Patent EA-005031-B1 (EA)
Title: Substituted polycyclic aryl and heteroarylpyrazinones useful for selective inhibition of the coagulation cascade
Inventor: SOUTH MICHAEL S
IPC: A61K31/4965
Filed: 2000-05-18
Abstract: 1. The compound having the Formula: or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R<32>, the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R<36>, a carbon adjacent to R<32> and two atoms from the carbon at the point of attachment is optionally substituted by R<33>, a carbon adjacent to R<36> and two atoms from the carbon at the point of attachment is optionally substituted by R<35>, and any carbon adjacent to both R<33> and R<35> is optionally substituted by R<34>; R<32>, R<33>, R<34>, R<35> and R<36> are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, C1-10 alkylthio, amidosulfonyl, monoC1-10 alkyl amidosulfonyl, diC1-10 alkyl amidosulfonyl, C1-10 alkyl, halo, haloC1-10 alkyl, haloalkoxy, hydroxyC1-10 alkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q<B>; A is selected from the group consisting of single covalent bond and (CH(R<15>))pa-(W<7>)rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 3, and W<7> is selected from the group consisting of (R<7>)NC(O) and N(R<7>); R<7> is selected from the group consisting of hydrido, hydroxy and C1-10 alkyl; R<15> is selected from the group consisting of hydrido, halo, C1-10 alkyl, and haloC1-10 alkyl; R<1> is selected from the group consisting of hydrido, C1-10 alkyl, cyano, haloC1-10 alkyl, and halo; R<2> is Z<0>-Q; Z<0> is selected from the group consisting of single covalent bond and CH2; Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R<9>, the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R<13>, a carbon adjacent to R<9> and two atoms from the carbon at the point of attachment is optionally substituted by R<10>, a carbon adjacent to R<13> and two atoms from the carbon at the point of attachment is optionally substituted by R<12>, and any carbon adjacent to both R<10> and R<12> is optionally substituted by R<11>; R<9>, R<11> and R<13> are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, C1-10 alkylthio, C1-10 alkylsulfonamido, C1-10 alkylsulfinyl, C1-10 alkylsulfonyl, amidosulfonyl, monoC1-10 alkyl amidosulfonyl, C1-10 alkyl, alkoxy, halo, haloC1-10 alkyl, haloalkoxy, hydroxyC1-10 alkyl, carboxy, carboxamido, and cyano; R<10> and R<12> are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, C1-10 alkyl, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, C1-10 alkylsulfonamido, amidosulfonyl, monoC1-10 alkyl amidosulfonyl, diC1-10 alkyl amidosulfonyl, hydroxyC1-10 alkyl, aminoC1-10 alkyl, carboalkoxy, carboxy, carboxyC1-10 alkyl, amidocarbonyl, halo, haloC1-10 alkyl, and cyano; Y<0> is a group of formula (IV): wherein D<5>, D<6>, J<5> and J<6> are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, K<2> is C, no more than one of D<5>, D<6>, J<5> and J<6> is O, no more than one of D<5>, D<6>, J<5> and J<6> is S, one of D<5>, D<6>, J<5> and J<6> must be a covalent bond when two of D<5>, D<6>, J<5> and J<6> are O and S, and no more than four of D<5>, D<6>, J<5> and J<6> are N; R<16>, R<17>, R<18> and R<19> are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloC1-10 alkylthio, alkoxy, hydroxy, amino, lower alkylamino, C1-10 alkylthio, C1-10 alkylsulfinyl, C1-10 alkylsulfonyl, alkanoyl, haloalkanoyl, C1-10 alkyl, halo, haloC1-10 alkyl, haloalkoxy, hydroxyC1-10 alkyl, aminoC1-10 