR ¹ ', O (CH 2) ₂ (CH ₂ ) t R ¹ and S (CH ₂ ) ₂ (CH ₂ ) t R ¹ , or are linked together to form a 5-8 membered saturated, partially saturated or unsaturated ring system containing 0-2 R ⁴ is substituted with 0-2 heteroatoms selected from the group consisting of N, O and S: R ^{1 is} at each occurrence selected from H, C 1-3 alkyl, halogen, (CF 2) r CF 3, OR ² , NR ² R ^2a , C (O) R ^2c , (CF 2) _r CO ₂ R ^2c , S (O) ) pR ^2b, NR ² (CH 2) ROR ^2, NR ² C (O) R ^2b, NR ² C (O) 2 R ^2b, C (O) NR ² R ^2a, SO 2 NR ² R ^2a mRNA ² SO ₂ R ^2b; A is selected from one of the following carbocyclic and heterocyclic systems substituted with 0-2 R ⁴ : phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl and imidazolyl; B is selected from: Y, Χ-Υ, NR ² R ^2a , C (= NR ² ) NR ² R ^2a, and NR ² C (= NR ² ) NR ² R ^2a ; 376 X is selected from CH ₂ , -CR ² (CR ² R ^2b ) (CH ₂ ) r, -C (O) -, -C (= NR) -, -CH (NR ² R ^2a ) I -C (O) NR ² -, -NR ² C (O) -, -NR ² C (O) NR ² -, -NR ² -, and -O-; Y is NR ² R _2a , provided that Χ-Υ does not form an NN or ON bond; alternatively, Y is selected from one of such carbocyclic and heteroaryl systems substituted with 0-2 R ^4a ; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, 1-thiazolyl, oxadiazolyl, thiadolazole 2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl and 1,3,4-triazolyl; R ^{4 is} at each occurrence selected from = O, OH, Cl, F, C 1-4 alkyl, (CH ² ) _r R ² R ^2a , (CH 2) _r C (O) R ^2b , NR ² C (O) R ^2b , C (O) NR ² R ^2a , CH (= NH) NH ₂ , NHC (= NH) NH ₂ , SO ₂ NR ² R ^2a , NR ² SO ₂ -C ₁ . _4- alkyl, NR ² SO ² R ⁵ , S (O) PR ⁵ and (CF ₂ ) _r CF ₃ ; R ^{4a is} at each occurrence selected from = O, OH, Cl, F, Ci. _4- alkyl, (CH ₂ ) _r NR ² R ^2a , (CH ₂ ) _r C (O) R ^2b , NR ² C (O) R ^2b , C (O) NR ² R ^2a , CH (= NH) NH 2, NHC (= NH) NH ₂ , SO ₂ NR ² R ^2a , NR ² SO ₂ -Ci. _4- alkyl, NR ² SO ² R ⁵ , S (O) PR ⁵ , (CF ₂ ) _r CF ₃ and 1-CF ₃ -tetrazol-2-yl; R ^{5 is in} each case selected from CF ₃ , Ci. ₆ -alk (lo, phenyl substituted with 0-2 R ^5, and benzyl substituted with 0-2 ^R6; R ^{5 is} at each occurrence selected from H, = O, OH, OR ² , Cl, F, CH ₃ CN, NO ₂ ,. (CH ₂ ) _r NR ² R ^2a , (CH ₂ ) _r C (O) R ^2b , NR ² C (O) R ^2b , CH (= NH) NH 2, NHC (= NH) NH ₂ and SO ₂ NR ² R ^2a ; R ^{7 is} at each occurrence selected from H, OH, Ci. ₆ embryo, Ci. _6- alkali (carbonyl, Ci-e-alkoxy, Ci- ₄ -aikoksikarbonilo, benzyl, Ce-io-aryloxy, _{C6-io-aryloxycarbonyl,} C6-io arilmetilkarbonilo, C. ₄ -alkylcarbonyloxy-C 1-6. ₄ -alkoxycarbonyl, C 8-10 arylcarbonyloxy-C 1-4 alkoxycarbonyl, C 1-6 alkylaminocarbonyl, phenylaminocarbonyl and phenylCi. _4- alkoxycarbonyl; 377 R ^{8 is in} each case selected from H, O ₆ -alkyl and benzyl: or else R ⁷ and R ⁸ together form a morpholine group; and R ^{9 is} at each occurrence selected from H, C 1 -C 6 alkyl and benzyl. 17. A compound according to claim 16 wherein: E is phenyl substituted with R or 2-pyridyl substituted with R; R is selected from H, Cl, F, OCH ₃ , CH ₃ , OCF ₃ and CF ₃ ; Z is selected from C (O) CH ₂ and C (O) NH, provided that Z does not form an NN bond to group A; R ^1a is selected from H, CH3, CH2CH3 Cl, F, CF 3, OCH 3, NR ² R ^2a, S (O) pR ^2b, CH 2 S (O) pR ^2b CH2NR ² S (O) pR ^2b, C (O) R ^2c , CH ² C (O) R ^2c , C (O) NR ² R ^2a and SO ₂ NR ² R ^2a ; R ^lb is selected from H, CH3, CH2CH3, Cl, F, CF 3, OCH 3, NR ² R ^2a, S (O) pR ^2b, CH 2 S (O) pR ^2b CH2NR ² S (O) pR ^2b, C (O ) R ^2c , CH ² C (O) R ^2c , C (O) NR ² R ^2a and SO ₂ NR ² R ^2a ; A is selected from one of the following carbocyclic and heterocyclic systems substituted with 0-2 R ⁴ : phenyl, pyridyl, pyrimidyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl and imidazolyl: B is selected from: Y and Χ-Υ; X is selected from CH ₂ , -CR ² (CR ² R ^2b ) -, -C (O) -, -C (= NR) -, -CH (NR ² R ^2a ) -, -C (O) NR ² -. , -NR ² C (O) -, -NR ² C (O) NR ² -, -NR ² -, and -O-; Y is NR ² R _2a , provided that Χ-Υ does not form an NN or ON bond; otherwise, Y is selected from one of the following carbocyclic and heterocyclic systems substituted with 0-2 R ^4a : phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, 1-thiazolyl, oxadiazolyl, thiadolazole 2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl and 1,3,4-triazolyl; R ^{2 is} at each occurrence selected from H, CF ₃ , CH ₃ , benzyl and phenyl; 378 R ^{2a is} at each occurrence selected from H, CF ₃ , CH ₃ , benzyl and phenyl; R ^2b in any event, is selected from CF _3, OCH ₃ CH _3l, benzyl and phenyl; R ^{2c is} at each occurrence selected from CF ₃ OH, OCH ₃ , CH ₃ , benzyl and phenyl; alternatively R ² and R ^{2a is} a 5- or 6-membered saturated, partially unsaturated or unsaturated ring containing 0-1 additional heteroatoms selected from the group consisting of N, O and S; R ^{3 is} at each occurrence selected from H, CH ₃ , CH ₂ CH ₃ and phenyl; R ^{3a is} at each occurrence selected from H, CH ₃ , CH ₂ CH ₃ and phenyl; R ^{4 is} at each occurrence selected from OH, Cl, F, CH ₃ , CH ₂ CH ₃ , NR ² R ^2a , CH ₂ NR ² R ^2a , C (O) R ^2b , NR ² C (O) R ^2b , C (O) NR ² R ^2a, and CF ₃ ; R ^{4a is} at each occurrence selected from OH, Cl, F, CH ₃ , CH ₂ CH ₃ , NR ² R ^2a , CH ₂ NR ² R ^2a , C (O) R ^2b , C (O) NR ² R ^2a , SO ² NR ² R ^2a , S (O) PR ⁵ , CF ₃ and 1-CF ₃ tetrazol-2-yl; R ^{5 is in} each case selected from CF ₃ , C 1-6 alkyl, phenyl substituted with 0-2 R ⁶ and benzyl substituted with 0-2 R ⁶ ; R ^{6 is} at each occurrence selected from H, OH, OCH 3, Cl, F, CH 3, CN, NO ² NR ² R ^2a , CH ² NR ² R ^2a and SO ₂ NR ² R ^2a ; R ^{7 is} at each occurrence selected from H, OH, Ci. _3- alkyl, C 1-4 alkylcarbonyl, Ci. ₃ -alkoxy, Ci- ₄ -aikoksikarbonilo, benzyl, phenoxy, fenoksikarboniio, benzylcarbonyl, C1.4-alkilkarboniioksi-C1.4alkoksikarbonilo, phenylcarbonyloxy-Ci. _4- alkoxycarbonyl, Ci. ₆ alkylaminocarbonyl, phenylaminocarbonyl and phenyl-Ci. _4- alkoxycarbonyl; R ^{8 is} at each occurrence selected from H, CH ₃ and benzyl; otherwise R ⁷ and R ⁸ together form a morpholine group; and R ^{9 is} at each occurrence selected from H, CH ₃ and benzyl. 18. The compound of claim 17, wherein: R ^1a is absent or selected from H, CH 3, CH 2 CH 3, Cl, F, CF 3, OCH 3, NR ² R ^2a , S (O) p R ^2b , C (O) NR ² R ^2a , CH 2 S (O) p R ^2b , CH ² NR ² S (O) p R ^2b , C (O) R ^2c , CH ² C (O) R ^2c and SO ₂ NR ² R ^2a ; R ^1b is absent or selected from H, CH 3, CH 2 CH 3, Cl, F, CF 3, OCH 3, NR ² R ^2a , S (O) p R ^2b , C (O) NR ² R ^2a , CH 2 S (O) p R ^2b , CH2NR ² S (O) pR ^2b, C (O) R ^2b, CH 2 C (O) R ^2b, NR ₂ irSO ² R ^2b; 379 A is selected from one of the following carbocyclic and heterocyclic systems substituted with 0-2 R ⁴ : phenyl, pyridyl and pyrimidyl; B is selected from: Y and Χ-Υ; X is selected from -C (O) - and O; Y is NR ² R 2a, provided that Χ-Y does not form an ON bond; otherwise, Y is selected from one of the following carbocyclic and heterocyclic systems substituted with 0-2 R ^4a : phenyl, piperazinyl, pyridyl, pyrimidyl, morpholinyl, pyrrolidinyl, imidazolyl and 1,2,3-triazolyl; R ^{2 is} at each occurrence selected from H, CF ₃ , CH 3, benzyl and phenyl; R ^{2a is} at each occurrence selected from H, CF ₃ , CH ₃ , benzyl and phenyl; R ^{2b is in} each case selected from CF ₃ , OCH ₃ , CH ₃ , benzyl and phenyl; R ^{2c is in} each case selected from CF ₃ , OH, OCH ₃ , CH ₃ , benzyl and phenyl: otherwise R ² and R ^2a form a ring selected from pyrrolidinyl, piperazinyl and morpholine; R ^{4 is} at each occurrence selected from Cl, F, CH 3, NR ² R ^2a and CF 3; R ^{4a is} at each occurrence selected from Cl, F, CH 3, SO ² NR ² R ^2a , S (O) PR ⁵ and CF 3; R ^{5 is in} each case selected from CF 3 and CH ₃ . 19. The compound of claim 1, wherein it is selected from the group consisting of: 1- (3-amidinophenyl) -2 - [[(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrrole; 1- (3-amidinophenyl) -2 - [[(2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrrole; 1- (3-amidirrophenyl) -2 - [[(2'-aminosulfonyl- [1,1 T] -biphen-4-yl) aminocarbonyl] 4-bromopyrrole; 1- (3-amidinophenyl) -2 - [[5- (2'-aminosulfonyl-phenyl-1-yl) pyridin-2-yl] aminocarbonyl] pyrrole; 1-benzyl-3 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -4- (3amidinophenyl) pyrrole; 1-benzyl-3 - [(2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -4 (3-amidinophenyl) pyrrole; 1- (3-amidinophenyl) -4 - [(2'-aminosulfonyl- [1,1] biphen-4-yl) aminocarbonyl] imidazole; 1- (3-Aminophenyl) -4 - [(2 '- tert -butylaminosulfonyl- [1,1'] - biphen-4yl) aminocarbonyl] -imidazole; 380 1- (3-amidinophenyl) -2 - [(2'-aminosulfonyl- [1,1] t-biphen-4-H) aminocarbonyl] imidazole; 1- (3-amidinophenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 