EP1178970A1 - Pyrimidinones aryle et heteroaryle polycycliques substituees utilisees comme anticoagulants - Google Patents
Pyrimidinones aryle et heteroaryle polycycliques substituees utilisees comme anticoagulantsInfo
- Publication number
- EP1178970A1 EP1178970A1 EP00931928A EP00931928A EP1178970A1 EP 1178970 A1 EP1178970 A1 EP 1178970A1 EP 00931928 A EP00931928 A EP 00931928A EP 00931928 A EP00931928 A EP 00931928A EP 1178970 A1 EP1178970 A1 EP 1178970A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- group
- hydrido
- amino
- carbon
- hydroxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 125000001072 heteroaryl group Chemical group 0.000 title claims description 41
- 239000003146 anticoagulant agent Substances 0.000 title abstract description 9
- 229940127219 anticoagulant drug Drugs 0.000 title abstract description 7
- -1 heteroaryl pyrimidinone compounds Chemical class 0.000 claims abstract description 1732
- 150000001875 compounds Chemical class 0.000 claims abstract description 68
- 238000000034 method Methods 0.000 claims abstract description 15
- 239000000203 mixture Substances 0.000 claims abstract description 13
- 230000001732 thrombotic effect Effects 0.000 claims abstract description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 600
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 443
- 125000000217 alkyl group Chemical group 0.000 claims description 210
- 229910052760 oxygen Inorganic materials 0.000 claims description 202
- 229910052757 nitrogen Inorganic materials 0.000 claims description 194
- 125000004429 atom Chemical group 0.000 claims description 177
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 174
- 125000001188 haloalkyl group Chemical group 0.000 claims description 164
- 229910052717 sulfur Inorganic materials 0.000 claims description 162
- 125000001145 hydrido group Chemical group *[H] 0.000 claims description 158
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 154
- 125000005843 halogen group Chemical group 0.000 claims description 148
- 125000003282 alkyl amino group Chemical group 0.000 claims description 142
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 119
- 125000003545 alkoxy group Chemical group 0.000 claims description 118
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 107
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 92
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 92
- 125000004414 alkyl thio group Chemical group 0.000 claims description 87
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 87
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 78
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 72
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 69
- 125000001153 fluoro group Chemical group F* 0.000 claims description 69
- 125000000033 alkoxyamino group Chemical group 0.000 claims description 68
- 125000000623 heterocyclic group Chemical group 0.000 claims description 63
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 62
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 61
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 60
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 59
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 57
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 57
- 150000003839 salts Chemical class 0.000 claims description 55
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims description 48
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 45
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 45
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 45
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 44
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 43
- 125000003118 aryl group Chemical group 0.000 claims description 43
- 125000001246 bromo group Chemical group Br* 0.000 claims description 41
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 41
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 41
- 125000005518 carboxamido group Chemical group 0.000 claims description 40
- 125000003342 alkenyl group Chemical group 0.000 claims description 39
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 39
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 37
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 36
- 125000004995 haloalkylthio group Chemical group 0.000 claims description 36
- 125000004076 pyridyl group Chemical group 0.000 claims description 36
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 33
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 33
- 125000003435 aroyl group Chemical group 0.000 claims description 31
- 125000005422 alkyl sulfonamido group Chemical group 0.000 claims description 30
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 28
- LLAPDLPYIYKTGQ-UHFFFAOYSA-N 1-aminoethyl Chemical group C[CH]N LLAPDLPYIYKTGQ-UHFFFAOYSA-N 0.000 claims description 27
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 26
- 125000001424 substituent group Chemical group 0.000 claims description 26
- 125000000304 alkynyl group Chemical group 0.000 claims description 24
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 24
- 125000000262 haloalkenyl group Chemical group 0.000 claims description 22
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 21
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 21
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 21
- 239000001301 oxygen Substances 0.000 claims description 21
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 20
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 20
- 125000006350 alkyl thio alkyl group Chemical group 0.000 claims description 20
- 239000011593 sulfur Substances 0.000 claims description 20
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 19
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 19
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 19
- 150000001721 carbon Chemical group 0.000 claims description 19
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 19
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 18
- 125000004994 halo alkoxy alkyl group Chemical group 0.000 claims description 18
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 18
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 claims description 18
- UUFQTNFCRMXOAE-UHFFFAOYSA-N 1-methylmethylene Chemical compound C[CH] UUFQTNFCRMXOAE-UHFFFAOYSA-N 0.000 claims description 17
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 claims description 16
- SZPWXAOBLNYOHY-UHFFFAOYSA-N [C]1=CC=NC2=CC=CC=C12 Chemical group [C]1=CC=NC2=CC=CC=C12 SZPWXAOBLNYOHY-UHFFFAOYSA-N 0.000 claims description 16
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 16
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 16
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 claims description 15
- 241000124008 Mammalia Species 0.000 claims description 15
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 15
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims description 15
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 14
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 14
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 14
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 13
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 13
- 210000004369 blood Anatomy 0.000 claims description 13
- 239000008280 blood Substances 0.000 claims description 13
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 13
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 13
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 13
- 208000007536 Thrombosis Diseases 0.000 claims description 12
- 125000004688 alkyl sulfonyl alkyl group Chemical group 0.000 claims description 12
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 12
- 230000015572 biosynthetic process Effects 0.000 claims description 12
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 claims description 12
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 11
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 11
- 230000002401 inhibitory effect Effects 0.000 claims description 11
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 11
- 125000004665 trialkylsilyl group Chemical group 0.000 claims description 11
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 10
- 125000005466 alkylenyl group Chemical group 0.000 claims description 10
- 125000004273 azetidin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])C1([H])* 0.000 claims description 10
- 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 claims description 10
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 claims description 10
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 10
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 10
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 10
- OKTJSMMVPCPJKN-OUBTZVSYSA-N Carbon-13 Chemical compound [13C] OKTJSMMVPCPJKN-OUBTZVSYSA-N 0.000 claims description 9
- 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 claims description 9
- 125000004423 acyloxy group Chemical group 0.000 claims description 8
- 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 claims description 8
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 7
- 125000006125 ethylsulfonyl group Chemical group 0.000 claims description 7
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 7
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 claims description 7
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 claims description 7
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 7
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 7
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 claims description 6
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 claims description 6
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 claims description 6
- 150000001408 amides Chemical group 0.000 claims description 6
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 6
- 125000006040 2-hexenyl group Chemical group 0.000 claims description 5
- 125000006029 2-methyl-2-butenyl group Chemical group 0.000 claims description 5
- 125000006024 2-pentenyl group Chemical group 0.000 claims description 5
- 125000006041 3-hexenyl group Chemical group 0.000 claims description 5
- 125000006042 4-hexenyl group Chemical group 0.000 claims description 5
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 5
- 210000001772 blood platelet Anatomy 0.000 claims description 5
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 5
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 claims description 5
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 5
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 4
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 125000006031 2-methyl-3-butenyl group Chemical group 0.000 claims description 3
- 125000006032 3-methyl-3-butenyl group Chemical group 0.000 claims description 3
- 125000006043 5-hexenyl group Chemical group 0.000 claims description 3
- 208000005189 Embolism Diseases 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 125000005034 trifluormethylthio group Chemical group FC(S*)(F)F 0.000 claims description 3
- 125000006075 1-ethyl-3-butenyl group Chemical group 0.000 claims description 2
- 206010002388 Angina unstable Diseases 0.000 claims description 2
- 206010051055 Deep vein thrombosis Diseases 0.000 claims description 2
- 206010014498 Embolic stroke Diseases 0.000 claims description 2
- 208000010378 Pulmonary Embolism Diseases 0.000 claims description 2
- 208000007814 Unstable Angina Diseases 0.000 claims description 2
- 206010047249 Venous thrombosis Diseases 0.000 claims description 2
- 201000004332 intermediate coronary syndrome Diseases 0.000 claims description 2
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 claims description 2
- LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical group NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 claims 83
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims 55
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 48
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 37
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims 30
- 229930192474 thiophene Natural products 0.000 claims 25
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 18
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims 16
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims 16
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims 15
- 125000001589 carboacyl group Chemical group 0.000 claims 15
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 14
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims 13
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims 12
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims 12
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims 12
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 12
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 12
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims 10
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims 10
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 10
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims 10
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 9
