Patent EA-004515-B1 (EA)
Title: Nitrogen containing heterobicycles as factor xa inhibitors
Inventor: FEVIG JOHN
IPC: A61K31/44
Filed: 1999-12-17
Abstract: 1. A compound of the formula: comprising different condensed F rings, in the mentioned compound a fragment of the formula presented as one of the following structure Z is N, CR<1A> or NR<3>; L is N or C, with the proviso that when L is N, Z is N or CR<1A> and when L is C, Z is NR<3>; wherein a cycle F is selected from wherein compounds of the above mentioned formulas are substituted with 0-2 R<3>; G is selected from A is selected from one of the following carbocyclic and heterocyclic systems, which are substituted with 0-2 R<4>: phenyl, piperidine, piperazinyl, pyrydile, pyrimidile, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oksazolyl, isoksazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oksadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oksadiazolyl, 1,2,4-oksadiazolyl, 1,2,5-oksadiazolyl, 1,3,4-oksadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoksazolyl, benzthiazolyl, indazolyl, benzoksazolyl, benzisothiazolyl and isoindazolyl; B is selected from: H, Y and X-Y; 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<0>-, -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 CH2NR<2>R<2A> or CH2CH2NR<2>R<2A>; alternatively Y is selected from one of the following carbocyclic and heterocyclic system, which are substituted with 0-2 R<4A>: Cyclopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl, pyrydile, pyrimidile, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oksazolyl, isoksazolyl, isoksazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oksadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oksadiazolyl, 1,2,4-oksadiazolyl, 1,2,5-oksadiazolyl, 1,3,4-oksadiazolyl, 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; and S is O, provided that if a compound is 1,4,5,6-tetrahydropyrazolo[3,4-c]pyridin-7-oh Y is nitrogen containing non-aromatic heterocycle attached through nitrogen atom, wherein a) B is X-Y, or b) Y is substituted with at least one R<4A>, which is not H or alkyl. 2. A compound of Claim 1 of the formula: wherein Z is N, CR<1A> or NR<3>; L is N or C, provided that when L is N, Z is N or CR<1A>, and if L is C, Z is NR<3>; where cycle F is selected from where compounds of the mentioned formulas are substituted with 0-2 R<3>; G is selected from 3. A compound of Claim 2, wherein G is selected from: 4. A compound of Claim 3, wherein: A is selected from phenyl, pyridil and pyrimidil and substituted with 0-2 R<4>; and B is selected from X-Y, phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl and imidazolyl and substituted with 0-1 R<4A>; R<2>, at each occurrence, is selected from H, CH3, CH2CH3, cyclopropylmethyl, cyclobutyl and cyclopentyl; R<2A>, at each occurrence, is H or CH3; alternatively, R<2> and R<2A> together with atom, to which they are attached, are adjacent to pyrrolidine formation substituted with 0-2 R<4B>; R<4>, at each occurrence, is selected from OH, (CH2)rOR<2>, halo, C1-4-alkyl, (CH2)rNR<2>R<2A> and (CF2)rCF3; R<4A> is selected from C1-4-alkyl, CF3, (CH2)rOR<2>, (CH2)rNR<2>NR<2A>, S(O)pR<5>, SO2NR<2>R<2A> and 1-CF3-tetrazole-2-yl; R<4B>, at each occurrence, is selected from H, CH3 and OH; R<5>, at each occurrence, is selected from CF3, C1-6alkyl, phenyl and benzyl; X is CH2 or C(O); Y is selected from pyrrolidino and morpholino; and r, at each occurrence, is selected from 0,1 and 2, provided that if a compound is 1,4,5,6-tetrahydropyrazolo[3,4-c]pyridin-oh, Y is nitrogen containing non-aromatic heterocycle, attached through nitrogen atom, wherein a) B is X-Y, or b) Y is substituted with, at least, one R<4A>, which is not H or alkyl. 