Details for Patent: 6,632,815

Title:	Inhibitors of factor Xa
Abstract:	Novel compounds, their salts and compositions related thereto having activity against mammalian factor Xa are disclosed. The compounds are useful in vitro or in vivo for preventing or treating coagulation disorders.
Inventor(s):	Zhu; Bing-Yan (Belmont, CA), Jia; Zhaozhong Jon (South San Francisco, CA), Huang; Wenrong (Cupertino, CA), Song; Yonghong (Foster City, CA), Kanter; James (South San Francisco, CA), Scarborough; Robert M. (Half Moon Bay, CA)
Assignee:	Millennium Pharmaceuticals, Inc. (Cambridge, MA)
Filing Date:	Feb 28, 2001
Application Number:	09/794,214
Claims:	1. A compound of formula (I): 2. The compound of claim 1, wherein: A is phenyl, which is substituted with 0-2 R.sup.1 groups; each R.sup.1 is a member independently selected from the group consisting of: halo, --C.sub.1-4 alkyl, --CN, --NO.sub.2, --(CH.sub.2).sub.m --N(--R.sup.2,R.sup.3), --C(.dbd.O) --N(--R.sup.2,--R.sup.3), --S(.dbd.O).sub.2 --N(--R.sup.2,--R.sup.3), --S(.dbd.O).sub.2,--R.sup.2, --(CH.sub.2).sub.m --C(.dbd.NR.sup.3)--R.sup.2, --(CH.sub.2).sub.m --C(.dbd.NR.sup.2)--N(R.sup.2,R.sup.3), --(CH.sub.2).sub.m --N(R.sup.2)--C(.dbd.NR.sup.2)--N(R.sup.2, R.sup.3), --CF.sub.3, --(CH.sub.2).sub.m --O--R.sup.2 and a 5-6 membered aromatic heterocyclic ring having 1-4 heteroatoms each independently selected from the group consisting of N, O and S; each of R.sup.2 and R.sup.3 is independently selected from the group consisting of: --H, --C.sub.1-4 alkyl and --C.sub.0-4 alkyl-(carbocyclic aryl); m is an integer of 0-2; Q is a direct link; D is phenyl, which is substituted with 0-2 R.sup.1a groups; each R.sup.1a is a member independently selected from the group consisting of: halo, --C.sub.1-4 alkyl, --CN, --NO.sub.2, --(CH.sub.2).sub.n, --N(--R.sup.2a, --R.sup.3a), --S(.dbd.O).sub.2 --N(--R.sup.2a, --R.sup.3a), --S(.dbd.O).sub.2 --R.sup.2a, --CF.sub.3, --(CH.sub.2).sub.n --OR.sup.2a, --C(.dbd.O)--O--R.sup.2a, --C(.dbd.O)--N(--R.sup.2a, --R.sup.3a) and a 5-6 membered aromatic heterocyclic ring having 1-4 heteroatoms each independently selected from the group consisting of N, O and S; n is an integer of 0-2; each of R.sup.2a and R.sup.3a is independently selected from the group consisting of: --H, --C.sub.1-4 alkyl, and --C.sub.1-4 alkyl-(carbocyclic aryl); E is --NH--C(.dbd.O)--; G is pyrazolyl, which is substituted with 0-2 R.sup.1b groups; each R.sup.1b is a member independently selected from the group consisting of: halo, --C.sub.1-4 alkyl, --CN, --NO.sub.2, --N(--R.sup.2b, --R.sup.3b), --C(.dbd.O)--N(--R.sup.2b, --R.sup.3b), --S(.dbd.O).sub.2 --N(--R.sup.2b, --R.sup.3b), --S(.dbd.O).sub.2 --R.sup.2b, --CF.sub.3, --O--R.sup.2b, --O--CH.sub.2 --CH.sub.2 --O--R.sup.2b, --O--CH.sub.2 --C(.dbd.O)--O--R.sup.2b, --N(--R.sup.2b)--CH.sub.2 --CH.sub.2 --O--R.sup.2b, --N(--CH.sub.2 --CH.sub.2 --O--R.sup.2b).sub.2, --N(--R.sup.2b)--C(.dbd.O)--R.sup.3b, --N(--R.sup.2b)--S(.dbd.O).sub.2 --R.sup.3b and a 5-6 membered heterocyclic ring having 1-4 heteroatoms each independently selected from the group consisting of N, O and S; each of R.sup.2b and R.sup.3b is independently selected from the group consisting of: --H, --C.sub.1-4 