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims 8
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims 7
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims 7
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims 6
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 claims 5
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims 5
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 claims 5
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims 5
- 125000003974 3-carbamimidamidopropyl group Chemical group C(N)(=N)NCCC* 0.000 claims 5
- 125000004917 3-methyl-2-butyl group Chemical group CC(C(C)*)C 0.000 claims 5
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 claims 5
- SXIFAEWFOJETOA-UHFFFAOYSA-N 4-hydroxy-butyl Chemical group [CH2]CCCO SXIFAEWFOJETOA-UHFFFAOYSA-N 0.000 claims 5
- 125000004920 4-methyl-2-pentyl group Chemical group CC(CC(C)*)C 0.000 claims 5
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims 5
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims 4
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims 4
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 4
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims 4
- HUTNOYOBQPAKIA-UHFFFAOYSA-N 1h-pyrazin-2-one Chemical group OC1=CN=CC=N1 HUTNOYOBQPAKIA-UHFFFAOYSA-N 0.000 claims 3
- ZYHQGITXIJDDKC-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethyl]aniline Chemical group NC1=CC=CC=C1CCC1=CC=CC=C1N ZYHQGITXIJDDKC-UHFFFAOYSA-N 0.000 claims 3
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 3
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims 3
- 206010028980 Neoplasm Diseases 0.000 claims 2
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 claims 2
- 208000001435 Thromboembolism Diseases 0.000 claims 2
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical group C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims 2
- 201000011510 cancer Diseases 0.000 claims 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 2
- 239000003937 drug carrier Substances 0.000 claims 2
- 125000006074 1-ethyl-2-butenyl group Chemical group 0.000 claims 1
- 125000006052 1-methyl-3-pentenyl group Chemical group 0.000 claims 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 230000001269 cardiogenic effect Effects 0.000 claims 1
- 238000002512 chemotherapy Methods 0.000 claims 1
- 239000002319 fibrinogen receptor antagonist Substances 0.000 claims 1
- 125000004464 hydroxyphenyl group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000004576 sand Substances 0.000 claims 1
- JFALSRSLKYAFGM-UHFFFAOYSA-N uranium(0) Chemical compound [U] JFALSRSLKYAFGM-UHFFFAOYSA-N 0.000 claims 1
- 230000015271 coagulation Effects 0.000 abstract description 7
- 238000005345 coagulation Methods 0.000 abstract description 7
- 208000026106 cerebrovascular disease Diseases 0.000 abstract description 4
- 208000029078 coronary artery disease Diseases 0.000 abstract description 4
- 210000004351 coronary vessel Anatomy 0.000 abstract description 4
- 238000002560 therapeutic procedure Methods 0.000 abstract description 4
- 108010022999 Serine Proteases Proteins 0.000 abstract description 3
- 102000012479 Serine Proteases Human genes 0.000 abstract description 3
- 239000003112 inhibitor Substances 0.000 abstract description 2
- 230000002265 prevention Effects 0.000 abstract description 2
- 238000011282 treatment Methods 0.000 abstract description 2
- 125000006850 spacer group Chemical group 0.000 description 57
- 125000000392 cycloalkenyl group Chemical group 0.000 description 33
- 125000002252 acyl group Chemical group 0.000 description 29
- 239000011669 selenium Substances 0.000 description 28
- 125000004433 nitrogen atom Chemical group N* 0.000 description 18
- JJWKPURADFRFRB-UHFFFAOYSA-N carbonyl sulfide Chemical compound O=C=S JJWKPURADFRFRB-UHFFFAOYSA-N 0.000 description 17
- 125000005326 heteroaryloxy alkyl group Chemical group 0.000 description 14
- 125000004487 4-tetrahydropyranyl group Chemical group [H]C1([H])OC([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 12
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 11
- 125000005164 aryl thioalkyl group Chemical group 0.000 description 10
- 125000005347 halocycloalkyl group Chemical group 0.000 description 10
- 108010073385 Fibrin Proteins 0.000 description 9
- 102000009123 Fibrin Human genes 0.000 description 9
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 9
- 229950003499 fibrin Drugs 0.000 description 9
- 125000004104 aryloxy group Chemical group 0.000 description 8
- 125000005356 cycloalkylalkenyl group Chemical group 0.000 description 8
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 8
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical class OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 8
- 206010053567 Coagulopathies Diseases 0.000 description 7
- 125000005452 alkenyloxyalkyl group Chemical group 0.000 description 7
- 125000001769 aryl amino group Chemical group 0.000 description 7
- 125000005110 aryl thio group Chemical group 0.000 description 7
- 230000035602 clotting Effects 0.000 description 7
- 125000006769 halocycloalkoxy group Chemical group 0.000 description 7
- 125000005241 heteroarylamino group Chemical group 0.000 description 7
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 description 7
- 125000002947 alkylene group Chemical group 0.000 description 6
- 125000001691 aryl alkyl amino group Chemical group 0.000 description 6
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 5
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 5
- 108090000190 Thrombin Proteins 0.000 description 5
- 125000005354 acylalkyl group Chemical group 0.000 description 5
- 125000003302 alkenyloxy group Chemical group 0.000 description 5
- 125000005140 aralkylsulfonyl group Chemical group 0.000 description 5
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 5
- 239000003114 blood coagulation factor Substances 0.000 description 5
- 125000005144 cycloalkylsulfonyl group Chemical group 0.000 description 5
- 125000002573 ethenylidene group Chemical group [*]=C=C([H])[H] 0.000 description 5
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 5
- 125000005143 heteroarylsulfonyl group Chemical group 0.000 description 5
- 229960004072 thrombin Drugs 0.000 description 5
- 125000005135 aryl sulfinyl group Chemical group 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 125000004966 cyanoalkyl group Chemical group 0.000 description 4
- 125000005149 cycloalkylsulfinyl group Chemical group 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 125000005553 heteroaryloxy group Chemical group 0.000 description 4
- 125000005150 heteroarylsulfinyl group Chemical group 0.000 description 4
- 102000035195 Peptidases Human genes 0.000 description 3
- 108091005804 Peptidases Proteins 0.000 description 3
- 239000004365 Protease Substances 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 125000005018 aryl alkenyl group Chemical group 0.000 description 3
- 125000005421 aryl sulfonamido group Chemical group 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 150000003857 carboxamides Chemical class 0.000 description 3
- 125000004465 cycloalkenyloxy group Chemical group 0.000 description 3
- 125000000000 cycloalkoxy group Chemical group 0.000 description 3
- 125000004858 cycloalkoxyalkyl group Chemical group 0.000 description 3
- 125000006310 cycloalkyl amino group Chemical group 0.000 description 3
- 125000005112 cycloalkylalkoxy group Chemical group 0.000 description 3
- 125000004441 haloalkylsulfonyl group Chemical group 0.000 description 3
- 125000004475 heteroaralkyl group Chemical group 0.000 description 3
- 125000004447 heteroarylalkenyl group Chemical group 0.000 description 3
- 125000005368 heteroarylthio group Chemical group 0.000 description 3
- 125000005844 heterocyclyloxy group Chemical group 0.000 description 3
- 125000004468 heterocyclylthio group Chemical group 0.000 description 3
- 208000010125 myocardial infarction Diseases 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 3
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 3
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 3
- 229910052721 tungsten Inorganic materials 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- 125000006028 1-methyl-2-butenyl group Chemical group 0.000 description 2
- 125000006519 CCH3 Chemical group 0.000 description 2
- 108010062466 Enzyme Precursors Proteins 0.000 description 2
- 102000010911 Enzyme Precursors Human genes 0.000 description 2
- RLTPOGIGJILWFY-UHFFFAOYSA-N [N].O=C1N=CC=CN1 Chemical group [N].O=C1N=CC=CN1 RLTPOGIGJILWFY-UHFFFAOYSA-N 0.000 description 2
- 125000004442 acylamino group Chemical group 0.000 description 2
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 125000004967 formylalkyl group Chemical group 0.000 description 2
- 125000004440 haloalkylsulfinyl group Chemical group 0.000 description 2
- 230000023597 hemostasis Effects 0.000 description 2
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 2
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 125000001766 1,2,4-oxadiazol-3-yl group Chemical group [H]C1=NC(*)=NO1 0.000 description 1
- 125000006048 1-methyl-2-pentenyl group Chemical group 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010003178 Arterial thrombosis Diseases 0.000 description 1
- 206010003658 Atrial Fibrillation Diseases 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 102100023804 Coagulation factor VII Human genes 0.000 description 1
- 108010023321 Factor VII Proteins 0.000 description 1
- 108010074105 Factor Va Proteins 0.000 description 1
- 108010074860 Factor Xa Proteins 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 108010094028 Prothrombin Proteins 0.000 description 1
- 102100027378 Prothrombin Human genes 0.000 description 1
- 206010038563 Reocclusion Diseases 0.000 description 1
- 108010000499 Thromboplastin Proteins 0.000 description 1
- 102000002262 Thromboplastin Human genes 0.000 description 1
- 206010043647 Thrombotic Stroke Diseases 0.000 description 1
- 208000032109 Transient ischaemic attack Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 125000004687 alkyl sulfinyl alkyl group Chemical group 0.000 description 1
- 125000005237 alkyleneamino group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 150000005840 aryl radicals Chemical class 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 239000003601 chymase inhibitor Substances 0.000 description 1
- 229940105772 coagulation factor vii Drugs 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 208000009190 disseminated intravascular coagulation Diseases 0.000 description 1
- 230000002497 edematous effect Effects 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000006624 extrinsic pathway Effects 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000002439 hemostatic effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 125000004274 oxetan-2-yl group Chemical group [H]C1([H])OC([H])(*)C1([H])[H] 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229940039716 prothrombin Drugs 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 125000004963 sulfonylalkyl group Chemical group 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
- C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
- C07D253/06—1,2,4-Triazines
- C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
- C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- This invention is in the field of anticoagulant therapy, and specifically relates to compounds, compositions and methods for preventing and treating thrombotic conditions such as coronary artery and cerebrovascular disease. More particularly, the invention relates to substituted polycyclic aryl and heteroaryl pyrimidinone compounds that inhibit serine proteases of the coa ⁇ *gCulation cascade.
- Physiological systems control the fluidity of blood in mammals [Majerus, P. W. et al: Anticoagulant, Thrombolytic, and Antiplplatelet Drugs. In Hardman, J. G. and Limbird, L. E., editors: Goodman & Gilman's The Pharmacological Basis of Therapeutics. 9th edition. New York, McGraw-Hill Book Co., 1996, pp. 1341-1343]. Blood must remain fluid within the vascular systems and yet be able to undergo hemostasis, cessation of blood loss from a damaged vessel, quickly. Hemostasis or clotting begins when platelets first adhere to macromolecules in subendothelian regions of an injured and or damaged vessels. These platelets aggregate to form the primary hemostatic plug and stimulate local activation of plasma coagulation factors leading to generation of a fibrin clot that reinforces the aggregated platelets.
- Plasma coagulation factors include factors II, V, VII, VIII, IX, X, XI, and XII; these are also called protease zymogens. These coagulation factors or protease zymogens are activated by serine proteases leading to coagulation in a so called “coagulation cascade” or chain reaction [Handin, R. L: Bleeding and Thrombosis. In Wilson, J., et al. editors: Harrison's Principles of Internal Medicine. 12th Edition, New York, McGraw-Hill Book Co., 1991,p.350]. Coagulation or clotting occurs in two ways through different pathways.
- An intrinsic or contact pathway leads from XII to Xlla to XIa to IXa and to the conversion of X to Xa.