5. A compound of Claim 4, 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-metoxyphenyl; and B is selected from the group: 2-(aminosulfonyl)phenyl, 2-(methylaminosulfonyl)phenyl, 1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl, 2-(N,N-dimethylaminomethyl)phenyl, 2-(N-pyrrolidinmethyl)phenyl, 1-methyl-2-imidazolyl, 2-methyl-1-imidazolyl, 2-(N-(cyclopropylmethyl)aminomethyl)phenyl, 2-(N-(cyclobutyl)aminomethyl)phenyl, 2-(N-(cyclopentyl)aminomethyl)phenyl and 2-(N-(3-hydroxypyrrolidinyl)methyl)phenyl. 6. A compound of Claim 1, selected from the group comprising: 1-[4-methoxyphenyl]-3-cyano-6-[2'-methylsulfonyl-3-fluoro[1,1']biphen-4-yl]-1,4-dihydropyrazolo[4,3-d]pyrimidin-5,7-dion; 1-[4-methoxyphenyl]-3-(methoxycarbonyl)-6-[2'-aminosulfonyl-3-fluoro[1,1']biphen-4-yl]-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-on; 1-[4-methoxyphenyl]-3-(aminocarbonyl)-6-[2'-aminosulfonyl-3-fluoro[1,1']biphen-4-yl]-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-on; 1-[4-methoxyphenyl]-3-(methoxycarbonyl)-6-[2'-aminosulfonyl[1,1']biphen-4-yl]-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-on; 1-[4-methoxyphenyl]-6-[2'-aminosulfonyl[1,1']biphen-4-yl]-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-on-3-carboxylic acid; 1-[4-methoxyphenyl]-3-(aminocarbonyl)-6-[2'-aminosulfonyl[1,1']biphen-4-yl]-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-on; 1-[4-methoxyphenyl]-3-cyano-6-[2'-aminosulfonyl[1,1']biphen-4-yl]-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-on; 1-[4-methoxyphenyl]-3-(aminomethyl)-6-[2'-aminosulfonyl[1,1']biphen-4-yl]-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-on; 1-[4-methoxyphenyl]-3-(ethoxycarbonyl)-6-[4-(2-methylimidazole-1'-yl)phenyl]-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-on; 1-[4-methoxyphenyl]-3-(aminocarbonyl)-6-[4-(2-methylimidazole-1'-yl)phenyl]-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-on; 1-[4-methoxyphenyl]-3-(ethoxycarbonyl)-6-[2'-N-pyrrolidinyl-methyl[1,1']biphen-4-yl]-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-on; 1-[4-methoxyphenyl]-3-(ethoxycarbonyl)-6-[2'-N-pyrrolidinyl-methyl[1,1']biphen-4-yl]-1,4,5,6-tetrahydropyrazolo[4,3-d]pyrimidin-7-on; 1-[4-methoxyphenyl]-3-(aminocarbonyl)-6-[2'-N-pyrrolidinyl-methyl[1,1']biphen-4-yl]-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-on; 1-[4-methoxyphenyl]-3-cyano-6-[2'-N-pyrrolidinmethyl[1,1']biphen-4-yl]-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-on; 1-[4-methoxyphenyl]-3-(ethoxycarbonyl)-6-[2-fluoro-4-(2-dimethylaminomethylimidazole-1'-yl)phenyl]-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-on; 1-[2-aminomethylphenyl]-3-(ethoxycarbonyl)-6-[2'-methylsulfonyl[1,1']-biphen-4-yl]-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-on; 1-[3-aminoiminomethylphenyl]-3-methyl-6-[2'-aminosulfonyl[1,1']-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo[3,4-c]pyridin-7-on; 