'J-biphen-4-yl) carbonylamino] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [(2 '- (5 ^; ' -CF 3 -tetrazolyl) - [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] 4-chloro-3-methyl-pyrazole; 1- (3-amidophenyl) -5 - ((2'-t-b utilaminosulfonyl - [1,1 '] - biphen-4-yl) aminocarbonyl] -3-trifluoromethyl-pyrazole; 1- (3-amidinophenyl) -4-methoxy-5 - ((2 ^: -aminosulfonyl- [1,1 T] -biphen-4-yl) aminocarbonyl] -3-trifluoromethyl-pyrazole; 1- (3-amidinophenyl) -3-methyl-5- (4 '- (imidazol-1-yl) phenyl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [(4 '- (2'-sulfonylmethyl) phenoxyphenyl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4yl) methylcarbonylpyrazole; 1- (3-amidinophenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] 1,2,3-triazole; 1- (3-amidinophenyl) -5 - [(2'-trifluoromethyl- [1,1 '] - biphen-4-yl) aminocarbonyl] tetrazole; 1- (3-amidinophenyl) -5 - [(2'-aminosulfonyl-3-chloro- [1,1 '] - biphen-4-yl) methylthio) tetrazole; 1- (3-amidinophenyl) -5 - ^[(2, -aminosulfonil-3-chloro- [1,1 '] - biphen4-yl) metilsulfoksido] tetrazole; 1- (3-amidinophenyl) -5 - [(2'-aminosulfonyl-3-chloro- [1,1 '] - biphen-4yl) methylsulfonyl] tetrazole; 1- (3-amidinophenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] tetrazole; 1- (3-amidinophenyl) -3-methyl-2 - [[5- (2 ^: aminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-2 - [[5- (2'-aminosulfonylphenyl-1-yl) pyrimidin-2-yl] aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [(2'-aminosulfonyl-2-chloro- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [(2'-aminosulfonyl-2-fluoro [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [(2'-aminosulfonyl-4'-fluoro [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [(2'4-trifluoromethyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [(3-chloro-2'-trifluoromethyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [(3-fluoro-2'-trifluoromethyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole; 381 1- (3-amidinophenyl) -3-methyl-2 - [[5- (2'-trifluoromethylphenyl-1-yl) pyridin-2-yl] aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [(2'-fluoro- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [(3-chloro-2'-fluoro- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [(2'-methylsulfonyl- [1,1 T] -biphen-4-yl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 T] -biphen-4-yl) (N'methyl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-n-butyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-n-butyl-5 - [{(2'-aminosulfonylphenyl-1-yl) pyridin-2-yl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-n-butyl-5 - [{(2'-trifluoromethylphenyl-1-yl) pyridin-2-yl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -5 - [(2'-methylsulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-trifluoromethyl-pyrazole; 1- (3-amidinophenyl) -5 - [(2'-trifluoromethyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-trifluoromethyl-pyrazole; 1- (3-amidinophenyl) -4-methoxy-5 - [(2'-trifluoromethyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-trifluoromethyl-pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [(4-trifluoromethylphenyl] aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -4-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] imidazole; 1- (3-amidinophenyl) -5 - [(2'-aminosulfonylphenyl-1-yl) pyridin-2-yl) aminocarbonyl] -1,2,3-triazole; 1- (3-amidinophenyl) -5 - [(2'-trifluoromethyl- [1,1 '] - biphen-4-yl) aminocarbonyl] 1,2,3-triazole; 1- (3-amidinophenyl) -5 - [(2'-aminosulfonyl- [1,1] biphen-4-yl) aminocarbonyl] ~ 3-trifluoromethyl-1,2,4-triazole; 3-methyl-1- (3-amidinophenyl) -5- (4 '- (4' '- chlorophenyl) thiazol-2'yl) aminocarbonyl] pyrazole; 1- (3-amidino) phenyl-3-methyl-5 - [(2'-trifluoromethylsulfido [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole; 1- (3-amidino) phenyl-3-methyl-5 - [(2''-trifluoromethylsulfoxido [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole; 1- (3-amidino) phenyl-3-methyl-5 '- [(2'-trifluoromethylsulfonyl- [1,1'] - biphen-4-yl) aminocarbonyl] pyrazole; 1- (3-amidino) phenyl-3-methyl-5- [4 '- (carboxymethyl) phenylaminocarbonyl] pyrazole; 1- (3-amidino) phenyl-3-methyl-5- [4 '- (N, N-dimethylaminocarbonyl) phenylaminocarbonyl] pyrazole; 1- (3-amidino) phenyl-3-methyl-5- [4 '- (N, N-dimethylaminosulfonyl) phenylaminocarbonyl] pyrazole; 1- (3-amidino) phenyl-3-methyl-5 - [(4'-tert-butylaminosulfonylphenyl) aminocarbonyl] pyrazole; 382 1- (3-amidino) phenyl-3-methyl-5 - [(4'-aminosulfonylphenyl) aminocarbonyl] pyrazole; 1- (3-amidino) phenyl-3-methyl-5 - [(4'-trifluoromethylphenyl) aminocarbonyl] pyrazole; 1- (3-amidino) phenyl -3-methyl-5 - [(4'-benzenesulfonylpiperidyl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) -N-methylaminocarbonyl] -3-methyl-pyrazole; 1- (3-Aminophenyl) -5 - [(4'-fluoro- [1,1 '] -biphen-4-yl) aminocarbonyl] -3-methylpyrazole; 1- (3-amidinophenyl) -5 - [[5- (2'-aminosulfonylphenyl) pyridin-2-yl] aminocarbonyl] -3-methylphyrazole; 1- (3-Cyanophenyl) -5 - [[5- (2'-aminosulfonylphenyl) pyridin-2-yl] aminocarbonyl] -3-methylpyrazole: 1- (3-amidinophenyl) -5 - [(2'-trifluoromethyl- [1,1 '] - biphen-4-yl) -aminocarbonyl] -3-methyl-pyrazole; 1- (3-aminocarbonylphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methylpyrazole: and 1- (3-amidinophenyl) -5 - [(2'-aminosulfonyl) -3-chloro- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methylpyrazole; and a pharmaceutically acceptable salt thereof. 20. A compound according to claim 1 wherein it is selected from the group consisting of: 1- (3-amidinophenyl) -5 - [(2'-trifluoromethyl-3-chloro- [1,1 'J-biphen-4-yl) aminocarbonyl] -3-methyl-pyrazole; 1- (3-amidinophenyl) -5 - [(2'-aminosulfonyl) - [1,1 '] - biphen-4-yl) aminocarbonyl] 3-n-butylpyrazole; 1- (3-amidinophenyl) -5 - [(2'-trifluoromethyl- [1,1 '] - biphen-4-yl) -aminocarbonyl] -3n-butylpyrazole; 1- (3-amidinophenyl) -5 - [[5- (2'-aminosulfonylphenyl) pyridin-2-yl] aminocarbonyl] -3-n-butylpyrazole; 1- (3-Aminophenyl) -5 - [(2'-trifluoromethyl- [1,1 '] - biphen-4-yl) -aminocarbonyl] -3-trifluoromethyl-4-methoxypyrazole; 1- (3-amidinophenyl) -5 - [(2'-trifluoromethyl- [1,3] biphen-4-yl) aminocarbonyl] -3-trifluoromethylpyrazole; 1- (3-amidinophenyl) -5 - [(2'-sulfonylmethyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-trifluoromethyl-pyrazole; 1- (3-amidinophenyl) -5 - [(2'-aminosulfonyl-3-bromo- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methylpyrazole; 1- (3-aminocarbonylphenyl) -5 - [(2'-aminosulfonyl-3-bromo- [1,1 '] - biphen-4yl) aminocarbonyl] -3-methylpyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [(2'-aminosulfonyl) - [1,1 '] - biphen-4-yl) methylcarbonyl] pyrazole; 1- (3-Amyrocarbonylphenyl) -5- [5 - [(2'-aminosulfonylphen-1-yl) pyridin-2-yl] aminocarbonyl] -3-methylpyrazole; 383 1- (3-amidinophenyl) -5 - [[5- (2'-t-butylaminosulfonylphenyl) pyrimidin-2-yl] aminocarbonyl] -3-trifluoromethylpyrazole; 1- (3-amidinophenyl) -5 - [[5- (2'-aminosulfonylphenyl) pyrimidin-2-yl] aminocarbonyl] -3-trifluoromethylpyrazole; 1- (3-aminocarbonylphenyl) -5 - [[5- (2'-aminosulfonylphenyl) pyrimidin-2-yl] aminocarbonyl] -3-trifluoromethylpyrazole; 1- (3-cyanophenyl) -5 - [((4 '- (imidazol-1-yl) phenyl) aminocarbonyl] -3-trifluoromethylpyrazole; 1- (3-amidinophenyl) -5 - [(4 '- (morpholin-1-yl) phenyl) aminocarbonyl] -3-trifluoromethylpyrazole; 1- (3-aminocarbonylphenyl) -5 - [(4 '- (morpholin-1-yl) phenyl) aminocarbonyl] -3-trifluoromethylpyrazole; 1- (3-amidinophenyl) -5 - [[5- (2'-aminosulfonylphenyl) pyridin-2-yl] aminocarbonyl] -3-trifluoromethylpyrazole: 1- (3-aminocarbonylphenyl) -5 - [[5- (2'-aminosulfonylphenyl) pyridin-2-yl] aminocarbonyl] -3-trifluoromethylpyrazole; 1- (3-amidinophenyl) -5 - [(4 '- (3-methyltetrazol-1-ylphenyl) aminocarbonyl] -3-trifluoromethylpyrazole; 1- (3-amidinophenyl) -5- (2'-naphthylaminosulfonyl) -3-methylpyrazole: 1- (3-amidinophenyl) -5 - [(4-bromophenyl) aminosulfonyl] -3-methylpyrazole; 1- (3-aminomethylphenyl) -5 - [(2'-aminosulfonyl) - [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methylpyrazole; 1- (3-aminomethylphenyl) -5 - [(2'-aminosulfonyl) - [1,1 '] - biphen-4-yl) aminocarbonyl] -3-trifluoromethylpyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [((2'-trifluoromethylphenyl) pyrid-2-yl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [((2'-aminosulfonyl-1-yl) pyrimidin-5-yl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [(2'-fluoro- [1,1 '] - biphen-4-yl) aminocarbonylpyrazole; 