EP1178964A1 - Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade - Google Patents
Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascadeInfo
- Publication number
- EP1178964A1 EP1178964A1 EP00930092A EP00930092A EP1178964A1 EP 1178964 A1 EP1178964 A1 EP 1178964A1 EP 00930092 A EP00930092 A EP 00930092A EP 00930092 A EP00930092 A EP 00930092A EP 1178964 A1 EP1178964 A1 EP 1178964A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- group
- hydrido
- carbon
- amino
- 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- Withdrawn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
- -1 heteroaryl pyridones Chemical class 0.000 title claims abstract description 1745
- 230000015271 coagulation Effects 0.000 title abstract description 10
- 238000005345 coagulation Methods 0.000 title abstract description 10
- 230000005764 inhibitory process Effects 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 67
- 150000003839 salts Chemical class 0.000 claims abstract description 54
- 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 558
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 430
- 125000001145 hydrido group Chemical group *[H] 0.000 claims description 404
- 229910052757 nitrogen Inorganic materials 0.000 claims description 224
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 214
- 125000000217 alkyl group Chemical group 0.000 claims description 183
- 125000004429 atom Chemical group 0.000 claims description 177
- 229910052760 oxygen Inorganic materials 0.000 claims description 175
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 164
- 229910052717 sulfur Inorganic materials 0.000 claims description 152
- 125000001188 haloalkyl group Chemical group 0.000 claims description 148
- 125000005843 halogen group Chemical group 0.000 claims description 130
- 125000003282 alkyl amino group Chemical group 0.000 claims description 123
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 107
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 104
- 125000003545 alkoxy group Chemical group 0.000 claims description 98
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 92
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 88
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 79
- 125000006850 spacer group Chemical group 0.000 claims description 79
- 125000004414 alkyl thio group Chemical group 0.000 claims description 75
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 73
- 125000000033 alkoxyamino group Chemical group 0.000 claims description 64
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 54
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 53
- 125000000623 heterocyclic group Chemical group 0.000 claims description 46
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 40
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 38
- 125000005518 carboxamido group Chemical group 0.000 claims description 37
- 125000001072 heteroaryl group Chemical group 0.000 claims description 35
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 35
- 125000003118 aryl group Chemical group 0.000 claims description 34
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 33
- 125000004995 haloalkylthio group Chemical group 0.000 claims description 33
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 32
- 125000003342 alkenyl group Chemical group 0.000 claims description 29
- 125000005422 alkyl sulfonamido group Chemical group 0.000 claims description 28
- 150000001721 carbon Chemical group 0.000 claims description 25
- 125000004076 pyridyl group Chemical group 0.000 claims description 24
- 125000003435 aroyl group Chemical group 0.000 claims description 23
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 23
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 20
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 19
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 18
- 125000000304 alkynyl group Chemical group 0.000 claims description 17
- 125000000753 cycloalkyl group Chemical group 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
- 241000124008 Mammalia Species 0.000 claims description 15
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 14
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 14
- 239000001301 oxygen Substances 0.000 claims description 14
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims description 14
- 239000011593 sulfur Substances 0.000 claims description 14
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 13
- 210000004369 blood Anatomy 0.000 claims description 13
- 239000008280 blood Substances 0.000 claims description 13
- 125000000262 haloalkenyl group Chemical group 0.000 claims description 13
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 12
- 208000007536 Thrombosis Diseases 0.000 claims description 12
- 125000006350 alkyl thio 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
- 125000004994 halo alkoxy alkyl group Chemical group 0.000 claims description 12
- 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 11
- 230000002401 inhibitory effect Effects 0.000 claims description 11
- 125000004487 4-tetrahydropyranyl group Chemical group [H]C1([H])OC([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 10
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 125000003396 thiol group Chemical class [H]S* 0.000 claims description 10
- 125000005466 alkylenyl group Chemical group 0.000 claims description 9
- 125000004665 trialkylsilyl group Chemical group 0.000 claims description 9
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 8
- 125000004423 acyloxy group Chemical group 0.000 claims description 7
- 150000001408 amides Chemical group 0.000 claims description 6
- 210000001772 blood platelet Anatomy 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
- HUTNOYOBQPAKIA-UHFFFAOYSA-N 1h-pyrazin-2-one Chemical group OC1=CN=CC=N1 HUTNOYOBQPAKIA-UHFFFAOYSA-N 0.000 claims description 4
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 4
- 125000004688 alkyl sulfonyl alkyl group Chemical group 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 208000005189 Embolism Diseases 0.000 claims description 3
- 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
- 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 128
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 121
- 125000001153 fluoro group Chemical group F* 0.000 claims 104
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims 94
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 79
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims 72
- 125000001309 chloro group Chemical group Cl* 0.000 claims 62
