CA2321538A1 - Disubstituted pyrazolines and triazolines as factor xa inhibitors - Google Patents

Disubstituted pyrazolines and triazolines as factor xa inhibitors Download PDF

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CA2321538A1
CA2321538A1 CA002321538A CA2321538A CA2321538A1 CA 2321538 A1 CA2321538 A1 CA 2321538A1 CA 002321538 A CA002321538 A CA 002321538A CA 2321538 A CA2321538 A CA 2321538A CA 2321538 A1 CA2321538 A1 CA 2321538A1
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phenyl
occurrence
nr2r2a
imidazolyl
pyridyl
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Donald J. P. Pinto
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Bristol Myers Squibb Pharma Co
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D231/00Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/06Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D249/00Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/081,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/101,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Abstract

The present application describes disubstituted pyrazolines and triazolines of formulae (I) and (II), or pharmaceutically acceptable salt forms thereof, wherein one of M1 and M2 may be N and D may be a variety of N-containing groups, which are useful as inhibitors of factor Xa.

Description

TITLE
DISUBSTITUTED PYR.AZOLINES AND TRIAZOLINES AS FACTOR XA
INHIBITORS
FIELD OF THE INVENTION
This invention relates generally to disubstituted pyrazolines and triazolines which are inhibitors of trypsin-iike serine protease enzymes, especially factor Xa, pharmaceutical compositions containing the same, and methods of using the same as anticoagulant agents for treatment and prevention of thromboembolic disorders.
BACKGROUND OF THE INVENTION
WO 95/18111 addresses fibrinogen receptor antagonists, containing basic and acidic termini, of the formula:
L _ ~NRs~C \ R9 R U V ~ Rio wherein R1 represents the basic termini, U is an alkylene or heteroatom linker, V may be a heterocycle, and the right hand portion of the molecule represents the acidic termini. The presently claimed compounds do not contain the acidic termini of WO 95/18111.
In U.S. Patent No. 5,463,071, Himmelsbach et al depict cell aggregation inhibitors which are 5-membered heterocycles of the formula:
X~1 X~Xs X~-X4 wherein the heterocycle may be aromatic and groups A-B-C- and F-E-D- are attached to the ring system. A-B-C- can be a wide variety of substituents including a basic group attached to an aromatic ring. The F-E-D- group, however, would appear to be an acidic functionality which differs from the present Substitute Sheet (Rule 26) invention. Furthermore, use of these compounds as inhibitors of factor Xa is not discussed.
WO 97/47299 describes amidino and guanidino heterocyclic protease inhibitors of the formula: ' wherein W contains an amidino, guanidino, or imino group attached to a variety of moieties including phenyl and piperidinyl, Y is a O, N, S, or C linker or is absent, X is a heterocycle, Z is a two atom linker containing at least one heteroatom, and R1 is a variety of groups including cycloalkyl, aryl, heteroaryl, and araalkyl all of which are optionally substituted. A variety of proteases are described as possible targets for these compounds including Factor Xa.
The presently claimed compounds differ in that they do not contain the combination R1-Z or Y-W.
2 describes isoxazolines, isothiazolines, and pyrazolines of the formula:
(CH2)rR2 ~(CHz)m -(U)u - V - (Z)u (D)u X
N Y '(CH2)nR2 Y
ai wherein X is O, S or NR15. Though the pyrazolines of WO
97/23212 are indicated to be factor Xa inhibitors, they are not considered part of the present invention.
Activated factor Xa, whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation. The generation of thrombin, the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca2+ and phospholipid). Since it is calculated that one molecule of Substit4~z Sheet (Rule 26) WO 99/50255 PC'T/US99/06310 factor Xa can generate 138 molecules of thrombin (Elodi, S., Varadi, K.: Optimization of conditions for the catalytic effect of the factor IXa-factor VIII Complex: Probable role of the complex in the amplification of blood coagulation.
Thromb. Res. 1979, 15, 617--629), inhibition of factor Xa may be more efficient than inactivation of thrombin in interrupting the blood coagulation system.
Therefore, efficacious and specific inhibitors of factor Xa are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. It is thus desirable to discover new factor Xa inhibitors.
SUMMARY OF THE INVENTION
Accordingly, one object of the present invention~is to provide novel disubstituted pyrazolines and triazolines which are useful as factor Xa inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating thromboembolic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of formulae I and II:
Substitute Sheet (Rule 26) Rya ~B
Z'A
Rtb \ / \Z A. \ Rib , N B N
p~E.G~ J s p~E~G~ J s I II
or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, B, D, E, G, M, Z, Rla, Rlb, and s are defined S below, are effective factor Xa inhibitors.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[1] Thus, in a first embodiment, the present invention provides novel compounds of formulae I or II:
Rta iB
Z'A
~LM2 Rib ~~ ~R~b N\ ~~---A. N\ Rib N B N
p.E.GX J s p~E~G~ J s I II
or a stereoisomer or pharmaceutically acceptable salt thereof, 15 wherein;
Ml is N or CRlc ;
M2 is NRla or CRlaRla, provided that only one of M1 and M2 is a 20 N atom;
D is selected from C(=NR8)NR~R9, NHC(=NR8)NR~R9, NRBCH(=NR~), C(O)NR~Rg, and CR8R9NR~R8;
E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, and piperidinyl substituted with 1 R;
alternatively, D-E-G together represent pyridyl substituted with 1 R;
Substitute Sheet (Rule 26) R is selected from H, C1, F, Br, I, (CH2)tOR3, C~_4 alkyl, OCF3, CF3, C(01NR~Ra, and (CR8R9)tNR~RB;
G is selected from NHCH2, OCH2, and SCH2, provided that when s is 0, then G is absent;
Z is selected from a C1_4 alkylene, (CH2)r0(CH2)r, (CH2)rNR3(CH2)r, (CH2)rC(O)(CH2)r, (CH2)rC(O)0(CH2)r, (CH2)rOC(0)(CH~)r. (CH2)rC(O)NR3(CH2)r~
(CHZ)rNR3C(O)(CH?)r, (CH2)rOC(O)O(CHZ)r~
(CH2)rOC(0)NR3(CH2)r, (CHZ)rNR3C(O)O(CHZ)r, (CH2)rNR3C(O)NR3(CH?)r, (CH2)rS(O)D(CHZ)r, (CH2)rSOZNR'(CHZ)r, (CH2)rNR3S02(CH2)r. and (CH2)rNR3S02NR'(CH2)r, provided that Z does not form a N-N, N-O, N-S, NCH2N, NCH20, or NCH2S bond with group A;
Rla and Rlb are, at each occurrence, independently selected from H, -(CH2)r-R'-', NCH2R1", OCH2R1'~, SCHZR~", N(CH2)2(CH2)tRl', O(CH2)2(CH2)tRi', and S(CH2)2(CH2)tRm ;
Rlc is selected from H, -(CH2)q-R1', C1_3 alkyl, C(O)R2c, (CF2)rC02R2c, C(O)NRZR2a, C3-6 carbocyclic residue substituted with 0-2 R4, and S-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;
R1' is selected from H, C1_3 alkyl, halo, (CF2)rCF3, OR2, NRzR2a, C(0)R2c, OC(O)R2. (CF2)rCOzR2c, S(O)pR2b, NR2(CH2)rOR2, NR2C(O)R2b, NR2C(O)NHR2b, NR2C(O)2R2a OC(O)NRZb, C(01NR2R2a, S02NR2R2a, NR2SOZR2b, C3_6 carbocyclic residue substituted with 0-2 R4, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R4;
R1" is selected from H, C (O) R2b, C (O) NR2R2a, S (O) R2b, S (O) 2R2b, arid S02NR2R2a.
Substitute Sheet (Rule 26) R2, at each occurrence, is selected from H, CF3, C1_6 alkyl, benzyl, C3_6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2a, at each occurrence, is selected from H, CF3, C1_6 alkyl, benzyl, C3_6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2b, at each occurrence, is selected from CF3, C,_4 alkoxy, C1_6 alkyl, benzyl, C3_6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2~, at each occurrence, is selected from CF3, OH, C,_4 alkoxy, C1_6 alkyl, benzyl, C3_d carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
alternatively, R2 and R2a combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4b which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
R3, at each occurrence, is selected from H, C1_4 alkyl, and phenyl;
R3a, at each occurrence, is selected from H, C~_4 alkyl, and phenyl;
A is selected from:
Substitute Sheet ; pule 26) C3-to carbocyclic residue substituted with 0-2 R4, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S
substituted with 0-2 R4;
B is selected from:
X-Y. NR2R2a, C(=NR2)NR2R2a, NR2C(=NR2)NR2R2a, C3-1o carbocyclic residue substituted with 0-2 R4a, 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 R4a X is selected from C1_4 alkylene, -CR2(CR2R2b)(CH2)t-, -C(0)-, -C(=NR)-, -CR2(NR1"R2)-, -CR2(OR2)-, -CR2(SR2)-, -C(O)CR2R2a_ _CR2R2aC(O), -S(O)p-, -S(O)pCR2R2a_ -CR2R2aS .(0) p-, -S (0) 2NR2_ ~ _~2S (O) 2- ~ -~2S (0) ZCR2RZa_ -CR2R2aS(O)2NR2_~ _~2g(O)2N'R2_, -C(O)NR2_, _NR2C(O)-, -C(0)NR2CR~R2a_ _Ng2C(O)CR2R2a_ _CR2R2aC(O)Ng2_~
-CR2R2aNR2C(O)-, - .NR2C(O)O-. -OC(O)NR2-, -NR2C(O)NR2_ - " ,NR2-, -NR2CR2R2a_ _CR2R2a~2_ 0 _CR2R2a0_, and -OCR2R2a_.
Y is selected from:
(CH~)rNR2R2a, provided that X-Y do not form a N-N, O-N, or S-N bond, C3-1o carbocyclic residue substituted with 0-2 R4a, 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 R4a;
R4, at each occurrence, is selected from =O, (CH2)rOR2, halo, C1_4 alkyl, -CN, N02, (CH2)rNR2R2a, (CH2)rC(O)R2b~
NR2C(0)R2b, C(O)NR2R2a, NR2C(O)NR~R~a, CH(=NR2)NR2R2a, NHC(=NR2)NR2R2a, S02NR2R2a, NR2S02NR2R2a, NR2S02-C1_4 alkyl, NR2S02R5, S(O)pR5, (CF2)rCF3, NCH2R1". OCH2R1", SCH2R1", N(CH2)2(CH2)tRl~, O(CH2)2(CH2)tRl~, and S(CH2)2(CH2)tRl~, Substitute Sheet (Rule 26) alternatively, one R4 is a 5-6 membered aromatic heterocycle containing from I-4 heteroatoms selected from the group consisting of N, 0, and S;
R4a, at each occurrence, is selected from =0, (CH2)rOR2, halo, C1_4 alkyl, -CN, NO?. (CH2)rNR2R2a, (CH2)rC(O)RZb, NR2C(0)R2b C(O)NR2R2a. NR2C(O)NR2R2a. CH(=NR2)NR2R2a, NHC(=NRZ)NR2R2a, S02NR2R2a, NR2S02NR2R2a. NR~SOZ-C1_4 alkyl, NR2S02R5, S(O)pRS, and (CF2)rCF3;
alternatively, one Rya is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-1 R5;
R4b, at each occurrence, is selected from =O, (CHZ)rORs, halo, C1_q alkyl, -CN, NO2, (CHZ)rNR3R3a, (CH2)rC(O)R', NR3C (O) R3a, C (O) NR3R3a, NR3C (O)NR3R3a, CH (=NR3 ) NR3R3a, NH3C(=NRj)NR3R3a, S02NR3R3a, NR3SOZNR3R3a, NR3S02-C1_4 alkyl, NR3SOzCF3, NR3S02-phenyl, S (O)pCF3, S (O)p-C1_4 alkyl, S(O)p-phenyl, and (CFZ)rCF3;
R5, at each occurrence, is selected from CF3, C1_6 alkyl, phenyl substituted with 0-2 Rs, and benzyl substituted with 0-2 R6;
R6, at each occurrence, is selected from H, OH, (CH2)rOR2, halo, C1_4 alkyl, CN, N02, (CH2)rNR2RZa,(CH2)rC(O)R2b NR2C(O)R2b, NR2C(O)NR2R2a, CH(=NH)NH2, NHC(=NH)NH2, S02NR2R2a, NR2SOZNR2R2a, and NR2S02C1_4 alkyl;
R~, at each occurrence, is selected from H, OH, C1_6 alkyl, C1_6 alkylcarbonyl, C1_6 alkoxy, C1_4 alkoxycarbonyl, (CH2)n-phenyl, C6_io aryloxy, C6_lo aryloxycarbonyl, C6_lo arylmethylcarbonyl, C1_4 alkylcarbonyloxy C1-4 alkoxycarbonyl, C6_1o arylcarbonyloxy C1_4 alkoxycarbonyl, C1_6 alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C1_4 alkoxycarbonyl;
Substit~. .: Sheet (Rule 26) R8, at each occurrence, is selected from H, C1_s alkyl and (CHZ)n-phenyl;
alternatively, R~ and Ra combine to form a 5 or 6 membered saturated, ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, 0, and S;
R9, at each occurrence, is selected from H, C1_6 alkyl and (CH2)n-phenyl;
n, at each occurrence, is selected from 0, 1, 2, and 3;
m, at each occurrence, is selected from 0, 1, and 2;
p, at each occurrence, is selected from 0, h, and 2;
q, at each occurrence is selected from 1 and 2;
r, at each occurrence, is selected from 0, 1, 2, and 3;
s, at each occurrence, is selected from 0, 1, and 2; and, t, at each occurrence, is selected from 0 and 1.
[2~ In a preferred embodiment, the present invention provides novel compounds of fornnulae Ia-Ib:
~ Rta Rta Rta Rta Rtb ~/ Rtb N\N Z~4.B N\N Z~A~B
I
p.~ la p.E Ib wherein;
Substitute Sheet (Rule 26) Z is selected from a CH20, OCH2, CH2NH, NHCH2, C(O), CH2C(O), C(O)CH2, NHC(O), C{O)NH, CH2S(O)2, S(O)2(CH2), S02NH, and NHS02, provided that Z does not form a N-N, N-O, NCH2N, or NCH20 bond with group A;
A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4;
phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-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, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl;
B is selected from: Y, X-Y, NR2R2a, C(=NR2)NR2R2a, and NR2C(=NR2)NR2R2a;
X is selected from C,_q alkylene, -C(O)-, -C(=NR)-, -CR2 (NR2RZa) -, -C (O) CR2R2a_ -CR2R2aC (0) , -C (O) NR2-, -NR2C (0) -, -C (O) NR2CR2R2a- _~2C {O) CR2R2a_ -CR2R2aC ( 0 ) NR2 - , -CR2 R2aNR2C ( O ) - , -NR2 C ( O ) NR2 - , -NR2 _ , _~2CR2R2a_ _CR2R2a~2- O -CR2R2a0_ and -OCR2R2a_-Y is NR2R2a, provided that X-Y do not forth a N-N or O-N bond;
alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a;
cylcopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, Substitute Sheet (Rule 26) isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-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, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl;
alternatively, Y is selected from the following bicyclic heteroaryl ring systems:
R9 ~ R4 11 N~~ ~ ~ R4-\\
R4 N ~ N R9 ~K \ ~ R4 ~ \ ~' R4 a h a , ~ R4 R , / ~ N '1 N R4 ~K \ N arid N ~\ R4 ;
~~ ''~~s K is selected from O, S, NH, and N.
[3] In a more preferred embodiment, the present invention provides novel compounds of formulae Ia-Ib, wherein;
Z is selected from a C(O), CH2C(O), C(0)CH2, NHC(O), C(0)NH, C(O)N(CH3), CH2S(O)2, S(O)2(CH2), S02NH, and NHS02, provided that Z does not form a N-N or NCH2N bond with group A.
(4] In an even more preferred embodiment, the present invention provides novel compounds of formulae Ia-Ib, wherein;
E is phenyl substituted with R or 2-pyridyl substituted with R;

Substitute Sheet (Rule 26) WO 99/50255 PCTlUS99/06310 D is selected from C(O)NH2, C(=NH)NH2, CHZNH2, CH2NHCH3, CH(CH3)NHZ, and C(CH3)2NH2; and, R is selected from H, OCH3, C1, and F.
[5] In a further preferred embodiment, the present invention provides novel compounds of formulae Ia-Ib, wherein;
D-E is selected from 3-amidinophenyl, 3-aminomethylphenyl, 3-aminocarbonylphenyl, 3-(methylaminomethyl)phenyl, 3-(1-aminoethyl)phenyl, 3-(2-amino-2-propyl)phenyl, 4-chloro-3-amidinophenyl, 4-chloro-3-aminomethylphenyl, 4-chloro-3-(methylaminomethyl)phenyl, 4-fluoro-3-amidinophenyl, 4-fluoro-3-aminomethylphenyl, 4-fluoro-3-(methylaminomethyl)phenyl, 6-amidinopyrid-2-yl, 5-aminomethylpyrid-2-yl, 6-aminocarbonylpyrid-2-yl, 6-(methylaminomethyl)pyrid-2-yl, 6-(1-aminoethyl)pyrid-2-yl, and 6-(2-amino-2-propyl)pyrid-2-yl.
[6] In another even more preferred embodiment, the present invention provides novel compounds of formulae Ia-Ib, wherein;
Z is C(O)CH~ and CONH, provided that Z does not form a N-N
bond with group A;
A is selected from phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R4; and, B is selected from X-Y, phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1 R4a;
R4, at each occurrence, is selected from OH, (CH2)rOR2, halo, C1_q alkyl. (CH2)rNR2R2a~ arid (CF2)rCF3:

Substitute Sheet (Rule 26) WO 99/50255 PC'f/US99/06310 R4a is selected from C1_q alkyl, CF3, S(O)pR~, S02NR2RZa, and 1-CF3-tetrazol-2-yl;
R5, at each occurrence, is selected from CF3, C1_6 alkyl, phenyl, and benzyl;
X is CHZ or C(O); and, Y is selected from pyrrolidino and morpholino.
[7] In another further preferred embodiment, the present invention provides novel compounds of formulae Ia-Ib, wherein;
A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-C1-phenyl, 3-C1-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and, B is selected from the group: 2-CF3-phenyl, 2-(aminosulfonyl)phenyl, 2-(methylaminosulfonyl)phenyl, 2-(dimethylaminosulfonyl)phenyl, 1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl, 4-morpholino, 2-(1'-CF3-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.
[8] In another even more preferred embodiment, the present invention provides novel compounds of formulae Ia-Ib, wherein;
E is phenyl substituted with R or 2-pyridyl substituted with R;
D is selected from C(O)NH2, C(=Nfi)NH2, CH2NH2, CH2NHCH3, CH ( CH3 ) NH2 , and C ( CH3 ) 2NH2 % and , R is selected from H, OCH3, C1, and F;

Substitute Sheet (Rule 26) WO 99/50255 PCT/US99f06310 Z is C(O)CH2 and CONH, provided that Z does not form a N-N
bond with group A;
A is selected from phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R4; and, B is selected from X-Y, phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1 R4a;
R4, at each occurrence, is selected from OH, (CH2)rOR2, halo, C1_4 alkyl, (CH2)rNR2R2a, arid (CFz)rCF3;
R4a is selected from C1_4 alkyl, CF3, S(O)pR~, S02NR2R2a, and I-CF3-tetrazol-2-yl;
RS, at each occurrence, is selected from CF3, CZ_6 alkyl, phenyl, and benzyl;
X is CHZ or C(O); and, Y is selected from pyrrolidino and morpholino.
(9] In another further preferred embodiment, the present invention provides novel compounds of formulae Ia-Ib, wherein;
D-E is selected from 3-amidinophenyl, 3-aminomethylphenyl, 3-aminocarbonylphenyl, 3-(methylaminomethyl)phenyl, 3-(1-aminoethyl)phenyl, 3-(2-amino-2-propyl)phenyl, 4-chloro-3-amidinophenyl, 4-chloro-3-aminomethylphenyl, 4-chloro-3-(methylaminomethyl)phenyl, 4-fluoro-3-amidinophenyl, 4-fluoro-3-aminomethylphenyl, 4-fluoro-3-(methylaminomethyl)phenyl, 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-2-propyl)pyrid-2-yl;

