Nitrogen containing heteroaromatics as factor Xa inhibitors

A compound of formulae Ib:

• ##STR266## wherein, groups D--E-- and --Z--A--B are attached to adjacent atoms on the ring;
• J is N or NH;
• D is selected from CN, C(.dbd.NR.sup.8)NR.sup.7 R.sup.9, NHC(.dbd.NR.sup.8)NR.sup.7 R.sup.9, NR.sup.8 C(.dbd.NR.sup.7), C(O)NR.sup.7 R.sup.8, and (CR.sup.8 R.sup.9).sub.t NR.sup.7 R.sup.8, provided that D is substituted meta or para to G on E;
• E is phenyl substituted with 1 R;
• R is selected from H, halogen, (CH.sub.2).sub.t OR.sup.3, C.sub.1-4 alkyl, OCF.sub.3, and CF.sub.3 ;
• G is absent or is selected from NHCH.sub.2, OCH.sub.2, and SCH.sub.2, provided that when s is 0, then G is attached to a carbon atom on ring M;
• Z is selected from a C(O), CH.sub.2 C(O), C(O)CH.sub.2, NHC(O), C(O)NH, CH.sub.2 S(O).sub.2, and S(O).sub.2 (CH.sub.2), provided that Z does not form a N--N or NCH.sub.2 N bond with ring M or group A;
• R.sup.1a and R.sup.1b are independently absent or selected from --(CH.sub.2).sub.r --R.sup.1', NCH.sub.2 R.sup.1", OCH.sub.2 R.sup.1", SCH.sub.2 R.sup.1", N(CH.sub.2).sub.2 (CH.sub.2).sub.t R.sup.1', O(CH.sub.2).sub.2 (CH.sub.2).sub.t R.sup.1', and S(CH.sub.2).sub.2 (CH.sub.2).sub.t R.sup.1', or combined to form a 5-8 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R.sup.4 and which contains from 0-2 heteroatoms selected from the group consisting of N, O, and S;
• R.sup.1' is selected from H, C.sub.1-3 alkyl, halo, (CF.sub.2).sub.r CF.sub.3, OR.sup.2, NR.sup.2 R.sup.2a, C(O)R.sup.2c, OC(O)R.sup.2, (CF.sub.2).sub.r CO.sub.2 R.sup.2c, S(O).sub.p R.sup.2b, NR.sup.2 (CH.sub.2).sub.r OR.sup.2, NR.sup.2 C(O)R.sup.2b, NR.sup.2 C(O)NHR.sup.2b, NR.sup.2 C(O).sub.2 R.sup.2a, OC(O)NR.sup.2b, C(O)NR.sup.2 R.sup.2a, SO.sub.2 NR.sup.2 R.sup.2a, NR.sup.2 SO.sub.2 R.sup.2b, C.sub.3-6 carbocyclic residue substituted with 0-2 R.sup.4, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R.sup.4 ;
• R.sup.1" is selected from H, C(O)R.sup.2b, C(O)NR.sup.2 R.sup.2a, S(O)R.sup.2b, S(O).sub.2 R.sup.2b, and SO.sub.2 NR.sup.2 R.sup.2a ;
• R.sup.2, at each occurrence, is selected from H, CF.sub.3, C.sub.1-6 alkyl, benzyl, C.sub.3-6 carbocyclic residue substituted with 0-2 R.sup.4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R.sup.4b ;
• R.sup.2a, at each occurrence, is selected from H, CF.sub.3, C.sub.1-6 alkyl, benzyl, C.sub.3-6 carbocyclic residue substituted with 0-2 R.sup.4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R.sup.4b ;
• R.sup.2b, at each occurrence, is selected from CF.sub.3, C.sub.1-4 alkoxy, C.sub.1-6 alkyl, benzyl, C.sub.3-6 carbocyclic residue substituted with 0-2 R.sub.4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R.sup.4b ;
