Patent EA-003056-B1 (EA)
Title: NITROGEN CONTAINING HETEROAROMATICS AS FACTOR Xa INHIBITORS, PHARMACEUTICAL COMPOSITION AND METHOD OF USE
Inventor: PINTO DONALD JOSEPH PHILLIP
IPC: C07D409/12
Filed: 1997-12-15
Abstract: comprising: administering to a patient in need the1. A compound of formula I:   or a stereoisomer orund according to Claim 1 or a pharmaceutically acceptable salt thereof. 26. A compound selected fromprovided that if M contains 2 N atoms then R<1b> is not present and if M contains 3 N atoms then R<1a> and R<1b> are not present; J is N or NH; D is selected from CN, C(=NR<8>)NR<7>R<9>, NHC(=NR<8>)NRidino)phenyl-3-methyl-5-[(4'-tert-butylaminosulfonR<9>)tNR<7>R<8>, provided that D is substituted meyl-3-methyl-5-[(4'aminosulfonylphenyl) aminocarbonyridyl, pyrimidyl, pyrazinyl, pyridazinyl, and piptrifluoromethylphenyl)-aminocarbonyl] pyrazole; orG together represent pyridyl substituted with 1 R;compound according to claim 1 is selected from thealkyl, OCF3, and CF3; G is absent or is selected from NHCH2, OCH2, and SCH2, provided that when s isl]-3 -methyl-pyrazole; 1-(3-aminomethylphenyl)-5-[(2'-aminosulfonylphenyl-[1,1']-biphen-4-yl)aminocarbonyl]-3 -fluoromethyl-pyrazole 1-(3-aminomethylphenyl)-5-[((2'-aminosulfonylphenyl) pyridin-2-yl] aminocarbonyl)-3-methyl-pyrazole 1-(3-aminomethylpC(O)NR<3>(CH2)r, (CH2)rNR<3>C(O)O(CH2)r, (CH2)rNR<3>C(O)NR<3>(CH2)r, (CH2)rS(O)p(CH2)r, (CH2)rSO2NR<3>(CH2)r, (CH2)rNR<3>SO2(CH2)r and (CH2)rNR<3>SO2NR<3>(CH2)r, provided that Z does not form a N-N, Ne; 1-(3-aminomethylphenyl)-5-[(2'-sulfonylmethyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethylt or selected from -(CH2)r-R<1>', NCH2R<1>", OCH2Ronyl-3-fluoro-[1,1'])-biphen-4-yl) aminocarbonyl]-3 -trifluoromethyl-pyrazole 1-(3-aminomethylphenyl)-5-[(3-fluoro-2'-methylsulfonyl-[1,1']- biphen-4-yl)aminocarbonyl]-3 -fluoromethyl-pyrazole 1-(3-aminomethyl)phenyl-5-[(2'-aminosulfonyl-[1,1']-bipheroup consisting of N, O, and S; R<1>', is selected-aminomethylphenyl)-5-[(2'-methylsulfonyl-[1,1']- R<2a>, C(O)R<2c>, OC(O)R<2>, (CF2)rCO2R<2c>, S(O)p3-aminomethylphenyl)-5-[(2'-aminosulfonyl-3-fluoroNHR<2b>, NR<2>C(O)2R<2a>, OC(O)NR<2b>, C(O)NR<2>R<2a>, SO2NR<2>R<2a>, NR<2>SO2R<2b>, C3-6carbocyclic-4-(N-morpholino)phenyl)aminocarbonyl]pyrazole; 1-red heterocyclic system containing from 1-4 heteroro-4-(2-methylimidazol-1-yl)phenyl)aminocarbonyl)pyrazole; or pharmaceutically acceptable salts thereof. 28. A compound according to claim 27 is  1-(3-aminomethyl)phenyl-5-[(2'-aminosulfonyl-[1,1']- brence, is selected from H, CF3, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R<4b>, and 5-6 membered heterocyclic system containithylphenyl)-5-[(2'-aminosulfonyl-[1,1']- biphen-4-yl)aminocarbonyl]-3 fluoromethyl-pyrazole or pharmaceutically acceptable salts thereof. 30. A compouF3, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R<4b>, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms seletable salts thereof. 31. A compound according to ctituted with 0-2 R<4b>; R<2b>, at each occurrence,lidinocarbonyl)phenyl) aminocarbonyl] -3-trifluoronzyl, C3-6 carbocyclic residue substituted with 0-2 R<4b>, and 5-6 membered heterocyclic system contis 1-(3-aminomethylphenyl)-5-[(2-fluoro-4-(N-pyrrop consisting of N, O, and S and substituted with 0methyl-pyrazole; or pharmaceutically acceptable sarom CF3, OH, C1-4 alkoxy, C1-6 alkyl, benzyl, C3-6is 1-(3-aminomethylphenyl)-5-[(2'-sulfonylmethyl-[1,1'] - biphen-4-yl)aminocarbonyl]-3 -trifluorometm 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 R<4b>; 1-(3-aminomethylphenyl)-5-[(2'-aminosulfonyl-3-fluoro-[1,1'] - biphen-4-yl)aminocarbonyl]-3 -trifluosaturated ring substituted with 0-2 R<4b> which cosalts thereof. 35. A compound according to claim 27 is 1-(3-aminomethylphenyl)-5-[(3-fluoro-2'-methylsulfonyl-[1,1'] - biphen-4-yl)aminocarbonyl]-3 -trifluoromethyl-pyrazole, or pharmaceutically acceptable salts thereof. 