1-[2-aminomethylphenyl]-3-methyl-6-[2'-aminosulfonyl[1,1']-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo[3,4-c]pyridin-7-on; 1-[3-aminobenzisoxazole-5'-yl]-3-methyl-6-[2'-aminosulfonyl[1,1']-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo[3,4-c]pyridin-7-on; 1-[4-methoxyphenyl]-3-cyano-6-[2'-N,N-dimethylaminomethyl[1,1']biphen-4-yl]-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-on; 1-[4-methoxyphenyl]-3-cyano-5-methyl-6-[2'-N,N-dimethylamino-methyl[1,1']biphen-4-yl]-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-on; 1-[2-aminomethylphenyl]-3-cyano-6-[2'-methylsulfonyl-3-fluoro[1,1']biphen-4-yl]-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-on; 1-[4-methoxylphenyl]-3-trifluoromethyl-4-methyl-6-[2'-aminosulfonyl[1,1']biphen-4-yl]-1,6-dihydropyrazolo[3,4-d]pyridazin-7-on; 1-[4-methoxylphenyl]-3-trifluoromethyl-4-methyl-6-[2'-N-pyrrolidinilmethyl[1,1']biphen-4-yl]-1,6-dihydropyrazolo[3,4-d]pyridazin-7-on; 1-[3-aminobenzisoxazole-5'-yl]-3-trifluoromethyl-6-[4-(1-methylimidazole-2'-yl)phenyl]-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-on; 1-[4-methoxylphenyl]-3-(ethoxycarbonyl)-6-[2'-hydroxymethyl-3-fluoro[1,1']biphen-4-yl]-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-on; 1-[4-methoxylphenyl]-3-(ethoxycarbonyl)-6-[2'-N-pyrrolidinyl-methyl-3-fluoro[1,1']biphen-4-yl]-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-on; 1-[4-methoxylphenyl]-3-(aminocarbonyl)-6-[2'-N-pyrrolidinyl-methyl-3-fluoro[1,1']biphen-4-yl]-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-on; 1-[4-methoxylphenyl]-3-(aminocarbonyl)-6-[2'-(3-(R)-hydroxy-N-pyrrolidinylmethyl)-3-fluoro[1,1']biphen-4-yl]-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-on; 1-[4-methoxylphenyl]-3-(N-formylaminomethyl)-6-[2'-methylsulfonyl-3-fluoro[1,1']biphen-4-yl]-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-on; 1-[3-aminobenzisoxazole-5'-yl]-3-(ethoxycarbonyl)-6-[2'-hydromethyl[1,1']biphen-4-yl]-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-on; 1-[3-aminobenzisoxazole-5'-yl]-3-(ethoxycarbonyl)-6-[2'-N-pyrrolidinylmethyl[1,1']biphen-4-yl]-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-on; 1-[4-methoxylphenyl]-3-trifluoromethyl-7-[2'-methylsulfonyl-[1,1']biphen-4-yl]-4,5,6,7-dihydropyrazolo[3,4-c]azepin-8-on; 1-[4-methoxylphenyl]-3-trifluoromethyl-7-[2'-aminosulfonyl-3-fluoro[1,1']biphen-4-yl]-4,5,6,7-tetrahydropyrazolo[3,4-c]azepin-8-on; 1-[4-methoxylphenyl]-3-trifluoromethyl-7-[2'-N-pyrrolidinylmethyl[1,1']biphen-4-yl]-4,5,6,7-tetrahydropyrazolo[3,4-c]azepin-8-on; 1-[3-aminobenzisoxazole-5'-yl]-3-trifluoromethyl-7-[2'-N-pyrrolidinylmethyl[1,1']biphen-4-yl]-4,5,6,7-tetrahydropyrazolo[3,4-c]azepin-8-on; 1-[3-aminobenzisoxazole-5'-yl]-3-trifluoromethyl-7-[2'-N-dimethylaminomethyl[1,1']biphen-4-yl]-4,5,6,7-tetrahydropyrazolo[3,4-c]azepin-8-on; 1-[3-aminobenzisoxazole-5'-yl]-3-trifluoromethyl-7-[2'-N-isopropylaminomethyl[1,1']biphen-4-yl]-4,5,6,7-tetrahydropyrazolo[3,4-c]azepin-8-on; 1-[3-aminobenzisoxazole-5'-yl]-3-trifluoromethyl-7-[2'-(3-(R)-hydroxy-N-pyrrolidinyl)methyl[1,1']biphen-4-yl]-4,5,6,7-tetrahydropyrazolo[3,4-c]azepin-8-on; 1-[3-aminobenzisoxazole-5'-yl]-3-trifluoromethyl-7-[2'-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-3-fluoro[1,1']biphen-4-yl]-4,5,6,7-tetrahydropyrazolo[3,4-c]azepin-