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 62
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims 60
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims 58
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims 50
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 49
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 48
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims 43
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims 43
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 42
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims 40
- 125000001246 bromo group Chemical group Br* 0.000 claims 39
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 38
- 229910014033 C-OH Inorganic materials 0.000 claims 36
- 229910014570 C—OH Inorganic materials 0.000 claims 36
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims 36
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims 29
- 229930192474 thiophene Natural products 0.000 claims 24
- LLAPDLPYIYKTGQ-UHFFFAOYSA-N 1-aminoethyl Chemical group C[CH]N LLAPDLPYIYKTGQ-UHFFFAOYSA-N 0.000 claims 23
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims 23
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims 23
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 23
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 claims 22
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims 22
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 21
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 19
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims 18
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims 18
- 125000001589 carboacyl group Chemical group 0.000 claims 18
- 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 18
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims 18
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 18
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 claims 18
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims 17
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims 17
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 17
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 17
- UUFQTNFCRMXOAE-UHFFFAOYSA-N 1-methylmethylene Chemical compound C[CH] UUFQTNFCRMXOAE-UHFFFAOYSA-N 0.000 claims 16
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims 16
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 16
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims 16
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims 15
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 15
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims 15
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 15
- 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 15
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims 14
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 14
- 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 claims 13
- 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 13
- 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 claims 13
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims 12
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims 12
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims 12
- 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 claims 12
- 125000004273 azetidin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])C1([H])* 0.000 claims 12
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims 12
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims 12
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims 11
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims 11
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims 11
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims 11
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims 10
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims 10
- OKTJSMMVPCPJKN-OUBTZVSYSA-N Carbon-13 Chemical compound [13C] OKTJSMMVPCPJKN-OUBTZVSYSA-N 0.000 claims 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 9
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims 9
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 claims 8
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims 8
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims 8
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 claims 8
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims 8
- 125000003974 3-carbamimidamidopropyl group Chemical group C(N)(=N)NCCC* 0.000 claims 8
- 125000004917 3-methyl-2-butyl group Chemical group CC(C(C)*)C 0.000 claims 8
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 claims 8
- SXIFAEWFOJETOA-UHFFFAOYSA-N 4-hydroxy-butyl Chemical group [CH2]CCCO SXIFAEWFOJETOA-UHFFFAOYSA-N 0.000 claims 8
- 125000004920 4-methyl-2-pentyl group Chemical group CC(CC(C)*)C 0.000 claims 8
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 claims 8
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 8
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims 8
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims 7
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims 7
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims 7
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 7
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 claims 6
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 claims 6
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims 6
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims 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 6
- 125000006125 ethylsulfonyl group Chemical group 0.000 claims 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 6
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims 6
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 claims 6
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 claims 6
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims 6
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims 6
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims 6
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 5
- ZYHQGITXIJDDKC-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethyl]aniline Chemical group NC1=CC=CC=C1CCC1=CC=CC=C1N ZYHQGITXIJDDKC-UHFFFAOYSA-N 0.000 claims 5
- 125000006040 2-hexenyl group Chemical group 0.000 claims 5
- 125000006029 2-methyl-2-butenyl group Chemical group 0.000 claims 5
- 125000006024 2-pentenyl group Chemical group 0.000 claims 5
- 125000006041 3-hexenyl group Chemical group 0.000 claims 5
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 claims 5
- 125000006042 4-hexenyl group Chemical group 0.000 claims 5
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 5
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 5
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims 5
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 5
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims 5
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 claims 5
- 125000006519 CCH3 Chemical group 0.000 claims 4
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 4
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 claims 3
- 229910006074 SO2NH2 Inorganic materials 0.000 claims 3
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 claims 3
- 125000006074 1-ethyl-2-butenyl group Chemical group 0.000 claims 2
- 125000006052 1-methyl-3-pentenyl group Chemical group 0.000 claims 2
- 125000006031 2-methyl-3-butenyl group Chemical group 0.000 claims 2
- 125000006032 3-methyl-3-butenyl group Chemical group 0.000 claims 2
- 125000006043 5-hexenyl group Chemical group 0.000 claims 2
- 206010028980 Neoplasm Diseases 0.000 claims 2
- 208000001435 Thromboembolism Diseases 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
- 229910052739 hydrogen Inorganic materials 0.000 claims 2
- 125000004312 morpholin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC([H])(*)C1([H])[H] 0.000 claims 2
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- 230000002497 edematous effect Effects 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
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- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
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- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- TYLGVQVJCVFREB-UHFFFAOYSA-N pyrido[3,4-b]pyrazine Chemical class C1=NC=CC2=NC=CN=C21 TYLGVQVJCVFREB-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- 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
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- 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
- A61P9/00—Drugs for disorders of the cardiovascular system
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- 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
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/76—Nitrogen atoms to which a second hetero atom is attached
- C07D213/77—Hydrazine radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/38—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- 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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
-
- 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 pyridone compounds that inhibit serine proteases of the coagulation 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. I.: 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 Pyridones, 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
- 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 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 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 consisting of spacer pairs R and R , R and R , R and R , and R
- 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 32 33 of attachment of B to A with one or more of the group consisting of R , R , ⁇ ,34 ⁇ 35 _, 36 R , R , and R ;
- 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 carbons and a nitrogen adjacent to the carbon atom at the point of attachment are optionally
- R 33 optionally substituted with R , and a ring carbon or nitrogen four atoms from
- A is selected from the group consisting of single covalent bond,
- 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-oxoacyl;
- ⁇ 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;
- R , R and X are independently selected from the group consisting of Z -Q, hydrido, alkyl, alkenyl, and halo;
- R and X are independently 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;
- W, X, Y, and Z are independently selected from the group consisting of C(R ), C(R 10 ), C(R 11 ), C(R 12 ), N, N(R 1 °), O, S and a covalent bond with the provisos that W, X, Y, and Z can be independently selected to be a covalent bond when one of W, X, Y, and Z is selected from the group consisting of N, N(R ), O, and S, no more than one of W, X, Y, and Z can be selected from the group consisting of O and S, and no more than three of W, X, Y, and Z can be selected from the group consisting of N and N(R );
- X and R and R and R spacer pairs are independently optionally selected to be taken together to form a spacer pair wherein the spacer pair forms 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 from 5 through 8 contiguous members and a partially saturated heterocyclyl ring having from 5 through 8 contiguous members, wherein said spacer pair is optionally substituted with
- Z is selected from the group consisting of covalent single bond
- 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), C(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R 41 ), (R 41 )NC(O), C(S)N(R 41 ),
- 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, halocycloalkoxyalkyl, haloalken
- 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
- 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;
- 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,
- T is selected from the group consisting of single covalent
- E is optionally EX 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 )) ⁇ wherein k is selected from an integer from 1 through 2 and G is selected from the group consisting of O, S, and
- E E° iiss ooppttiioonnaallllyy EE wwhheenn KK iiss GG--((CCHH((RR )))) kk , 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 ? ),
- 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 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 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;
- 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 independendy 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 is hydroxy, alkoxy, alkylamino, amino, and
- R , R , R , and R are independently 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;
- s 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, 23-morpholinyl, 2,4- morpholinyl, 2,6-mo ⁇ holinyl, 3,4-morpholinyl, 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, 13-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4- pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2,3-
- 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 optiionally 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-cyclopentyI, 23-morpholinyl, 2,4-mo ⁇ holinyl, 2,5-mo ⁇ holinyl, 2,6-mo ⁇ holinyl, 3,4- mo ⁇ holinyl, 3,5-mo ⁇ holinyl, 1,2-piperazinyl, 13 -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, 2,3-piperidin