Substitute Sheet (Rule 26) WO 99/50255 PC'T/US99/06310 A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-C1-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and, H is selected from the group: 2-CF3-phenyl, 2-(aminosulfonyl)phenyl, 2-(methylaminosulfonyl)phenyl, 2-(dimethylaminosulfonyl)phenyl, 1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl, 4-morpholino, 2-(1'-CF3-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] In a still further preferred embodiment, the present invention provides a novel compound of formula Ia.
[11] In another still further preferred embodiment, the present invention provides a novel compound of formula Ib.
[12] In another even more preferred embodiment, the present invention provides novel compounds of formulae Ia-Ib, wherein;
D is selected from C (=NR8)NR~R9, C (O)NR~R8, NR~RB, and CH2NR~Rg;
E is phenyl substituted with R or pyridyl substituted with R;
R is selected from H, C1, F, OR3, CH3, CH2CH3, OCF3, and CF3;
Z is selected from C(O), CH2C(O), C(O)CH2, NHC(O), and C(O)NH, provided that Z does not form a N-N bond with group A;
- Substitute Sheet (Rule 26) Rla and Rlb are, at each occurrence, independently selected from H, - (CH2 ) r-R1' , NCH2R1" , OCH2R1" , SCH2R1" , N(CHZ)2(CH2)tRl~, 0(CH2)2(CH2)tRl~, and S(CH2)2(CH2)tRl~;
R1~ is selected from H, -(CH2)q-R1~, C1_3 alkyl, C(O)R2c, (CF2)rC02R2~, and C(O)NR2R2a;
R1', at each occurrence, is selected from H, C1_3 alkyl, halo, (CF2)rCF3, OR2, NR2R2a, C(0)R2~, (CF2)rC02R2~, S(O)pR2b, NR2(CH2)rOR2. NR2C(0)R2b, NR2C(O)2R2b, C(O)NR2R2a S02NR2R2a, and NRZS02R2b.
A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4;
phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, and imidazolyl;
B is selected from: Y, X-Y, NR2R2a, C(=NR2)NR2R2a, and NR2C(=NR2)NR2R2a;
X is selected from CH2, -CR2(CR2R2b)(CH2)t-, -C(O)-, -C(=NR)-, -CH(NR2R2a)-, -C(0)NR2-, -NR2C(O)-, -NR2C(O)NRZ-, -NR2-, and O;
Y is NR2R2a, provided that X-Y do not form a N-N or O-N bond;
alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2.4-thiadiazolyl, 1~
Substitute Sheet (Rule 26) 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;
R4, at each occurrence, is selected from =0, OH, C1, F, C1_4 alkyl . (CH2 ) rNR2R2a, (CH2 ) rC (O) R2b, NR2C (O) R2b, C (O) NR2R2a, CH(=NH)NH2, NHC(=NH)NH2, S02NR2R2a, NR2S02-C1_4 alkyl, NR2S02R5, S(0)pRS, and (CF2)rCF3;
R4a, at each occurrence, is selected from =O, OH, C1, F, C1_q alkyl, (CH2)rNR2R2a, (CH2)rC(O)R2b NRZC(O)RZb. C(0)NR2R2a, CH(=NH)NH2, NHC(=NH)NH2, S02NR2R2a, NR2S02-C~_4 alkyl, NR2S02R5, S(O)pRS, (CF2)rCF3, and 1-CF3-tetrazol-2-yl;
R5, at each occurrence, is selected from CF3, C1_6 alkyl, phenyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6;
R6, at each occurrence, is selected from H, =O, OH, OR2, C1, F, CH3, CN, NOZ. (CH2)rNR2R2a, (CH2)rC(O)R2b, NR2C(0)RZb, CH(=NH)NH2, NHC(=NH)NH2, and S02NR2R2a_ R~, at each occurrence, is selected from H, OH, C~_6 alkyl, C1_6 alkylcarbonyl, C1_6 alkoxy, Ci_9 alkoxycarbonyl, benzyl, C6-1o aryloxy, C6_lo aryloxycarbonyl, C6_10 arylmethylcarbonyl, C1_4 alkylcarbonyloxy C~_q alkoxycarbonyl, C6_1o arylcarbonyloxy C1_4 alkoxycarbonyl, C1_6 alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C1_4 alkoxycarbonyl;
R8, at each occurrence, is selected from H, C1_6 alkyl and benzyl; and alternatively, R~ and R8 combine to form a morpholino group;
and, R9, at each occurrence, is selected from H, C1_6 alkyl and benzyl.

f ubstitute Sheet (Rule 26}

WO 99/50255 PCT/IlS99/06310 (13] In a another further preferred embodiment, the present invention provides novel compounds of formulae Ia-Ib, wherein;
E is phenyl substituted with R or 2-pyridyl substituted with R;
R is selected from H, C1, F, OCH3, CH3, OCF3, and CF3;
Z is selected from a C(O)CH2 and C(O)NH, provided that Z does not form a N-N bond with group A;
Rla, at each occurrence, is selected from H. CH3, CH2CH3, C1, F, CF3, OCH3, NR2R2a, S(O)pR2b, CHZS(0)pR2b, CH2NR2S(O)pR2b, C(0)R2~, CH2C(O)R2~, C(O)NR~R2a, and S02NR2R2a;
Rlb is selected from H, CH3, CHZCH3, C1, F, CF3, OCH3, NR2R2a S (O) pR~b, CH2S (O) pR2b, CH2NR2S (O) pR2b, C (O) R2~, CH2C (O) R2~, C(O)NR2R2a, arid S02NR2R2a;
R1~ is selected from H, CH3 , CH2CH3 , CF3, CHZS (O) pR2b, CH2NR2S(0)pR2b, C(0)R2~, CH2C(0)R2~, and C(O)NR2R2a;
A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4;
phenyl, pyridyl, pyrimidyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyi, pyrazolyl, and imidazolyl;
B is selected from: Y and X-Y;
X is selected from CH2, -CR2(CR2R2b)-, -C(0)-, -C(=NR)-, -CH(NR2R2a) -, -C (O)NR2-, -NR2C (0) -, -NRzC (O)NR2_ _~2_ and O;
Y is NR2R2a, provided that X-Y do not form a N-N or O-N bond;

Substitute Sheet (Rule 26) WO 99/50255 PCTlUS99/06310 alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a;
phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-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, and 1,3,4-triazolyl;
R2, at each occurrence, is selected from H, CF3, CH3, benzyl, and phenyl;
R2a, at each occurrence, is selected from H, CF3, CH3, benzyl, and phenyl;
R2b, at each occurrence, is selected from CF3, OCH3, CH3, benzyl, and phenyl;
R2~, at each occurrence, is selected from CF3, OH, OCH3, CH3, benzyl, and phenyl;
alternatively, R2 and R2a combine to form a 5 or 6 membered saturated, partially unsaturated, or unsaturated ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, 0, and S;
R3, at each occurrence, is selected from H, CH3, CH2CH3, and phenyl;
R3a, at each occurrence, is selected from H, CH3, CHZCH3, and phenyl;

Substitute :Tbeet (Rule 26) R4, at each occurrence, is selected from OH, C1, F, CH3, CH2CH3, NR2R2a. CH?NR2R2a, C(O)R2b, NR2C(O)R2b, C(O)NR2R2a, and CF3 ;
R4a, at each occurrence, is selected from OH, C1, F, CH3, CH2CH3. NR2R2a, CH2NRZR2a, C(O)R2b, C(O)NR2R~a, S02NR2R2a, S(O)pRS, CF3, and 1-CF3-tetrazol-2-yl;
R5, at each occurrence, is selected from CF3, C1_6 alkyl, phenyl substituted with 0-2 R6, and benzyl substituted wi th 1 R6 ;
R6, at each occurrence, is selected from H, OH, OCH3, C1, F, CH3, CN, N02, NR2R2a, CHZDlR~R2a, arid S02NR2R2a;
R~, at each occurrence, is selected from H, OH, C1_3 alkyl, Ci_3 alkylcarbonyl, C1_3 alkoxy, C1_4 alkoxycarbonyl, benzyi, phenoxy, phenoxycarbonyl, benzylcarbonyl, C1_4 alkylcarbonyloxy C1_4 alkoxycarbonyl, phenylcarbonyloxy C1_4 alkoxycarbonyl, C1_6 alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C1_4 alkoxycarbonyl;
R8, at each occurrence, is selected from H, CH3, and benzyl;
and, alternatively, R~ and R8 combine to form a morpholino group;
R9, at each occurrence, is selected from H, CH3, and benzyl.
[14] In a another still further preferred embodiment, the present invention provides novel compounds of formulae Ia-Ib, wherein;
Rla, at each occurrence, is selected from H, CH3, CH2CH3, C1, F, CF3, OCH3, NR2R2a, S(O)pR2b, C(O)NR2R2a, CH2S(O)pR2b CH2NR2S(0)pR2b, C(O)R2~, CH2C(O)R2~, arid S02NR2R2a.
Substitute Sheet (Rule 26) Rlb is selected from H, CH3 , CHZCH3 , C1, F , CF3 , OCH3 , NR2R2a S(O)pR2b, C(0)NR2R2a, CHZS(O)pR2b, CH2NR2S(O)pR2b, C(O)R2b, CHIC (O) R2b, and S02NR2RZa;
Rl~ is selected from H, CH3 , CH2CH3 , CF3 , C (O ) NR2R2a CHZS(O)pR2b, CHZNR2S(O)pR2b, C(O)R2b, and CH2C(O)R2b;
A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4;
phenyl, pyridyl, and pyrimidyl;
B is selected from: Y and X-Y;
X is selected from -C(O)- and O;
Y is NR2R2a, provided that X-Y do not form a O-N bond;
alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a;
phenyl, piperazinyl, pyridyl, pyrimidyl, morpholinyl, pyrrolidinyl, imidazolyl, and 1,2,3-triazolyl;
R2, at each occurrence, is selected from H, CF3, CH3, benzyl, and phenyl;
R2a, at each occurrence, is selected from H, CF3, CH3, benzyl, and phenyl;
R2b, at each occurrence, is selected from CF3, OCH3, CH3, benzyl, and phenyl;
R2~, at each occurrence, is selected from CF3, OH, OCH3, CH3, benzyl, and phenyl;
alternatively, R2 and R2a combine to form a ring system selected from pyrrolidinyl, piperazinyl and morpholino;

Substitute Sheet (Ru!e 26) R4, at each occurrence, is selected from Cl, F, CH3, NR2R2a, and CF3;
R4a, at each occurrence, is selected from C1, F, CH3, S02NR2R2a, S(O)pRS, and CF3; and, R5, at each occurrence, is selected from CF3 and CH3.
to [15] Specifically preferred compounds of the present invention are selected from the group:
1-(3-amidinophenyl)-5-([(2'-methylsulfonyl-(1,1']-biphen-4-yl)-aminocarbonyl]-3-trifluoromethyl-pyrazoline; and, 1-(3-aminomethylphenyl)-5-[[(2'-methylsulfonyl-[1,1')-biphen-4-yl)-aminocarbonyl]-3-trifluoromethyl-pyrazoline;
and pharmaceutically acceptable salts thereof.
In a second embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
In a third embodiment, the present invention provides a novel method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
DEFINITIONS
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an Substitute Sheet (Rule 26) WO 99/50255 PCTlUS99106310 asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and traps geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric fornl is specifically indicated.
The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., =O), then 2 hydrogens on the atom are replaced.
When any variable (e.g., R6) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R°, then said group may optionally be substituted with up to two R6 groups and R6 at each occurrence is selected independently from the definition of R6. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

Substitute Sheet (Rule 26) As used herein, "Cl_6 alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl; "Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like.
"Halo" or "halogen" as used herein refers to fluoro, chloro, bromo, and iodo; and "counterion" is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, anti the like.
As used herein, "carbocycle" or "carbocyclic residue" is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic.
Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyi, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, the term "heterocycle" or "heterocyclic system" is intended to mean a stable 5- to 7- membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically Substitute Sheet (Rule 26) noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S
and 0 atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term "aromatic heterocyclic system" is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, O and S. It is preferred that the total number of S and 0 atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, ~i-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro(2,3-b)tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl., oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, Substitute Sheet (Rule 26) quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazoiyl, 1,3,4-triazolyl, xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycoiic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, malefic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, Substitute Sheet (Rule 26) sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two;
generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
"Prodrugs" are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the - compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively.
Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like. Preferred prodrugs are amidine prodrugs wherein D is C(=NR~)NH2 or its tautomer C(=NH)NHR~ and R~ is selected from OH, C1_4 alkoxy, C6_1o aryloxy, C1_4 alkoxycarbonyl, C6_10 aryloxycarbonyl, C6_1o arylmethylcarbonyl, C1_4 alkylcarbonyloxy Ci_4 alkoxycarbonyl, and C6_1o arylcarbonyloxy C1_4 alkoxycarbonyl. More preferred prodrugs are where R~ is Substitute Sheet (kale 26) WO 99/50255 PCTIUS99/063t0 OH, methoxy, ethoxy, benzyloxycarbonyl, methoxycarbonyl, and methylcarbonyloxymethoxycarbonyl.
"Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
SYNTHESIS
The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic 25 chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991). All references cited herein are hereby incorporated in their entirety herein by reference.
Pyrazolines of this invention can be easily prepared via [3+2] cycloaddition of bromo or chloro hydrazone with an appropriate acrylate according to the methodology described by .

Substitute Sheet (Rule 26) WO 99/50255 PCT/US99/063t0 Tewari R. S. and Parihar Tetrahedron 1983, 39, 129-136, or Krayushkin, M. M. et. al Izv. Akad. Nauk, Ser. Khim. 1994 , 1, 114-117.
Roc Br R

~NH ~NH
1. R~~CHO
\ MeOH heat. ~ ~C02Et 2. NBS. CCh ~ ~ ~ Et3 N. CH~CI
~Ra D D
Pyrazoline 5-esters can also be prepared by the treatment of an appropriately substituted hydrazone with lead tetraacetate and an appropriate acrylate in a THF/benzene solvent system according to the procedure of Sasaki T, et. al.
Bull. Chem Soc. Jpn. 1970, 43, 1254.
R" H
N
~N H Et \ ~C02 Et Pb(OAc)4, CH,CI
D
Another method of obtaining pyrazoline 5-esters is the condensation of an appropriate phenyl or heteroaryl hydrazine with an approptiate 2-oxoglutaconate according to Blitzke, T.
et. al . J. Prakt:. Chem. 1993, 335 (8) , 683 .

Substitute Sheet (Rule 2G) R1c H
HzN~ N\ / 'CO Et R1c Et02 C
~i EtOH
D
Alternatively the pyrazoline ester can be prepared by treatment of a diazo-trifluoromethyl derivative with excess acrylate or acrolein in the presence of excess pyridine (Doyle, M. O. et. al. J. Heterocyclic Chem. 1983, 20, 943).
R' N' ~02Et PY~idine ~ ~ ~H
R~c~N~ + X~ N~N~C02Et H
IO Cycloadditions as described above but with di-substituted olefins should result in the formation of regio-adducts which can be easily separated by standard chromatographic techniques.
R1~ Br R tc RH R ~c C02Et / ~H / ~~. H
N~NH ~N~C02Et + ~N~R~a Rta ~C 02 Et EtgN, CH,CI?
~ D \D
It is understood by those in the art of organic synthesis that such cycloadditions can also be carried out with a wide variety of electron withdrawing olefins with functionalities such as vitro, sulfonyl, sulfonamido, nitrile, phosphate etc.
These in turn can be derivatized to appropriate compounds of the present invention.
Substitute Sheet ~::Zule 26~

WO 99/50255 PCT/US99i06310 The pyrazoline carboxyesters obtained via any of the above mentioned methodologies can be converted to the amide derivatives via the acid, acid chloride coupling methodlogies or a direct Weinreb (trimethylaluminum, aniline in dichloromethane) coupling technique known to those in the art of organic synthesis. A variety of anilines or amines can be coupled via these methodologies to afford the desired compounds.
R~' ~ Roc Rta 1. Hydrolyse 2. Oxalyl chloride ~ ~H
Et 3. BANH2, DMAP N~N~CONH-A-B
or BANH2, Me3Al to Alternatively the ester can be hydrolysed and converted to an amino functionality via the Curtius rearrangement. This in turn can be derivatised to obtain an amido, sulfonamido or urea derivative.

Substitute Sheet (Rule 26) WO 99/50255 PCTlUS99/06310 Rta Rtc H
/ H 1. Hydrolyse N 2. Oxalyl chloride ~N C02Et N~3 3. Trap with appropriate \ nucleophile e.g.
NH,, A-B
D
1. Hydrolyse R t~ Rta 2. Oxaiyl chloride H
1. Hydrolyse 3. ~~ gACOCI N~ ~NHCO-A-B
2. Oxalyl chloride N
NaN3, tBuOH
3. TFA. BASO,CI \
R t~ Rta H
,. H
N~N~NHS02-A-B
1\
Pyrazolines wherein s is other than 0 can be prepared by alkylation of an appropriate pyrazoline.
R'' 'Br C02Et The electrophile can consist of simple alkyl halides to heteroaryl alkyl halides. Some of the heteroaryl alkyl groups can include pyridyl, pyrimidyl, imidazolyl etc.
In cases wherein D is a nitrile can be further converted to an amidine functionality via the standard Pinner-amidine reaction sequence known to those in the art or can be Subsrr~~:e Sheet (Rule 26) WO 99150255 PCTlUS99/06310 converted to the benzylamine via reduction in an acidic media or can be converted to the secondary and tertiary amine via the DIBAH/MeMgCl or MeMgBr/CeCl3 methodologies outlined below.
Rta tc H R ~1 a H I. HCI/MeOH I H
N~ CONH-A-B ?_ (NH4)zCOs, ~N CONH-A-B
MeOH
~\CN ' ~J NH
1. AcOH, MeOH
[H) Pd/C H N
M Mg MeMgBr Rtc Rta H
Rtc Rta ~ ' rH
H CONH-A-B
H N~ ~N
N Rtc Rta ~N~CONH-A-B H \
N
' ~H ~ J
~N CONH-A-B

Compounds wherein D is a nitro can be reduced under catalytic Pd/C/MeOH techniques or SnClz/EtOAc or Zn/AcOH
conditions to afford the desired amino derivatives.
Enantiomers of the pyrazolines can be easily obtained either via lipase hydrolysis of its esters or resolution with common chiral bases known to those in the art.
1,2,3-Triazolines can be synthesized via the cycloaddition methodology however in this case the dipole is an aryl azide and the dipolarophile is a variety of olefins bearing an electron withdrawing group such as an ester, amide or sulfonamide.

Substitute Sheet (Rule 26) WO 99/50255 PC'T/US99/06310 Rta H
N3 Rta~ N\N C02Et C02Et + regioisomer Reflux / R4 D '\D
1,2,4-Triazolines can be prepared via the methods of Sandhy J. S. et. al. Heterocycles 1985, 23(5), 1143, and Heterocycles 1985, 23(5), 1123, by the method described in the scheme below.
Rt Fs Rta C F ~C02 Et ~ N H
_ ~N ~ N\ / 'C02Et C02Et Ra R4 Rta/N\O.
The triazoline esters can then subjected to the standard coupling procedures discussed above to afford the desired amide analogs. These can then further modified to the prepare compounds of the present invention.
Compounds of the present invention wherein AB is a biphenylamine or similar amine may be prepared as shown in the following scheme. 4-Bromoaniline can be protected as Boc-derivative and coupled to a phenylboronic acid under Suzuki conditions (Bioorg. Med. Chem. Lett. 1994, 189).
Deprotection with TFA provides the aminobiphenyl compound.
Other similar amines wherein A and/or B are heterocycles can be prepared by the same method using anpropiately substituted boronic acids and arylbromide. The bromoaniline can also be Substitute Sheet (Rule 26) linked to the core ring structures first as described above, and then undergo a Suzuki reaction to give the desired product.
rrxsoc NHZ NHBOC B(OH)2 I NBOC ) 2o j I Ra \ I R \ I z'~a .~ I
Ra~ Ra --~ / /
Br Br Pd ( 0 ) Ra \ \
Compounds of the present invention wherein A-B is A-X-Y
can be prepared like the piperazine derivative shown below.
0 0 /~ ~\ /j Boc VNH PhSO~ Boc ~N \\ // Tg~ U
CH2C12 /Et3N Ra ~ ~J Ra The following scheme shows how one can couple cyclic groups wherein X=NH, O, or S.
NHz XH
NO2 \ / 1 Ra I 1 Ra \ a / , 4 / reduction a R
Halo Base, DMF I /
x = NH, o, s When B is defined as X-Y, the following description applies. Groups A and B are available either through commercial sources, known in the literature or readily synthesized by the adaptation of standard procedures known to practioners skilled in the art of organic synthesis. The required reactive functional groups appended to analogs of A
and B are also available either through commercial sources, known in the literature or readily synthesized by the adaptation of standard procedures known to practioners skilled in the art of organic synthesis. In the tables that follow Substitute Sheet (Rule 26) the chemistry required to effect the coupling of A to B is outlined.
Table A: Preparation of Amide, Ester, Urea, Sulfonamide and Sulfamide linkages between A and B.
then the to give the Rxiz. reactive following product No. if A contains . substituent of A-X-Y .