36. A compound according to claim 27 is 1-(3-aminomethylphenyl)-5-[(2'-aminosul4>, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 Rim 27 is 1-(3-aminomethylphenyl)-5-[(2'-methylsulfonyl-[1,1'] - biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole, or pharmaceutically acceptable salts the0 membered heterocyclic system containing from 1-4-aminomethylphenyl)-5-[(2'-aminosulfonyl-3-fluoro-[1,1'] - biphen-4-yl) aminocarbonyl]-3 -methyl-pyrselected from C1-4 alkylene, -CR<2>(CR<2>R<2b>)(CH2)t-, -C(O)-, -C(=NR)-, -CR<2>(NR<2>R<2a>)-, CR<2>omethylphenyl)-5-[(3-fluoro-2'-methylsulfonyl-[1,1'] - biphen-4-yl)aminocarbonyl]-3 -trifluoromethyl-pyrazole, or pharmaceutically acceptable salts thS(O)2-, -NR<2>S(O)2CR<2>R<2a>-, -CR<2>R<2a>S(O)2NR(3-aminomethylphenyl)-3-methyl-5-[(3-fluoro-4-(N-morpholino)phenyl)aminocarbonyl]pyrazole; or pharmaceutically acceptable salts thereof. 41. A compound according to claim 27 is  1-(3-aminomethylphenylR<2>CR<2>R<2a>-, -CR<2>R<2a>NR<2>-, O, -CR<2>R<2a>O- and -OCR<2>R<2a>-; Y is selected from: (CH2)tNRutically acceptable salts thereof. 42. A compound according to claim 27 wherein the pharmaceuticallyed with 0-2 R<4a>, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 R<4a>; R<4>, at each occurrence, is selected from =O, (CH2)rOR<2>, halo, C1-4 alkyl, -CN, NO2, (CH2)rNR<2>R<2a>, (CH2)rC(O)R<2b>, NR<2>Csulfonic acid, oxalic acid. 43. A compound accordiNR<2>)NR<2>R<2a>, NHC(=NR<2>)NR<2>R<2a>, SO2NR<2>Rable salt is salt of hydrochloric acid. A pharmace2>SO2R<5>, S(O)pR<5>, (CF2)rCF3, NCH2R<1>", OCH2R<1>", SCH2R<1>", N(CH2)2(CH2)tR<1>', O(CH2)2(CH2)tRe amount of a compound according to any of Claim 1> is a 5-6 membered aromatic heterocycle containin44. A pharmaceutical composition, comprising pharmsisting of N, O, and S; R<4a>, at each occurrence, is selected from =O, (CH2)rOR<2>, halo, C1-4 alkyl, -CN, NO2, (CH2)rNR<2>R<2a>, (CH2)rC(O)R<2b>, NRlt thereof. 45. A method for treating or preventing a thromboembolic disorder, associated with disorder of factor Xa, comprising: administering to a patient in need thereof a therapeutically effectiveely, one R<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<5>; R<4b>, at each occurrence, is selected from =O, (CH2)rOR<3>, halo, C1-4 alkyl, -CN, NO2, (CH2)rNR<3>R<3a>, (CH2)rC(O)R<3>, NR<3>C(O)R<3a>, C(O)NR<3>R<3a>, NR<3>C(O)NR<3>R<3a>, C(=NR<3>)NR<3>R<3a>, NH3C(=NR<3>)NR<3>R<3a>, SO2NR<3>R<3a>, NR<3>SO2NR<3>R<3a>, NR<3>SO2-C1-4 alkyl, NR<3>SO2CF3, NR<3>SO2-phenyl, S(O)pCF3, S(O)p-C1-4 alkyl, S(O)p- phenyl and (CF2)rCF3; R<5>, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl substituted with 0-2 R<6>, and benzyl substituted with 0-2 R<6>; R<6>, at each occurrence, is selected from H, OH, (CH2)rOR<2>, halo, C1-4 alkyl, -CN, NO2, (CH2)rNR<2>R<2a>, (CH2)rC(O)R<2b>, NR<2>C(O)R<2b>, NR<2>C(O)NR<2>R<2a>, C(=NH)NH2, NHC(=NH)NH2, SO2NR<2>R<2a>, NR<2>SO2NR<2>R<2a> and NR<2>SO2C1-4 alkyl; R<7>, at each occurrence, is selected from H, OH, C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxy, C1-4 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; R<8>, at each occurrence, is selected from H, C1-6 alkyl and (CH2)n-phenyl; alternatively, R<7> and R<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<9>, 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; 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-(CH2)s- and -Z-A-B are not both substituted or unsubstituted biphenylmethylene group. 2. A compound according to Claim 1, wherein the compound is of formulae Ia-Ih:   wherein, groups D-E- and -Z-A-B are attached to adjacent atoms on the ring; 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 ring M or group A; A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R<4>; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-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, NR<2>R<2a>, C(=NR<2>)NR<2>R<2a>, and NR<2>C (=NR<2>)NR<2>R<2a>; X is selected from C1-4 alkylene, -C(O)-, -C(=NR)-, -CR<2>(NR<2>R<2a>)-, -C(O)CR<2>R<2a>-, -CR<2>R<2a>C(O), -C(O)NR<2>-, -NR<2>C(O)-, -C(O)NR<2>CR<2>R<2a>-, -NR<2>C(O)CR<2>R<2a>-, -CR<2>R<2a>C(O)NR<2>-, -CR<2>R<2a>NR<2>C(O)-, -NR<2>C(O)NR<2>-, -NR<2>-, -NR<2>CR<2>R<2a>-, -CR<2>R<2a>NR<2>-, O, - CR<2>R<2a>O- and -OCR<2>R<2a>-; Y is NR<2>R<2a>, provided that 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<4a>; cylcopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl,