Patent EA-003210-B1 (EA)
Title: Novel guanidine mimics as factor xa inhibitors
Inventor: LAM PATRICK Y
IPC: A61K31/416
Filed: 1998-06-18
Abstract: 1. A compound of formula I: or a stereoisomer or pharmaceutically acceptable salt thereof, wherein; ring D is selected from -CH2N=CH-, -CH2CH2N=CH-, a 5-6 membered aromatic system containing from 0-2 heteroatoms selected from the group N, O, and S; ring D is substituted with 0-2 R, provided that when ring D is unsubstituted, it contains at least one heteratom; ring E contains 0-2 N atom and is substituted by 0-1 R R is selected from Cl, F, Br, I, OH, C1-3 alkoxy, NH2 NH(C1-3 alkyl), N(C1-3 alkyl)2, CH2NH2, CH2NH(C1-3 alkyl), CH2N(C1-3 alkyl)2, CH2CH2NH2, CH2CH2NH(C1-3 alkyl), and CH2CH2N(C1-3 alkyl)2; M is selected from the group: J is O or S; J<A> is NH or NR<1A>; Z is selected from a bond, C1-4 alkylene, (CH2)rO(CH2)r, (CH2)rNR<3>(CH2)r, (CH2)rC(O)(CH2)r, (CH2)rC(O)O(CH2)r, (CH2)rOC(O)(CH2)r, (CH2)rC(O)NR<3>(CH2)r, (CH2)rNR<3>C(O)(CH2)r, (CH2)rOC(O)O(CH2)r, (CH2)rOC(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, N-O, N-S, NCH2N, NCHvO or NCH2S bond with ring M or group A; R<1A> and R<1B> are independently absent or selected from -(CH2)r-R<1>', -CH=CH-R<1>', NCH2R<1>", OCH2R<1>", SCH2R<1>", NH(CH2)2(CH2)t R<1>', O(CH2)2(CH2)tR<1>' and S(CH2)2(CH2)tR<1>'; alternatively, R<1A> and R<1B>, when attached to adjacent carbon atoms, together with the atoms to which they are attached form a 5-8 membered saturated, partially saturated or saturated ring substituted with 0-2 R<4> and which contains from 0-2 heteroatoms selected from the group consisting of N, O, and S; alternatively, when Z is C(O)NH and R<1A> is attached to a ring carbon adjacent to Z, then R<1A> is a C(O) which replaces the amide hydrogen of Z to form a cyclic imide; R<1'> is selected from H, C1-3 alkyl, F, Cl, Br, I, -CN, -CHO, (CF2)rCF3, (CH2)rOR<2>, NR<2>R<2A>, C(O)R<2C>, OC(O)R<2>, (CF2)rCO2R<2C>, S(O)pR<2B>, NR<2>(CH2)rOR<2>, CH(=NR<2C>)NR<2>R<2A>, NR<2>C(O)R<2B>, NR<2>C(O)NHR<2B>, NR<2>C(O)2R<2A>, OC(O)NR<2A>R<2B>, C(O)NR<2>R<2A>, C(O)NR<2>(CH2)rOR<2>, SO2NR<2>R<2A>, NR<2>SO2R<2B>, C3-6 carbocyclic residue substituted with 0-2 R<4>, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R<4>; R<1>" is selected from H, CH(CH2OR<2>)2, C(O)R<2C>, C(O)NR<2>R<2A>, S(O)R<2B>, S(O)2R<2B> and SO2NR<2>R<2A>; R<2>, at each occurrence, 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 containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R<4B>; R<2A>, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, phenethyl, C3-6 carbocyclic residue substituted with 0-2 R<4B>, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R<4B>; R<2B>, at each occurrence, is selected from CF3, C1-4 alkoxy, 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 