Y is 1 A-NHR2 as a C1C(O)-Y A-NR2-C(O)-Y

substituent 2 a secondary NH C1C(O)-Y A-C(0)-Y

as part of a rin or chain 3 A-OH as a C1C(0)-Y A-O-C(O)-Y

substituent 4 A-NHR2 as a C1C(0)-CR2R2a-Y A-NR2-C(O)-CR2R2a-y substituent 5 a secondary NH C1C(O)-CR2R2a-Y A-C(O)-CR2R2a_y as part of a rin or chain 6 A-OH as a C1C(O)-CR2R2a-Y A-O-C(O)-CR2R2a_y substituent 7 A-NHR3 as a C1C(O)NR2-Y A-NR2-C(0)NR2-Y

substituent 8 a secondary NH C1C(O)NR2-Y A-C(O)NR2-Y

as part of a rin or chain 9 A-OH as a C1C(O)NR2-Y A-O-C(O)NR2-Y

substituent A-NHR2 as a C1S02-Y A-NR2-S02-Y

substituent 11 a secondary NH C1S02-Y A-S02-Y

as part of a rin or chain 12 A-NHR2 as a C1S02-CR2R2a-Y A-NR2-S02-CR2R2a_y substituent Substitute Sheet ~:.~.le 26) 13 a secondary NH C1S02-CR2R2a-Y A-S02-CR2R2a_y as part of a rin or chain 14 A-NHR2 as a C1S02-NR2-Y A-NR2-S02-NR2_y substituent 15 a secondary NH C1S02-NR2-Y A-S02-NR2-Y

as part of a rin or chain 16 A-C(O)C1 HO-Y as a A-C(0)-O-Y

substituent 17 A-C(O)C1 NHR2-Y as a A-C(O)-NR2-Y

substituent 18 A-C(0)C1 l a secondary NH A-C(O)-Y

as part of a rin or chain 19 A-CR2R2aC(O)C1 HO-Y as a A-CR2R2aC(O)-O-Y

substituent 20 A-CR2R2aC(O)C1 NHR2-Y as a A-CR2R2aC(0)-NR2-Y

substituent 21 A-CR2R2aC(O)Cl a secondary NH A-CR2R2aC(0)-Y

as part of a rin or chain 22 A-S02C1 NFiR2-Y as a A-S02-NR2_y substituent 23 A-S02C1 a secondary NH A-S02-Y

as part of a rin or chain 24 A-CR2R2aS02C1 NHR2-Y as a A-CR2R2aS02-NR2_y substituent 25 A-CR2R2aS02C1 a secondary NH A-CR2R2aS02-Y

as part of a rin or chain The chemistry of Table A can be carried out in aprotic solvents such as a chlorocarbon, pyridine, benzene or toluene, at temperatures ranging from -20~C to the reflux point of the solvent and with or without a trialkylamine base.

Substitute Sheet (Rule 26) Table 8: Preparation of ketone linkages betweea A and B_ then the reactiveto give the Ram. if A contains substituent of following product No. Y is A-X-Y

1 A-C(0)C1 BrM -Y A-C(O)-Y

2 A-CR2R2aC(O)C1 BrM -Y A-CR2R2a2C(O)-Y

3 A-C!0)C1 BrM CR2R2a-Y A-C(O)CRZR2a_y 4 A-CR2R2aC(O)C1 BrMgCR2R2a-Y A-CR2R2aC(O)CR2R2a_ Y

The coupling chemistry of Table B can be carried out by a variety of methods. The Grignard reagent required for Y is prepared from a halogen analog of Y in dry ether, dimethoxyethane or tetrahydrofuran at O~C to the reflux point of the solvent. This Grignard reagent can be reacted directly under very controlled conditions, that is low temeprature (-20~C or lower) and with a large excess of acid chloride or with catalytic or stoichiometric copper bromide~dimethyl sulfide complex in dimethyl sulfide as a solvent or with a variant thereof. Other methods available include transforming the Grignard reagent to the cadmium reagent and coupling according to the procedure of Carson and Prout (Org. Syn. Col.
Vol. 3 (1955) 601) or a coupling mediated by Fe(acac)3 according to Fiandanese et al.(Tetrahedron Lett., (1984) 4805), or a coupling mediated by manganese (II) catalysis (Cahiez and Laboue, Tetrahedron Lett., 33(31), (1992) 4437).

Substit, ~~, Sheet (Rule 26) WO 99/50255 PC"f/US99/06310 Table C: Preparation of ether aad thioethar linkages bett~r~aen A and B
then the reactive to give the Rxn.if A contains substituent of following No. Y is roduct A-X-Y

1 A-OH Br-Y A-O-Y

2 A-CR2R2a-OH Br-Y A-CR2R2a0-Y

3 A-OH Br-CR2R2a-Y A-OCR2R2a-y 4 A-SH Br-Y A-S-Y

A-CR2R2a-SH Br-Y A-CR2R2aS-Y

6 A-SH Br-CR2R2a-Y A-SCR2R2a-y The ether and thioether linkages of Table C can be 5 prepared by reacting the two components in a polar aprotic solvent such as acetone, dimethylforrnamide or dimethylsulfoxide in the presence of a base such as potassium carbonate, sodium hydride or potassium t-butoxide at temperature ranging from ambient temperature to the reflux point of the solvent used.
Table D: Preparation of -SO- and -S02- linkages from thioethers of Table 3.
and it is oxidized and it is oxidized with m-chloroper-with Alumina (wet)/benzoic acid (Satoh if the Oxone (Greenhalgh, et al., Chem. Lett.

Rxn.starting Synlett,(1992) 235)(1992) 381), the No. material is the roduct is roduct is 1 A-S-Y A-S(O)-Y A-S02-Y

2 A-CR2R2aS-Y A-CR2R2aS(O)-Y A-CR2R2aS02-Y

3 A-SCR2R2a-Y A-S(O)CR2R2a-Y A-S02CR2R2a_y The thioethers of Table C serve as a convenient starting material for the preparation of the sulfoxide and sulfone analogs of Table D. A combination of wet alumina and oxone can provide a reliable reagent for the oxidation of the Substitute Sheet (Rule 26) thioether to the sulfoxide while m-chloroperbenzoic acid oxidation will give the sulfone.
Table E: Methods of Preparing Group E
Rxn Q D is to then a transformation that may be used be is _ -cN -c ! =NH i) HCI MeOH
a NH2 E CN E C

ii) NH30Ac, MeOH ~ NH

2 -CN -CH2NH2 LiAIH4 Et20 -co2H -cH2NH2 i) iBuOC(O)CI

NMM, THF

then NaBH4, H.,OrfHF

ii) MsCI, Et3N, CH.,CL_, -OH iii) NaN3, DMF

iv) SnCl2, MeOH

4 -co2H -NH2 i) iBuOC(O)CI

NMM, THF

then NaN3 and heat ii) tBuOH, reflux OH iii)HCI, Et20 In Table E several methods of transforming a functional group Q into group D of Formula 1 are shown. While not all possible functional groups for Q and D are listed and the synthetic methods suggested are not comprehensive, Table E is meant to illustrate strategies and transformations available to a practitioner skilled in the art of organic synthesis for preparing compounds of Formula 1. In reaction 1 of Table E
the transformation of a nitrite into an amidine by the Pinner methodology is shown; in reaction 2 the direct reduction of a nitrite by a hydride reducing agent to a methylene amine is illustrated. In reaction 3, the utility of a carboxylic acid, which may be readily derived from its ester or a nitrite if necessary, in the preparation of a methylene amine is shown.
This synthetic route is exceptionally flexible because of the :,ubstitute Sheet (Rule 26) WO 99/50255 PCTlUS99/06310 several stable intermediates prepared en route to the final product. As outlined, formation of an activated analog, such as the mixed anhydride, allows for the mild reduction of the acid to the methylene alcohol, this may in turn be transformed into a leaving group by sulfonylation or halogenation or protected with a suitable protecting group to be transformed later in the synthesis as the chemistry demands. Once the methylene alcohol is so activated, displacement by an efficient nitrogen nucleophile, such as azide anion, can again provide another suitably stable analog, -the methylene azide-which may be used as a protected form of the methylene amine or transformed directly into the methylene amine group by reduction. Reaction 4 addresses the problem of appending the amine functionality directly through a bond to group E of Formula 1. Once again, the carboxylic acid provides a convenient entre into this selection for group D. The well-know Curtius rearrangement is illustrated here; an activated acid analog can be used to form an acyl azide which upon thermal decomposition is rearranged to the corresponding isocyanate. The isocyanate intermediate may then be captured as a stable carbamate by the addition of a suitable alcohol and further heating. This carbamate can be used as a stable protecting group for the amine or cleaved directly to the desired D. Alternatively, it may be convenient to quench the isocyanate intermediate with water to give the amine directly.
One diastereomer of a compound of Formula I may display superior activity compared with the others. Thus, the following stereochemistries are considered to be a part of the present invention.
Rta R9a Rtc Rta R1a N\ ....",Z~ N~
N ~B N B
p-~ p.E
Ial Ia2 Substitute Sheet (Rule 26) Rta Rta Rta Rta N Rtb N Rtb N\N I~~~Z A~B N\N Z ~B
I I
D.E D.E
Ib~ Ib2 Rtc Rta Rtc Rta ' Rtb ~' ,, Rtb N\ ~~ ~A~B N\ ~ Z A~B
N N
I I
p~E D.E
Ic1 Ic2 Rtc RtaZ' B tc Rta B
A R ,,Z,A~
R1b ~ 1b N\N Rtb N\N~.Rtb p.E~G~~ s p~E.G~~ s IIal IIa2 to R Z~A B RtaZ' g A
Rtb ~/ , Rtb \N Rtb N\N Rtb ,E, ~Js /( D G p.E.G~~ s IIbl IIb2 When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Steven D. Young, et al, Antimicrobial Agents and Chemotheraphy, 1995, 2602-2605. A chiral compound of Formula I may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g., Andrew S. Thompson, et al, Tet. lett. 1995, 36, 8937-8940).
Other features of the invention will become apparent in the course of the following descriptions of exemplary Substitute Sheet (Rule 26) WO 99/50255 PC'T/US99/06310 embodiments which are given for illustration of the invention and are not intended to be limiting thereof.
EXAMPhES
8xamples 1 aad 2 1-(3-Amidiaophenyl)-5-[[(2'-methylsulf onyl-[1,1']
biphen-4-yl)-aminocarbonyl]-3-trifluoromethyl pyrazoliae and 1-(3-aminomethylphenyl)-5-[[(2' methyisulfoayl-[1,1']-biphen-4-yl)-aminocarbonyl]-3-trifluoromethyl-pyrazoline Part A: To a methanolic solution containing meta-cyanophenyl-hydrazine (2 g, 15.03 mmol) was added trifluoromethylacetaldehyde hydrate (1.74 g, 15.03 mmol). The reaction mixture was heated to gentle reflex overnight.
Methanol was stripped off to afford yellow crystals of pure hydrazone (2.99g, 93~). 1HNMR (CDC13)8: 10.10 (bs, 1H), 7.33 (m, 2H), 7.10 (m, 2H) ppm; ESI (-ve) mass spectrum analysis m/z (relative intensity) 212 (M-H, 100).
Part B: NCS (1.02 g, 7.69 mmol) was added to a DMF (25 mL) - solution of the compound prepared in part A (1.64 g, 7.69 mmol). The reaction mixture was stirred at room temperature over night, quenched with water (500 mL) and organics extracted with ethyl acetate (2x100 mL) dried (MgS04) and evaporated to a reddish brown oil. The oil was redissolved in chloroform (25 mL) and to this solution was added ethyl acrylate (10 mL) followed by slow addition of triethylamine (0.81 mL, 5.75 mmoL). The reaction mixture was refluxed for 18h cooled and quenched with dil. hydrochloric acid (1N, 20 mL). The organic layer was separated and evaporated to an oil. Chromatography on silica gel (7:3, Hexane:ethylacetate) afforded a colorless oil which solidified on standing (1.5 g, 62~). 'HNMR(CDC13)b: 7.40-7.22 (m, 4H), 4.89 (dd, J = 6.2 and 13.4Hz, 1H), 4.24 (q, 2H), 3.63-3.50 (dd, J = 1.9 and 13.2Hz, 1H) , 3.38 (dd, J = 1.9 and l4Hz, 1H) , 1.23 (t, 3H) ppm; ESI
mass spectrum analysis m/z (relative intensity) 312 (M+H, 100) .

Substitute Sheet (Rule 26) WO 99/53255 PC'T/US99/063 t 0 Part C: The product from part B was treated with 2'-methylsulfonyl-4-amino-[1,1']biphenyl under Weinreb conditions (trimethylaluminum in dichloromethane) to afford pure coupled product (oil) after silica gel column chromatography (hexane: ethyl acetate 7:3). 1HNMR(CDC13)8: 8.40 (bs, 1H), 8.17 (dd, J = 1.1 and 7.SHz, 1H), 7.65-7.25 (m, 11H), 4.90 (m, 1H), 3.78 (m, 1H), 3.38 (dd, J = 1.5 and 8.lHz, 1H), 2.69 s, 3H);
ESI (-ve) mass spectrum analysis m/z (rel. intensity) 511 (M-H, 100 ) .
Part D: The product from part C was subjected to the Pinner amidine reaction sequence (HC1/MeOH followed by ammonium carbonate in methanol), purified via standard HPLC
purification, lyophilization to afford (40~ yield) of Example 1 as colorless crystals. 1HNMR(DMS06)8: 9.36 (bs, 1.5H), 9.00 (bs, l.5Hz), 8.06 (d, J = 7.7Hz, 1H), 7.53-7.78 (m, 6H), 7.35 (d, J = 8.lHz, 3H), 7.27 (d, J = 8.OHz, 1H), 7.17 (d, J =
8.5Hz, 1H), 5.33 (dd, J = 6.2 and 13.2Hz, 1H), 3.76 (t, 1H), 3.40 (d, J = 3.lHz, 1H), 2.84(s, 3H) ppm; ESI (+ve) mass spectum analysis m/z (relative intensity) 530 (M+H, 100).
Additionally, the compound form Part C was subjected to reduction using 10~ Pd/C in an acidic medium (methanol/acetic acid). Purification via standard HPLC techniques and lyophilization afforded the benzylamine (10~ yield).
1H1VI~(DMS06)8: 8.07 (bs, 2H), 8.01 (d, J = 8Hz, 1H), 7.70 (m, 1H), 7.59 (m, 3H), 7.28 (m, 4H), 6.95 (d, J = 8Hz, 1H), 6.83 (dd, J = 1/5 and 8Hz, 1H), 6.40 (bs, 2H), 5.22 (dd, J = 6.5 and l3Hz, 1H), 4.00 (m, 1H), 3.71 (m, 1H), 3.34 (dd, J = 1.5 and 8Hz, 1H), 2.84 (s, 3H) ppm; ESI mass spectrum analysis m/z (relative intensity) 517 (M+H, 100).
The following tables contain representative examples of the present invention. Each entry in each table is intended to be paired with each formulae at the start of the table.
For example, in Table 1, example 1 is intended to be paired Substitute Sheet (Rule Z6) WO 99/50255 PC'TIUS99/06310 with each of formulae a-ttt and in Table 2, example 1 is intended to be paired with each of formulae a-ss.
The following groups are intended for group A in the following tables.
\ / B \ /
2-pyridyi 3-pyridyl 2-pyrimidyl C F

\ / B \ /

5-pyrimidyl 2-CI-phenyl 2-F-phenyl F
\ /~--B
F
2.6-diF-phenyl Substitute Sheet (Rule 26) Table 1 Rlc N/ II H / H
.N N~A~B N.N N~A~g O O
~NH2 ~NH2 CI F b a Rtc / ~H
N.N N.A.B ~B ~B
O
C ~ ~ H3C

a c Rtc N/ II H / H
.N N~A~B N.N N~A~B
O / O
C(=NH)NH2 C(=NH)NH2 CI
f Rtc N N N~A~B A~B N N N~A~B
/ ~H / II H
O O
C \ C(=NH)NH2 -f)NH2 HsC \ C(=NH)NH2 i j Substitute Sheet (Rule 26) Roc R1c ~H
N.N N~A~B
O
C(O)NH2 Cl F
k I
3 a.B

m n o Htc R1c R1c N B N/ H / H N/ N B
N ~ wA~ N N~A.B N,N N.A~B .N wA~
O O O O
i CH2NHMe H3C ~-NHp C(=NH)NH2 C(O)NH2 P 4 r s S ~bstitute Sheet (Rule 26) Qtc Rtc ~H
~N N~~
~HN , O
CI F
a v t otc Rtc N/ H
.N N~A~B
Me MeHN

Y
Rtc Rtc N N N~A~B N~ N~A~B
NHMe ~ ~ NHMe F ~ H3C0 bb Substitute Sheet (Rule 26) WO 99/50255 PC'T/tlS99/06310 Qtc Qtc H H
N~A~I N~A~B

_ . _ dd ee cc p hh Rtc H H
N~ N~A~B N/ N~A~B N~A~B
N N
O O
CH2NH2 ~ I CH2NH2 IpNH2 F
CI
kk Substitute Cheet (Rule 26) WO 99150255 PCT/US99/063i0 Rtc ~ Rtc N N~~~A~B N N~~~A~B
MeHNH~C O MeHNH2C NH2C O
~i ~I
OCH3 CI F nn mm Rtc .B B N~N ~A~B
MeHNH2 MeHNH2C MeHNH2C / O
HgCO
0o pp qq R1c .B N / ~~ ~B N / ~A~B
N A N O
O
Me ~ I CH2NHMe ~ I CH2NHMe F ~ H~CO
ss rr Substitute Sheet (Rule 26) A'B
MeH
w ww uu Rtc Roc N~N H N~N N B
~A~B ~N NwA~B .N wA~
MeHN MeHN
i ~ i F ~ H3C0 xx YY
Rtc R1c ~'-N ~ H
~N N~ ,B N~ ~N~A~B N~ N~A~B
N~ A N' 11 ~N
~O
NHMe ~ I NHMe ~ ( NHMe F ~ H3C0 aaa bbb etc Rtc h--N
Substitute Sheet (Rule 26) WO 99/50255 PCTlUS99/06310 R1c R1c ~N ~N
H ~ H
.A~B N.N~N~A~B N,N Il N.A.B
H2NH2C , O H2NH2C / O ' ddd CI ~e F fff Qtc Roc Rtc -N ?-N
N N N~A~B N N~N~A~B
H2C , O H2NH2C / O
F ~ HgC
99g hhh iii ctc A'B

kkk JJl Substitute Sheet (Rule 26) WO 99/50255 PC'fNS99106310 R~
N H
N.N~~~A~B ,B
~NH2 / ~O( MeHNH
CI
nnn o00 atc mmm i/ H ~/ H
N~A~B ~N~t~A~B N~N~N~A~B
MeH
pFP Roc qqq rrr Roc ~N H // -N
N~N~N\A~B ~ ~N~A~B
N