1- (3-amidinophenyl) -3-methyl-5- [3-chloro- (2'-fluoro- [1,1] T-biphen-4-yl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [(3-fluoro-2'-fluoro- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [(3-fluoro-2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5- [5- (2'-fluorophen-1-yl) pyrid-2-yl] aminocarbonylpyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [[5- (2'-tetrabutylaminosulfonylphenyl] pyrimidin-2-yl] aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [[5- (2'-aminosulfonylphenyl) - [1,6] dihydropyrimidin-2-yl] aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [(4- (pyrid-3'-yl) phen-1-yl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [[2- (2'-pyridyl) ethyl] aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [(3-phenylpropyl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5- [4- (pyrid-2'-yl) phen-1-ylaminocarbonylpyrazole; 384 1- (3-amidinophenyl) -3-methyl-5 - {(4- (isopropyloxy) phenyl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5-i (5- (2'-trifluoromethylphenyl) pyrimidin-2-yl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - {(4- (piperidinosulfonyl) phenyl) aminocarbonyl} pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [(4- (piperidinocarbonyl) phenyl) aminocarbonyl] pyrazole; 1- (3-amidino-4-fluorophenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole; 1- (3-aminocarbonyl-4-fluorophenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen4-yl) aminocarbonyl] pyrazole; 1-methyl-3- (3-amidino) phenyl-4 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole; and 1- (3-amidinophenyl) -3-methyl-5 - [[4- (pyrazol-4'-yl) phen-1-yl] aminocarbonyl] pyrazole; and a pharmaceutically acceptable salt thereof. 21. A compound according to claim 1, wherein it is selected from the group consisting of: 1- (3-amidinophenyl) -3-methyl-5 - ([5- (2'-methylsulfonylphenyl) pyrid-2-ylaminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - ([5- (2'-methylsulfonylphenyl) pyrimidin-2-yl] aminocarbonyl) pyrazole; 1- (3-cyanophenyl) -3-methyl-5 - ([5- (2'-methylsulfonylphenyl) pyrimid-2-thiaminocarbonyl] pyrazole; 1- (3-aminocarbonylphenyl) -3-methyl-5 - ([5- (2'-methylsulfonylphenyl) pyrimidin-2-yl] aminocarbonyl) pyrazole; 1- (3- (N-aminoamidino) phenyl) -3-methyl-5 - [(2'-tert-butylaminosulfonyl- [1,1'j] biphen-4-yl) aminocarbonyl] pyrazole; 1- (3- (N-aminoamidino) phenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4ii) aminocarbonyl] pyrazole; 1- (3- (N-methyl-N-hydroxyamidino) phenyl) -3-methyl-5 - [(4'-t-butylaminosulfonyl [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole; 1- (3- (N-methylamidino) phenyl) -3-methyl-5 - [(2'-tert-butylaminosulfonyl- [1,1 '] biphen-4-yl) aminocarbonyl] pyrazole; 1- (3- (N-methylamidino) phenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1'-biphen-4-yl] aminocarbonyl) pyrazole; 1- (3-amidinophenyl) -5 - [(2'-aminosulfonylphenyl) pyridin-2-ylaminocarbonyl] tetrazole; 1- (3-aminocarbonylphenyl) -5 - {[5- (2'-aminosulfonylphenyl) pyridin-2-ylaminocarbonyl] tetrazole; 1- (3-amidinophenyl) -5 - {[5- (2'-trifluoromethylphen-1-yl) pyridin-2-yl] aminocarbonyl] tetrazole; 1- (3-amidinophenyl) -5 - [(4'-bromophen-1-yl) aminocarbonyl] tetrazolo; 1- (3-aminocarbonylphenyl) -5 - {[5- (2'-trifluoromethylphen-1 (i) pyridin-2-yl] aminocarbonyl} tetrazole; 385 5- (3-amidinophenyl) -1 - [(2 '-trifluoromethyl - [1,1'] - benzen-4-yl) methyl] tetrazole; 1 - [(3-amidinophenyl) methyl] -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole; 1 - [(4-amidinophenyl) methyl] -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -2 - [(2'-aminosulfonyl- [1,1 T] -biphen-4-yl) aminocarbonyl] imidazole; 1- (3-amidinophenyl) -4-methyl-2 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] imidazole; 1- (3-amidinophenyl) -5-chloro-4-methyl-2 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] imidazole; 5- (3-amidinophenyl) -2-methyl-4 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] imidazole; 1- (3-amidinophenyl) -3-methyl-5 - [(4 '- (benzimidazol-1-yl) phen-1-yl) aminocarbonyl] pyrazole; 1- (3-aminocarbonylphenyl) -3-methyl-5 - [(4'-benzimidazol-1-yl) phen-1-yl) aminocarbonyl] pyrazole; 1- (3-amidinophenic) - 3-methyl-5 - [(4 '- (2-methylimidazol-1-yl) phenyl) aminocarbonyl] pyrazole; 1- (3-aminocarbonylphenyl) -3-methyl-5 - [(4 ^: - (2-methylimidazol-1-yl) phenyl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [(4 '- (1,2,3-triazol-2-yl) phenyl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - ((4'-cyclohexylphenyl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [[1,1 '] - biphen-4 