- Xa with factor Va converts prothrombin (II) to thrombin (Ila) leading to conversion of fibrinogen to fibrin. Polymerization of fibrin leads to a fibrin clot.
- An extrinsic pathway is initiated by the conversion of coagulation factor VII to Vila by Xa. The presence of Tissue Factor and Vila accelerates formation of Xa in the presence of calcium ion and phospholipids. Formation of Xa leads to thrombin, fibrin, and a fibrin clot as described above. The presence of one or more of these many different coagulation factors and two distinct pathways of clotting could enable the efficacious, selective control and better understanding of parts of the coagulation or clotting process.
- thrombosis results when platelet aggregation and/or a fibrin clot blocks (i.e., occludes) a blood vessel.
- Arterial thrombosis may result in ischemic necrosis of the tissue supplied by the artery.
- a myocardial infarction or heart attack can result.
- a thrombosis occurring in a vein may cause tissues drained by the vein to become edematous and inflamed.
- Thrombosis of a deep vein may be complicated by a pulmonary embolism.
- Preventing or treating clots in a blood vessel may be therapeutically useful by inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, inhibiting embolus formation, and for treating or preventing unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular build up of fibrin, and reocclusion or restenosis of recanalized vessels.
- the present invention relates to a class of compounds comprising Substituted Polycyclic Aryl and Heteroaryl pyrimidinones, which are beneficial in anticoagulant therapy for the treatment and prevention of a variety of thrombotic conditions including coronary artery and cerebrovascular disease, as given in Formula (I):
- J is selected from the group consisting of O and S;
- J is optionally selected from the group consisting of CH-R and N-R
- R is a linear spacer moiety having a chain length of 1 to 4 atoms linked to the point of bonding of a substituent selected from the group
- J is optionally selected from the group consisting of CH-R and N-R
- R is a linear spacer moiety having a chain length of 1 to 4 atoms
- J is optionally selected from the group consisting of CH-R and N-R
- R is a linear spacer moiety having a chain length of 1 to 4 atoms
- K must be a covalent bond when two of D , D , J , J and K are O and S,
- R , R , R , R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
- R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aryloylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfiny
- R , R , R , R , and R are independently optionally
- R and R , R and R , R and R , and R and R are independently optionally selected to form a spacer pair wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group
- R and R , R and R , R and R , and R and R are independently optionally selected to form a spacer pair wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group
- 3 4 3 4 consisting of C, N, O, and S, no more than one of D , D , J , and J is O, no
- R , R , R , and R are each independendy selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
- B is optionally selected from the group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkenyl, C3-C8 alkylenyl, C3-C8 alkynyl, C2-C8 haloalkyl, and C3-C8 haloalkenyl wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group consisting of R 2, R33 *
- B is optionally selected from the group consisting of C3-C15 cycloalkyl, C5-C10 cycloalkenyl, C4-C12 saturated heterocyclyl, and C4-C9 partially saturated heterocyclyl, wherein each ring carbon is optionally
- a ring carbon other than the ring carbon at the point of attachment of B to A is optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment is
- R9 to the position and two atoms from the point of attachment is optionally
- R 12 33 adjacent to the R position is optionally substituted with R , and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent
- A is selected from the group consisting of single covalent bond, (W 7 ) rr -(CH(R 15 )) pa and (CH(R 15 )) pa -(W 7 ) rr wherein rr is an integer
- W is selected from the group consisting of O, S, C(O), C(S), C(O)S, C(S)O, C(O)N(R 7 ), C(S)N(R 7 ), (R 7 )NC(O), (R ? )NC(S), S(O), S(O) 2 ,
- R and R are independently selected from the group consisting of hydrido, hydroxy, alkyl, alkenyl, aryl, aralkyl, aryloxy, alkoxy, alkenyloxy, alkylthio, alkylamino, arylthio, arylamino, acyl, aroyl, heteroaroyl, aralkoxyalkyl, heteroaralkoxyalkyl, , aryloxyalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, aralkoxyalkyl, heteroaralkoxyalkyl, alkylsulfmylalkyl, alkylsulfonylalkyl, heteroaryl, heteroaryloxy, heteroarylamino, heteroaralkyl, heteroaralkylamino, and heteroaryloxyalkyl;
- R , R , R , R , R , R , R and R are independently selected from the group consisting of amidino, hydroxyamino, hydrido, hydroxy, halo, cyano, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, aminoalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkylalkoxy, alkylsulfmylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl
- R and R are independently selected from other than formyl and 2-oxoacyl;
- R and R when bonded to different carbons, are optionally taken together to form a group selected from the group consisting of covalent bond, alkylene, haloalkylene, and a linear moiety spacer selected to form a ring selected from the group consisting of cycloalkyl ring having from 5 through 8 contiguous members, cycloalkenyl ring having from 5 through 8 contiguous members, and a heterocyclyl having from 5 through 8 contiguous members;
- R and R when bonded to different carbons, are optionally taken together to form a group selected from the group consisting of covalent bond, alkylene, haloalkylene, and a linear moiety spacer selected to form a ring selected from the group consisting of a cycloalkyl ring having from 5 through 8 contiguous members, a cycloalkenyl ring having from 5 through 8 contiguous members, and a heterocyclyl having from 5 through 8 contiguous members;
- R and R when bonded to different carbons, are optionally taken together to form a group selected from the group consisting of covalent bond, alkylene, haloalkylene, and a linear moiety spacer selected to form a ring selected from the group consisting of cycloalkyl ring having from 5 through 8 contiguous members, cycloalkenyl ring having from 5 through 8 contiguous members, and a heterocyclyl having from 5 through 8 contiguous members;
- ⁇ is selected from the group consisting of NR , O, C(O), C(S), S,
- R is selected from the group consisting of hydrido, hydroxy, amino, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxy, aralkoxy, alkoxy, alkenyloxy, alkylthio, arylthio, aralkoxyalkyl, heteroaralkoxyalkyl, aryloxyalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, aralkoxyalkyl, heteroaralkoxyalkyl, alkylsulfmylalkyl, alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, hal
- R and R when bonded to the same carbon, are optionally taken
- N alkylene, haloalkylene, and a linear moiety spacer having from 2 through 7 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl ring having from 3 through 8 contiguous members, a cycloalkenyl ring having from 3 through 8 contiguous members, and a heterocyclyl ring having from 3 through 8 contiguous members;
- M is selected from the group consisting of N and R -C; 1 0
- R and R are independently selected from the group consisting of Z - Q, hydrido, alkyl, alkenyl, and halo;
- R is optionally selected from the group consisting of amino, aminoalkyl, alkylamino, amidino, guanidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, alkylthio, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, heteroarylamino, nitro, arylamino, aralkylamino, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, hydroxyhaloalkyl, cyano, and phosphono; R is optionally selected from the group consisting of amidino, guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, heteroarylamino, amino, nitro, alkylamino,
- R , R and R , R and R , and R ⁇ and R is used at the same time;
- Z is selected from the group consisting of covalent single bond
- W ⁇ -(CH(R )) p wherein g and p are integers independently selected from 0 through 3 and W is selected from the group consisting of O, S, C(O), C(S),
- CR R C; vinylidene), ethynylidene (CsC; 1,2-ethynyl), 1,2-cyclopropyl,
- R and R are independently selected from the group consisting of hydrido, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, acyl, aroyl, aralkanoyl, heteroaroyl, aralkoxyalkyl, alkylsulfmylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocyclo
- R and R are optionally taken together to form a linear moiety spacer having from 2 through 7 contiguous atoms and forming a ring selected from the group consisting of a cycloalkyl ring having from 3 through 8 contiguous members, a cycloalkenyl ring having from 3 through 8 contiguous members, and a heterocyclyl ring having from 3 through 8 contiguous members;
- Q is formula (II):
- D , D , J , J and K are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
- 1 2 1 2 1 1 can be O, no more than one of D , D , J , J and K can be S, one of D ,
- D , J , J and K must be a covalent bond when two of D , D , J , J and r K are O and S, and , no more th , an f r-our o -fr D-,1 , T D 2 , J ⁇ l , J ⁇ and K 1 can L be N ⁇ ,
- R , R , R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
- Q is optionally selected from formula (III):
- 3 4 3 4 consisting of C, N, O, and S, no more than one of D , D , J , and J is O, no
- R , R , R , and R are N with the proviso that R , R , R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
- Q is optionally selected from the group consisting of hydrido, alkyl, alkoxy, alkylamino, alkylthio, haloalkylthio, alkenyl, alkynyl, saturated heterocyclyl, partially saturated heterocyclyl, acyl, aroyl, heteroaroyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkenyl, haloalkyl, haloalkoxy, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, halo
- 4a 4b K is (CR R ) n wherein n is an integer selected from 1 through 4;
- R and R are independently selected from the group consisting of halo, hydrido, hydroxy, cyano, hydroxyalkyl, alkyl, alkenyl, aryl, aralkyl, aralkoxyalkyl, aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, aralkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, cyanoalkyl, alkylsulfmylalkyl, alkylsulfonylalkyl, haloalkylsulfinyl, arylsulfinylalkyl, arylsulfonyl
- R and R when bonded to the same carbon, are optionally taken together to form a group selected from the group consisting of oxo, thiono, and a linear spacer moiety having from 2 through 7 contiguous atoms connected to form a ring selected from the group consisting of a cycloalkyl ring having 3 through 8 contiguous members, a cycloalkenyl ring having 5 through 8 contiguous members, and a heterocyclyl ring having 5 through 8 contiguous 4a 4b members with the proviso that R and R taken together is other than oxo or thiono when the common carbon is directly bonded to the pyrimidinone nitrogen; o 1 4a 4b 1
- E is E , when K is (CR R ) n , wherein E is selected from the group consisting of a covalent single bond, O, S, C(O), C(S), C(O)O, C(S)O,
- 14 K is optionally selected to be (CH(R ))j-T wherein j is selected from a integer from 0 through 3 and T is selected from the group consisting of single
- E is optionally E , when K is (CH(R ))j-T, wherein E is selected from the group consisting of a covalent single bond, C(O), C(S), C(O)O,
- K is optionally selected to be G-(CH(R )) j , wherein k is selected from an integer from 1 through 3 and G is selected from the group consisting of O,
- R is other than hydroxy, cyano, halo, amino, alkylamino, dialkylamino, and sulfhydryl when k is 1; o 3 15 3
- E is optionally E when K is G-(CH(R ) wherein E is selected from the group consisting of a covalent single bond, O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R ? ), (R ? )NC(O), C(S)N(R 7 ),
- D , D , J , and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
- K is independently selected from the group
- D , D , J , and J are N when K is carbon with the provisos that R , R ,