selected from the group consisting of N, O, and S substituted with 0-2 R<4B>; R<2C>, at each occurrence, is selected from CF3, OH, C1-4 alkoxy, 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 selected from the group consisting of N, O, and S substituted with 0-2 R<4B>; alternatively, R<2> and R<2A>, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R<4B> and containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S; R<3>, at each occurrence, is selected from H, C1-4 alkyl, and phenyl; R<3A>, at each occurrence, is selected from H, C1-4 alkyl, and phenyl; R<3B>, at each occurrence, is selected from H, C1-4 alkyl, and phenyl; R<3C>, at each occurrence, is selected from C1-4 alkyl, and phenyl; A is selected from: C3-10 carbocyclic residue substituted with 0-2 R<4>, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R<4>; B is selected from: H, Y, and X-Y; X is selected from C1-4 alkylene, -CR<2> (CR<2>R<2B>) (CH2)t-, -C(O)-, -C(=NR<1>")-, -CR<2>(NR<1''>R<2>)-, -CR<2>(OR<2>)-, - CR<2>(SR<2>)-, -C(O)CR<2>R<2A>-, -CR<2>R<2A>C(O)-, -S(O)p-, -S(O)pCR<2>R<2A>-, -CR<2>R<2A>S(O)p-, -S(O)1NR<2>-, -NR<2>S(O)2-, -NR<2>S(O)2CR<2>R<2A>-, -CR<2>R<2A>S(O)2NR<2>-, -NR<2>S(O)2NR<2>-, -C(O)NR<2>-, -NR<2>C(O)-, -C(O)NR<2>CR<2>R<2A>-, -NR<2>C(O)CR<2>R<2A>-, -CR<2>R<2A>C(O)NR<2>-, -CR<2>R<2A>NR<2>C(O)-, -NR<2>C(O)O-, -OC(O)NR<2>-, -NR<2>C(O)NR<2>-, -NR<2>-, -NR<2>CR<2>R<2A>-, -CR<2>R<2A>NR<2>-, O, -CR<2>R<2A>O- and -OCR<2>R<2A>-; Y is selected from: (CH2)rNR<2>R<2A>, provided that X-Y do not form a N-N, O-N, or S-N bond, C3-10 carbocyclic residue substituted with 0-2 R<4A>, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R<4A>; R<4>, at each occurrence, is selected from H, =O, (CH2)rOR<2>, F, Cl, Br, I, C1-4 alkyl, -CN, NO2, (CH2)rNR<2>R<2A>, (CH2)rC(O)R<2A>, NR<2>C(O)R<2B>, C(O)NR<2>R<2A>, NR<2>C(O)NR<2>R<2A>, CH(-NR<2>)NR<2>R<2A>, CH(=NS(O)2R<5>)NR<2>R<2A>, NHC(=NR<2>)NR<2>R<2A>, C(O)NHC(=NR<2>)NR<2>R<2A>, SO2NR<2>R<2A>, NR<2>SO2NR<2>R<2A>, NR<2>SO2-C1-4 alkyl, NR<2>SO2R<5>, S(O)pR<5>, (CF2)rCF3, NCH2R<1>", OCH2R<1>", SCH2R<1>", N(CH2)2(CH2)tR<1>', O(CH2)2(CH2)tR<1>' and S(CH2)2(CH2)tR<1>';alternatively, one R<4> is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S; provided that if B is H, then R<4> is other than tetrazole, C(O)-alkoxy, and C(O)NR<2>R<2A>; R<4A>, at each occurrence, is selected from H, =O, (CH2)rOR<2>, (CH2)r-F, (CH2)r-Br, (CH2)r-Cl, I, C1-4 alkyl, -CN, NO2, (CH2)rNR<2>R<2A>, (CH2)rNR<2>R<2B>, (CH2)rC(O)R<2C>, NR<2>C(O)R<2B>, C(O)NR<2>R<2A>, C(O)NH(CH2)2NR<2>R<2A>, NR<2>C(O)NR<2>R<2A>, CH(=NR<2>)NR<2>R<2A>, NHC(=NR<2>)NR<2>R<2A>, SO2NR<2>R<2A>, NR<2>SO2NR<2>R<2A>, NR<2>SO2-C1-4 alkyl, C(O)NHSO2-C1-4 alkyl, NR<2>SO2R<5>, S(O)pR<5> and (CF2)rCF3; alternatively, 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 