1- (3-amidinophenyl) -3-methyl-5 - ((4'-morpholinophenyl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [(4 '- ( (2-trifluoromethyl) tetrazol-1-yl) phenyl) aminocarbonyl] pyrazole; 1- (3-aminomethylphenyl) -3-methyl-5 - [(4 '- ((2-trifluoromethyl) tetrazol-1-yl) phenyl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [(4 '- (N, N-dimethylamino) carbonylamino) phenyl] aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [(4 '- (N, N-diethylamino) phenyl) aminocarbonyl] pyrazole; 1- (3-aminocarbonylphenyl) -3-methyl-5 - [(4 '- (N, N-diethylamino) phenyl) aminocarbonylpyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [(4 '- (1-tetrazolyl) phenyl) aminocarbonyl] pyrazole; 1- (3-aminocarbonylphenyl) -3-methyl-5 - [(4 '- (1-tetrazolyl) phenyl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [(4 '- (N-acetylpiperazin-1-yl) phenyl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [(4 '- (N-tert-butyloxycarbonylpiperazin-1-yl) phenyl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - ((4'-piperazin-1-yl) phenyl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-trifluoromethyl-5 - ((4'-cyclohexylphenyl) aminocarbonyl) pyrazole; 386 1- (3-amidinophenyl) -3-methyl-5 - [(4 '- (N-morpholino) -3'-chlorophenyl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] 3- (methylthio) pyrazole; 1- (3-amidinophenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] 3- (methylsulfinyl) pyrazole; 1- (3-amidinophenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] 3- (methylsulfonyl) pyrazole; 1- (3-aminocarbonylphenyl) -5 - [(2'-trifluoromethyl- [1,1 '] - biphen-4-yl) methyltetrazole; 1- (3-aminocarbonylphenyl) -5 - {[(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) methyl} tetrazole; 1- (3-amidinophenyl) -5 - [(4'-cyclopentyloxyphenyl) aminocarbonyl] -3-methylpyrazole; 1- (3-amidinophenyl) -5 - [(3 - ((pyrid-2-yl) methylamino) phenyl) aminocarbonyl] -3-methylpyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [(4 '- (N-imidazolyl) phenyl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-trifluoromethyl-5 - [(4 '- (N-morpholino) -3-chlorophenyl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [(4 '- (N-pyrrolidinocarbonyl) -3'-chlorophenyl) aminocarbonyl] pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [(4 '- (N-morpholinocarbonyl) -3-chlorophenyl) aminocarbonyl] pyrazole; 1- (3-cyanophenyl) -5 - [(4 '- (N-imidazolyl) phenyl) aminocarbonyl] -3-trifluoromethylpyrazole; 1- (3-amidinophenyl) -5 - [(4 '- (N-imidazolyl) phenyl) aminocarbonyl] -3-trifluoromethylpyrazole; 1- (3-amidinophenyl) -5 - [(4 '- (N-methyltetrazolon-1-yl) phenyl) aminocarbonyl] -3-trifluoromethyl-pyrazole; and 1- (3'-Aminocarbonylphenyl) -5 - [(2'-aminosulfonylphenyl- [1,1 '] - biphen-4yl) methylcarbonyl] -3-methyl-pyrazole; and a pharmaceutically acceptable salt thereof. 22. A compound according to claim 1 wherein it is selected from the group consisting of: 1- (3-amidinophenyl) -5- [4 '- (pyrrolidinomethyl) phenyl) aminocarbonyl] -3-methylpyrazole; 1- (3-aminophenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole; 1- (2'-Aminophenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole; 1- (3-amino-4'-chlorophenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole; 1- (3-amino-4'-fluorophenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole; 387 1- (3-amino-4'-methoxyphenyl) -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole; 1- (3-amino-4'-chlorophenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] tetrazole; 1- (3-amino-4'-chlorophenyl) -5 - {[(2'-aminosulfonylphenyl) pyridin-2-yl] aminocarbonyl} tetrazoto; 1- (3-amino-4'-methoxyphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] tetrazole; 1- (3-Aminomethylphenyl) -5 - [(2'-aminosulfonylphenyl) pyrid-2-yl] aminocarbonyl] 3-methylpyrazole; 1- (3-Aminomethyl-4'-methyl-phenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) -aminocarbonyl] -3-methyl-pyrazole; 1- (3-aminomethyl-4'-fluorophenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methyl-pyrazole; 1- (3-aminomethylphenyl) -5 - [(4 '- (N-pyrrolidinocarbonyl) phenyl) aminocarbonyl] 3-trifluoromethyl-pyrazole; 1- (3-ethylcarboxamide-idinophenyl) -5 - [(2'-aminosulfonyl - [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methyl-pyrazole; 1- (3- (1'-imino-1 '- (N-morpholino)) methyl) phenyl) -5 - [(2'-tert-butylaminosulfonyl [1,1'] - biphen-4-yl) aminocarbonyl ] -3-methyl- [pyrazole; 1- (3- (1'-imino-r- (N-morpholino)) methyl) phenyl) -5 - [(2'-aminosulfonyl- [1,1 '] biphen-4-yl) aminocarbonyl] -3-methylpyrazole; 1- [3- [N - ((5-methyl-2-oxo-1,3-dioxol-4-yl) methoxycarbonyl) amidino] phenyl] 5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methylpyrazole; 1- (pyrid-2-yl) -3-methyl-5 - [(3-fluoro-2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole; 1- (6-Bromopyridin-2-yl) -3-methyl-5 - [(3-fluoro-2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole; 1- (3-Amino-4-chlorophenyl) -5 - [(2'-aminosulfonyl-3-chloro- [1,1 T] -biphen-4-yl) aminocarbonyl] tetrazole; 1- (3-amino-4-chlorophenyl) -5 - [(4 '- (1-pyrrolidinocarbonyl) phenyl) aminocarbonyl] tetrazole; 1- (3-aminomethylphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] tetrazole; 1- (3-Aminomethylphenyl) -5 - [(2'-aminosulfonyl-3-fluoro [1,1 '] - biphen-4-yl) aminocarbonyl] tetrazole: 1- (3-Aminomethylphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] imidazole; 1- (3-Aminomethylphenyl) -5 - [(2'-methylsulfonylmethyl- [1,1 '] - biphen-4-yl) aminocarbonyl] imidazole; 1- (3-amidinophenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] imidazole; 1- [3- (methylaminomethyl) phenyl] -5 - [(2'-aminosulfonyl-3-fluoro [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methylpyrazole; 1- [3- (methylaminomethyl) phenyl] -5 - [(2'-methylsulfonyl-3-fluoro [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methylpyrazole; 1- (3-aminomethylphenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -4-methoxy-3-trifluoromethyl-pyrazole; 388 1- (3-aminomethylphenyl) -5 - [(2-fluoro-4- (N-pyrrolidinocarbonyl) phenyl) aminocarbonyl] -3-trifluoromethylpyrazole; 1- (3-Aminomethylphenyl) -5 - [(3-fluoro-4- (N-pyrrolidinocarbonyl) phenyl) aminocarbonyl] -3-trifluoromethylpyrazole: 1- (3-aminomethylphenyl) -5 - [(2'-sulfonylmethyl- [1,1 'J-biphen-4-yl) aminocarbonyl] 3-trifluoromethyl-pyrazole; 1- (3-Aminomethylphenyl) -5 - [(2'-aminosulfonyl-3-fluoro [1,1 '] - biphen-4-yl) aminocarbonyl] -3-trifluoromethyl-pyrazole: 1- (3-Aminomethylphenyl) -5 - [(2'-aminosulfonylphenyl- [1,6-dihydro] pyrimidin-2-yl) aminocarbonyl] -3-trifluoromethyl-pyrazole: 1- (3-aminomethylphenyl) -5 - {(5- (2'-aminosulfonylphenyl) pyrimidin-2-yl) aminocarbonyl] -3-trifluoromethylpyrazole; 1- [3- (2'-Ethylaminophenyl) -5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-trifluoromethyl-pyrazole; 1 * [3- (1- (N-morpholino) imino) phenyl) -5 - [(2'-aminosulfonyl-3-fluoro [1,1 biphen-4-yl) aminocarbonyl] -3-trifluoromethyl-pyrazole ; 1- (3-aminomethylphenyl) -5- [2- (2'-aminosulfonyl- [1,1 '] - biphen-4-yl) -1-hydroxyethyl] -3-trifluoromethyl-pyrazole; 1- (3-aminomethylphenyl) -5 - [(3-fluoro-2'-methylsulfonyl- [1,1'J-biphen-4-yl) aminocarbonyl] -3-trifluoromethyl-pyrazole; 1- (3-aminomethylphenyl) -5 - [(5- (2'-methylsulfonylphenyl) pyrimidin-2-yl) aminocarbonyl] -3-trifluoromethyl-pyrazole; 1- (3-amidinophenyl) -5 - [(3-fluoro-2'-methylsulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-trifluoromethyl-pyrazole; and 1- (3-amidinophenyl) -5 - [(3-fluoro-2'-aminosulfone (- [1,1 '] - biphen-4-yl) aminocarbonyl) -3-trifluoromethyl-pyrazole; and a pharmaceutically acceptable salt thereof. 23. The compound of claim 1, wherein it is selected from the group consisting of: 1- (3-aminomethyl) phenyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) carbonylmethyl] -3-trifluoromethyl-pyrazole; 1- (3-aminomethyl) phenyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3- (methylsulfonylmethyl) pyrazole; . 1- (3-amidino) phenyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) -aminocarbonyl] -3- (methylaminosulfonylmethyl) pyrazole; 1- (3-Aminomethylphenyl) -5 - [(2'-aminosulfonyl-3-fluoro [1,1 '] - biphen-4-yl) aminocarbonyl] -3- (methylaminosulfonylmethyl) pyrazole; 1- (3- (N-Carboxymethyl) amidinophenyl) -5 - [(5- (2'-aminosulfonylphenyl) pyrimidin-2-yl) aminocarbonyl] -3-methylpyrazole; 1- (3-aminomethylphenyl) -5 - [(2'-methylsulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methylpyrazole; 1- (3-aminomethylphenyl) -5 - [(2'-aminosulfonyl-3-methyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-trifluoromethyl-pyrazole; 1- (3-aminomethylphenyl) -5 - [(3-fluoro-2'-methylsulfonyl- [1,1 'J-biphen-4-yl) aminocarbonyl] -1,2,3-triazole; 389 