CH2NHMe ~ ( H2NHMe F \
c sss Ex # Rl~ A B

1 CH3 phenyl 2-(aminosulfonyl)phenyl 2 CH3 phenyl 2-(methylaminosulfonyl)phenyl 3 CH3 phenyl 1-pyrrolidinocarbonyl 4 CH3 phenyl 2-(methylsulfonyl)phenyl CH3 phenyl 4-morpholino 6 CH3 phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 7 CH3 phenyl 4-morpholinocarbonyl 8 CH3 phenyl 2-methyl-1-imidazolyl 9 CH3 phenyl 5-methyl-1-imidazolyl CH3 phenyl 2-methylsulfonyl-1-imidazolyl 11 CH3 2-pyridyl 2-(aminosulfonyl)phenyl 12 CH3 2-pyridyl 2-(methylaminosulfonyl)phenyl 13 CH3 2-pyridyl 1-pyrrolidinocarbonyl 14 CH3 2-pyridyl 2-(methylsulfonyl)phenyl CH3 2-pyridyl 4-morpholino 16 CH3 2-pyridyl 2-(1'-CF3-tetrazol-2-yl)phenyl 17 CH3 2-pyridyl 4-morpholinocarbonyl Substitute Sheet (Rule 26) WO 99/50255 PCT/US99f06310 18 CH3 2-pyridyl 2-methyl-1-imidazolyl 19 CH3 2-pyridyl 5-methyl-1-imidazolyl 20 CH3 2-pyridvl 2-methylsulfonyl-1-imidazolyl 21 CH3 3-pyridyl 2-(aminosulfonyl)phenyl 22 CH3 3-pyridyl 2-(methylaminosulfonyl)phenyl 23 CH3 3-pyridyl 1-pyrrolidinocarbonyl 24 CH3 3-pyridyl 2-(methylsulfonyl)phenyl 25 CH3 3-pyridyl 4-morpholino 26 CH3 3-pyridyl 2-(1'-CF3-tetrazol-2-yl)phenyl 27 CH3 3-pyridyl 4-morpholinocarbonyl 28 CH3 3-pyridyl 2-methyl-1-imidazolyl 29 CH3 3-pyridyl 5-methyl-1-imidazolyl 30 CH3 3-pyridyl 2-methylsulfonyl-1-imidazolyl 31 CH3 2-pyrimidyl 2-(aminosulfonyl)phenyl 32 CH3 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 33 CH3 2-pyrimidyl 1-pyrrolidinocarbonyl 34 CH3 2-pyrimidyl 2-(methylsulfonyl)phenyl 35 CH3 2-pyrimidyl 4-morpholino 36 CH3 2-pyrimidyl 2-(1'-CF3-tetrazol-2-yl)phenyl 37 CH3 2-pyrimidyl 4-morpholinocarbonyl 38 CH3 2-pyrimidyl 2-methyl-1-imidazolyl 39 CH3 2-pyrimidyl 5-methyl-1-imidazolyl 40 CHz 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 41 CH3 5-pyrimidyl 2-(aminosulfonyl)phenyl 42 CH3 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 43 CH3 5-pyrimidyl 1-pyrrolidinocarbonyl 44 CH3 5-pyrimidyl 2-(methylsulfonyl)phenyl 45 CH3 5-pyrimidyl 4-morpholino 46 CH3 5-pyrimidyl 2-(1'-CF3-tetrazol-2-yl)phenyl 47 CH3 5-pyrimidyl 4-morpholinocarbonyl 48 CH3 5-pyrimidyl 2-methyl-1-imidazolyl 49 CH3 5-pyrimidyl 5-methyl-1-imidazolyl 50 CH3 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 51 CH3 2-C1-phenyl 2-(aminosulfonyl)phenyl 52 CH3 2-C1-phenyl 2-(methylaminosulfonyl)phenyl 53 CH3 2-C1-phenyl 1-pyrrolidinocarbonyl 54 CH3 2-C1-phenyl 2-(methylsulfonyl)phenyl Substitute Sheet (Rule 26) WO 99150255 PCTlUS99/06310 55 CH3 2-C1-phenyl 4-morpholino 56 CH3 2-C1-phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 57 CH3 2-CI-phenyl 4-morpholinocarbonyl 58 CH3 2-C1-phenyl 2-methyl-1-imidazolyl 59 CH3 2-C1-phenyl 5-methyl-1-imidazolyl 60 CH3 2-C1-phenyl 2-methylsulfonyl-1-imidazolyl 61 CH3 2-F-phenyl 2-(aminosulfonyl)phenyl 62 CH3 2-F-phenyl 2-(methylaminosulfonyl)phenyl 63 CH3 2-F-phenyl 1-pyrrolidinocarbonyl 64 CH3 2-F-phenyl 2-(methylsulfonyl)phenyl 65 CH3 2-F-phenyl 4-morpholino 66 CH3 2-F-phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 67 CH3 2-F-phenyl 4-morpholinocarbonyl 68 CH3 2-F-phenyl 2-methyl-1-imidazolyl 69 CH3 2-F-phenyl 5-methyl-1-imidazolyl 70 CH3 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 71 CH3 2,6-diF-phenyl2-(aminosulfonyl)phenyl 72 CH3 2,6-diF-phenyl2-(methylaminosulfonyl)phenyl 73 CH3 2,6-diF-phenyl1-pyrrolidinocarbonyl 74 CH3 2,6-diF-phenyl2-(methylsulfonyl)phenyl 75 CH3 2,6-diF-phenyl4-morpholino 76 CH3 2,6-diF-phenyl2-(1'-CF3-tetrazol-2-yl)phenyl 77 CHg 2,6-diF-phenyl4-morpholinocarbonyl 78 CH3 2,6-diF-phenyl2-methyl-1-imidazolyl 79 CH3 2,6-diF-phenyl5-methyl-1-imidazolyl 80 CH3 2,6-diF-phenyl2-methylsulfonyl-1-imidazolyl 81 CH2CH3 phenyl 2-(aminosulfonyl)phenyl 82 CH2CH3 phenyl 2-(methylaminosulfonyl)phenyl 83 CH2CH3 phenyl 1-pyrrolidinocarbonyl 84 CH2CH3 phenyl 2-(methylsulfonyl)phenyl 85 CH2CH3 phenyl 4-morpholino 86 CH2CH3 phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 87 CH2CH3 phenyl 4-morpholinocarbonyl 88 CH2CH3 phenyl 2-methyl-1-imidazolyl 89 CH2CH3 phenyl 5-methyl-1-imidazolyl 90 CH2CH3 phenyl 2-methylsulfonyl-1-imidazolyl 91 CH2CH3 2-pyridyl 2-(aminosulfonyl)phenyl Substitute Sheet (Rule 26) 92 CH2CH3 2-pyridyl 2-(methylaminosulfonyl)phenyl 93 CH~CH3 2-pyridyl 1-pyrrolidinocarbonyl 94 CH~CH3 2-pyridyl 2-(methylsulfonyl)phenyl 95 CH2CH3 2-pyridyl 4-morpholino 96 CH2CH; 2-pyridyl 2-(1'-CF3-tetrazol-2-yl)phenyl 97 CH2CH3 2-pyridyl 4-morpholinocarbonyl 98 CH2CH3 2-pyridyl 2-methyl-1-imidazolyl 99 CH2CH3 2-pyridyl 5-methyl-1-imidazolyl 100 CH2CH-~ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 101 CH2CH3 3-pyridyl 2-(aminosulfonyl)phenyl 102 CHZCH3 3-pyridyl 2-(methylaminosulfonyl)phenyl 103 CHZCH3 3-pyridyl 1-pyrrolidinocarbonyl 104 CHZCH3 3-pyridyl 2-(methylsulfonyl)phenyl 105 CHZCH3 3-pyridyl 4-morpholino 106 CH2CH3 3-pyridyl 2-(1'-CF3-tetrazol-2-yl)phenyl 107 CH2CH3 3-pyridyl 4-morpholinocarbonyl 108 CH2CH3 3-pyridyl 2-methyl-1-imidazolyl 109 CH2CH3 3-pyridyl 5-methyl-1-imidazolyl 110 CH2CH3 3-pyridyl 2-methylsulfonyl-1-imidazolvl 111 CH2CH3 2-pyrimidyl 2-(aminosulfonyl)phenyl 112 CHZCH3 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 113 CHZCH3 2-pyrimidyl 1-pyrrolidinocarbonyl 114 CH2CH3 2-pyrimidyl 2-(methylsulfonyl)phenyl 115 CH2CH3 2-pyrimidyl 4-mozpholino 116 CH2CH3 2-pyrimidyl 2-(1'-CF3-tetrazol-2-yl)phenyl 117 CH2CH3 2-pyrimidyl 4-morpholinocarbonyl 118 CH2CH3 2-pyrimidyl 2-methyl-1-imidazolyl 119 CH2CH3 2-pyrimidyl 5-methyl-1-imidazolyl 120 CH2CH3 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 121 CHZCH3 5-pyrimidyl 2-(aminosulfonyl)phenyl 122 CH2CH3 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 123 CH2CH3 5-pyrimidyl 1-pyrrolidinocarbonyl 124 CH2CH3 5-pyrimidyl 2-(methylsulfonyl)phenyl 125 CH2CH3 5-pyrimidyl 4-morpholino 126 CH2CH3 5-pyrimidyl 2-(1'-CF3-tetrazol-2-yl)phenyl 127 CH2CH3 5-pyrimidyl 4-morpholinocarbonyl 128 CIi2CH3 5-pyrimidyl 2-methyl-1-imidazolyl Substitute Sheet (Rule 26) 129 CH2CH3 5-pyrimidyl 5-methyl-1-imidazolyl 130 CH2CH3 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 131 CH2CH3 2-Cl-phenyl 2-(aminosulfonyl)phenyl 132 CHZCHz 2-C1-phenyl 2-(methylaminosulfonyl)phenyl 133 CH2CH3 2-C1-phenyl 1-pyrrolidinocarbonyl 134 CH2CH3 2-C1-phenyl 2-(methylsulfonyl)phenyi 135 CH2CH3 2-Cl-phenyl 4-morpholino 136 CH2CH3 2-C1-phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 137 CH2CH3 2-C1-phenyl 4-morpholinocarbonyl 138 CH2CH3 2-C1-phenyl 2-methyl-1-imidazolyl 139 CH2CH3 2-C1-phenyl 5-methyl-1-imidazolyl 140 CH2CH3 2-C1-phenyl 2-methylsulfonyl-1-imidazolyl 141 CH2CH3 2-F-phenyl 2-(aminosulfonyl)phenyl 142 CH2CH3 2-F-phenyl 2-(methylaminosulfonyl)phenyl 143 CH2CH3 2-F-phenyl 1-pyrrolidinocarbonyl 144 CHZCH3 2-F-phenyl 2-(methylsulfonyl)phenyl 145 CH2CH3 2-F-phenyl 4-morpholino 146 CH2CH3 2-F-phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 147 CH2CH3 2-F-phenyl 4-morpholinocarbonyl 148 CH2CH3 2-F-phenyl 2-methyl-1-imidazolyl 149 CH2CH3 2-F-phenyl 5-methyl-1-imidazolyl 150 CH2CH3 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 151 CH2CH3 2,6-diF-phenyl2-(aminosulfonyl)phenyl 152 CH2CH3 2,6-diF-phenyl2-(methylaminosulfonyl)phenyl 153 CH2CH3 2,6-diF-phenyl1-pyrrolidinocarbonyl 154 CH2CH3 2,6-diF-phenyl2-(methylsulfonyl)phenyl 155 CH2CH3 2,6-diF-phenyl4-morpholino 156 CHZCH3 2,6-diF-phenyl2-(1'-CF3-tetrazol-2-yl)phenyl 157 CH2CH3 2,6-diF-phenyl4-morpholinocarbonyl 158 CH2CH3 2,6-diF-phenyl2-methyl-1-imidazolyl 159 CH2CH3 2,6-diF-phenyl5-methyl-1-imidazolyl 160 CH2CH3 2,6-diF-phenyl2-methylsulfonyl-1-imidazolyl 161 CF3 phenyl 2-(aminosulfonyl)phenyl 162 CF3 phenyl 2-(methylaminosulfonyl)phenyl 163 CF3 phenyl 1-pyrrolidinocarbonyl 164 CF3 phenyl 2-(methylsulfonyl)phenyl 165 CF3 phenyl 4-morpholino Substitute Sheet (Mule 26) WO 99/50255 PCTlUS99/06310 166 CF3 phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 167 CF3 phenyl 4-morpholinocarbonyl 168 CF3 phenyl 2-methyl-1-imidazolyl 169 CF3 phenyl 5-methyl-1-imidazolyl 170 CF3 phenyl 2-methylsulfonyl-1-imidazolyl 171 CF3 2-pyridyl 2-(aminosulfonyl)phenyl 172 CF3 2-pyridyl 2-(methylaminosulfonyl)phenyl 173 CF3 2-pyridyl 1-pyrrolidinocarbonyl 174 CF3 2-pyridyl 2-(methylsulfonyl)phenyl 175 CF3 2-pyridyl 4-morpholino 176 CF3 2-pyridyl 2-(1'-CF3-tetrazol-2-yl)phenyl 177 CF3 2-pyridyl 4-morpholinocarbonyl 178 CF3 2-pyridyl 2-methyl-1-imidazolyl 179 CF3 2-pyridyl 5-methyl-1-imidazolyl 180 CF3 2-pyridyl 2-methylsulfonyl-1-imidazolyl 181 CF3 3-pvridyl 2-(aminosulfonyl)phenyl 182 CF3 3-pyridyl 2-(methylaminosulfonyl)phenyl 183 CF3 3-pyridyl 1-pyrrolidinocarbonyl 184 CF3 3-pvridyl 2-(methylsulfonyl)phenyl 185 CF3 3-pyridyl 4-morpholino 186 CF3 3-pyridyl 2-(1'-CF3-tetrazol-2-yl)phenyl 187 CF3 3-pyridyl 4-morpholinocarbonyl 188 CF3 3-pyridyl 2-methyl-1-imidazolyl 189 CF3 3-pyridyl 5-methyl-1-imidazolyl 190 CF3 3-pyridyl 2-methylsulfonyl-1-imidazolyl 191 CF3 2-pyrimidyl 2-(aminosulfonyl)phenyl 192 CF3 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 193 CF3 2-pyrimidyl 1-pyrrolidinocarbonyl 194 CF3 2-pyrimidyl 2-(methylsulfonyl)phenyl 195 CF3 2-pyrimidyl 4-morpholino 196 CF3 2-pyrimidyl 2-(1'-CF3-tetrazol-2-yl)phenyl 197 CF3 2-pyrimidyl 4-morpholinocarbonyl 198 CF3 2-pyrimidyl 2-methyl-1-imidazolyl 199 CF3 2-pyrimidyl 5-methyl-1-imidazolyl 200 CF3 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 201 CF3 5-pyrimidyl 2-(aminosulfonyl)phenyl 202 CF3 5-pyrimidyl 2-(methylaminosulfonyl)phenyl Substitute Sheet (Rule 2~~