- R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
- R and R are independently optionally taken together to form a linear moiety spacer having from 3 through 6 contiguous atoms connected to form a ring selected from the group consisting of a cycloalkenyl ring having from 5 through 8 contiguous members, a partially saturated heterocyclyl ring having from 5 through 8 contiguous members, a heteroaryl having from 5 through 6 contiguous members, and an aryl;
- R and R are independently optionally taken together to form a linear moiety spacer having from 3 through 6 contiguous atoms connected to form a ring selected from the group consisting of a cycloalkenyl ring having from 5 through 8 contiguous members, a partially saturated heterocyclyl ring having from 5 through 8 contiguous members, a heteroaryl having from 5 through 6 contiguous members, and an aryl; b 20 21
- Q is selected from the group consisting of NR R ,
- R , and R are independently selected from the group consisting of hydrido, amino, alkyl, hydroxy, alkoxy, aminoalkylenyl, alkylamino, dialkylamino, and
- R , R , and R must be other than be hydroxy, alkoxy, alkylamino,
- R and R , R and R , and R and R are independently optionally selected to form a spacer pair wherein a spacer pair is taken together to form a linear moiety having from 4 through 7 contiguous atoms connecting the points of bonding of said spacer pair members to form a heterocyclyl ring having 5 through 8 contiguous members with the proviso that no more than
- R and R is used at the same time
- Q is optionally selected from the group consisting of
- R 23 24 26 of R , R , and R can be hydroxy, alkoxy, alkyleneamino, alkylamino,
- Q is optionally selected from the group consisting of
- R and R can be hydroxy, alkoxy, alkylamino, amino, or dialkylamino when any two of
- R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylenylamino, amino, alkylamino, dialkylamino, and hydroxyalkyl;
- R and R are optionally taken together to form a linear spacer moiety having from 4 through 7 contiguous atoms connecting the points of bonding to form a heterocyclyl ring having 5 through 8 contiguous members;
- 26 R are independently optionally selected to form a spacer pair wherein a spacer pair is taken together from the points of bonding of selected spacer pair members to form the group L-U-V wherein L, U, and V are independently selected from the group consisting of O, S, C(O), C(S), C(J H ) 2 S(O), SO 2 , OP(OR 3 1 )R 30 ,
- R 30 (O)POP(O)R 30 , Si(R 29 )R 28 , Si(R 29 )R 28 Si(R 29 )R 28 ,
- P(S)R C(R ) C(R ), DC(R )(R )D, OP(OR )R , P(O)R , P(S)R , 28 29 30
- J H is independently selected from the group consisting of OR , SR and
- 27 R is selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfmylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, halocycloalkyl, halocycloalkenyl,
- R and R are independently selected from the group consisting of hydrido, hydroxy, thiol, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfmylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenyl, cycloal
- R and R are optionally taken to form a linear moiety spacer group having from 2 through 7 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl ring having from 3 through 8 contiguous members, a cycloalkenyl ring having from 3 through 8 contiguous members, and a heterocyclyl ring having from 3 through 8 contiguous members;
- 26 R are independently optionally selected to form a spacer pair wherein a spacer pair is taken together from the points of bonding of selected spacer pair members to form the group L-U-V wherein L, U, and V are independently selected from the group of 1,2-disubstituted radicals consisting of a cycloalkyl radical, a cycloalkenyl radical wherein cycloalkyl and cycloalkenyl radicals are substituted with one or
- Q is selected from the group consisting of a single covalent bond.
- W is selected from 1 through 4, and W is selected from the group consisting of O,
- CR R C; vinylidene), ethynylidene (GsC; 1,2-ethynyl), 1,2-cyclopropyl,
- R are selected from other than halo and cyano when direcdy bonded to N
- R and R when bonded to different carbons, are optionally taken together to form a linear moiety spacer having from 1 through 7 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl ring having from 3 through 8 contiguous members, a cycloalkenyl ring having from 3 through 8 contiguous members, and a heterocyclyl ring having from 3 through 8 contiguous members;
- R and R when bonded to different carbons, are taken together to form a linear moiety spacer having from 1 through 7 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl ring having from 3 through 8 contiguous members, a cycloalkenyl ring having from 3 through 8 contiguous members, and a heterocyclyl ring having from 3 through 8 contiguous members;
- R and R when bonded to different carbons, are taken together to form a linear moiety spacer having from 1 through 7 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl ring having from 3 through 8 contiguous members, a cycloalkenyl ring having from 3 through 8 contiguous members, and a heterocyclyl ring having from 3 through 8 contiguous members; 37 38
- R and R when bonded to the same carbon, are taken together to form a group selected from a group consisting of oxo, thiono, alkylene, haloalkylene, and a linear moiety spacer having from 2 through 7 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl ring having from 3 through 8 contiguous members, a cycloalkenyl ring having from
- Y is optionally Q -Q wherein Q is selected from the group
- W is selected from the group consisting of W is selected from the group consisting of O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R 14 ), (R 14 )NC(O), C(S)N(R 14 ), (R 14 )NC(S),
- Y° is optionally Q b -Q SSS wherein Q SSS is (C ⁇ R 38 )),. ⁇ . r is an
- W * ⁇ is selected from the group consisting of 1,1-cyclopropyl, 1,2-cyclopropyl, 1,1 -cyclobutyl, 1,2-cyclobutyl, 1,2- cyclohexyl, 13-cyclohexyl, 1,4-cyclohexyl, 1,2-cyclopentyl, 13-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,5-morpholinyl, 2,6-morpholinyl, 3,4- morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyI, 1,4- piperazinyl, 2,3-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 1,4-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,5- piperidinyl, 2,6-piperazinyl,
- Y° is optionally Q b -( ss ⁇ wherein Q SSSr is (CH(R 38 )) r -W 4 , r is an
- W is selected from the group consisting of
- Y° is optionally Q b -Q SSSS wherein Q SSSS is (CH(R 38 )) r -W 5 , r is an
- W ⁇ is selected from the group consisting of
- 1,4-indenyl 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7-indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3,4-indenyl, 3,5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuranyl, 2,5-benzofuranyl, 2,6-benzofuranyl, 2,7-benzofuranyl, 3,4-benzofuranyl, 3,5-benzofuranyl, 3,6-benzofuranyI, 3,7-benzofuranyl, 2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7- benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6-benzothiophenyl, 3,7-benzothiophenyl, 3,5-benz
- Y is optionally Q -Q wherein Q is (CH(R )) r -W , r is an
- W is selected from the group consisting of
- 1,4-indenyl 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7-indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3,4-indenyl, 3,5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuranyl, 2,5-benzofuranyl, 2,6-benzofuranyl, 2,7-benzofuranyl, 3,4-benzofuranyl, 3,5-benzofuranyl, 3,6-benzofuranyl, 3,7-benzofuranyl, 2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7- benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6-benzothiophenyl, 3,7-benzothiophenyl, 3,5-benz
- hydrido containing nitrogen member of the ring of the W other than the points of attachment is optionally substituted with one or more of the group consisting of R , R , R , and R , with the proviso that Q is bonded to
- J is selected from the group consisting of O and S; J is optionally selected from the group consisting of CH-R and N-R
- R is a linear spacer moiety having a chain length of 1 to 4 atoms linked to the point of bonding of a substituent selected from the group
- D , D , J , J and K are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
- K must be a covalent bond when two of D , D , J , J and K are O and S,
- R , R , R , R , and R are each independendy selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
- R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aryloylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulf onylalkyl, aralkylsulfinyl, aralkyl sulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfin
- R , R , R , R , and R are independently optionally
- R and R , R and R , and R and R are independently optionally selected to form a spacer pair wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group
- R and R , R and R , R and R , and R and R are independently optionally selected to form a spacer pair wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group
- B is optionally selected from the group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, C2-C8 haloalkyl, and C3-C8 haloalkenyl wherein each member of group B may be optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group consisting of
- B is optionally selected from the group consisting of C3-C15 cycloalkyl, C5-C10 cycloalkenyl, C4-C12 saturated heterocyclyl, and C4-C9 partially saturated heterocyclyl, wherein each ring carbon is optionally
- a ring carbon other than the ring carbon at the point of attachment of B to A is optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment is
- attachment and adjacent to the R position is optionally substituted with R , a ring carbon or nitrogen atom three atoms from the point of attachment and
- R 12 33 adjacent to the R position is optionally substituted with R , and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent
- A is selected from the group consisting of single covalent bond, (W 7 ) rr -(CH(R 15 )) pa and (CH(R 15 )) pa -(W ) felicit wherein rr is an integer
- pa is an integer selected from 0 through 6
- W is selected from the group consisting of O, S, C(O), C(S), C(O)S, C(S)O,
- R and R are independently selected from the group consisting of hydrido, hydroxy, alkyl, acyl, aroyl, heteroaroyl, and alkoxyalkyl;
- R , R , R , and R are independently selected from the group consisting of hydrido, hydroxy, halo, cyano, hydroxyalkyl, alkoxy, alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl; R and R can be independently selected from the group consisting of acyl, aroyl, and heteroaroyl with the proviso that acyl is selected from other than formyl and 2-oxo
- 5 ⁇ is selected from the group consisting of NR , O, C(O), C(S), S,
- R is selected from the group consisting of hydrido, hydroxy, amino, alkyl, alkoxy, alkoxyalkyl, haloalkyl, acyl, aroyl, and heteroaroyl;
- R and R are independently selected from the group consisting of hydrido, hydroxy, halo, cyano, hydroxyalkyl, acyl, aroyl, heteroaroyl, acylamido, alkoxy, alkyl, alkoxyalkyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, alkylsulfonyl, haloalkylsulfonyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;
- M is selected from the group consisting of N and R -C;
- R 2 and R 1 are independently selected from the group consisting of Z 0 - Q, hydrido, alkyl, alkenyl, and halo;
- R is optionally selected from the group consisting of amino, aminoalkyl, alkylamino, amidino, guanidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, alkylthio, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, heteroarylamino, nitro, arylamino, aralkylamino, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, hydroxyhaloalkyl, cyano, and phosphono;
- Z is selected from the group consisting of covalent single bond
- CR R C; vinylidene), ethynylidene (C ⁇ C; 1,2-ethynyl), 1,2-cyclopropyl,
- R and R are independently selected from the group consisting of amidino, hydroxyamino, hydrido, hydroxy, amino, halo, cyano, aryloxy, hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, alkoxy, alkyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkylalkoxy, alkoxyalkyl, heteroaryloxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy.