1- (3-Aminomethyl-4-methyl) -phenyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) -aminocarbonyl] -3-methyl-pyrazole; 1- (3-aminomethyl-4-fluoro) phenyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methylpyrazole; 1- (3-Aminomethyl-4-chloro) -phenyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methyl-pyrazole; 1- (3-aminomethyl-4-fluoro) phenyl-5 - [(2'-aminosulfonyl-3-fluoro [1,1 '] - biphen-4yl) aminocarbonyl] -3-trifluoromethyl-pyrazole; 1- (3-Aminomethyl) phenyl-5 - [(2'-aminosulfonyl-3-fluoro [1,1 '] - biphen-4-yl) aminocarbonyl] -3-methylpyrazole; 1- (3-aminomethyl) phenyl-5 - [(3-fluoro-2'-methylsulfonyl- [1,1'-biphen-4-yl) aminocarbonyl] -3-trifluoromethyl-pyrazole; 1- (3-amidinophenyl) -3-methyl-5 - [(3-fluoro-4- (N-morpholino) phenyl) aminocarbonyl] pyrazole; 1- (3-aminomethylphenyl) -3-methyl-5 - [(3-fluoro-4- (N-morpholino) phenyl) aminocarbonyl] pyrazole; 1- (3-aminomethylphenyl) -3-trifluoromethyl-5 - [(3-fluoro-4- (2-methylimidazol-1-yl) phenyl) aminocarbonyl] pyrazole; 1- (3-cyanophenyl) -3-trifluoromethyl-5 - (([1, T] -biphen-4-yl) oxymethyl) pyrazole; 1- (3-amidinophenyl) -3-trifluoromethyl-5 - (<[1,1 '] - biphen-4-yl) oxymethyl) pyrazole; 1- (3-Carboxamidophenyl) -3-trifluoromethyl-5 - (([1, T] -biphen-4-yl) oxymethyl) pyrazole; 1- (3-amidinophenyl) -3-trifluoromethyl-5 - ((2-fluoro-4- (N-morpholino) phenyl) aminocarbonyl) pyrazole; 1- (3-Carboxamidophenyl) -3-trifluoromethyl-5 - ((2-fluoro-4- (N-morpholino) phenyl) aminocarbonyl) pyrazole; 1- (3-Aminomethylphenyl) - 3-trifluoromethyl-5 - ((3-trifluoromethyl-4- (N-mololino) phenyl) aminocarbonyl) pyrazole; 1- (3-aminomethylphenyl) -3-ethyl-5 - [(3-fluoro-2'-tert-butylaminosulfonyl- [1,1 '] biphen-4-yl) aminocarbonyl] pyrazole; 1- (3-Aminomethylphenyl) -3-ethyl-5 - [(3-fluoro-2'-methylsulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole; 1- (3-aminomethylphenyl) -3-ethyl-5 - [(2-fluoro-4- (2-methylsulfonylimidazol-1-yl) phenyl)] aminocarbonyl) pyrazole; 1 - [(6- (aminomethyl) pyrid-2-yl)] - 3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4yl) aminocarbonyl] pyrazole; 1 - [(6- (N-hydroxyamidino) pyrid-2-yl)] - 3-methyl-5 - [(2'-tert-butylaminosulfonyl- [1,1 '] - biphen-4-yl) -aminocarbonyl] pyrazole; 1- [6-amidinopyrid-2-yl] -3-methyl-5 - [(2'-aminosulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole; 1- [6-amidinopyrid-2-yl] -3-methyl-5- [3-fluoro- (2'-methylsulfonyl- [1,1'] -biphen-4-yl) -aminocarbonyl] pyrazole; 1- (3-aminomethylphenyl) -3-methyl-5 - ((2-methoxy-4- (N-morpholino) phenyl) aminocarbonyl) pyrazole; 1- (3-aminomethylphenyl) -3-methyl-5- [4 '- (3 "-methyl-5" -oxo-3 "-pyrazolin-2" -yl) phenyl) aminocarbonyl] pyrazole; 1- [3- (aminomethyl) phenyl] -5 - [(2'-methylsulfonyl- [1,1] biphen-4-yl) aminocarbonyl] -3- (methylthio) pyrazole; 390 1- (3-aminomethyl-4-fluorophenyl) -3-trifluoromethyl-5 - [(3-fluoro-2'-methylsulfonyl [1,1 '] - benzen-4-yl) aminocarbonyl] pyrazole; 1- [3- (Aminomethyl) -phenyl] -5- [3-fluoro-2'-methylsulfonyl- [1,1 '] -biphen-4-yl) aminocarbonyl] pyrazole-3-carboxylic acid ethyl ester: 1- [3- (aminomethyl) -phenyl] -5- [3-fluoro-2'-methylsulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] pyrazole-3-carboxylic acid; 1- [3- (aminomethyl) -phenyl] -3- [aminocarbonyl] -5- [3-fluoro-2'-methylsulfonyl [1,1] -biphen-4-yl) -aminocarbonyl] pyrazole; 1- [3- (Aminomethyl) -phenyl] -3-trifluoromethyl-5 - [(3-fluoro-2'-methylsulfonyl- [1,1] biphen-4-yl) aminocarbonyl] pyrazole-4-carboxylic acid ethyl ester; 1- [3- (aminomethyl) phenyl] -5 - [(3-fluoro-2'-methylsulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3- (methylthio) pyrazole; 1- [3- (aminomethyl) phenyl] -5 - [(3-fluoro-2'-methylsulfonyl- [1,1 '] - biphen-4-yl) aminocarbonyl] -3- (methylsulfonyl) pyrazole; 1- [3- (aminomethyl) phenyl] -5 - [(4- (5- (methoxyaminocarbonyl) imidazol-1-yl) phen-1-yl) aminocarbonyl] -3-trifluoromethyl-pyrazole; and 1-3-aminomethylphenyl) -5 - [(4- (5-methyl-1,2,3-triazol-1-yl) phen-1-yl) aminocarbonyl] -3-trifluoromethyl-pyrazole; and a pharmaceutically acceptable salt thereof. 24. A pharmaceutical composition comprising an effective amount of a pharmaceutically acceptable carrier and compound of claim 1 or a pharmaceutically acceptable salt thereof. A compound according to claim 1 for use in the treatment or prophylaxis of thromboembolic disorders.