WO 99/50255 PCTlUS99/06310 203 CF3 5-pyrimidyl 1-pyrrolidinocarbonyl 204 CF3 5-pyrimidyl 2-(methylsulfonyl)phenyl 205 CF3 5-pyrimidyl 4-morpholino 206 CF3 5-pyrimidyl 2-(1'-CF3-tetrazol-2-yl)phenyl 207 CF3 5-pyrimidyl 4-morpholinocarbonyl 208 CF3 5-pyrimidyl 2-methyl-1-imidazolyl 209 CF3 5-pyrimidyl 5-methyl-1-imidazolyl 210 CF3 5-pvrimidvl 2-methvlsulfonyl-1-imidazolyl 211 CF3 2-Cl-phenyl 2-(aminosulfonyl)phenyl 212 CF3 2-C1-phenyl 2-(methylaminosulfonyl)phenyl 213 CF3 2-C1-phenyl 1-pyrrolidinocarbonyl 214 CF3 2-C1-phenyl 2-(methylsulfonyl)phenyl 215 CF3 2-C1-phenyl 4-morpholino .
216 CF3 2-C1-phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 217 CF3 2-C1-phenyl 4-morpholinocarbonyl 218 CF3 2-C1-phenyl 2-methyl-1-imidazolyl 219 CF3 2-C1-phenyl 5-methyl-1-imidazolyl 220 CF3 2-C1- henyl 2-methylsulfonyl-1-imidazolyl 221 CF3 2-F-phenyl 2-(aminosulfonyl)phenyl 222 CF3 2-F-phenyl 2-(methylaminosulfonyl)phenyl 223 CF3 2-F-phenyl 1-pyrrolidinocarbonyl 224 CF3 2-F-phenyl 2-(methylsulfonyl)phenyl 225 CF3 2-F-phenyl 4-morpholino 226 CF3 2-F-phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 227 CF3 2-F-phenyl 4-morpholinocarbonyl 228 CF3 2-F-phenyl 2-methyl-1-imidazolyl 229 CF3 2-F-phenyl 5-methyl-1-imidazolyl 230 CF3 2-F- henvl 2-methvlsulfonyl-1-imidazolyl 231 CF3 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 232 CF; 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 233 CF3 2,6-diF-phenyl 1-pyrrolidinocarbonyl 234 CF3 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 235 CF3 2,6-diF-phenyl 4-mozpholino 236 CF3 2,6-diF-phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 237 CF3 2,6-diF-phenyl 4-morpholinocarbonyl 238 CF3 2,6-diF-phenyl 2-methyl-1-imidazolyl 239 CF3 2,6-diF-phenyl 5-methyl-1-imidazolyl Substitute Sheet (Rule 26) WO 99/50255 PC'T/US99/06310 240 CF3 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 241 SCH3 phenyl 2-(aminosulfonyl)phenyl 242 SCH3 phenyl 2-(methylaminosulfonyl)phenyl 243 SCH3 phenyl 1-pyrrolidinocarbonyl 244 SCH3 phenyl 2-(methylsulfonyl)phenyl 245 SCH3 phenyl 4-morpholino 246 SCH3 phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 247 SCH3 phenyl 4-morpholinocarbonyl 248 SCH3 phenyl 2-methyl-1-imidazolyl 249 SCH3 phenyl 5-methyl-1-imidazolyl 250 SCH3 phenyl 2-methylsulfonyl-1-imidazolyl 251 SCH3 2-pyridyl 2-(aminosulfonyl)phenyl 252 SCH3 2-pyridyl 2-(methylaminosulfonyl)phenyl 253 SCH3 2-pyridyl 1-pyrrolidinocarbonyl 254 SCH3 2-pyridyl 2-(methylsulfonyl)phenyl 255 SCH3 2-pyridyl 4-morpholino 256 SCH3 2-pyridyl 2-(2'-CF3-tetrazol-2-yl)phenyl 257 SCH3 2-pyridyl 4-morpholinocarbonyl 258 SCH3 2-pyridyl 2-methyl-1-imidazolyl 259 SCH3 2-pyridyl 5-methyl-1-imidazolyl 260 SCH3 2-pyridyl 2-methylsulfonyl-1-imidazolyl 261 SCH3 3-pyridyl 2-(aminosulfonyl)phenyl 262 SCH3 3-pyridyl 2-(methylaminosulfonyl)phenyl 263 SCH3 3-pyridyl 1-pyrrolidinocarbonyl 264 SCH3 3-pyridyl 2-(methylsulfonyl)phenyl 265 SCH3 3-pyridyl 4-morpholino 266 SCH3 3-pyridyl 2-(1'-CF3-tetrazol-2-yl)phenyl 267 SCH3 3-pyridyl 4-morpholinocarbonyl 268 SCH3 3-pyridyl 2-methyl-1-imidazolyl 269 SCH3 3-pyridyl 5-methyl-1-imidazolyl 270 SCH3 3-pyridyl 2-methylsulfonvl-1-imidazolvl 271 SCH3 2-pyrimidyl 2-(aminosulfonyl)phenyl 272 SCH3 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 273 SCH3 2-pyrimidyl 1-pyrrolidinocarbonyl 274 SCH3 2-pyrimidyl 2-(methylsulfonyl)phenyl 275 SCH3 2-pyrimidyl 4-morpholino 276 SCH3 2-pyrimidyl 2-(1'-CF3-tetrazol-2-yl)phenyl Substitute Shez.. ; R~rte 26) WO 99/50255 PC'fJUS99/06310 277 SCH3 2-pyrimidyl 4-morpholinocarbonyl 278 SCH3 2-pyrimidyl 2-methyl-1-imidazolyl 279 SCH3 2-pyrimidyl 5-methyl-1-imidazolyl 2g0 SCH3 2- yrimidyl 2-methylsulfonyl-1-imidazolyl 281 SCH3 5-pyrimidyl 2-(aminosulfonyl)phenyl 282 SCH3 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 283 SCH3 5-pyrimidyl 1-pyrrolidinocarbonyl 284 SCH3 5-pyrimidyl 2-(methylsulfonyl)phenyl 285 SCH3 5-pyrimidyl 4-morpholino 286 SCH3 5-pyrimidyl 2-(1'-CF3-tetrazol-2-yl)phenyl 287 SCH3 5-pyrimidyl 4-morpholinocarbonyl 288 SCH3 5-pyrimidyl 2-methyl-1-imidazolyl 2$g SCH3 5-pyrimidyl 5-methyl-1-imidazolyl 290 SCH3 5-pvrimidvl 2-methvlsulfonyl-1-imidazolyl 291 SCH3 2-C1-phenyl 2-(aminosulfonyl)phenyl 292 SCH3 2-C1-phenyl 2-(methylaminosulfonyl)phenyl 293 SCH3 2-C1-phenyl 1-pyrrolidinocarbonyl 294 SCH3 2-C1-phenyl 2-(methylsulfonyi)phenyl 295 SCH3 2-C1-phenyl 4-morpholino 296 SCH3 2-C1-phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 297 SCH3 2-Cl-phenyl 4-morpholinocarbonyl 298 SCH3 2-C1-phenyl 2-methyl-1-imidazolyl 299 SCH3 2-C1-phenyl 5-methyl-1-imidazolyl 300 SCH3 2-C1-phenyl 2-methvlsulfonyl-1-imidazolyl 301 SCH3 2-F-phenyl 2-(aminosulfonyl)phenyl 302 SCH3 2-F-phenyl 2-(methylaminosulfonyl)phenyl 303 SCH3 2-F-phenyl 1-pyrrolidinocarbonyl 304 SCH3 2-F-phenyl 2-(methylsulfonyl)phenyl 305 SCH3 2-F-phenyl 4-morpholino 306 SCH3 2-F-phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 307 SCH3 2-F-phenyl 4-morpholinocarbonyl 308 SCH3 2-F-phenyl 2-methyl-1-imidazolyl 309 SCH3 2-F-phenyl 5-methyl-1-imidazolyl 310 SCH3 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 311 SCH3 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 312 SCH3 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 313 SCH3 2,6-diF-phenyl 1-pyrrolidinocarbonyl Substitute Sheet (Rule 26) 314 SCH3 2,6-diF-phenyl2-(methylsulfonyl)phenyl 315 SCH3 2,6-diF-phenyl4-morpholino 316 SCH3 2,6-diF-phenyl2-(1'-CF3-tetrazol-2-yl)phenyl 317 SCH3 2,6-diF-phenyl4-morpholinocarbonyl 318 SCH3 2,6-diF-phenyl2-methyl-1-imidazolyl 319 SCH3 2,6-diF-phenyl5-methyl-1-imidazolyl 320 SCH3 2,6-diF- henyl2-methylsulfonyl-1-imidazolyl 321 SOCH3 phenyl 2-(aminosulfonyl)phenyl 322 SOCH3 phenyl 2-(methylaminosulfonyl)phenyl 323 SOCH3 phenyl 1-pyrrolidinocarbonyl 324 SOCH3 phenyl 2-(methylsulfonyl)phenyl 325 SOCH3 phenyl 4-morpholino 326 SOCH3 phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 327 SOCH3 phenyl 4-morpholinocarbonyl 328 SOCH3 phenyl 2-methyl-1-imidazolyl 329 SOCH3 phenyl 5-methyl-1-imidazolyl 330 SOCH3 phenyl 2-methylsulfonyl-1-imidazolyl 331 SOCH3 2-pyridyl 2-(aminosulfonyl)phenyl 332 SOCH3 2-pyridyl 2-(methylaminosulfonyl)phenyl 333 SOCH3 2-pyridyl 1-pyrrolidinocarbonyl 334 SOCH3 2-pyridyl 2-(methylsulfonyl)phenyl 335 SOCH3 2-pyridyl 4-morpholino 336 SOCH3 2-pyridyl 2-(1'-CF3-tetrazol-2-yl)phenyl 337 SOCH3 2-pyridyl 4-morpholinocarbonyi 338 SOCH3 2-pyridyl 2-methyl-1-imidazolyl 339 SOCH3 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-morpholino 346 SOCH3 3-pyridyl 2-(1'-CF3-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-methylsulfonyl-1-imidazolyl Subsr~. : :e Sheet (Rule 26) WO 99/50255 PC'T/US99/06310 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-mozpholino 356 SOCH3 2-pyrimidyl 2-(1'-CF3-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-(aminosulf onyl)phenyl 362 SOCH3 5-pyrimidyl 2-(methylaminosuifonyl)phenyl 363 SOCH3 5-pyrimidyl 1-pyrrolidinocarbonyl 364 SOCH3 5-pyrimidyl 2-(methylsulfonyl)phenyl 365 SOCH3 5-pyrimidyl 4-morpholino 366 SOCH3 S-pyrimidyl 2-(1'-CF3-tetrazol-2-yl)phenyl 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-imidazolvl 371 SOCH3 2-C1-phenyl 2-(aminosulfonyl)phenyl 372 SOCH3 2-C1-phenyl 2-(methylaminosulfonyl)phenyl 373 SOCH3 2-C1-phenyl 1-pyrrolidinocarbonyl 374 SOCH3 2-C1-phenyl 2-(methylsulfonyl)phenyl 375 SOCH3 2-C1-phenyl 4-morpholino 376 SOCH3 2-C1-phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 377 SOCH3 2-C1-phenyl 4-morpholinocarbonyl 378 SOCH3 2-C1-phenyl 2-methyl-1-imidazolyl 379 SOCH3 2-C1-phenyl 5-methyl-1-imidazolyl 380 SOCH3 2-C1-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-morpholino 386 SOCH3 2-F-phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 387 SOCH3 2-F-phenyl 4-morpholinocarbonyl Substitute Sheet (Rule 26) 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-phenyl2-(aminosulfonyl)phenyl 392 SOCH3 2,6-diF-phenyl2-(methylaminosulfonyl)phenyl 393 SOCH3 2,6-diF-phenyl1-pyrrolidinocarbonyl 394 SOCH3 2,6-diF-phenyl2-(methylsulfonyl)phenyl 395 SOCH3 2,6-diF-phenyl4-morpholino 396 SOCH3 2,6-diF-phenyl2-(1'-CF3-tetrazol-2-yl)phenyl 397 SOCH3 2,6-diF-phenyl4-morpholinocarbonyl 398 SOCH3 2,6-diF-phenyl2-methyl-1-imidazolyl 399 SOCH3 2,6-diF-phenyl5-methyl-1-imidazolyl 400 SOCH3 2,6-diF-phenyl2-methylsulfonyl-1-imidazolyl 401 S02CH3 phenyl 2-(aminosulfonyl)phenyl 402 S02CH3 phenyl 2-(methylaminosulfonyl)phenyl 403 SOzCH3 phenyl 1-pyrrolidinocarbonyl 404 S02CH3 phenyl 2-(methylsulfonyl)phenyl 405 S02CH3 phenyl 4-morpholino 406 S02CH3 phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 407 S02CH3 phenyl 4-morpholinocarbonyl 408 S02CH3 phenyl 2-methyl-1-imidazolyl 409 S02CH3 phenyl 5-methyl-1-imidazolyl 410 S02CH3 phenyl 2-methylsulfonyl-1-imidazolyl 411 S02CH3 2-pyridyl 2-(aminosulfonyl)phenyl 412 S02CH3 2-pyridyl 2-(methylaminosulfonyl)phenyl 413 S02CH3 2-pyridyl 1-pyrrolidinocarbonyl 414 S02CH3 2-pyridyl 2-(methylsulfonyl)phenyl 415 S02CH3 2-pyridyl 4-morpholino 416 S02CH3 2-pyridyl 2-(1'-CF3-tetrazol-2-yl)phenyl 417 S02CH3 2-pyridyl 4-morpholinocarbonyl 418 S02CH3 2-pyridyl 2-methyl-1-imidazolyl 419 S02CH3 2-pyridyl 5-methyl-1-imidazolyl 420 S02CH3 2-pvridyl 2-methylsulfonvl-1-imidazolyl 421 S02CH3 3-pyridyl 2-(aminosulfonyl)phenyl 422 S02CH3 3-pyridyl 2-(methylaminosulfonyl)phenyl 423 S02CH3 3-pyridyl 1-pyrrolidinocarbonyl 424 S02CH3 3-pyridyi 2-(methylsulfonyl)phenyl Substitute Sbeet (Rule 26) 425 S02CH3 3-pyridyl 4-morpholino 426 S02CH3 3-pyridyl 2-(1'-CF3-tetrazol-2-yl)phenyl 427 S02CH3 3-pyridyl 4-morpholinocarbonyl 428 5023 3-pyridyl 2-methyl-1-imidazolyl 429 S02CH3 3-pyridyl 5-methyl-1-imidazolyl 430 S02CH3 3- yridyl 2-methylsulfonyl-1-imidazolyl 431 S02CH3 2-pyrimidyl 2-(aminosulfonyl)phenyl 432 S02CH3 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 433 SOzCH3 2-pyrimidyl 1-pyrrolidinocarbonyl 434 S02CH3 2-pyrimidyl 2-(methylsulfonyl)phenyl 435 S02CH3 2-pyrimidyl 4-morpholino 436 S02CH3 2-pyrimidyl 2-(1'-CF3-tetrazol-2-yl)phenyl 437 S02CH3 2-pyrimidyl 4-morpholinocarbonyl 438 SOZCH3 2-pyrimidyl 2-methyl-1-imidazolyl 439 S02CH3 2-pyrimidyl 5-methyl-1-imidazolyl 440 S02CH3 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 441 SOZCH3 5-pyrimidyl 2-(aminosulfonyl)phenyl 442 S02CH3 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 443 S02CH3 5-pyrimidyl 1-pyrrolidinocarbonyl 444 S02CH3 5-pyrimidyl 2-(methylsulfonyl)phenyl 445 S02CH3 5-pyrimidyl 4-morpholino 446 SOZCH3 5-pyrimidyl 2-(1'-CF3-tetrazol-2-yl)phenyl 447 S02CH3 5-pyrimidyl 4-morpholinocarbonyl 448 S02CH3 5-pyrimidyl 2-methyl-1-imidazolyl 449 S02CH3 5-pyrimidyl 5-methyl-1-imidazolyl 450 S02CH3 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 451 SOzCH3 2-C1-phenyl 2-(aminosulfonyl)phenyl 452 SOZCH3 2-C1-phenyl 2-(methylaminosulfonyl)phenyl 453 S02CH3 2-C1-phenyl 1-pyrrolidinocarbonyl 454 S02CH3 2-C1-phenyl 2-(methylsulfonyl)phenyl 455 S02CH3 2-C1-phenyl 4-morpholino 456 S02CH3 2-C1-phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 457 S02CH3 2-C1-phenyl 4-morpholinocarbonyl 458 S02CH3 2-Cl-phenyl 2-methyl-1-imidazolyl 459 SOZCH3 2-Cl-phenyl 5-methyl-1-imidazolyl 460 S02CH3 2-C1- henvl 2-methvlsulfonvl-1-imidazolyl 461 S02CH3 2-F-phenyl 2-(aminosulfonyl)phenyl Substit v ~ Sheet {Rule 26) 462 S02CH3 2-F-phenyl 2-(methylaminosulfonyl)phenyl 463 S02CH; 2-F-phenyl 1-pyrrolidinocarbonyl 464 S02CH3 2-F-phenyl 2-(methylsulfonyl)phenyl 465 S02CH3 2-F-phenyl 4-morpholino 466 S02CH3 2-F-phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 467 S02CH3 2-F-phenyl 4-morpholinocarbonyl 468 S02CH3 2-F-phenyl 2-methyl-1-imidazolyl 469 S02CH3 2-F-phenyl 5-methyl-1-imidazolyl 470 S02CH3 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 471 S02CH3 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 472 S02CH3 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 473 S02CH3 2,6-diF-phenyl 1-pyrrolidinocarbonyl 474 SOZCH3 2,6-diF-phenyl 2-(methylsulfonyl)phenyi 475 S02CH3 2,6-diF-phenyl 4-morpholino 476 S02CH3 2,6-diF-phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 477 S02CH3 2,6-diF-phenyl 4-morpholinocarbonyl 478 SOZCH3 2,6-diF-phenyl 2-methyl-1-imidazolyl 479 SOZCH3 2,6-diF-phenyl 5-methyl-1-imidazolyl 480 SOZCH3 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 481 CH2NH- phenyl 2-(aminosulfonyl)phenyl 482 CH2NH- phenyl 2-(methylaminosulfonyl)phenyl 483 CH2NH- phenyl 2-pyrrolidinocarbonyl 484 CH2NH- phenyl 2-(methylsulfonyl)phenyl 485 CH2NH- phenyl 4-morpholino 486 CH2NH- phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 487 CH2NH- phenyl 4-morpholinocarbonyl 488 CH2NH- phenyl 2-methyl-1-imidazolyl 489 CH2NH- phenyl 5-methyl-1-imidazolyl Substitute Sheet _ ~.ule 26) 490 CH2NH- phenyl 2-methylsulfonyl-1-imidazolyl 491 CH2NH- 2-pyridyl 2-(aminosulfonyl)phenyl 492 CH2NH- 2-pyridyl 2-(methylaminosulfonyl)phenyl 493 CH2NH- 2-pyridyl 1-pyrrolidinocarbonyl 494 CHZNH- 2-pyridyl 2-(methylsulfonyl)phenyl 495 CH2NH- 2-pyridyl 4-morpholino 496 CH2NH- 2-pyridyl ' 2-(1'-CF3-tetrazol-2-yl)phenyl 497 CH2NH- 2-pyridyl 4-morpholinocarbonyl 498 CH2NH- 2-pyridyl 2-methyl-1-imidazolyl 499 CHZNH- 2-pyridyl 5-methyl-1-imidazolyl 500 CH2NH- 2-pyridyl 2-methylsulfonyl-1-imidazolyl 501 CH2NH- 3-pyridyl 2-(aminosulfonyl)phenyl 502 CH2NH- 3-pyridyl 2-(methylaminosulfonyl)phenyl 503 CH2NH- 3-pyridyl 1-pyrrolidinocarbonyl 504 CH2NH- 3-pyridyl 2-(methylsulfonyl)phenyl 505 CH2NH- 3-pyridyl 4-morpholino 506 CH2NH- 3-pyridyl 2-(1'-CF3-tetrazol-2-yl)phenyl 507 CH2NH- 3-pyridyl 4-morpholinocarbonyl Substitute Sheet (Rule 26) 508 CH2NH- 3-pyridyl 2-methyl-1-imidazolyl SOzCH3 509 CH2NH- 3-pyridyl 5-methyl-1-imidazolyl 510 CH2NH- 3-pyridyl 2-methylsulfonyl-1-imidazolyl 511 CH2NH- 2-pyrimidyl 2-(aminosulfonyl)phenyl 512 CHZNH- 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 513 CH2NH- 2-pyrimidyl 1-pyrrolidinocarbonyl 514 CH2NH- 2-pyrimidyl 2-(methylsulfonyl)phenyl 515 CH2NH- 2-pyrimidyl 4-morpholino 516 CH2NH- 2-pyrimidyl 2-(1'-CF3-tetrazol-2-yl)phenyl 517 CH2NH- 2-pyrimidyl 4-morpholinocarbonyl 518 CHZNH- 2-pyrimidyl 2-methyl-1-imidazolyl 519 CH2NH- 2-pyrimidyl 5-methyl-1-imidazolyl 520 CH2NH- 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 521 CH2NH- 5-pyrimidyl 2-(aminosulfonyl)phenyl 522 CH2NH- 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 523 CH2NH- 5-pyrimidyl 1-pyrrolidinocarbonyl SOzCH3 524 CHZNH- 5-pyrimidyl 2-(methylsulfonyl)phenyl 525 CH2NH- 5-pyrimidyl 4-morpholino Substi. :~ se Sheet (Rule 26) 526 CH2~- 5-pyrimidyl 2-(1'-CF3-tetrazol-2-yl)phenyi 527 CH2NH- 5-pyrimidyl 4-morpholinocarbonyl 528 CH2NH- 5-pyrimidyl 2-methyl-1-imidazolyl 529 CHZNFi- 5-pyrimidyl 5-methyl-1-imidazolyl 530 CH2NH- 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 531 CHZNH- 2-C1-phenyl 2-(aminosulfonyl)phenyl 532 CH2NH- 2-C1-phenyl 2-(methylaminosulfonyl)phenyl 533 CHZNH- 2-C1-phenyl 1-pyrrolidinocarbonyl 534 CH2NH- 2-C1-phenyl 2-(methylsulfonyl)phenyl 535 CH2NH- 2-C1-phenyl 4-mozpholino 536 CH2NFi- 2-C1-phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 537 CHZNFi- 2-C1-phenyl 4-morpholinocarbonyl 538 CH2NH- 2-C1-phenyl 2-methyl-1-imidazolyl 539 CH2NH- 2-C1-phenyl 5-methyl-1-imidazolyl SOzCH3 540 CH2NH- 2-C1-phenyl 2-methylsulfonyl-1-imidazolyl 541 CH2NFi- 2-F-phenyl 2-(aminosulfonyl)phenyl 542 CH2NH- 2-F-phenyl 2-(methylaminosulfonyl)phenyl 543 CH2NH- 2-F-phenyl 1-pyrrolidinocarbonyl Substitute Sheet (Rule 26) WO 99/50255 PC'T/US99/06310 544 CH2NH- 2-F-phenyl 2-(methylsulfonyl)phenyl 545 CHZNH- 2-F-phenyl 4-morpholino 546 CH2NH- 2-F-phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 547 CH2NH- 2-F-phenyl 4-morpholinocarbonyl 548 CHZNH- 2-F-phenyl 2-methyl-1-imidazolyl 549 CH2NH- 2-F-phenyl 5-methyl-1-imidazolyl 550 CH2NH- 2-F-phenyl 2-methylsulfonyl-1-imidazolyl SO~CH3 551 CH2NH- 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 552 CH2NH- 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 553 CH2NH- 2,6-diF-phenyl I-pyrrolidinocarbonyl 554 CH2NH- 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 555 CH2NH- 2,6-diF-phenyl 4-morpholino 556 CH2NH- 2,6-diF-phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 557 CH2NH- 2,6-diF-phenyl 4-morpholinocarbonyl 558 CH2NH- 2,6-diF-phenyl 2-methyl-1-imidazolyl 559 CHZNH- 2,6-diF-phenyl 5-methyl-1-imidazolyl 560 CH2NH- 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 561 C1 phenyl 2-(aminosulfonyl)phenyl 562 C1 phenyl 2-(methylaminosulfonyl)phenyl 