- halocycloalkoxyalkyl halocycloalkenyloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaralkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, alkylsulfonyl, haloalkylsulfonyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfonyl, cycloalkylsulfonyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfonyl, and aralkylsulf onylalkyl;
- Q is formula (II):
- D , D , J , J and K are independendy selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
- K must be a covalent bond when two of D , D , J , J and K are O and S,
- R , R , R , R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
- 3 4 3 4 consisting of C, N, O, and S, no more than one of D , D , J , and J is O, no 3 4 3 4 1 2 more than one of D , D , J , and J is S, and no more than three of D , D ,
- R , R , and R are N with the proviso that R , R , R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
- Q is optionally selected from the group consisting of hydrido, alkyl, alkoxy, alkylamino, alkylthio, haloalkylthio, alkenyl, alkynyl, saturated heterocyclyl, partially saturated heterocyclyl, acyl, aroyl, heteroaroyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkenyl, haloalkyl, haloalkoxy, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, and halocycloalkenyloxyalkyl with the proviso that Z is selected from other than a single covalent bond when Q is hydrido;
- 4a 4b K is (CR R ) n wherein n is an integer selected from 1 through 2;
- R and R are independently selected from the group consisting of halo, hydrido, hydroxy, cyano, hydroxyalkyl, alkyl, alkenyl, alkoxyalkyl, aralkyl, heteroaralkyl, alkylthioalkyl, haloalkyl, haloalkenyl, and cyanoalkyl; o 1 4a 4b 1
- E is E , when K is (CR R ) n , wherein E is selected from the group consisting of a covalent single bond, O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R ? ), (R ? )NC(O), C(S)N(R ? ), (R ? )NC(S),
- CsC 1,2-ethynyl
- C ⁇ CR 4 ⁇ ' 14 K is optionally (CH(R )):-T wherein j is selected from a integer from
- T is selected from the group consisting of single covalent
- E is optionally E , when K is (CH(R )):-T, wherein E is selected from the group consisting of a covalent single bond, C(O), C(S), C(O)O.
- K is optionally G-(CH(R )) jc wherein k is selected from an integer from 1 through 2 and G is selected from the group consisting of O, S, and
- R is other than hydroxy, cyano, halo, amino, alkylamino, dialkylamino, and sulfhydryl when k is 1; o ⁇ 3 15 . 3
- E is optionally E when K is G-(CH(R )) ⁇ , wherein E is selected from the group consisting of a covalent single bond, O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R 7 ), (R ? )NC(O), C(S)N(R ? ),
- D , D , J , and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
- K is independently selected from the group
- D , D , J , and J are N when K is carbon with the provisos that R , R ,
- R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
- R and R are optionally independendy taken together to form a linear moiety spacer having from 3 through 6 contiguous atoms connected to form a ring selected from the group consisting of a cycloalkenyl ring having from 5 through 8 contiguous members, a partially saturated heterocyclyl ring having from 5 through 8 contiguous members, a heteroaryl having from 5 through 6 contiguous members, and an aryl; b 20 21
- Q is selected from the group consisting of NR R ,
- R , and R are independently selected from the group consisting of hydrido, amino, alkyl, hydroxy, alkoxy, aminoalkylenyl, alkylamino, dialkylamino, and
- R , R , and R must be other than be hydroxy, alkoxy, alkylamino,
- R and R is used at the same time
- Q is optionally selected from the group consisting of
- R 23 24 26 of R , R , and R is hydroxy, alkoxy, alkylamino, amino, and
- Q is optionally selected from the group consisting of
- said Q group is bonded directiy to a carbon atom
- J _, , , R , R , and R are independendy selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, aminoalkylenyl, alkylamino, dialkylamino, amino, and hydroxyalkyl;
- R and R are optionally taken together to form a linear spacer moiety having from 4 through 7 contiguous atoms connecting the points of bonding to form a heterocyclyl ring having 5 through 8 contiguous members;
- Q is selected from the group consisting of a single covalent bond
- az is an integer selected from 0 through 1
- b is an integer selected from 1 through 4
- W is selected from the group consisting of O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R 14 ),
- W ⁇ is selected from the group
- 1,2-ethynyl 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 13- cyclohexyl, 1,2-cyclopentyl, 13-cyclopentyl, 2,3-mo holinyl, 2,4- morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2- piperazinyl, 13-piperazinyl, 23- ⁇ iperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 13- ⁇ iperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4- piperidinyl, 1,2-pyrrolidinyl, 13-pyrrolidinyl, 23-pyrrolidinyl, 2,4- pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2,3-tetra
- R and R are selected from other than halo and cyano when
- Y is optionally Q -Q wherein Q is selected from the group
- W is selected from the group consisting of W is selected from the group consisting of O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R 14 ), (R 14 )NC(O), C(S)N(R 14 ), (R 14 )NC(S),
- R 38 ) f , (CH(R 14 )) C , and (CH(R 14 )) e are bonded to E°;
- Y° is optiionally Q b -Q s$s wherein Q SSS is (CH(R 38 )) r -W 3 , r is an
- w is selected from the group consisting of
- Y° is optionally Q b -Q SSSr wherein Q SSSr is (CH(R 38 )) r -W 4 r is an
- W is selected from the group consisting of
- Y is optionally Q -Q wherein Q is (CH(R )) r -W , r is an
- W " ⁇ is selected from the group consisting of 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7-indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3,4-indenyl, 3,5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuranyl, 2,5-benzofuranyl, 2,6-benzofuranyl, 2,7-benzofuranyl, 3,4-benzofuranyl, 3,5-benzofuranyl, 3,6-benzofuranyl, 3,7-benzofuranyl, 2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7- benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6-benzothiophenyl, 3,4
- Y° is optionally Q b -Q ssssr wherein Q SSSsr is (CH(R 38 )) r -W , r is an
- W is selected from the group consisting of 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7-indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3,4-indenyl, 3,5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuranyl, 2,5-benzofuranyl, 2,6-benzofuranyl, 2,7-benzofuranyl, 3,4-benzofuranyl, 3,5-benzofuranyl, 3,6-benzofuranyl, 3,7-benzofuranyl, 2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7- benzothiophenyl, 3, 4- benzothiophenyl, 3,5-benzothiophenyl, 3,6- benzothiophenyl, 3,5-benzothi
- J is selected from the group consisting of O and S;
- D , D , J , J and K are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
- K must be a covalent bond when two of D , D , J , J and K are O and S,
- D R 9 , DR 10 , DR 1 1 , D is. 12 , DR 13 , ⁇ R 16 , DK 17 , DR 18 , DR 19 , DR 32 , D R 33 , DR 34 ,
- R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aryloylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulf onylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfin
- R , R , R , R , R , and R are independently optionally
- B is optionally selected from the group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, C2-C8 haloalkyl, and C3-C8 haloalkenyl wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point
- B is optionally selected from the group consisting of C3-C12 cycloalkyl, C5-C10 cycloalkenyl, and C4-C9 saturated heterocyclyl, wherein
- each ring carbon is optionally substituted with R
- a ring carbon other than the ring carbon at the point of attachment of B to A is optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time
- R 12 optionally substituted with R , a ring carbon or nitrogen atom three atoms
- A is selected from the group consisting of single covalent bond
- W 7 7 is selected from the group consisting of O, S, C(O), C(O)N(R ), C(S)N(R ),
- R and R are independently selected from the group consisting of hydrido, hydroxy, alkyl, and alkoxyalkyl;
- R , R , R , and R are independently selected from the group consisting of hydrido, hydroxy, halo, alkyl, alkoxyalkyl, haloalkyl, haloalkoxy, and haloalkoxyalkyl;
- R and R can be independently selected from the group consisting of aroyl and heteroaroyl ;
- 5 ⁇ is selected from the group consisting of NR , C(O), and S(O) ;
- R is selected from the group consisting of hydrido, hydroxy, alkyl, and alkoxy;
- R and R are independently selected from the group consisting of hydrido, hydroxy, halo, hydroxyalkyl, alkyl, alkoxyalkyl, haloalkyl, haloalkoxy, and haloalkoxyalkyl;
- M is selected from the group consisting of N and R -C;
- R is selected from the group consisting of hydrido, alkyl, alkenyl, cyano, halo, haloalkyl, haloalkoxy, haloalkylthio, amino, aminoalkyl, alkylamino, amidino, guanidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, alkylthio, and phosphono;
- R 2 is Z°-Q
- Z is selected from the group consisting of covalent single bond
- h are integers independently selected from 0 through 2 and W ⁇ is selected
- R and R are independently selected from the group consisting of amidino, hydroxyamino, hydrido, hydroxy, amino, and alkyl;
- Q is selected from the group consisting of hydrido, with the proviso that Z is other than a covalent single bond, the formula (II):
- D , D , J , J and K are independendy selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
- K must be a covalent bond when two of D , D , J , J and K are O and S, 1 2 1 2 1 and no more than four of D , D , J , J and K is N, with the proviso that r , 9 ⁇ 10 l 2 j n 13 u . J J , , . . L
- R , R , R , R , and R are each independendy selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
- K is (CR JR ) n wherein n is an integer selected from 1 through 2;
- R and R are independently selected from the group consisting of halo, hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl;
- E is selected from the group consisting of a covalent single bond,
- D , D , J , and J are independendy selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
- K is C, no more than one of D , D , J , and J
- R , R , and R are each independendy selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; b 20 21
- Q is selected from the group consisting of NR R ,
- R , and R are independendy selected from the group consisting of hydrido, alkyl, hydroxy, amino, aminoalkylenyl, dialkylamino, alkylamino, and
- Q is optionally selected from the group consisting of
- R 23 24 26 of R , R , and R is hydroxy, alkylamino, amino, or dialkylamino when
- R , R , R , and R are independendy selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylenylamino, dialkylamino, alkylamino, and hydroxyalkyl;
- Q is selected from the group consisting of a single covalent bond
- W is selected from the group
- W ⁇ is selected from the group