alkyl and --C.sub.1-4 alkyl-(carbocyclic aryl); J is a direct link; X is naphthyl, which is substituted with 0-3 R.sup.1c groups; each R.sup.1c is a member independently selected from the group consisting of: halo, --C.sub.1-4 alkyl, --CN, --NO.sub.2, --N(--R.sup.2c, --R.sup.3c), --C(.dbd.O)--N(--R.sup.2c, --R.sup.3c), --C(.dbd.NH)--N(--R.sup.2c, --R.sup.3c), --C(.dbd.NMe)--N(--R.sup.2c, --R.sup.3c), --S(.dbd.O).sub.2 --N(--R.sup.2c, --R.sup.3c), --S(.dbd.O).sub.2 --R.sup.2c, --S(.dbd.O).sub.2 --O.sup.-, --CF.sub.3, --O--R.sup.2c, --O--CH.sub.2 --CH.sub.2 --O--R.sup.2c, --O--CH.sub.2 --C(.dbd.O)--O--R.sup.2c, --N(--CH.sub.2 --CH.sub.2 --O--R.sup.2c).sub.2, --(CH.sub.2).sub.z --N(--R.sup.2c)--C(.dbd.O)--R.sup.3c, --(CH.sub.2).sub.z --N(--R.sup.2c)--S(.dbd.O).sub.2 --R.sup.3c, and a 5-6 membered heterocyclic ring having 1-4 heteroatoms each independently selected from the group consisting of N, O and S; z is an integer of 0-2; each of R.sup.2c and R.sup.3c is independently selected from the group consisting of: --H, --C.sub.1-4 alkyl and --C.sub.1-4 alkyl-(carbocyclic aryl); or all pharmaceutically acceptable diastereomers, enantiomers or mixtures thereof, salts, hydrates or solvates thereof. 3. The compound of claim 1, wherein: A is selected from the group consisting of: ##STR1000## Q is a direct link; D is selected from the group consisting of: ##STR1001## E is --NH--C(.dbd.O)--; G is the following formula: ##STR1002## each R.sup.1b is a member independently selected from the group consisting of: --H, --Me, --CF.sub.3, --F, --Cl, --Br, --SO.sub.2 Me, --CN, --CONH.sub.2, --CONMe.sub.2, --NH.sub.2, --NO.sub.2, --NHCOMe, --NHSO.sub.2 Me, --CH.sub.2 NH.sub.2 and --CO.sub.2 H; J is a direct link; X is selected from the group consisting of: ##STR1003## ##STR1004## ##STR1005## ##STR1006## ##STR1007## ##STR1008## ##STR1009## ##STR1010## ##STR1011## ##STR1012## or all pharmaceutically acceptable diastereomers, enantiomers or mixtures thereof, salts, hydrates or solvates thereof. 4. The compound of claim 1, wherein: A is phenyl, which is substituted with 0-2 R.sup.1 groups; each R.sup.1 is a member independently selected from the group consisting of: --S(.dbd.O).sub.2 --N(--R.sup.2, --R.sup.3), 5(.dbd.O).sub.2 --R.sup.2, --CH.sub.2 N(--R.sup.2, --R.sup.3), --CN and halo; each of R.sup.2 and R.sup.3 is independently selected from the group consisting of: --H and --C.sub.1-4 alkyl; Q is a direct link; D is phenyl, which is substituted with 0-2 R.sup.1a groups; each R.sup.1a is a member independently selected from the group consisting of: --H and halo; E is --NH--C(.dbd.O)--; G is pyrazolyl, which is substituted with 0-2 R.sup.1b groups; each R.sup.1b is a member independently selected from the group consisting of: --Me, --Et, --CF.sub.3, --C(.dbd.0)--NH.sub.2, --NH.sub.2, --NH--C(.dbd.O)--Me, --NH--S(.dbd.O).sub.2 --Me, --SMe, --S(.dbd.O).sub.2 --Me and halo; J is a direct link; X is naphthyl, which is substituted with 0-3 R.sup.1c groups; each R.sup.1c is a member independently selected from the group consisting of: halo, --Me, --CF.sub.3, --OH, --OMe, --NH.sub.2, --CN, --NO.sub.2, --CH.sub.2 OH, --C.sub.1-5 alkyl, --C(.dbd.O)--N(--R.sup.2c, --R.sup.3c), --S(.dbd.O).sub.2 --R.sup.2c, --S(.dbd.O).sub.2 --N(--R.sup.2c, --R.sup.3c), --S(.dbd.O).sub.2 --OH, --C(.dbd.NH)--N(--R.sup.2c, --R.sup.3c), 2-imidazolin-2-yl and 1-methyl-2-imidazolin-2-yl; each of R.sup.2c and R.sup.3c is independently selected from the group consisting of: --H, --OH, --NH.sub.2 and --C.sub.1-4 alkyl; or all pharmaceutically acceptable diastereomers, enantiomers or mixtures thereof, salts, hydrates or solvates thereof. 