563 C1 phenyl 1-pyrrolidinocarbonyl Substitute Sheet (Rule 26) WO 99/50255 PCTlUS99/06310 564 C1 phenyl 2-(methylsulfonyl)phenyl 565 C1 phenyl 4-morpholino 566 C1 phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 567 C1 phenyl 4-morpholinocarbonyl 568 C1 phenyl 2-methyl-1-imidazolyl 569 C1 phenyl 5-methyl-1-imidazolyl _ 570 C1 phenyl 2-methvlsulfonyl-1-imidazolyl 571 C1 2-pyridyl 2-(aminosulfonyl)phenyl 572 C1 2-pyridyl 2-(methylaminosulfonyl)phenyl 573 C1 2-pyridyl 1-pyrrolidinocarbonyl 574 C1 2-pyridyl 2-(methylsulfonyl)phenyl 575 C1 2-pyridyl 4-morpholino 576 C1 2-pyridyl 2-(1'-CF3-tetrazol-2-yl,)phenyl 577 C1 2-pyridyl 4-morpholinocarbonyl 578 C1 2-pyridyl 2-methyl-1-imidazolyl 579 C1 2-pyridyl 5-methyl-1-imidazolyl 580 C1 2- yridyl 2-methvlsulfonvl-1-imidazolyl 581 C1 3-pyridyl 2-(aminosulfonyl)phenyl 582 C1 3-pyridyl 2-(methylaminosulfonyl)phenyl 583 C1 3-pyridyl 1-pyrrolidinocarbonyl 584 C1 3-pyridyl 2-(methylsulfonyl)phenyl 585 C1 3-pyridyl 4-morpholino 586 C1 3-pyridyl 2-(1'-CF3-tetrazol-2-yl)phenyl 587 C1 3-pyridyl 4-morpholinocarbonyl 588 C1 3-pyridyl 2-methyl-1-imidazolyl 589 C1 3-pyridyl 5-methyl-1-imidazolyl 590 C1 3- yridyl 2-methvlsulfonyl-1-imidazolvl 591 C1 2-pyrimidyl 2-(aminosulfonyl)phenyl 592 C1 2-pyrimidyl 2-(metrylaminosulfonyl)phenyl 593 C1 2-pyrimidyl 1-pyrrolidinocarbonyl 594 C1 2-pyrimidyl 2-(methylsulfonyl)phenyl 595 C1 2-pyrimidyl 4-morpholino 596 C1 2-pyrimidyl 2-(1'-CF3-tetrazol-2-yl)phenyl 597 C1 2-pyrimidyl 4-morpholinocarbonyl 598 C1 2-pyrimidyl 2-methyl-1-imidazolyl 599 C1 2-pyrimidyl 5-methyl-1-imidazolyl 600 C1 2-pvrimidvl 2-methylsulfonyl-1-imidazolyl Substitute Sheet (Rule 26) 601 C1 5-pyrimidyl 2-(aminosulfonyl)phenyl 602 C1 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 603 C1 5-pyrimidyl 1-pyrrolidinocarbonyl 604 C1 5-pyrimidyl 2-(methylsulfonyl)phenyl 605 C1 5-pyrimidyl 4-morpholino 606 C1 5-pyrimidyl 2-(1'-CF3-tetrazol-2-yl)phenyl 607 C1 5-pyrimidyl 4-morpholinocarbonyl 608 C1 5-pyrimidyl 2-methyl-1-imidazolyl 609 C1 5-pyrimidyl 5-methyl-1-imidazolyl 610 C1 5-pyrimidyl 2-methyisulfonyl-1 -imidazolyl 611 C1 2-C1-phenyl 2-(aminosulfonyl)phenyl 612 C1 2-C1-phenyl 2-(methylaminosulfonyl)phenyl 613 C1 2-C1-phenyl 1-pyrrolidinocarbonyl 614 C1 2-C1-phenyl 2-(methylsulfonyl)phenyl 615 C1 2-C1-phenyl 4-morpholino 616 C1 2-C1-phenyl 2-(1'-CF3-tet~razol-2-yl)phenyl 617 C1 2-C1-phenyl 4-morpholinocarbonyl 618 C1 2-C1-phenyl 2-methyl-1-imidazolyl 619 C1 2-C1-phenyl 5-methyl-1-imidazolyl 620 C1 2-C1-phenyl 2-methylsulfonyl-1-imidazolyl 621 C1 2-F-phenyl 2-(aminosulfonyl)phenyl 622 C1 2-F-phenyl 2-(methylaminosulfonyl)phenyl 623 C1 2-F-phenyl 1-pyrrolidinocarbonyl 624 CZ 2-F-phenyl 2-(methylsulfonyl)phenyl 625 C1 2-F-phenyl 4-morpholino 626 C1 2-F-phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 627 C1 2-F-phenyl 4-morpholinocarbonyl 628 C1 2-F-phenyl 2-methyl-1-imidazolyl 629 C1 2-F-phenyl 5-methyl-1-imidazolyl 630 C1 2-F- henyl 2-methylsulfonyl-1-imidazolyl 631 C1 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 632 C1 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 633 C1 2,6-diF-phenyl 1-pyrrolidinocarbonyl 634 C1 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 635 C1 2,6-diF-phenyl 4-morpholino 636 C1 2.6-diF-phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 637 C1 2,6-diF-phenyl 4-morpholinocarbonyl Substitute Sheet (Rule 26) WO 99/50255 PC'f/US99/06310 638 C1 2,6-diF-phenyl 2-methyl-1-imidazolyl 639 C1 2,6-diF-phenyl 5-methyl-1-imidazolyl 640 C1 2,6-diF-phenyl 2-methylsulfonvl-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-morpholino 646 F phenyl 2-(1'-CF3-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-methvlsulfonyl-1-imidazolvl 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-morpholino 656 F 2-pyridyl 2-(1'-CF3-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-morpholino 666 F 3-pyridyl 2-(1'-CF3-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-(rnethylsulfonyl)phenyl Substitute Sheet (Rule 26) 675 F 2-pyrimidyl 4-morpholino 676 F 2-pyrimidyl 2-(1'-CF3-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-(methylsuifonyl)phenyl 685 F 5-pyrimidyl 4-morpholino 686 F 5-pyrimidyl 2-(1'-CF3-tetrazol-2-yl)phenyl 687 F 5-pyrimidyl 4-morpholinocarbon~rl 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-C1-phenyl 2-(aminosulfonyl)phenyl 692 F 2-C1-phenyl 2-(methylaminosulfonyl)phenyl 693 F 2-C1-phenyl 1-pyrrolidinocarbonyl 694 F 2-C1-phenyl 2-(methylsulfonyl)phenyl 695 F 2-C1-phenyl 4-morpholino 696 F 2-C1-phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 697 F 2-Cl-phenyl 4-morpholinocarbonyl 698 F 2-C1-phenyl 2-methyl-i-imidazolyl 699 F 2-C1-phenyl 5-methyl-1-imidazolyl 700 F 2-C1-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 I-pyrrolidinocarbonyl 704 F 2-F-phenyl 2-(methylsulfonyl)phenyl 705 F 2-F-phenyl 4-morpholino 706 F 2-F-phenyl 2-(1'-CF3-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 ' Substitute Sheet (Rule 26) 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-morpholino 716 F 2,6-diF-phenyl 2-(1'-CF3-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 COzCH3 phenyl 2-(aminosulfonyl)phenyl 722 C02CH3 phenyl 2-(methylaminosulfonyl)phenyl 723 C02CH3 phenyl 1-pyrrolidinocarbonyl 724 C02CH3 phenyl 2-(methylsulfonyl)phenyl 725 COZCH3 phenyl 4-morpholino 726 C02CH3 phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 727 COZCH3 phenyl 4-morpholinocarbonyl 728 C02CH3 phenyl 2-methyl-1-imidazolyl 729 C02CH3 phenyl 5-methyl-1-imidazolyl 730 C02CH3 phenyl 2-methylsulfonyl-1-imidazolyl 731 C02CH3 2-pyridyl 2-(aminosulfonyl)phenyl 732 C02CH3 2-pyridyl 2-(methylaminosulfonyl)phenyl 733 C02CH3 2-pyridyl 1-pyrrolidinocarbonyl 734 COZCH3 2-pyridyl 2-(methylsulfonyl)phenyl 735 CO~CH3 2-pyridyl 4-morpholino 736 C02CH3 2-pyridyl 2-(1'-CF3-tetrazol-2-yl)phenyl 737 C02CH3 2-pyridyl 4-mozpholinocarbonyl 738 C02CH3 2-pyridyl 2-methyl-1-imidazolyl 739 C02CH3 2-pyridyl 5-methyl-1-imidazolyl 740 C02CH3 2-pyridyl 2-methylsulfonyl-1-imidazolyl 741 C02CH3 3-pyridyl 2-(aminosulfonyl)phenyl 742 C02CH3 3-pyridyl 2-(methylaminosulfonyl)phenyl 743 C02CH3 3-pyridyl 1-pyrrolidinocarbonyl 744 C02CH3 3-pyridyl 2-(methylsulfonyl)phenyl 745 CO?CH3 3-pyridyl 4-morpholino 746 C02CH3 3-pyridyl 2-(1'-CF3-tetrazol-2-yl)phenyl 747 COzCH3 3-pyridyl 4-morpholinocarbonyl 748 C02CH3 3-pyridyl 2-methyl-1-imidazolyl Substitute Sheet (Rule 26) WO 99/50255 PCTlUS99106310 749 C02CH3 3-pyridyl 5-methyl-1-imidazolyl 750 C02CH3 3-pyridyl 2-methylsulfonyl-1-imidazolyl 751 C02CH3 2-pyrimidyl 2-(aminosulfonyl)phenyl 752 C02CH3 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 753 C02CH3 2-pyrimidyl 1-pyrrolidinocarbonyl 754 C02CH3 2-pyrimidyl 2-(methylsulfonyl)phenyl 755 C02CH3 2-pyrimidyl 4-morpholino 756 C02CH3 2-pyrimidyl 2-(1'-CF3-tetrazol-2-yl)phenyl 757 C02CH3 2-pyrimidyl 4-morpholinocarbonyl 758 C02CH3 2-pyrimidyl 2-methyl-1-imidazolyl 759 COZCH3 2-pyrimidyl 5-methyl-1-imidazolyl 760 C02CH3 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 761 COZCH3 5-pyrimidyl 2-(aminosulfonyl)phenyl 762 C02CH3 5-gyrimidyl 2-(methylaminosulfonyl)phenyl 763 C02CH3 5-pyrimidyl 1-pyrrolidinocarbonyl 764 C02CH3 5-pyrimidyl 2-(methylsulfonyl)phenyl 765 C02CH3 5-pyrimidyl 4-morpholino 766 C02CH~ 5-pyrimidyl 2-(1'-CF3-tetrazol-2-yl)phenyl 767 C02CH3 5-pyrimidyl 4-morpholinocarbonyl 768 C02CH~ 5-pyrimidyl 2-methyl-1-imidazolyl 769 COZCH3 5-pyrimidyl 5-methyl-1-imidazolyl 770 C02CH3 5-pyrimidvl 2-methylsulfonvl-1-imidazolyl 771 COZCH3 2-C1-phenyl 2-(aminosulfonyl)phenyl 772 C02CH3 2-C1-phenyl 2-(methylaminosulfonyl)phenyl 773 C02CH3 2-C1-phenyl 1-pyrrolidinocarbonyl 774 C02CH3 2-C1-phenyl 2-(methylsulfonyl)phenyl 775 C02CH3 2-Cl-phenyl 4-morpholino 776 C02CH3 2-C1-phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 777 C02CH3 2-C1-phenyl 4-morpholinocarbonyl 778 C02CH3 2-C1-phenyl 2-methyl-1-imidazolyl 779 C02CH3 2-C1-phenyl 5-methyl-1-imidazolyl 780 C02CH3 2-C1-phenyl 2-methvlsulfonvl-1-imidazolvl 781 C02CH3 2-F-phenyl 2-(aminosulfonyl)phenyl 782 C02CH3 2-F-phenyl 2-(methylaminosulfonyl)phenyl 783 C02CH3 2-F-phenyl 1-pyrrolidinocarbonyl 784 C02CH3 2-F-phenyl 2-(methylsulfonyl)phenyl 785 C02CH3 2-F-phenyl 4-morpholino Substitute Sheet (Rule 26) 786 C02CH3 2-F-phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 787 C02CH3 2-F-phenyl 4-morpholinocarbonyl 788 C02CH3 2-F-phenyl 2-methyl-1-imidazolyl 789 C02CH3 2-F-phenyl 5-methyl-1-imidazolyl 790 C02CH3 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 791 C02CH3 2,6-diF-phenyl2-(aminosulfonyl)phenyl 792 C02CH3 2,6-diF-phenyl2-(methylaminosulfonyl)phenyl 793 C02CH3 2,6-diF-phenyl1-pyrrolidinocarbonyl 794 C02CH3 2,6-diF-phenyl2-(methylsulfonyl)phenyl 795 C02CH3 2,6-diF-phenyl4-morpholino 796 C02CH3 2,6-diF-phenyl2-(1'-CF3-tetrazol-2-yl)phenyl 797 COZCH3 2,6-diF-phenyl4-morpholinocarbonyl 798 COZCH3 2,6-diF-phenyl2-methyl-1-imidazolyl 799 C02CH3 2,6-diF-phenyl5-methyl-1-imidazolyl 800 C02CH3 2,6-diF-z~henyl2-methylsulfonyl-1-imidazolyl 801 CH20CH3 phenyl 2-(aminosulfonyl)phenyl 802 CH20CH3 phenyl 2-(methylaminosulfonyl)phenyl 803 CH20CH3 phenyl I-pyrrolidinocarbonyl 804 CHZOCH3 phenyl 2-(methylsulfonyl)phenyl 805 CH20CH3 phenyl 4-morpholino 806 CH20CH3 phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 807 CH20CH3 phenyl 4-morpholinocarbonyl 808 CH20CH3 phenyl 2-methyl-1-imidazolyl 809 CH20CH3 phenyl 5-methyl-1-imidazoiyl 810 CH20CH3 phenyl 2-methylsulfonyl-1-imidazolyl 811 CH20CH3 2-pyridyl 2-(aminosulfonyl)phenyl 8I2 CH20CH3 2-pyridyl 2-(methylaminosulfonyl)phenyl 813 CHZOCH3 2-pyridyl 1-pyrrolidinocarbonyl 814 CH20CH3 2-pyridyl 2-(methylsulfonyl)phenyl 815 CH20CH3 2-pyridyl 4-morpholino 816 CH20CH3 2-pyridyl 2-(1'-CF3-tetrazol-2-yl)phenyl 817 CH20CH3 2-pyridyl 4-morpholinocarbonyl 818 CH20CH3 2-pyridyl 2-methyl-1-imidazolyl 819 CH20CH3 2-pyridyl 5-methyl-1-imidazolyl 820 CH20CH3 2-pvridvl 2-methylsulfonyl-1-imidazolyl 821 CHZOCH3 3-pyridyl 2-(aminosulfonyl)phenyl 822 CH20CH3 3-pyridyl 2-(methylaminosulfonyi)phenyl ' Substitute Sheet (Rule 26) WO 99/50255 PC'T/US99/06310 823 CHZOCH3 3-pyridyl 1-pyrrolidinocarbonyl 824 CH20CH3 3-pyridyl 2-(methylsulfonyl)phenyl 825 CH20CH3 3-pyridyl 4-morpholino 826 CH20CH3 3-pyridyl 2-(1'-CF3-tetrazol-2-yl)phenyl 827 CHZOCH3 3-pyridyl 4-morpholinocarbonyl 828 CHZOCH3 3-pyridyl 2-methyl-1-imidazolyl 829 CH20CH3 3-pyridyl 5-methyl-1-imidazolyl 830 CH~OCH3 3- yridyl 2-methvlsulfonyl-1-imidazolyl 831 CH20CH3 2-pyrimidyl 2-(aminosulfonyl)phenyl 832 CH20CH3 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 833 CH20CH3 2-pyrimidyl 1-pyrrolidinocarbonyl 834 CH20CH3 2-pyrimidyl 2-(methylsulfonyl)phenyl 835 CH~OCH3 2-pyrimidyl 4-morpholino 836 CH20CH3 2-pyrimidyl 2-(1'-CF3-tetrazol-2-yl)phenyl 837 CH20CH3 2-pyrimidyl 4-morpholinocarbonyl 838 CHZOCH3 2-pyrimidyl 2-methyl-1-imidazolyl 839 CHZOCH3 2-pyrimidyl 5-methyl-1-imidazolyl 840 CH20CH3 2-pyrimidyl 2-methylsulfonyl-1-imidazolyi 841 CH20CH3 5-pyrimidyl 2-(aminosulfonyl)phenyl 842 CH20CH3 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 843 CHZOCH3 5-pyrimidyl 1-pyrrolidinocarbonyl 844 CH20CH3 5-pyrimidyl 2-(methylsulfonyl)phenyl 845 CH20CH3 5-pyrimidyl 4-morphoiino 846 CH~OCH3 S-pyrimidyl 2-(1'-CF3-tetrazol-2-yl)phenyl 847 CH20CH3 5-pyrimidyl 4-morpholinocarbonyl 848 CH20CH3 5-pyrimidyl 2-methyl-1-imidazolyl 849 CHZOCH3 5-pyrimidyl 5-methyl-1-imidazolyl 850 CH20CH3 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 851 CH20CH3 2-C1-phenyl 2-(aminosulfonyl)phenyl 852 CH20CH3 2-C1-phenyl 2-(methylaminosulfonyl)phenyl 853 CHZOCH3 2-C1-phenyl 1-pyrrolidinocarbonyl 854 CH20CH3 2-C1-phenyl 2-(methylsulfonyl)phenyl 855 CH20CH3 2-C1-phenyl 4-morpholino 856 CH20CH3 2-C1-phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 857 CH20CH3 2-C1-phenyl 4-morpholinocarbonyl 858 CH20CH3 2-C1-phenyl 2-methyl-1-imidazolyl 859 CH20CH3 2-C1-phenyl 5-methyl-1-imidazolyl Substitute Sheet (Rule 26) 860 CH20CH32-C1-phenyl 2-methylsulfonvl-1-imidazolyl 861 CH20CH32-F-phenyl 2-(aminosulfonyl)phenyl 862 CH20CH32-F-phenyl 2-(methylaminosulfonyl)phenyl 863 CHZOCH32-F-phenyl 1-pyrrolidinocarbonyl 864 CH20CH32-F-phenyl 2-(methylsulfonyl)phenyl 865 CH20CH32-F-phenyl 4-morpholino 866 CH20CH32-F-phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 867 CH20CH32-F-phenyl 4-morpholinocarbonyl 868 CH20CH32-F-phenyl 2-methyl-1-imidazolyl 869 CH20CH32-F-phenyl 5-methyl-1-imidazolyl 870 CH20CH32-F-phenyl 2-methylsulfonyl-1-imidazolyl 871 CH20CH32,6-diF-phenyl2-(aminosulfonyl)phenyl 872 CH20CH32,6-diF-phenyl2-(methylaminosulfonyl)phenyl 873 CH20CH32,6-diF-phenyl1-pyrrolidinocarbonyl 874 CHZOCH32,6-diF-phenyl2-(methylsulfonyl)phenyl 875 CH20CH32,6-diF-phenyl4-morpholino 876 CH20CH32,6-diF-phenyl2-(1'-CF3-tetrazol-2-yl)phenyl 877 CH20CH32,6-diF-phenyl4-morpholinocarbonyl 878 CH20CH;2,6-diF-phenyl2-methyl-1-imidazolyl 879 CH20CH32,6-diF-phenyl5-methyl-1-imidazolyl 880 CHZOCH32,6-diF-phenyl2-methylsulfonyl-1-imidazolyl 881 CONH2 phenyl 2-(aminosulfonyl)phenyl 882 CONH2 phenyl 2-(methylaminosulfonyl)phenyl 883 CONH2 phenyl 1-pyrrolidinocarbonyl 884 CONH2 phenyl 2-(methylsulfonyl)phenyl 885 CONH2 phenyl 4-morpholino 886 CONH2 phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 887 CONH2 phenyl 4-morpholinocarbonyl 888 CONH2 phenyl 2-methyl-1-imidazolyl 889 CONHZ phenyl 5-methyl-1-imidazolyl 890 CONH2 phenyl 2-methylsulfonyl-1-imidazolyl 891 CONH2 2-pyridyl 2-(aminosulfonyl)phenyl 892 CONH2 2-pyridyl 2-(methylaminosulfonyl)phenyl 893 CONH2 2-pyridyl 1-pyrrolidinocarbonyl 894 CONH2 2-pyridyl 2-(methylsulfonyl)phenyl 895 CONH2 2-pyridyl 4-morpholino 896 CONH2 2-pyridyl 2-(1'-CF3-tetrazol-2-yl)phenyl Substitute Sheet (Rule 26) 897 CONH2 2-pyridyl 4-morpholinocarbonyl 898 CONH2 2-pyridyl 2-methyl-1-imidazolyl 899 CONH2 2-pyridyl 5 -methyl-1-imidazolyl 900 CONH2 2-pyridyl 2-methylsulfonyl-1-imidazolyl 901 CONH2 3-pyridyl 2-(aminosulfonyl)phenyl 902 CONHZ 3-pyridyl 2-(methylaminosulfonyl)phenyl 903 CONH2 3-pyridyl 1-pyrrolidinocarbonyl 904 CONHZ 3-pyridyl 2-(methylsulfonyl)phenyl 905 CONH2 3-pyridyl 4-morpholino 906 CONH2 3-pyridyl 2-(1'-CF3-tetrazol-2-yl)phenyl 907 CONH2 3-pyridyl 4-morpholinocarbonyl 908 CONH2 3-pyridyl 2-methyl-1-imidazolyl 909 CONH2 3-pyridyl 5-methyl-1-imidazolyl 910 CONH~ 3-pyridvl 2-methylsulfonyl-1-imidazolyl 911 CONH2 2-pyrimidyl 2-(aminosulfonyl)phenyl 912 CONH2 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 913 CONH2 2-pyrimidyl 1-pyrrolidinocarbonyl 914 CONHZ 2-pyrimidyl 2-(methylsulfonyl)phenyl 915 CONH2 2-pyrimidyl 4-morpholino 916 CONH2 2-pyrimidyl 2-(1'-CF3-tetrazol-2-yl)phenyl 917 CONH2 2-pyrimidyl 4-morpholinocarbonyl 918 CONH2 2-pyrimidyl 2-methyl-1-imidazolyl 919 CONH2 2-pyrimidyl 5-methyl-1-imidazolyl 920 CONH~ 2-pyrimidvl 2-methylsulfonyl-1-imidazolvl 921 CONHZ 5-pyrimidyl 2-(aminosulfonyl)phenyl 922 CONHZ 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 923 CONH2 5-pyrimidyl 1-pyrrolidinocarbonyl 924 CONHZ 5-pyrimidyl 2-(methylsulfonyl)phenyl 925 CONH2 5-pyrimidyl 4-morpholino 926 CONH2 5-pyrimidyl 2-(1'-CF3-tetrazol-2-yl)phenyl 927 CONH2 5-pyrimidyl 4-morpholinocarbonyl 928 CONH2 5-pyrimidyl 2-methyl-1-imidazolyl 929 CONH2 5-pyrimidyl 5-methyl-1-imidazolyl 930 CONHZ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 931 CONH2 2-C1-phenyl 2-(aminosulfonyl)phenyl 932 CONH2 2-C1-phenyl 2-(methylaminosulfonyl)phenyl 933 CONH2 2-C1-phenyl 1-pyrrolidinocarbonyl Substitute Sheet (Rule 26) 934 CONH2 2-C1-phenyl 2-(methylsulfonyl)phenyl 935 CONH2 2-C1-phenyl 4-morpholino 936 CONH2 2-C1-phenyl 2-(I'-CF3-tetrazol-2-yl)phenyl 937 CONH2 2-C1-phenyl 4-morpholinocarbonyl 938 CONH2 2-C1-phenyl 2-methyl-1-imidazolyl 939 CONH2 2-C1-phenyl 5-methyl-1-imidazolyl 940 CONH~ 2-C1-phenyl 2-methylsulfonyl-1-imidazolyl 941 CONH2 2-F-phenyl 2-(aminosulfonyl)phenyl 942 CONH2 2-F-phenyl 2-(methylaminosulfonyl)phenyl 943 CONH2 2-F-phenyl 1-pyrrolidinocarbonyl 944 CONH2 2-F-phenyl 2-(methylsulfonyl)phenyl 945 CONH2 2-F-phenyl 4-morpholino 946 CONHZ 2-F-phenyl 2-(1'-CF3-tetrazol-2-yl)phenyi 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-methylsulfonvl-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)phenyl 955 CONH2 2,6-diF-phenyl 4-morpholino 956 CONH2 2,6-diF-phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 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 ' Substitute Sheet (Rule .26) Table 2 N
Ni H
.N N~A~B
/ ~ O