- 1,2-ethynyl 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3- cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-mo ⁇ holinyl, 2,4- mo ⁇ holinyl, 2,6-mo ⁇ holinyl, 3,4-mo ⁇ holinyl, 3,5-mo ⁇ holinyl, 1,2- piperazinyl, 1,3-piperazinyl, 23-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 13-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4- piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 23-pyrrolidinyl, 2,4- pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrol
- R and R are selected from other than halo and cyano when
- 0 b ss ss Y is optionally Q -Q wherein Q is selected from the group
- W is selected from 1 through 2
- W is selected from the group consisting of W
- W ⁇ is selected from the group consisting of
- Y is optionally Q -Q wherein Q is (CH(R )) r -W , r is an
- ⁇ is selected from the group consisting of 1,1-cyclopropyl, 1,2-cyclopropyl, 1,1 -cyclobutyl, 1,2-cyclobutyl, 1,2- cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-mo ⁇ holinyl, 2,4-mo ⁇ holinyl, 2,5-mo ⁇ holinyl, 2,6-mo ⁇ holinyl, 3,4- mo ⁇ holinyl, 3,5-mo ⁇ holinyl, 1,2-piperazinyl, 1,3-piperazinyl, 1,4- piperazinyl, 23-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 1,4-piperidinyl, 2,3- ⁇ iperidinyl, 2,4-piperid
- Y° is optionally Q b -Q sssr wherein Q SSSr is (CH(R 38 )) r -W 4 r is an
- W is selected from the group consisting of 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl, 1,2- cyclopentyl, 1,3-cyclopentyl, 2,3-mo ⁇ holinyl, 2,4-mo ⁇ holinyl, 2,5- mo ⁇ holinyl, 2,6-mo ⁇ holinyl, 3,4-mo ⁇ holinyl, 3,5-mo ⁇ holinyl, 1,2- piperazinyl, 1,3-piperazinyl, 1,4-piperazinyl, 2,3-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 1,4-piperidinyl, 2,3- piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl, 2,6-piperidinyl, 3,4-piperid
- Y° is optionally Q b -Q ssss wherein Q SSSS is (CH R 38 )) ⁇ 5 , r is an
- W ⁇ ⁇ is selected from the group consisting of 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7-indenyl, 2,6-indenyl, 2,Sindenyl, 2,4-indenyl, 3,4-indenyl, 3,5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuranyl, 2,5-benzofuranyl, 2,6-benzofuranyl, 2,7-benzofuranyl, 3,4-benzofuranyl, 3,5-benzofuranyl, 3,6-benzofuranyl, 3,7-benzofuranyl, 2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7- benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6- benzothiophenyl, 3,4
- Y° is optionally Q b -Q ssssr wherein Q SSSSr is (CH(R 38 )) r -W 6 , r is an
- W is selected from the group consisting of
- 1,4-indenyl 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7-indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3,4-indenyl, 3,5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuranyl, 2,5-benzofuranyl, 2,6-benzofuranyl, 2,7-benzofuranyl, 3,4-benzofuranyl, 3,5-benzofuranyl, 3,6-benzofuranyl, 3,7-benzofuranyl, 2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7- benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6- benzothiophenyl, 3,7-benzothiophenyl, 3, 7-
- J is O;
- B is the Formula:
- R , R , R , R , R , R , R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkylenedioxy, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxyl alkyl, hydroxy, amino, alkoxyamino, nitro, lower alkylamino, alkylthio, alkylthioalkyl, alkylsulfinyl, alkyl sulfonyl, alkylsulfonylalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulf
- R , R , R , R , and R are optionally selected from the group
- R 12 13 R , and R are substitutents for other than B;
- B is optionally selected from the group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B may be optionally substituted at any carbon up to and including 6 atoms from the point of 32 33 attachment of B to A with one or more of the group consisting of R , R ,
- B is selected from the group consisting of C3-C12 cycloalkyl and C4-
- each ring carbon may be optionally substituted with R
- a ring carbon other than the ring carbon at the point of attachment of B to A may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time
- ring carbons and a nitrogen adjacent to the carbon at the point of attachment may be optionally substituted
- R and R positions may be substituted with R ;
- A is selected from the group consisting of single covalent bond
- pa is an integer selected from 0 through 6
- W is an integer selected from 0 through 7
- 7 7 is selected from the group consisting of O, S, C(O), (R )NC(O), (R )NC(S),
- R is selected from the group consisting of hydrido, hydroxy, and alkyl;
- R is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl;
- ⁇ is selected from the group consisting of NH and NOH;
- M is selected from the group consisting of N and R -C;
- R is selected from the group consisting of hydrido, alkyl, alkenyl, cyano, halo, haloalkyl, haloalkoxy, haloalkylthio, amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl. alkoxyamino, thiol, and alkylthio;
- R 2 is Z°-Q; Z is selected from the group consisting of covalent single bond,
- CR CR , 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2- cyclohexyl, 1,3-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3- mo ⁇ holinyl, 2,4-mo ⁇ holinyl, 2,6-mo ⁇ holinyl, 3,4-mo ⁇ holinyl, 3,5- mo ⁇ holinyl, 1,2-piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl, 2,6- piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 23-piperidinyl, 2,4-piperidinyl, 2,6- piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3- pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl,
- R and R are independently selected from the group consisting of amidino, hydroxyamino, hydrido, hydroxy, amino, and alkyl;
- Q is selected from the group consisting of hydrido, with the proviso that Z is other than a covalent single bond, and the formula (II):
- D , D , J , J and K are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
- K must be a covalent bond when two of D , D , J , J and K are O and S,
- R , R , R , and R are each independendy selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
- 4a 4b K is (CR R ) n wherein n is an integer selected from 1 through 2;
- R and R are independently selected from the group consisting of halo, hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl; o 1 4a 4b 1
- E is E , when K is (CR R ) n , wherein E is selected from the
- D , D , J , and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
- K is C, no more than one of D , D , J , and J
- R , and R are each independendy selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
- R , R , R , and R are independendy selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, nitro, alkoxyamino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, alkenyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkylenylamino, haloalkoxyalkyl, carboalkoxy, and cyano; b 20 21
- Q is selected from the group consisting of NR R , aminoalkylenyl,
- Q be wherein Q be is hydrido, N(R 26 )C(NR 25 )N(R 23 )(R 24 ), and
- R , R , R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, aminoalkylenyl, amino, dialkylamino, alkylamino, and hydroxyalkyl; s Q is selected from the group consisting of a single covalent bond,
- W is selected from 1 through 3 and W is selected from the group consisting of
- R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
- R and R are independently selected from the group consisting of hydrido, alkyl, and haloalkyl;
- 38 R is optionally selected from the group consisting of aroyl and heteroaroyl;
- Y° is optionally Q Q"" wherein Q" is (CH(R )) e -W ⁇ -(CH(R " )) h ,
- e and h are integers independently selected from 1 through 2 and w 2
- Y is optionally selected from the group consisting of Q -Q and Q -
- Q SSSSr wherein Q SSSS is (CH(R 38 )) r -W 5 and Q SSSSr is (CH(R 38 )) r -W 6 , r is an integer selected from 1 through 2, and Vv and W are independently selected from the group consisting of 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7- indenyl, 2,7-indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3,4-indenyl, 3,5- indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuranyl, 2,5-benzofuranyl, 2.6- benzof uranyl , 2,7-benzofuranyl , 3 ,4- benzof urany 1 , 3 ,5-benzof urany 1 , 3 ,6- benzofuranyl, 3,7-benzofuranyl,
- J is O;
- B is the Formula:
- R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkylenedioxy, haloalkylthio, alkanoyloxy, alkoxy, hydroxy, amino, alkoxyamino, alkanoyl, haloalkanoyl, nitro, lower alkylamino, alkylthio, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyalkyl, alkylenylamino, carboalkoxy, carboxy, car
- B is optionally selected from the group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of
- B is selected from the group consisting of C3-C12 cycloalkyl and C4-
- each ring carbon may be optionally substituted with R
- a ring carbon other than the ring carbon at the point of attachment of B to A may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time
- ring carbons and a nitrogen adjacent to the carbon at the point of attachment may be optionally substituted
- atoms from the point of attachment may be substituted with R , a ring carbon
- R a ring carbon three atoms from the point of attachment and adjacent to
- R position may be substituted with R , and a ring carbon four atoms
- R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl, amidino, guanidino, alkyl enedi oxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxyalkyl, carboxy, carboxamido, and cyano;
- R , R , R , R , and R are optionally selected from the group
- R , and R are substitutents for other than B;
- A is selected from the group consisting of single covalent bond and
- R is selected from the group consisting of hydrido, hydroxy and alkyl
- R is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl; ⁇ is NH;
- M is selected from the group consisting of N and R -C;
- R is selected from the group consisting of hydrido, alkyl, cyano, halo, haloalkyl, haloalkoxy, amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio;
- R 2 is Z°-Q
- Z is selected from the group consisting of covalent single bond and
- W ⁇ is selected from the group consisting of
- CR CR , 1,2-cyclopro ⁇ yl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3- cyclohexyl, 1,2-cyclopentyl, 13-cyclopentyl, 2,3-mo ⁇ holinyl, 2,4- mo ⁇ holinyl, 2,6-mo ⁇ holinyl, 3,4-mo ⁇ holinyl, 3,5-mo ⁇ holinyl, 1,2- piperazinyl, 13-piperazinyl, 23-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 13-piperidinyl, 23-piperidinyl, 2,4-piperidinyl, 2,6- ⁇ iperidinyl, 3,4- piperidinyl, 1,2-pyrrolidinyl, 13 -pyrrolidinyl, 2,3-pyrrolidinyl, 2,4- pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrroli
- R and R are independently selected from the group consisting of hydrido, hydroxy, and amino;
- Q is selected from the group consisting of hydrido, with the proviso that Z is other than a covalent single bond, aryl, and heteroaryl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted
- K is CHR wherein R is selected from the group consisting of hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl; E is selected from the group consisting of a covalent single bond,
- D , D , J , and J are independendy 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 is C, no more than one of D , D , J , and J
- R , and R are each independendy selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; i, 16 17 passport 18 19 .