• R.sup.2c, at each occurrence, is selected from CF.sub.3, OH, C.sub.1-4 alkoxy, C.sub.1-6 alkyl, benzyl, C.sub.3-6 carbocyclic residue substituted with 0-2 R.sup.4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R.sup.4b ;
• alternatively, R.sup.2 and R.sup.2a combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R.sup.4b which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
• R.sup.3, at each occurrence, is selected from H, C.sub.1-4 alkyl, and phenyl;
• R.sup.3a, at each occurrence, is selected from H, C.sub.1-4 alkyl, and phenyl;
• A is selected from:
• phenyl substituted with 0-2 R.sup.4, and
• pyridyl substituted with 0-2 R.sup.4 ;
• B is selected from:
• Y, X--Y, NR.sup.2 R.sup.2a, C(.dbd.NR.sup.2)NR.sup.2 R.sup.2a, and NR.sup.2 C(.dbd.NR.sup.2)NR.sup.2 R.sup.2a ;
• X is selected from C.sub.1-4 alkylene, --C(O)--, --C(.dbd.NR)--, --CR.sup.2 (NR.sup.2 R.sup.2a)--, --C(O)CR.sup.2 R.sup.2a --, --CR.sup.2 R.sup.2a C(O), --C(O)NR.sup.2 --, --NR.sup.2 C(O)--, --C(O)NR.sup.2 CR.sup.2 R.sup.2a --, --NR.sup.2 C(O)CR.sup.2 R.sup.2a --, --CR.sup.2 R.sup.2a C(O)NR.sup.2 --, and --CR.sup.2 R.sup.2a NR.sup.2 C(O)--;
• Y is NR.sup.2 R.sup.2a, 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 R.sup.4a ;
• cyclopropyl, 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, and 1,3,4-triazolyl;
• R.sup.4, at each occurrence, is selected from .dbd.O, (CH.sub.2).sub.r OR.sup.2, halo, C.sub.1-4 alkyl, --CN, NO.sub.2, (CH.sub.2).sub.r NR.sup.2 R.sup.2a, (CH.sub.2).sub.r C(O)R.sup.2b, NR.sup.2 C(O)R.sup.2b, C(O)NR.sup.2 R.sup.2a, NR.sup.2 C(O)NR.sup.2 R.sup.2a, C(.dbd.NR.sup.2)NR.sup.2 R.sup.2a, NHC(.dbd.NR.sup.2)NR.sup.2 R.sup.2a, SO.sub.2 NR.sup.2 R.sup.2a, NR.sup.2 SO.sub.2 NR.sup.2 R.sup.2a, NR.sup.2 SO.sub.2 --C.sub.1-4 alkyl, NR.sup.2 SO.sub.2 R.sup.5, S(O).sub.p R.sup.5, (CF.sub.2).sub.r CF.sub.3, NCH.sub.2 R.sup.1", OCH.sub.2 R.sup.1", SCH.sub.2 R.sup.1", N(CH.sub.2).sub.2 (CH.sub.2).sub.t R.sup.1', O(CH.sub.2).sub.2 (CH.sub.2).sub.t R.sup.1', and S(CH.sub.2).sub.2 (CH.sub.2).sub.t R.sup.1',
• alternatively, one R.sup.4 is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
• R.sup.4a, at each occurrence, is selected from .dbd.O, (CH.sub.2).sub.r OR.sup.2, halo, C.sub.1-4 alkyl, --CN, NO.sub.2, (CH.sub.2).sub.r NR.sup.2 R.sup.2a, (CH.sub.2).sub.r C(O)R.sup.2b, NR.sup.2 C(O)R.sup.2b, C(O)NR.sup.2 R.sup.2a, NR.sup.2 C(O)NR.sup.2 R.sup.2a, C(.dbd.NR.sup.2)NR.sup.2 R.sup.2a, NHC(.dbd.NR.sup.2)NR.sup.2 R.sup.2a, SO.sub.2 NR.sup.2 R.sup.2a, NR.sup.2 SO.sub.2 NR.sup.2 R.sup.2a, NR.sup.2 SO.sub.2 --C.sub.1-4 alkyl, NR.sup.2 SO.sub.2 R.sup.5, S(O).sub.p R.sup.5, and (CF.sub.2).sub.r CF.sub.3 ;
• alternatively, one R.sup.4a is 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 R.sup.5 ;