CI
a v B
C
a c d ~C(=NH)NH2 ~C(=NH)NH

%I F
f g N~N~NwA~B B
~)NH2 F \ C(=NH)NH2 JH2 h i 1 Substitute Sheet (Rule 26) WO 99/50255 PCTlUS99/06310 N H N H
I~.N N~A~B t~.N N\A~B
O O
C(O)NH2 C(O)NH2 Cl F
k I
,B

m n N H N H N H
N,N N~A~B N.N N~A~B N,N N~A.B
O O ~ O
W ~ ~ W
NH2 C(=NH)NHp C(O)NH2 r P

aub~titute Sheet (Rule 26) N N
f~I,N NwA ~A~B f~.N iHV\A~B
MeHN / O MeHN , O

a 1~ N N\A~B N N N\A~B NN N\ ~B
N ~ A
MeHN , O MeHN / MeHN
F \ H3C0 v w x N N N H
I~I. ~N~A~B N.N NwA~B N.N NwA~B
N O i ~I
NHMe ~ i NHMe i ~ NHMe F ~ H3C0 as N~N~N~A~B N~N~N~A~B
H2NH2C~~ IO' H2NH2C~ ~ O
bb CI CC F dd H 'N H ~N H
~N NwA~B N~N NwA~B N.N N~A~B
H2NH2 / O HpNHp / H2NH2 CI ~ F ~ H3C0 ee ff 99 N H ~N H
1~~ ~N~A~B N.N N~A~B
' IIN
O U
HpNH2 ~ I H2NH2 C! ~ F
hh ii ll Substitute Sbeet (Rule 26) ~ H N
,N~N~A~B N,N N~A~B N, MeHNHzC / [O[ M9HNH~C / O MeHNH2C / O

kk II mm N H ~N H ~N H
N,N~N~A~B ~N N~A~B N.N ~A~B
MeHNH2C , ]O~ MeHNH2C , O MeHNH2C , O
C! ~ F ~ H~CO
nn oo PP
H N ~ A B
N N~~~A~B N~ ~~A~B N
~~O( O V
i I CH2NHMe ~ I H2NHMe ~ I HpNHMe CI ~ F ~ H3C0 qq rr ss Bx # A H

1 phenyl 2-(aminosulfonyl)phenyl 2 phenyl 2-(methylaminosulfonyl)phenyl 3 phenyl 1-pyrrolidinocarbonyl 4 phenyl 2-(methylsulfonyl)phenyl 5 phenyl 4-morpholino 6 phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 7 phenyl 4-morpholinocarbonyl 8 phenyl 2-methyl-1-imidazolyl 9 phenyl 5-methyl-1-imidazolyl 10 henyl 2-methylsulfonyl-1-imidazolyl 11 2-pyridyl 2-(aminosulfonyl)phenyl 12 2-pyridyl 2-(methylaminosulfonyl)phenyl 13 2-pyridyl 1-pyrrolidinocarbonyl 14 2-pyridyl 2-(methylsulfonyl)phenyl 15 2-pyridyl 4-morpholino 16 2-pyridyl 2-(1'-CF3-tetrazol-2-yl)phenyl 17 2-pyridyl 4-morpholinocarbonyl Substitute sheet (Rule 26) 18 2-pyridyl 2-methyl-1-imidazolyl 19 2-pyridyl 5-methyl-1-imidazolyl 20 2-pyridyl 2-methylsulfonyl-1-imidazolyl 21 3-pyridyl 2-(aminosulfonyl)phenyl 22 3-pyridyl 2-(methylaminosulfonyl)phenyl 23 3-pyridyl 1-pyrrolidinocarbonyl 24 3-pyridyl 2-(methylsulfonyl)phenyl 25 3-pyridyl 4-morpholino 26 3-pyridyl 2-(1'-CF3-tetrazol-2-yl)phenyl 27 3-pyridyl 4-morpholinocarbonyl 28 3-pyridyl 2-methyl-1-imidazolyl 29 3-pyridyl 5-methyl-1-imidazolyl 30 3-pyridyl 2-methvlsulfonvl-1-imidazolyl 31 2-pyrimidyl 2-(aminosulfonyl)phenyl 32 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 33 2-pyrimidyl 1-pyrrolidinbcarbonyl 34 2-pyrimidyl 2-(methylsulfonyl)phenyl 35 2-pyrimidyl 4-morpholino 36 2-pyrimidyl 2-(1'-CF3-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-methylsulfonvl-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-morpholino 46 5-pyrimidyl 2-(1'-CF3-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-C1-phenyl 2-(aminosulfonyl)phenyl 52 2-C1-phenyl 2-(methylaminosulfonyl)phenyl 53 2-C1-phenyl 1-pyrrolidinocarbonyl 54 2-C1-phenyl 2-(methylsulfonyl)phenyl Substitute Sheet (Rule 26) 55 2-Cl-phenyl 4-morpholino 56 2-C1-phenyl 2-(1'-CF3-tetrazol-2-yl)phenyl 57 2-C1-phenyl 4-morpholinocarbonyl 58 2-C1-phenyl 2-methyl-1-imidazolyl 59 2-C1-phenyl 5-methyl-1-imidazolyl 60 2-C1-phenyl 2-methylsulfonyl-1-imidazolvl 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-morpholino 66 2-F-phenyl 2-(1'-CF3-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-morpholino 76 2,6-diF-phenyl 2-(1'-CF3-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 ~Isfi,ilitv The compounds of this invention are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals. The term "thromboembolic disorders" as used herein includes arterial or venous cardiovascular or cerebrovascular thromboembolic disorders, including, for example, unstable angina, first or recurrent myocardial infarction, ischemic sudden death, transient IO ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, Substitute Sheet (Rule 26 j coronary and cerebral arterial thrombosis, cerebral embolism, kidney embolisms, and pulmonary embolisms. The anticoagulant effect of compounds of the present invention is believed to be due to inhibition of factor Xa or thrombin.
S The effectiveness of compounds of the present invention as inhibitors of factor Xa was determined using purified human factor Xa and synthetic substrate. The rate of factor Xa hydrolysis of chromogenic substrate 52222 (Kabi Pharmacia, Franklin, OH) was measured both in the absence and presence of compounds of the present invention. Hydrolysis of the substrate resulted in the release of pNA, which was monitored spectrophotometrically by measuring the increase in absorbance at 405 nM. A decrease in the rate of absorbance change at 405 nm in the presence of inhibitor is indicative of enzyme inhibition. The results of this assay are expressed as inhibitory constant, Ki.
Factor Xa detexminations were made in 0.10 M sodium phosphate buffer, pH 7.5, containing 0.20 M NaCl, and 0.5 ~
PEG 8000. The Micraelis constant, Km, for substrate hydrolysis was determined at 25°C using the method of Lineweaver and Burk. Values of Ki were determined by allowing 0.2-0.5 nM human factor Xa (Enzyme Research Laboratories, South Bend, IN) to react with the substrate (0.20 mM-1 mM) in the presence of inhibitor. Reactions were allowed to go for 30 minutes and the velocities (rate of absorbance change vs time) were measured in the time frame of 25-30 minutes. The following relationship was used to calculate Ki values:
(vo-vs)/vs = I/(Ki (1 + S/Km)) where:
vo is the velocity of the control in the absence of inhibitor;
vs is the velocity in the presence of inhibitor;
I is the concentration of inhibitor;
Ki is the dissociation constant of the enzyme: inhibitor complex;
S is the concentration of substrate;
Km is the Michaelis constant.

Substitute Sheet (Rule ~ :; ' Using the methodology described above, a compound of the present invention were found to exhibit a Ki of <10 uM, thereby confirming the utility of the compounds of the present invention as effective Xa inhibitors.
The antithrombotic effect of compounds of the present invention can be demonstrated in a rabbit arterio-venous (AV) shunt thrombosis model. In this model, rabbits weighing 2-3 kg anesthetized with a mixture of xylazine (10 mg/kg i.m.) and ketamine (50 mg/kg i.m.) are used. A saline-filled AV shunt device is connected between the femoral arterial and the femoral venous cannulae. The AV shunt device consists of a piece of 6-cm tygon tubing which contains a piece of silk thread. Blood will flow from the femoral artery via the AV-shunt into the femoral vein. The exposure of flowing blood to a silk thread will induce the formation of a significant thrombus. After forty minutes, the shunt is disconnected and the silk thread covered with thrombus is weighed. Test agents or vehicle will be given (i.v., i.p., s.c., or orally) prior to the opening of the AV shunt. The percentage inhibition of thrombus formation is determined for each treatment group.
The ID50 values (dose which produces 50~ inhibition of thrombus formation) are estimated by linear regression.
The compounds of formula (I) may also be useful as inhibitors of serine proteases, notably human thrombin, plasma kallikrein and plasmin. Because of their inhibitory action, these compounds are indicated for use in the prevention or treatment of physiological reactions, blood coagulation and inflammation, catalyzed by the aforesaid class of enzymes.
Specifically, the compounds have utility as drugs for the treatment of diseases arising from elevated thrombin activity such as myocardial infarction, and as reagents used as anticoagulants in the processing of blood to plasma for diagnostic and other commercial purposes.
Some compounds of the present invention were shown to be direct acting inhibitors of the serine protease thrombin by their ability to inhibit the cleavage of small molecule substrates by thrombin in a purified system. In vitro inhibition constants were determined by the method described Substitute Sheet (Rule 26) WO 99150255 PCTlUS99/06310 by Kettner et al. in J. Biol. Chem. 265, 18289-18297 (1990), herein incorporated by reference. In these assays, thrombin-mediated hydrolysis of the chromogenic substrate 52238 (Helena Laboratories, Beaumont, TX) was monitored spectrophotometrically. Addition of an inhibitor to the assay mixture results in decreased absorbance and is indicative of thrombin inhibition. Human thrombin (Enzyme Research Laboratories, Inc., South Bend, IN) at a concentration of 0.2 nM in 0.10 M sodium phosphate buffer, pH 7.5, 0.20 M NaCl, and 0.5~ PEG 6000, was incubated with various substrate concentrations ranging from 0.20 to 0.02 mM. After 25 to 30 minutes of incubation, thrombin activity was assayed by monitoring the rate of increase in absorbance at 405 n_,n which arises owing to substrate hydrolysis. Inhibition constants were derived from reciprocal plots of the reaction velocity as a function of substrate concentration using the standard method of Lineweaver and Burk. Using the methodology described above, some compounds of this invention were evaluated and found to exhibit a Ki of less than 10 um, thereby confirnning the utility of the compounds of the present invention as effective thrombin inhibitors.
The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents. These include other anti-coagulant or coagulation inhibitory agents, anti-platelet or platelet inhibitory agents, thrombin inhibitors, or thrombolytic or fibrinolytic agents.
The compounds are administered to a mammal in a therapeutically effective amount. By "therapeutically effective amount" it is meant an amount of a compound of Formula I that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to prevent or ameliorate the thromboembolic disease condition or the progression of the disease.
By "administered in combination" or "combination therapy"
it is meant that the compound of Formula I and one or more additional therapeutic agents are administered concurrently to the mammal being treated. 4iThen administered in combination Substitute Shc:e: ; rule 26) each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect. Other anticoagulant agents (or coagulation inhibitory ' agents) that may be used in combination with the compounds of this invention include warfarin and heparin, as well as other factor Xa inhibitors such as those described in the publications identified above under Background of the Invention.
The term anti-platelet agents (or platelet inhibitory agents), as used herein, denotes agents that inhibit platelet function such as by inhibiting the aggregation, adhesion or granular secretion of platelets. Such agents include, but are not limited to, the various known non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and piroxicam, including pharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA), and piroxicam are preferred. Other suitable anti-platelet agents include - ticlopidine, including pharmaceutically acceptable salts or prod rugs thereof. Ticlopidine is also a preferred compound since it is known to be gentle on the gastro-intestinal tract in use. Still other suitable platelet inhibitory agents include IIb/IIIa antagonists, thromboxane-A2-receptor antagonists and thromboxane-A2-synthetase inhibitors, as well as pharmaceutically acceptable salts or prodrugs thereof.
The term thrombin inhibitors (or anti-thrombin agents), as used herein, denotes inhibitors of the serine protease thrombin. By inhibiting thrombin, various thrombin-mediated processes, such as thrombin-mediated platelet activation (that is, for example, the aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-1 and/or serotonin) and/or fibrin formation are disrupted. A number of thrombin inhibitors are known to one of skill in the art and these inhibitors are contemplated to be used in combination with the present compounds. Such inhibitors include, but are Substitute Sheet (Rule 26) WO 99/50255 PCTlUS99/06310 not limited to, boroarginine derivatives, boropeptides, heparins, hirudin and argatroban, including pharmaceutically acceptable salts and prodrugs thereof. Boroarginine derivatives and boropeptides include N-acetyl and peptide derivatives of boronic acid, such as C-terminal a-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof. The term hirudin, as used herein, includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin. Boropeptide thrombin inhibitors include compounds described in Kettner et al., U.S. Patent No.
5,187,157 and European Patent Application Publication Number 293 881 A2, the disclosures of which are hereby incorporated herein by reference. Other suitable boroarginine derivatives and boropeptide thrombin inhibitors include those disclosed in PCT Application Publication Number 92/07869 and European Patent Application Publication Number 471,651 A2, the disclosures of which are hereby incorporated herein by reference.
The term thrombolytics (or fibrinolytic) agents (or thrombolytics or fibrinolytics), as used herein, denotes agents that lyse blood clots (thrombi). Such agents include tissue plasminogen activator, anistreplase, urokinase or streptokinase, including pharmaceutically acceptable salts or prodrugs thereof. The term anistreplase, as used herein, refers to anisoylated plasminogen streptokinase activator complex, as describes, for example, in European Patent Application No. 028,489, the disclosure of which is hereby incorporated herein by reference herein. The term urokinase, as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase.
Administration of the compounds of Formula I of the invention in combination with such additional therapeutic agent, may afford an efficacy advantage over the compounds and agents alone, and may do so while permitting the use of lower doses of each. A lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety.

SubSt.~..ie Sheet (Rule 26) The compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the inhibition of factor Xa. Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving factor Xa. For example, a compound of the present invention could be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This would ensure the experimenter that the assay was being performed properly and provide a basis for comparison, especially if the test compound was a derivative of the reference compound. V~lhen developing new assays or protocols, compounds according to the present invention could be used to test their effectiveness.
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 could be determined by addition of chromogenic substrate 52222 to a series of solutions containing test sample and optionally one of the compounds of the present invention. If production of pNA is observed in the solutions containing test sample, but not in the presence of a compound of the present invention, then one would conclude factor Xa was present.
Dosacre and Formulation The compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharniaceutical arts. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

Substitute Sheet (Rule 26) The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. A physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the thromboembolic disorder.
By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 1.0 to 20 mg/kg/day.
Intravenously, the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion.
Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
Compounds of this invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdennal routes, using transdermal skin patches. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined Substitute Sheet (Rule 26) with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, Substitute Sheet (Rule 26) polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95~ by weight based on the total weight of the composition.
Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like.
Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfate, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
Suitable pharmaceutical carriers are described in Remincrton's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.

Substitute Sheet ;;~.-cule 26) WO 99/50255 PC'T/US99106310 Representative useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:
C~sules A large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
Soft Gelatin CaDSUles A mixture of active ingredient in a digestable oil such as soybean oil, cottonseed oil or olive oil may be prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules should be washed and dried.
Tablets Tablets may be prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.
Injectable A parenteral composition suitable for administration by injection may be prepared by stirring 1.5$ by weight of active ingredient in 10~ by volume propylene glycol and water.
The solution should be made isotonic with sodium chloride and sterilized.
An aqueous suspension can be prepared for oral administration so that each 5 mL contain 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mL of vanillin.
Where the compounds of this invention are combined with other anticoagulant agents, for example, a daily dosage may be Substitute Sheet (Rule 26) WO 99/50255 PCTlUS99/06310 about 0.1 to 100 milligrams of the compound of Formula I and about 1 to 7.5 milligrams of the second anticoagulant, per kilogram of patient body weight. For a tablet dosage form, the compounds of this invention generally may be present in an amount of about 5 to 10 milligrams per dosage unit, and the second anti-coagulant in an amount of about I to 5 milligrams per dosage unit.
Where the compounds of Formula I are administered in combination with an anti-platelet agent, by way of general guidance, typically a daily dosage may be about 0.01 to 25 milligrams of the compound of Formula I and about 50 to 150 milligrams of the anti-platelet agent, preferably about 0.1 to 1 milligrams of the compound of Formula I and about 1 to 3 milligrams of antiplatelet agents, per kilogram of patient body weight.
Where the compounds of Formula I are adminstered in combination with thrombolytic agent, typically a daily dosage may be about 0.1 to 1 milligrams of the compound of Formula I, per kilogram of patient body weight and, in the case of the thrombolytic agents, the usual dosage of the thrombolyic agent when administered alone may be reduced by about 70-80~ when administered with a compound of Formula I.
Where two or more of the foregoing second therapeutic agents are administered with the compound of Fozmula I, generally the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the agent when administered alone, in view of the additive or synergistic effect of the therapeutic agents when administered in combination.
Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingredients. For this reason, when the compound of Formula I and a second therapeutic agent are combined in a single dosage unit they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced). For example, one active ingredient may be enteric coated. By enteric coating Substi:,~:~ce Sheet (Rule 26) one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. One of the active ingredients may also be coated with a material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a lowviscosity grade of hydroxypropyl methylcellulose (FiPMC) or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component.
These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time by the same manner, will be readily apparent to those skilled in the art, once armed with the present disclosure.
Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise that as specifically described herein.