and substituted with 0-1 R<5>; R<4B>, at each occurrence, is selected from H, =O, (CH2)rOR<3>, F, Cl, Br, I, C1-4 alkyl, -CN, NO2, (CH2)rNR<3>R<3A>, (CH2)rC(O)R<3>, (CH2)rC(O)OR<3C>, NR<3>C(O)R<3A>, C(O)NR<3>R<3A>, NR<3>C(O)NR<3>R<3A>, CH(=NR<3>)NR<3>R<3A>, NH<3>C(=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>, F, Cl, Br, I, 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>, CH(=NH)NH2, NHC(=NH)NH2, SO2NR<2>R<2A>, NR<2>SO2NR<2>R<2A> and NR<2>SO2-C1-4 alkyl; n is selected from 0, 1, 2, and 3; m is selected from 0, 1, and 2; p is selected from 0, 1, and 2; r is selected from 0, 1, 2, and 3; s is selected from 0, 1, and 2; and, t is selected from 0 and 1. provided that if (a) D ring is furan, thiophene, pyrrol, isoxazole, isothiazole or pyrazole, then Z is not a bond; (b) A is benzofuran, benzothiaphene, indole, benzisoxazole, benzoisothiazole or indazole, then (1) ring M is pyrazole or (2) Z is not a bond or C1-C4 alkylene. 2. A compound according to Claim 1, wherein: D-E is selected from the group: 1-aminoisoquinolin-7-yl; 1,3-diaminoisoquinolin-7-yl; 1,4-diaminoisoquinolin-7-yl; 1,5-diaminoisoquinolin-7-yl; 1,6-diaminoisoquinolin-7-yl; 1-amino-3-hydroxyisoquinolin-7-yl; 1-amino-4-hydroxyisoquinolin-7-yl; 1-amino-5-hydroxyisoquinolin-7-yl; 1-amino-6-hydroxyisoinolin-7-yl; 1-amino-3-methoxyisoquinolin-7-yl; 1-amino-4-methoxyisoquinolin-7-yl; 1-amino-5-methoxyisoquinolin-7-yl; 1-amino-6-methoxyisoquinolin-7-yl; 1-hydroxyisoquinolin-7-yl; 4-aminoquinazol-6-yl; 2,4-diaminoquinazol-6-yl; 4,7-diaminoquinazol-6-yl; 4,8-diaminoquinazol-6-yl; 1-aminophthalaz-7-yl; 1,4-diaminophthalaz-7-yl; 1,5-diaminophthalaz-7-yl; 1,6-diaminophthalaz-7-yl; 4-aminopterid-6-yl; 2,4-diaminopterid-6-yl; 4,6-diaminopterid-6-yl; 8-amino-1,7-naphthyrid-2-yl; 6,8-diamino-1,7-naphthyrid-2-yl; 5,8-diamino-1,7-naphthyrid-2-yl; 4,8-diamino-1,7-naphthyrid-2-yl; 3,8-diamino-1,7-naphthyrid-2-yl; 5-amino-2,6-naphthyrid-3-yl; 5,7-diamino-2,6-naphthyrid-3-yl; 5,8-diamino-2,6-naphthyrid-3-yl; 1,5-diamino-2,6-naphthyrid-3-yl; 5-amino-1,6-naphthyrid-3-yl; 5,7-diamino-1,6-naphthyrid-3-yl; 5,8-diamino-1,6-naphthyrid-3-yl; 2,5-diamino-1,6-naphthyrid-3-yl; 3-aminoindazol-5-yl; 3-hydroxyindazol-5-yl; 3-aminobenzisoxazol-5-yl; 3-hydroxybenzisoxazol-5-yl; 3-aminobenzisothiazol-5-yl; 3-hydroxybenzisothiazol-5-yl; 1-amino-3,4-dihydroisoquinolin-7-yl; and, 1-aminoisoindol-6-yl; M is selected from the group: Z is selected from (CH2)rC(O)(CH2)r, (CH2)rC(O)O(CH2)r, (CH2)rC(O)NR<3>(CH2)r, (CH2)rS(O)p(CH2)r and (CH2)rSO2NR<3>(CH2)r; and, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R<4A>; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazole, thiadiazole, triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, benzofuran, benzothiofuran, indole, benzimidazole, benzoxazole,