- ⁇ , , R , R , and R are independendy selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; R and R are optionally Q with the proviso that no more than one
- Q is selected from the group consisting of NR R , Q wherein Q is
- R , R , R , R , R , and R are independendy selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino;
- Q is selected from the group consisting of a single covalent bond
- W is selected from 1 through 3 and W is selected from the group consisting of
- R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
- R and R are independently selected from the group consisting of hydrido, alkyl, and haloalkyl;
- 38 R is optionally selected from the group consisting of aroyl and heteroaroyl;
- Y° is optionally Q b -Q SS wherein Q SS is (CH(R 14 )) e -W 2 -(CH(R 15 )) h ,
- hydrido acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q ;
- A is selected from the group consisting of single covalent bond and
- W is selected from the group
- R is selected from the group consisting of hydrido, hydroxy and alkyl
- R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
- R is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo;
- R 2 is Z°-Q;
- Z is selected from the group consisting of a covalent single bond, O,
- 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
- R 13 9 optionally substituted by R , a carbon adjacent to R and two atoms from the 10 carbon at the point of attachment is optionally substituted by R , a carbon
- R , R , and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; R and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialky
- K is CH 2 ;
- E° is C(O)N(H);
- Y 0 is fo ⁇ mula (IV):
- D , D , J , and J 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, 5 6 5 6 is optionally O, no more than one of D , D , J , and J is optionally S, one of
- D , D , J , and J must be a covalent bond when two of D , D , J , and J
- R , R , R , and R are independendy selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
- R and R are optionally Q with the proviso that no more than one of
- R and R is Q at the same time and that Q is Q ;
- Q is selected from the group consisting of NR R , Q wherein Q is
- 21 23 24 and R is hydroxy at the same time and that no more than one of R and R is hydroxy at the same time;
- R , R , R , and R are independendy selected from the group consisting of hydrido, alkyl, and hydroxy; s Q is selected from the group consisting of a single covalent bond,
- J is O
- B is optionally selected from the group consisting of hydrido, C2-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group
- 32 33 34 35 36 consisting of R , R , R , R , and R ; 32 33 34 35 36
- R , R , R , R , and R are independendy selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q ;
- A is selected from the group consisting of single covalent bond and
- W is selected from the group
- R is selected from the group consisting of hydrido, hydroxy and alkyl
- R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
- R is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo;
- R 2 is Z°-Q;
- TX is selected from the group consisting of covalent single bond, O, S,
- 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
- R 13 9 optionally substituted by R , a carbon adjacent to R and two atoms from the 10 carbon at the point of attachment is optionally substituted by R , a carbon
- R , R , and R are independendy selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; R and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, mono
- K is CH 2 ;
- E° is C(O)N(H); Y° is formula (IV):
- D , D , J , and J 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 is C, no more than one of D , D , J , and J is O, no more than one of D , D , J , and J is S, one of D , D , J , and J
- R . and R are each independendy selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
- ⁇ , , R , R , and R are independendy selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkylenylamino, and cyano;
- R and R are optionally Q with the proviso that no more than one
- Q is selected from the group consisting of NR R , Q wherein
- Q be is hydrido, C(NR 25 )NR 23 R 24 , and N(R 26 )C(NR 25 )N(R 23 )(R 24 ), with
- R , R , R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, and hydroxy; s Q is selected from the group consisting of a single covalent bond,
- J is O;
- B is selected from the group consisting of C3-C7 cycloalkyl and C4-
- each ring carbon may be optionally substituted with R
- a ring carbon other than the ring carbon at the point of attachment of B to A may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time
- ring carbons and a nitrogen adjacent to the carbon at the point of attachment may be optionally substituted
- atoms from the point of attachment may be substituted with R , a ring carbon
- R a ring carbon three atoms from the point of attachment and adjacent to
- R position may be substituted with R , and a ring carbon four atoms
- R , R , and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano;
- R and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, alkylenylamino, carboalkoxy, carboxy, carboxyalkyl, a idocarbonyl, halo, haloalkyl, and cyano; 33 34
- R and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q ;
- A is selected from the group consisting of single covalent bond and
- W is selected from the group
- R is selected from the group consisting of hydrido, hydroxy and alkyl
- R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
- ⁇ is NH
- M is selected from the group consisting of N and R -C;
- R is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo;
- R 2 is Z°-Q; Z is selected from the group consisting of covalent single bond, O, S,
- 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
- carbon at the point of attachment is optionally substituted by R , a carbon 13 adjacent to R and two atoms from the carbon at the point of attachment is
- D , D , J , and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
- K is C, no more than one of D , D , J , and J
- R , R , n R18 , and j n R19 are each ,_ i•nd_,epend--,end,y sel,ected--, to mai •ntai ⁇ n th , e tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
- R , R , R , and R are independendy selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkylenylamino, and cyano;
- R and R are optionally Q with the proviso that no more than one of
- R and R is Q at the same time and that Q is Q ;
- Q is selected from the group consisting of NR R , Q wherein Q is
- 21 23 24 and R is hydroxy at the same time and that no more than one of R and R is hydroxy at the same time;
- R , R , R , R , and R are independendy selected from the group consisting of hydrido, alkyl, and hydroxy; s Q is selected from the group consisting of a single covalent bond,
- J is O;
- B is the Formula:
- R , R , R , R , and R are independendy selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q ;
- A is selected from the group consisting of single covalent bond and
- W is N(R );
- R is selected from the group consisting of hydrido and alkyl
- R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
- R is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo;
- R 2 is Z°-Q;
- Z is a covalent single bond
- 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
- R , R , and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano;
- R and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxyamido, and cyano;
- K is CH 2 ;
- E° is C(O)N(H);
- D , D , J , and J are independendy selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
- K is C, no more than one of D , D , J , and J
- 5 6 5 6 5 6 5 6 5 6 5 6 is O, no more than one of D , D , J , and J is S, one of D , D , J , and J
- R , R , R , and R are independendy selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
- R and R are optionally Q with the proviso that no more than one of
- R and R is Q at the same time and that Q is Q ;
- Q is selected from the group consisting of NR R , Q wherein Q is
- R , R , R , and R are independently selected from the group consisting of hydrido and alkyl;
- Q S is CH 2 .