• R.sup.4b, at each occurrence, is selected from .dbd.O, (CH.sub.2).sub.r OR.sup.3, halo, C.sub.1-4 alkyl, --CN, NO.sub.2, (CH.sub.2).sub.r NR.sup.3 R.sup.3a, (CH.sub.2).sub.r C(O)R.sup.3, NR.sup.3 C(O)R.sup.3a, C(O)NR.sup.3 R.sup.3a, NR.sup.3 C(O)NR.sup.3 R.sup.3a, C(.dbd.NR.sup.3)NR.sup.3 R.sup.3a, NH.sup.3 C(.dbd.NR.sup.3)NR.sup.3 R.sup.3a, SO.sub.2 NR.sup.3 R.sup.3a, NR.sup.3 SO.sub.2 NR.sup.3 R.sup.3a, NR.sup.3 SO.sub.2 --C.sub.1-4 alkyl, NR.sup.3 SO.sub.2 CF.sub.3, NR.sup.3 SO.sub.2 -phenyl, S(O).sub.p CF.sub.3, S(O).sub.p --C.sub.1-4 alkyl, S(O).sub.p -phenyl, and (CF.sub.2).sub.r CF.sub.3 ;
• R.sup.5, at each occurrence, is selected from CF.sub.3, C.sub.1-6 alkyl, phenyl substituted with 0-2 R.sup.6, and benzyl substituted with 0-2 R.sup.6 ;
• R.sup.6, at each occurrence, is selected from H, OH, (CH.sub.2).sub.r OR.sup.2, halo, C.sub.1-4 alkyl, CN, NO.sub.2, (CH.sub.2).sub.r NR.sup.2 R.sup.2a, (CH.sub.2).sub.r C(O)R.sup.2b, NR.sup.2 C(O)R.sup.2b, NR.sup.2 C(O)NR.sup.2 R.sup.2a, C(.dbd.NH)NH.sub.2, NHC(.dbd.NH)NH.sub.2, SO.sub.2 NR.sup.2 R.sup.2a, NR.sup.2 SO.sub.2 NR.sup.2 R.sup.2a, and NR.sup.2 SO.sub.2 C.sub.1-4 alkyl;
• R.sup.7, at each occurrence, is selected from H, OH, C.sub.1-6 alkyl, C.sub.1-6 alkylcarbonyl, C.sub.1-6 alkoxy, C.sub.1-4 alkoxycarbonyl, (CH.sub.2).sub.n -phenyl, C.sub.6-10 aryloxy, C.sub.6-10 aryloxcarbonyl, C.sub.6-10 arylmethylcarbonyl, C.sub.1-4 alkylcarbonyloxy C.sub.1-4 alkoxycarbonyl, C.sub.6-10 arylcarbonyloxy C.sub.1-4 alkoxycarbonyl, C.sub.1-6 alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C.sub.1-4 alkoxycarbonyl;
• R.sup.8, at each occurrence, is selected from H, C.sub.1-6 alkyl and (CH.sub.2).sub.n -phenyl;
• alternatively, R.sup.7 and R.sup.8 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;
• R.sup.9, at each occurrence, is selected from H, C.sub.1-6 alkyl and (CH.sub.2).sub.n -phenyl;
• n, at each occurrence, is selected from 0, 1, 2, and 3;
• p, at each occurrence, is selected from 0, 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;
• provided that D--E--G--(CH.sub.2).sub.s -- and --Z--A--B are not both benzamidines and that --Z--A--B does not form a substituted or unsubstituted biphenylmethylene group.

A compound selected from the group:

• 1-(3-amidino)phenyl-3-methyl-5-[4'-(carboxymethyl)phenylaminocarbonyl]pyraz ole;
• 1-(3-amidino)phenyl-3-methyl-5-[4'-(N,N-dimethylaminosulfonyl)phenylaminoca rbonyl]pyrazole;
• 1-(3-amidino)phenyl-3-methyl-5-[(4'-tert-butylaminosulfonylphenyl)aminocarb onyl]pyrazole;
• 1-(3-amidino)phenyl-3-methyl-5-[(4'-aminosulfonylphenyl)aminocarbonyl]pyraz ole;
• and,
• 1-(3-amidino)phenyl-3-methyl-5-[(4'-trifluoromethylphenyl)aminocarbonyl]pyr azole;
• or a pharmaceutically acceptable salt thereof.