alkyl, and cyano; R<16> and R<19> are optionally Q<B> with the proviso that no more than one of R<16> and R<19> is Q<B> and that Q<B> is Q<BE>; Q<B> is selected from the group consisting of NR<20>R<21>, Q<BE>, wherein Q<BE> is hydrido, and C(NR<25>)NR<23>R<24>, with the proviso that no more than one of R<20> and R<21> is hydroxy and that no more than one of R<23> and R<24> is hydroxy at the same time; R<20>, R<21>, R<23>, R<24> and R<25> are independently selected from the group consisting of hydrido, C1-10 alkyl, and hydroxy; Q<S> is selected from the group consisting of a single covalent bond, CH2, and CH2CH2. 2. The compound as recited in Claim 1 or a pharmaceutically acceptable salt thereof, wherein: B is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 1,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R<32>, the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R<36>, a carbon adjacent to R<32> and two atoms from the carbon at the point of attachment is optionally substituted by R<33>, a carbon adjacent to R<36> and two atoms from the carbon at the point of attachment is optionally substituted by R<35>, and any carbon adjacent to both R<33> and R<35> is optionally substituted by R<34>; R<32>, R<33>, R<34>, R<35> and R<36> are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and Q<B>; A is selected from the group consisting of single covalent bond, NH, N(CH3), N(OH), CH2, CH3CH, CF3CH, NHC(O), N(CH3)C(O), C(O)NH, C(O)N(CH3), CH2CH2, CH2CH2CH2, CH3CHCH2 and CF3CHCH2; R<1> is selected from the group consisting of hydrido, methyl, ethyl, propyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, fluoro, chloro, and bromo; R<2> is Z<0>-Q; Z<0> is selected from the group consisting of single covalent bond and CH2; Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 1,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R<9>, the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R<13>, a carbon adjacent to R<9> and two atoms from the carbon at the point of attachment is optionally substituted by R<10>, a carbon adjacent to R<13> and two atoms from the carbon at the point of attachment is optionally substituted by R<12>, and any carbon adjacent to both R<10> and R<12> is optionally substituted by R<11>; R<9>, R<11> and R<13> are independently selected from the group consisting of hydrido, hydroxy, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano; R<10> and R<12> are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, fluoro, chloro, bromo, and cyano; Y<0> is selected from the group consisting of: 1-Q<B>-4-Q<S>-2-R<16>-3-R<17>-5-R<L8>-6-R<19> benzene, 2-Q<B>-5-Q<S>-6-R<17>-4-R<18>-2-R<19> pyridine, 3-Q<B>-6-Q<S>-2-R<16>-5-R<18>-4-R<19> pyridine, 2-Q<B>-4-Q<S>-3-R<16>-6-R<18> pyrazine, 3-Q<B>-6-Q<S>-2-R<18>-5-R<18>-4-R<19> pyridazine, 2-Q<B>-5-Q<S>-6-R<17>-4-R<18> pyrimidine, 5-Q<B>-2-Q<S>-3-R<16>-6-R<19> pyrimidine, 3-Q<B>-5-Q<S>-4-R<16>-2-R<19> thiophene, 2-Q<B>-5-Q<S>-3-R<16>-4-R<17> thiophene, 3-Q<B>-5-Q<S>-4-R<16>-2-R<19> furan, 2-Q<B>-5-Q<S>-3-R<16>-4-R<17> furan, 3-Q<B>-5-Q<S>-4-R<16>-2-R<19> pyrrole, 2-Q<B>-5-Q<S>-3-R<16>-4-R<17> pyrrole, 4-Q<B>-2-Q<S>-5-R<19> imidazole, 2-Q<B>-4-Q<S>-5-R<17> imidazole, 3-Q<B>-5-Q<S>-4-R<16> isoxazole, 5-Q<B>-3-Q<S>-4-R<16> isoxazole, 2-Q<B>-5-Q<S>-4-R<16> pyrazole, 4-Q<B>-2-Q<S>-5-R<19> thiazole and 2-Q<B>-5-Q<S>-4-R<17> thiazole; R<16>, R<17>, R<18> and R<19> are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, guanidino, met