Substitute Sheet (Rule 26)

Claims (17)

WHAT IS CLAIMED IS:
1. A compound of formula I:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;

M1 is N or CR1c;

M2 is NR1a or CR1aR1a, provided that only one of M1 and M2 is a N atom;

D is selected from C(=NR8)NR7R9, NHC(=NR8)NR7R9, NR8CH(=NR7), C(O)NR7R8, and CR8R9NR7R8;

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

alternatively, D-E-G together represent pyridyl substituted with 1 R;

R is selected from H, Cl, F, Br, I, (CH2)t OR3, C1-4 alkyl, OCF3, CF3, C(O)NR7R8, and (CR8R9)t NR7R8;

G is selected from NHCH2, OCH2, and SCH2, provided that when s is 0, then G is absent;

is selected from a C1-4 alkylene, (CH2)r O(CH2)r, (CH2)r NR3(CH2)r, (CH2)r C(O)(CH2)r, (CH2)r C(O)O(CH2)r, (CH2)r OC(O)(CH2)r, (CH2)r C(O)NR3(CH2)r, (CH2)r NR3C(O)(CH2)r, (CH2)r OC(O)O(Cu2)r, (CH2)r OC(O)NR3(CH2)r, (CH2)r NR3C(O)O(CH2)r, (CH2)r NR3C(O)NR3(CH2)r, (CH2)r S(O)p(CH2)r, (CH2)r SO2NR3(CH2)r, (CH2)r NR3SO2(CH2)r, and (CH2)r NR3SO2NR3(CH2)r, provided that Z does not form a N-N, N-O, N-S, NCH2N, NCH2O, or NCH2S bond with group A;
R1a and R1b are, at each occurrence, independently selected from H, -(CH2)r-R1', NCH2R1", OCH2R1", SCH2R1", N(CH2)2(CH2)t R1', O(CH2)2(CH2)t R1', and S(CH2)2(CH2)t R1';
R1c is selected from H, -(CH2)q-R1', C1-3 alkyl, C(O)R2c, (CF2)r CO2R2c, C(O)NR2R2a, C3-6 carbocyclic residue substituted with 0-2 R4, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;
R1' is selected from H, C1-3 alkyl, halo, (CF2)r CF3, OR2, NR2R2a, C(O)R2c, OC(O)R2, (CF2)r CO2R2c, S(O)p R2b, NR2(CH2)r OR2, NR2C(O)R2b, NR2C(O)NHR2b, NR2C(O)2R2a, OC(O)NR2b, C(O)NR2R2a, SO2NR2R2a, NR2SO2R2b, C3-6 carbocyclic residue substituted with 0-2 R4, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;
R1" is selected from H, C(O)R2b, C(O)NR2R2a, S(O)R2b, S(O)2R2b, and SO2NR2R2a;
R2, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2a, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;

R2b, at each occurrence, is selected from CF3, C1-4 alkoxy, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2c, at each occurrence, is selected from CF3, OH, C1-4 alkoxy, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
alternatively, R2 and R2a combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4b which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
R3a, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
A is selected from:
C3-10 carbocyclic residue substituted with 0-2 R4, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S
substituted with 0-2 R4;
B is selected from:
X-Y, NR2R2a, C(=NR2)NR2R2a, NR2C(=NR2)NR2R2a, C3-10 carbocyclic residue substituted with 0-2 R4a, 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 R4a;

X is selected from C1-4 alkylene, -CR2(CR2R2b)(CH2)t-, -C(O)-, -C(=NR)-, -CR2(NR1"R2)-, -CR2(OR2)-, -CR2(SR2)-, -C(O)CR2R2a-, -CR2R2a C(O), -S(O)p-, -S(O)p CR2R2a-, -CR2R2a S(O)p-, -S(O)2NR2-, -NR2S(O)2-, -NR2S(O)2CR2R2a--CR2R2a S(O)2NR2-, -NR2S(O)2NR2-, -C(O)NR2-, -NR2C(O)-, -C(O)NR2CR2R2a-, -NR2C(O)CR2R2a-, -CR2R2a C(O)NR2-, -CR2R2a NR2C(O)-, -NR2C(O)O-, -OC(O)NR2-, -NR2C(O)NR2-, -NR2-, -NR2CR2R2a-, -CR2R2a NR2-, O, -CR2R2a O-, and -OCR2R2a-;
Y is selected from:

(CH2)r NR2R2a, provided that X-Y do not form a N-N, O-N, or S-N bond, C3-10 carbocyclic residue substituted with 0-2 R4a, 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 R4a;
R4, at each occurrence, is selected from =O, (CH2)r OR2, halo, C1-4 alkyl, -CN, NO2, (CH2)r NR2R2a, (CH2)r C(O)R2b, NR2C(O)R2b, C(O)NR2R2a, NR2C(O)NR2R2a, CH(=NR2)NR2R2a, NHC(=NR2)NR2R2a, SO2NR2R2a, NR2SO2NR2R2a, NR2SO2-C1-4 alkyl, NR2SO2R5, S(O)p R5, (CF2)r CF3, NCH2R1", OCH2R1", SCH2R1", N(CH2)2(CH2)t R1', O(CH2)2(CH2)t R1', and S(CH2)2(CH2)t R1', alternatively, one R4 is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

R4a, at each occurrence, is selected from =O, (CH2)r OR2, halo, C1-4 alkyl, -CN, NO2, (CH2)r NR2R2a, (CH2)r C(O)R2b, NR2C(O)R2b, C(O)NR2R2a, NR2C(O)NR2R2a, CH(=NR2)NR2R2a, NHC(=NR2)NR2R2a, SO2NR2R2a, NR2SO2NR2R2a, NR2SO2-C1-4 alkyl, NR2SO2R5, S(O)p R5, and (CF2)r CF3;

alternatively, one R4a i5 a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R5;

R4b, at each occurrence, is selected from =O, (CH2)r OR3, halo, C1-4 alkyl, -CN, NO2, (CH2)r NR3R3a, (CH2)r C(O)R3, NR3C(O)R3a, C(O)NR3R3a, NR3C(O)NR3R3a, CH(=NR3)NR3R3a, NH3C(=NR3)NR3R3a, SO2NR3R3a, NR3SO2NR3R3a, NR3SO2-C1-4 alkyl, NR3SO2CF3, NR3SO2-phenyl, S(O)p CF3, S(O)p-C1-4 alkyl, S(O)p-phenyl, and (CF2)r CF3;

R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6;

R6, at each occurrence, is selected from H, OH, (CH2)r OR2, halo, C1-4 alkyl, CN, NO2, (CH2)r NR2R2a, (CH2)r C(O)R2b, NR2C(O)R2b, NR2C(O)NR2R2a, CH(=NH)NH2, NHC(=NH)NH2, SO2NR2R2a, NR2SO2NR2R2a, and NR2SO2C1-4 alkyl;

R7, at each occurrence, is selected from H, OH, C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxy, C2-4 alkoxycarbonyl, (CH2)n-phenyl, C6-10 aryloxy, C6-10 aryloxycarbonyl, C6-10 arylmethylcarbonyl, C1-4 alkylcarbonyloxy C1-4 alkoxycarbonyl, C6-10 arylcarbonyloxy C1-4 alkoxycarbonyl, C1-6 alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C1-4 alkoxycarbonyl;

R8, at each occurrence, is selected from H, C1-6 alkyl and (CH2)n-phenyl;
alternatively, R7 and R8 combine to form a 5 or 6 membered saturated, ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;

R9, at each occurrence, is selected from H, C1-6 alkyl and (CH2)n-phenyl;

n, at each occurrence, is selected from 0, 1, 2, and 3;
m, at each occurrence, is selected from 0, 1, and 2;
p, at each occurrence, is selected from 0, 1, and 2;
q, at each occurrence is selected from 1 and 2;
r, at each occurrence, is selected from 0, 1, 2, and 3;
s, at each occurrence, is selected from 0, 1, and 2; and, t, at each occurrence, is selected from 0 and 1.
2. A compound according to Claim 1, wherein the compound is of formula Ia or Ib:
~
wherein;
Z is selected from a CH2O, OCH2, CH2NH, NHCH2, C(O), CH2C(O), C(O)CH2, NHC(O), C(O)NH, CH2S(O)2, S(O)2(CH2), SO2NH, and NHSO2, provided that Z does not form a N-N, N-O, NCH2N, or NCH2O bond with group A;

A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4;
phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazoiyl, 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, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl;
B is selected from: Y, X-Y, NR2R2a, C(=NR2)NR2R2a, and NR2C(=NR2)NR2R2a;
X is selected from C1-4 alkylene, -C(O)-, -C(=NR)-, -CR2(NR2R2a)-, -C(O)CR2R2a-, -CR2R2a C(O), -C(O)NR2-, -NR2C(O)-, -C(O)NR2CR2R2a-, -NR2C(O)CR2R2a-, -CR2R2a C(O)NR2-, -CR2R2a NR2C(O)-, -NR2C(O)NR2-, -NR2-, -NR2CR2R2a-, -CR2R2a NR2-, O, -CR2R2a O-, and -OCR2R2a-;

Y is NR2R2a, provided that X-Y do not form a N-N or O-N bond;
alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a;
cylcopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-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, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl;
alternatively, Y is selected from the following bicyclic heteroaryl ring systems:

K is selected from O, S, NH, and N.
3. A compound according to Claim 2, wherein;
Z is selected from a C(O), CH2C(O), C(O)CH2, NHC(O), C(O)NH, C(O)N(CH3), CH2S(O)2, S(O)2(CH2), SO2NH, and NHSO2, provided that Z does not form a N-N or NCH2N bond with 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 C(O)NH2, C(=NH)NH2, CH2NH2, CH2NHCH3, CH(CH3)NH2, and C(CH3)2NH2; and, R is selected from H, OCH3, Cl, and F.
5. A compound according to Claim 4, wherein;
D-E is selected from 3-amidinophenyl, 3-aminomethylphenyl, 3-aminocarbonylphenyl, 3-(methylaminomethyl)phenyl, 3-(1-aminoethyl)phenyl, 3-(2-amino-2-propyl)phenyl, 4-chloro-3-amidinophenyl, 4-chloro-3-aminomethylphenyl, 4-chloro-3-(methylaminomethyl)phenyl, 4-fluoro-3-amidinophenyl, 4-fluoro-3-aminomethylphenyl, 4-fluoro-3-(methylaminomethyl)phenyl, 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-2-propyl)pyrid-2-yl.
6. A compound according to Claim 3, wherein;
Z is C(O)CH2 and CONH, provided that Z does not form a N-N
bond with group A;
A is selected from phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R4; and, B is selected from X-Y, phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1 R4a;
R4, at each occurrence, is selected from OH, (CH2)r OR2, halo, C1-4 alkyl, (CH2)r NR2R2a, and (CF2)r CF3;
R4a is selected from C1-4 alkyl, CF3, S(O)p R5, SO2NR2R2a, and 1-CF3-tetrazol-2-yl;
R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl, and benzyl;
X is CH2 or C(O); and, Y is selected from pyrrolidino and morpholino.
7. A compound according to Claim 6, wherein;
A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl, ~
2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and, B is selected from the group: 2-CF3-phenyl, 2-(aminosulfonyl)phenyl, 2-(methyiaminosulfonyl)phenyl, 2-(dimethylaminosulfonyl)phenyl, 1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl, 4-morpholino, 2-(1'-CF3-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.
8. A compound according to Claim 3, wherein;
E is phenyl substituted with R or 2-pyridyl substituted with R;
D is selected from C(O)NH2, C(=NH)NH2, CH2NH2, CH2NHCH3, CH(CH3)NH2, and C(CH3)2NH2; and, R is selected from H, OCH3, Cl, and F;
Z is C(O)CH2 and CONH, provided that Z does not form a N-N
bond with group A;
A is selected from phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R4; and, B is selected from X-Y, phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1 R4a;
R4, at each occurrence, is selected from OH, (CH2)r OR2, halo, C1-4 alkyl, (CH2)r NR2R2a, and (CF2)r CF3;
R4a is selected from C1-4 alkyl, CF3, S(O)p R5, SO2NR2R2a, and 1-CF3-tetrazol-2-yl;
R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl, and benzyl;

X is CH2 or C(O); and, Y is selected from pyrrolidino and morpholino.
9. A compound according to Claim 8 wherein;
D-E is selected from 3-amidinophenyl, 3-aminomethylphenyl, 3-aminocarbonylphenyl, 3-(methylaminomethyl)phenyl, 3-(1-aminoethyl)phenyl, 3-(2-amino-2-propyl)phenyl, 4-chloro-3-amidinophenyl, 4-chloro-3-aminomethylphenyl, 4-chloro-3-(methylaminomethyl)phenyl, 4-fluoro-3-amidinophenyl, 4-fluoro-3-aminomethylphenyl, 4-fluoro-3-(methylaminomethyl)phenyl, 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-2-propyl)pyrid-2-yl;
A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-C1-phenyl, 3-C1-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and, B is selected from the group: 2-CF3-phenyl, 2-(aminosulfonyl)phenyl, 2-(methylaminosulfonyl)phenyl, 2-(dimethylaminosulfonyl)phenyl, 1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl, 4-morpholino, 2-(1'-CF3-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, wherein the compound is of formula Ia.
11. A compound according to Claim 9, wherein the compound is of formula Ib.
12. A compound according to Claim 3, wherein;
D is selected from C(=NR8)NR7R9, C(O)NR7R8, NR7R8, and CH2NR7R8;
E is phenyl substituted with R or pyridyl substituted with R;
R is selected from H, Cl, F, OR3, CH3, CH2CH3, OCF3, and CF3;
Z is selected from C(O), CH2C(O), C(O)CH2, NHC(O), and C(O)NH, provided that Z does not form a N-N bond with group A;
R1a and R1b are, at each occurrence, independently selected from H, -(CH2)r-R1', NCH2R1", OCH2R1", SCH2R1", N(CH2)2(CH2)t R1', O(CH2)2(CH2)t R1', and S(CH2)2(CH2)t R1';

R1c is selected from H, -(CH2)q-R1', C1-3 alkyl, C(O)R2c, (CF2)r CO2R2c, and C(O)NR2R2a;

R1', at each occurrence, is selected from H, C1-3 alkyl, halo, (CF2)r CF3, OR2, NR2R2a, C(O)R2c, (CF2)r CO2R2c, S(O)p R2b, NR2(CH2)r OR2, NR2C(O)R2b, NR2C(O)2R2b, C(O)NR2R2a, SO2NR2R2a, and NR2SO2R2b;
A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4;
phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, and imidazolyl;
B is selected from: Y, X-Y, NR2R2a, C(=NR2)NR2R2a, and NR2C(=NR2)NR2R2a;

X is selected from CH2, -CR2(CR2R2b)(CH2)t-, -C(O)-, -C(=NR)-, -CH(NR2R2a)-, -C(O)NR2-, -NR2C(O)-. -NR2C(O)NR2-, -NR2-, and O;

Y is NR2R2a, provided that X-Y do not form a N-N or O-N bond;

alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a;
phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-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, and 1,3,4-triazolyl;

R4, at each occurrence, is selected from =O, OH, C1, F, C1-4 alkyl, (CH2)r NR2R2a, (CH2)r C(O)R2b, NR2C(O)R2b, C(O)NR2R2a, CH(=NH)NH2, NHC(=NH)NH2, SO2NR2R2a, NR2SO2-C1-4 alkyl, NR2SO2R5, S(O)p R5, and (CF2)r CF3;

R4a, at each occurrence, is selected from =O, OH, C1, F, C1-4 alkyl, (CH2)r NR2R2a, (CH2)r C(O)R2b, NR2C(O)R2b, C(O)NR2R2a, CH(=NH)NH2, NHC(=NH)NH2, SO2NR2R2a, NR2SO2-C1-4 alkyl, NR2SO2R5, S(O)p R5, (CF2)r CF3, and 1-CF3-tetrazol-2-yl;

R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6;

R6, at each occurrence, is selected from H, =O, OH, OR2, C1, F, CH3. CN, NO2, (CH2)r NR2R2a, (CH2)r C(O)R2b, NR2C(O)R2b, CH(=NH)NH2, NHC(=NH)NH2, and SO2NR2R2a;

R7, at each occurrence, is selected from H, OH, C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxy, C1-4 alkoxycarbonyl, benzyl, C6-10 aryloxy, C6-10 aryloxycarbonyl, C6-10 arylmethylcarbonyl, C1-4 alkylcarbonyloxy C1-4 alkoxycarbonyl, C6-10 arylcarbonyloxy C1-4 alkoxycarbonyl, C1-6 alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C1-4 alkoxycarbonyl;

R8, at each occurrence, is selected from H, C1-6 alkyl and benzyl; and alternatively, R7 and R8 combine to form a morpholino group;
and, R9, at each occurrence, is selected from H, C1-6 alkyl and benzyl.
13. A compound according to Claim 12, wherein;

E is phenyl substituted with R or 2-pyridyl substituted with R;
R is selected from H, C1, F, OCH3, CH3, OCF3, and CF3;
Z is selected from a C(O)CH2 and C(O)NH, provided that Z does not form a N-N bond with group A;
R1a, at each occurrence, is selected from H, CH3, CH2CH3, C1, F, CF3, OCH3, NR2R2a, S(O)p R2b, CH2S(O)p R2b, CH2NR2S (O) p R2b, C (O) R2c, CH2C (O) R2c, C (O)NR2R2a, and SO2NR2R2a;

R1b is selected from H, CH3, CH2CH3, C1, F, CF3, OCH3, NR2R2a, S (O) p R2b, CH2S (O) p R2b, CH2NR2S (O) p R2b, C (O) R2c, CH2C (O) R2c, C(O)NR2R2a, and SO2NR2R2a;

R1c is selected from H, CH3, CH2CH3, CF3, CH2S(O)p R2b, CH2NR2S (O) p R2b, C (O) R2c, CH2C (O) R2c, and C (O) NR2R2a;

A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4;
phenyl, pyridyl, pyrimidyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, and imidazolyl;

B is selected from: Y and X-Y;

X is selected from CH2, -CR2(CR2R2b)-, -C(O)-, -C(=NR)-, -CH(NR2R2a)-, -C(O)NR2-, -NR2C(O)-, -NR2C(O)NR2-, -NR2-, and O;

Y is NR2R2a, provided that X-Y do not form a N-N or O-N bond;

alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a;
phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 2,2,4-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;

R2, at each occurrence, is selected from H, CF3, CH3, benzyl, and phenyl;

R2a, at each occurrence, is selected from H, CF3, CH3, benzyl, and phenyl;

R2b, at each occurrence, is selected from CF3, OCH3, CH3, benzyl, and phenyl;

R2c, at each occurrence, is selected from CF3, OH, OCH3, CH3, benzyl, and phenyl;

alternatively, R2 and R2a combine to form a 5 or 6 membered saturated, partially unsaturated, or unsaturated ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;

R3, at each occurrence, is selected from H, CH3, CH2CH3, and phenyl;

R3a, at each occurrence, is selected from H, CH3, CH2CH3, and phenyl;
R4, at each occurrence, is selected from OH, C1, F, CH3, CH2CH3. NR2R2a, CH2NR2R2a, C(O)R2b, NR2C(O)R2b, C(O)NR2R2a, and CF3;

R4a, at each occurrence, is selected from OH, C1, F, CH3, CH2CH3, NR2R2a, CH2NR2R2a, C(O)R2b, C(O)NR2R2a, SO2NR2R2a, S(O)p R5, CF3, and 1-CF3-tetrazol-2-yl;

R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl substituted with 0-2 R6, and benzyl substituted wi th 1 R6 ;

R6, at each occurrence, is selected from H, OH, OCH3, Cl, F, CH3, CN, NO2, NR2R28, CH2NR2R2a, and SO2NR2R2a;

R7, at each occurrence, is selected from H, OH, C1-3 alkyl, C1-3 alkylcarbonyl, C1-3 alkoxy, C1-4 alkoxycarbonyl, benzyl, phenoxy, phenoxycarbonyl, benzylcarbonyl, C1-4 alkylcarbonyloxy C1-4 alkoxycarbonyl, phenylcarbonyloxy C1-4 alkoxycarbonyl, C1-6 alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C1-4 alkoxycarbonyl;

R8, at each occurrence, is selected from H, CH3, and benzyl;
and, alternatively, R7 and R8 combine to form a morpholino group;

R9, at each occurrence, is selected from H, CH3, and benzyl.
14. A compound according to Claim 13, wherein;

R1a, at each occurrence, is selected from H, CH3, CH2CH3, C1, F, CF3, OCH3, NR2R2a, S(O)pR2b, C(O)NR2R2a, CH2S(O)p R2b, CH2NR2S(O)p R2b, C(O)R2c, CH2C(O)R2c, and SO2NR2R2a;

R1b is selected from H, CH3, CH2CH3, C1, F, CF3, OCH3, NR2R2a, S (O)p R2b , C(O) NR2R2a , CH2S(O)p R2b, CH2NR2 S (O) p R2b, C(O) R2b, CH2C(O)R2b, and SO2NR2R2a;

R1c is selected from H, CH3, CH2CH3, CF3, C(O)NR2R2a, CH2S(O)p R2b, CH2NR2S(O)p R2b, C(O)R2b, and CH2C(O)R2b;

A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4;
phenyl, pyridyl, and pyrimidyl;

B is selected from: Y and X-Y;

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

Y is NR2R2a, provided that X-Y do not form a O-N bond;

alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a;

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

R2, at each occurrence, is selected from H, CF3, CH3, benzyl, and phenyl;

R2a, at each occurrence, is selected from H, CF3, CH3, benzyl, and phenyl;

R2b, at each occurrence, is selected from CF3, OCH3, CH3, benzyl, and phenyl;

R2c, at each occurrence, is selected from CF3, OH, OCH3, CH3, benzyl, and phenyl;

alternatively, R2 and R2a combine to form a ring system selected from pyrrolidinyl, piperazinyl and morpholino;

R4, at each occurrence, is selected from Cl, F, CH3, NR2R2a, and CF3;

R4a, at each occurrence, is selected from C1, F, CH3, SO2NR2R2a, S(O)pR5, and CF3; and, R5, at each occurrence, is selected from CF3 and CH3.
15. A compound according to Claim 1, wherein the compound is selected from the group:

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

and pharmaceutically acceptable salts thereof.
16. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to one of Claims 1-15 or a pharmaceutically acceptable salt thereof.
17. A method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to one of Claims 1-15 or a pharmaceutically acceptable salt thereof.
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US6630468B2 (en) 2003-10-07
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AU3110999A (en) 1999-10-18
EP1064270A2 (en) 2001-01-03
US6436985B2 (en) 2002-08-20
EP1064270B1 (en) 2004-10-06
US6191159B1 (en) 2001-02-20
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WO1999050255A2 (en) 1999-10-07
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