- J is O
- B is optionally selected from the group consisting of hydrido, C2-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group
- R , R , R , R , and R are independendy selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q ;
- A is selected from the group consisting of single covalent bond and
- W is N(R );
- R is selected from the group consisting of hydrido and alkyl:
- R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
- ⁇ is NH
- M is selected from the group consisting of N and R -C;
- R is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo;
- R 2 is Z°-Q
- Z is a covalent single bond
- 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
- R , R , and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano;
- R and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxyamido. and cyano;
- D , D , J , and J are independendy 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 is C, no more than one of D , D , J , and J
- 5 6 5 6 5 6 5 6 5 6 5 6 is O, no more than one of D , D , J , and J is S, one of D , D , J , and J
- R , and R are each independendy selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; 16 17 18 19
- R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
- R and R are optionally Q with the proviso that no more than one of
- R and R is Q at the same time and that Q is Q ;
- Q is selected from the group consisting of NR R , Q wherein Q is
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Abstract
L'invention concerne des composés de pyrimidinone aryle et hétéroaryle polycycliques substitués utilisés comme inhibiteurs de sérine protéases de la cascade de coagulation, ainsi que des composés, des compositions et des méthodes utilisés dans la thérapie anticoagulante pour le traitement et la prévention de nombreux états thrombotiques, tels que les coronaropathies et les affections cérébrovasculaires.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US13479499P | 1999-05-19 | 1999-05-19 | |
| US134794P | 1999-05-19 | ||
| PCT/US2000/009806 WO2000069832A1 (fr) | 1999-05-19 | 2000-05-17 | Pyrimidinones aryle et heteroaryle polycycliques substituees utilisees comme anticoagulants |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1178970A1 true EP1178970A1 (fr) | 2002-02-13 |
Family
ID=22465042
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP00931928A Withdrawn EP1178970A1 (fr) | 1999-05-19 | 2000-05-17 | Pyrimidinones aryle et heteroaryle polycycliques substituees utilisees comme anticoagulants |
Country Status (22)
| Country | Link |
|---|---|
| EP (1) | EP1178970A1 (fr) |
| JP (1) | JP2002544262A (fr) |
| KR (1) | KR20010114271A (fr) |
| CN (1) | CN1157380C (fr) |
| AR (1) | AR030021A1 (fr) |
| AU (2) | AU771718B2 (fr) |
| BR (1) | BR0010758A (fr) |
| CA (1) | CA2373614A1 (fr) |
| CZ (1) | CZ20014116A3 (fr) |
| EA (1) | EA004867B1 (fr) |
| HU (1) | HUP0201242A3 (fr) |
| IL (1) | IL146243A0 (fr) |
| MX (1) | MXPA01011804A (fr) |
| NO (1) | NO20015604L (fr) |
| NZ (1) | NZ514874A (fr) |
| PE (1) | PE20010229A1 (fr) |
| PL (1) | PL352827A1 (fr) |
| SK (1) | SK15852001A3 (fr) |
| TW (1) | TWI222445B (fr) |
| UY (1) | UY26156A1 (fr) |
| WO (1) | WO2000069832A1 (fr) |
| ZA (2) | ZA200109339B (fr) |
Families Citing this family (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6458952B1 (en) | 1999-05-19 | 2002-10-01 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl uracils useful for selective inhibition of the coagulation cascade |
| US6867217B1 (en) | 1999-05-19 | 2005-03-15 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade |
| US6664255B1 (en) | 1999-05-19 | 2003-12-16 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrazinones useful for selective inhibition of the coagulation cascade |
| US7015230B1 (en) | 1999-05-19 | 2006-03-21 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl uracils useful for selective inhibition of the coagulation cascade |
| US6653316B1 (en) | 1999-05-19 | 2003-11-25 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade |
| US6750342B1 (en) | 1999-05-19 | 2004-06-15 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade |
| NZ514877A (en) * | 1999-05-19 | 2004-10-29 | Pharmacia Corp | Substituted polycyclic aryl and heteroaryl uracils as anticoagulative agents |
| US6716838B1 (en) | 1999-05-19 | 2004-04-06 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl uracils as anticoagulative agents |
| WO2001068605A1 (fr) | 2000-03-13 | 2001-09-20 | Pharmacia Corporation | Benzenes polycycliques substitues aryle et heteroaryle utiles pour l'inhibition selective de la cascade de coagulation |
| US20020022604A1 (en) | 2000-04-05 | 2002-02-21 | South Michael S. | Polycyclic aryl and heteroaryl substituted 4-pyrones useful for selective inhibition of the coagulation cascade |
| US6693121B2 (en) | 2000-04-05 | 2004-02-17 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted 4-pyridones useful for selective inhibition of the coagulation cascade |
| EP1274676A2 (fr) | 2000-04-17 | 2003-01-15 | Pharmacia Corporation | 1,4-quinones polycycliques substituees par aryle et heteroaryles utiles pour l'inhibition selective des reactions en cascade provoquant la coagulation |
| WO2001087851A1 (fr) * | 2000-05-18 | 2001-11-22 | Pharmacia Corporation | Aryle polycyclique substitue et pyrimidinones d'heteroaryle utiles a l'inhibition selective de la coagulation |
| US6710058B2 (en) | 2000-11-06 | 2004-03-23 | Bristol-Myers Squibb Pharma Company | Monocyclic or bicyclic carbocycles and heterocycles as factor Xa inhibitors |
| US7119094B1 (en) | 2000-11-20 | 2006-10-10 | Warner-Lambert Company | Substituted polycyclic aryl and heteroarpyl pyrazinones useful for selective inhibition of the coagulation cascade |
| US7015223B1 (en) | 2000-11-20 | 2006-03-21 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl 1,2,4-triazinones useful for selective inhibition of the coagulation cascade |
| CA2430037A1 (fr) | 2000-11-20 | 2002-05-30 | Michael S. South | Aryl-et-heteroaryl-pyridines polycycliques substituees utiles dans l'inhibition selective de la cascade de la coagulation |
| US7105559B2 (en) | 2001-10-03 | 2006-09-12 | Pharmacia Corporation | Substituted 5-membered polycyclic compounds useful for selective inhibition of the coagulation cascade |
| EP1438292A1 (fr) | 2001-10-03 | 2004-07-21 | Pharmacia Corporation | Composes heterocycliques a 6 chainons utiles dans l'inhibition selective de la cascade de la coagulation |
| MXPA04003167A (es) * | 2001-10-03 | 2004-07-08 | Pharmacia Corp | Compuestos heterociclicos insaturados de 6 miembros utiles para la inhibicion selectiva de la cascada de coagulacion. |
| WO2003072107A1 (fr) * | 2002-02-22 | 2003-09-04 | Pharmacia & Upjohn Company | Pyrimidinones et pyrimidinthiones substitues |
| TW200307667A (en) | 2002-05-06 | 2003-12-16 | Bristol Myers Squibb Co | Sulfonylaminovalerolactams and derivatives thereof as factor Xa inhibitors |
| US7217794B2 (en) | 2003-04-02 | 2007-05-15 | Daiamed, Inc. | Compounds and methods for treatment of thrombosis |
| US7182738B2 (en) | 2003-04-23 | 2007-02-27 | Marctec, Llc | Patient monitoring apparatus and method for orthosis and other devices |
| AU2006255009B2 (en) * | 2005-06-07 | 2011-10-27 | Pharmacopeia L.L.C. | Azinone and diazinone V3 inhibitors for depression and stress disorders |
| CN104311537B (zh) * | 2014-09-19 | 2016-08-24 | 广东东阳光药业有限公司 | 含有嘧啶酮乙酰基取代基吡唑类化合物及其组合物及用途 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5441960A (en) * | 1992-04-16 | 1995-08-15 | Zeneca Limited | 1-pyrimidinylacetamide human leukocyte elastate inhibitors |
| EP0826671B1 (fr) * | 1995-04-27 | 2004-12-29 | Mitsubishi Pharma Corporation | Composes heterocycliques amides et leur utilisation medicinale |
-
2000
- 2000-05-17 EA EA200101214A patent/EA004867B1/ru not_active IP Right Cessation
- 2000-05-17 SK SK1585-2001A patent/SK15852001A3/sk unknown
- 2000-05-17 KR KR1020017014753A patent/KR20010114271A/ko not_active Application Discontinuation
- 2000-05-17 MX MXPA01011804A patent/MXPA01011804A/es unknown
- 2000-05-17 BR BR0010758-1A patent/BR0010758A/pt not_active IP Right Cessation
- 2000-05-17 PL PL00352827A patent/PL352827A1/xx not_active Application Discontinuation
- 2000-05-17 CA CA002373614A patent/CA2373614A1/fr not_active Abandoned
- 2000-05-17 NZ NZ514874A patent/NZ514874A/en unknown
- 2000-05-17 AU AU49734/00A patent/AU771718B2/en not_active Ceased
- 2000-05-17 EP EP00931928A patent/EP1178970A1/fr not_active Withdrawn
- 2000-05-17 CN CNB008077479A patent/CN1157380C/zh not_active Expired - Fee Related
- 2000-05-17 IL IL14624300A patent/IL146243A0/xx unknown
- 2000-05-17 HU HU0201242A patent/HUP0201242A3/hu unknown
- 2000-05-17 JP JP2000618249A patent/JP2002544262A/ja active Pending
- 2000-05-17 WO PCT/US2000/009806 patent/WO2000069832A1/fr not_active Application Discontinuation
- 2000-05-17 CZ CZ20014116A patent/CZ20014116A3/cs unknown
- 2000-05-19 AR ARP000102446A patent/AR030021A1/es unknown
- 2000-05-19 UY UY26156A patent/UY26156A1/es not_active Application Discontinuation
- 2000-06-09 PE PE2000000575A patent/PE20010229A1/es not_active Application Discontinuation
- 2000-07-25 TW TW089109595A patent/TWI222445B/zh not_active IP Right Cessation
-
2001
- 2001-11-13 ZA ZA200109339A patent/ZA200109339B/xx unknown
- 2001-11-16 NO NO20015604A patent/NO20015604L/no not_active Application Discontinuation
-
2004
- 2004-01-21 ZA ZA200400448A patent/ZA200400448B/xx unknown
- 2004-05-31 AU AU2004202375A patent/AU2004202375A1/en not_active Abandoned
Non-Patent Citations (1)
| Title |
|---|
| See references of WO0069832A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| SK15852001A3 (sk) | 2003-06-03 |
| CN1351593A (zh) | 2002-05-29 |
| ZA200400448B (en) | 2004-09-29 |
| NO20015604D0 (no) | 2001-11-16 |
| ZA200109339B (en) | 2004-05-26 |
| BR0010758A (pt) | 2003-06-10 |
| AU4973400A (en) | 2000-12-05 |
| CN1157380C (zh) | 2004-07-14 |
| CA2373614A1 (fr) | 2000-11-23 |
| TWI222445B (en) | 2004-10-21 |
| NZ514874A (en) | 2004-11-26 |
| PE20010229A1 (es) | 2001-03-07 |
| EA004867B1 (ru) | 2004-08-26 |
| HUP0201242A2 (hu) | 2002-12-28 |
| IL146243A0 (en) | 2002-07-25 |
| JP2002544262A (ja) | 2002-12-24 |
| AR030021A1 (es) | 2003-08-13 |
| CZ20014116A3 (cs) | 2002-06-12 |
| HUP0201242A3 (en) | 2003-02-28 |
| UY26156A1 (es) | 2000-12-29 |
| EA200101214A1 (ru) | 2002-06-27 |
| MXPA01011804A (es) | 2003-09-04 |
| AU2004202375A1 (en) | 2004-06-24 |
| NO20015604L (no) | 2002-01-11 |
| PL352827A1 (en) | 2003-09-08 |
| WO2000069832A1 (fr) | 2000-11-23 |
| AU771718B2 (en) | 2004-04-01 |
| KR20010114271A (ko) | 2001-12-31 |
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