5. The compound of claim 1, according to the following formula: ##STR1013## wherein: R.sup.1 selected from the group consisting of: --SO.sub.2 NH.sub.2, --SO.sub.2 Me, --CH.sub.2 NH.sub.2 and --CH.sub.2 NMe.sub.2 ; R.sup.1a is selected from the group consisting of: --H, --F, --Cl and --Br; R.sup.1c1 is selected from the group consisting of: --H, --F, --Cl, --Br, --NH.sub.2, --OH, --SO.sub.2 Me, --SO.sub.2 Et, --SO.sub.2 NH.sub.2, --NO.sub.2, --CN, --CONH.sub.2, --CH.sub.2 OH; p2 R.sup.1c2 is selected from the group consisting of: --H, --F, --Cl and --Br; R.sup.1c3 is selected from the group consisting of: --H, --F, --Cl and --Br; and G is the following formula: ##STR1014## wherein: R.sup.1b1 is selected from the group consisting of --H, --CH.sub.3 and --CF.sub.3. 6. The compound of claim 1, according to the following formula: ##STR1015## wherein: R.sup.1 selected from the group consisting of: --SO.sub.2 NH.sub.2, --SO.sub.2 Me, --CH.sub.2 NH.sub.2 and --CH.sub.2 NMe.sub.2 ; R.sup.1a is selected from the group consisting of: --H, --F, --Cl and --Br; R.sup.1c1 is selected from the group consisting of: --H, --F, --Cl, --Br, --NH.sub.2, --OH, --SO.sub.2 Me, --SO.sub.2 Et, --SO.sub.2 NH.sub.2, --NO.sub.2, --CN, --CONH.sub.2, --CH.sub.2 OH; R.sup.1c2 is selected from the group consisting of: --H, --F, --Cl and --Br; and G is the following formula: ##STR1016## wherein: R.sup.1b1 is selected from the group consisting of --H, --CH.sub.3 and --CF.sub.3. 7. A pharmaceutical composition for treating a condition in a mammal characterized by undesired thrombosis comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 1. 8. A method for treating a condition in a mammal characterized by undesired thrombosis comprising administering to said mammal a therapeutically effective amount of a compound of claim 1. 9. The method of claim 8, wherein the condition is selected from the group consisting of: acute coronary syndrome, myocardial infarction, unstable angina, refractory angina, occlusive coronary thrombus occurring post-thrombolytic therapy or post-coronary angioplasty, a thrombotically mediated cerebrovascular syndrome, embolic stroke, thrombotic stroke, transient ischemic attacks, venous thrombosis, deep venous thrombosis, pulmonary embolus, coagulopathy, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, thromboangiitis obliterans, thrombotic disease associated with heparin-induced thrombocytopenia, thrombotic complications associated with extracorporeal circulation, thrombotic complications associated with instrumentation, and thrombotic complications associated with the fitting of prosthetic devices. 10. A method for inhibiting the coagulation of biological samples, comprising the step of administering a compound of claim 1.