- 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 b -Q ssss wherein Q SSSS is (CH(R 38 )) r -W 5 , r is an
- ⁇ 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-benzotbiophenyl, 2,7- benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6- benzothiophenyl, 3,5-benz
- 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, 2,7-
- J is selected from the group consisting of O and S;
- B is formula (V):
- 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
- 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
- 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 10 is optionally substituted with R , a ring carbon or nitrogen adjacent to the
- R 12 33 to the R position is optionally substituted with R , and a ring carbon or
- R positions is optionally substituted with R ;
- A is selected from the group consisting of single covalent bond, (W ) rr -(CH(R 1 )) pa and (CH(R 15 )) pa -(W 7 ) rr wherein rr is an integer
- 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), 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
- ⁇ is selected from the group consisting of NR , C(O), and S(O) 2 ;
- 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;
- R and X are independendy 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;
- W, X, Y, and Z are independently selected from the group consisting of C(R ), C(R ), C(R H ), C(R 12 ), N, N(R 10 ), O, S and a covalent bond with the provisos that W, X, Y, and Z can be independently selected to be a covalent bond when one of W, X, Y, and Z is selected from the group
- W, X, Y, and Z can be selected from the group consisting of N and N(R );
- X and R and R and R spacer pairs are independently optionally selected to be taken together to form a spacer pair wherein the spacer pair forms 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 from 5 through 8 contiguous members and a partially saturated heterocyclyl ring having from 5 through 8 contiguous members, wherein said spacer pair is optionally substituted with
- R 1 and spacer pair R 1 and K ⁇ 7 is present at the same time;
- R 2 is Z 0 -Q;
- 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), S(O),
- 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 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 independently 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;
- E is selected from the group consisting of a covalent single bond,
- 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
- D , D , J , and J are N when K is carbon with the
- 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; h 20 1
- Q is selected from the group consisting of NR R ,
- R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, aminoalkylenyl, dialkylamino, alkylamino, and 20 21 hydroxyalkyl with the proviso that no more than one of R and R is hydroxy, amino, alkylamino, or dialkylamino at the same time;
- Q is optionally selected from the group consisting of
- R 23 24 26 of R , R , and R is hydroxy, alkylamino, am o, 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
- R and R are selected from other than halo and cyano when
- 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 b -Q sss wherein Q SSS is (CrKR 38 )),. ⁇ , r is a ; n
- ⁇ is selected from the group consisting of
- W is selected from the group consisting of
- . . . 4 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 provisos that (CH(R )) r is bonded to E b . 4 and Q is bonded to highest number substituent position of each W ;
- 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-benzofuranyl, 3,7-benzofuranyl, 2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothio ⁇ henyl, 2,7- benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6-benzothiophenyl, 3,7-benzothiophenyl, 2,7
- 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, 2,7-
- J is O;
- B is the Formula:
- 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, haloalkoxylalkyl, hydroxy, amino, alkoxyamino, nitro, lower alkylamino, alkylthio, alkylthioalkyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonylalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkylsulfonamido, alkyl
- R , R , R , and R are optionally 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,
- 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 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, ring carbons and a nitrogen adjacent to the
- R optionally substituted with R , a ring carbon or nitrogen three atoms from
- 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, ring carbons and nitrogen adjacent to the
- the point of attachment is optionally substituted with R , a ring carbon or
- R optionally substituted with R , a ring carbon or nitrogen three atoms from
- 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;
- R and X are independently 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;
- W, X, Y, and Z are independendy selected from the group consisting of C(R 9 ), C(R 10 ), C(R U ), C(R 12 ), N, N(R 10 ), O, S and a covalent bond with the provisos that W, X, Y, and Z can be independently selected to be a covalent bond when one of W, X, Y, and Z is selected from the group consisting of N, N(R ), O, and S, no more than one of W, X, Y, and Z can be selected from the group consisting of O and S, and no more than three of
- W, X, Y, and Z can be selected from the group consisting of N and N(R );
- X and R and R and R spacer pairs are independendy optionally selected to be taken together to form a spacer pair wherein the spacer pair forms 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 from 5 through 8 contiguous members and a partially saturated heterocyclyl ring having from 5 through 8 contiguous members, wherein said spacer pair is optionally substituted with
- R 1 and spacer pair R 1 and R 2 is present at the same time
- 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, 13-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 23- 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, 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, 3,4-pyrrolidinyl, 1,
- 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
- 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;
- 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 than one is a covalent bond, K is C, no more than one of D , D , J , and J
- R 18 19 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 independently 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;
- Q is selected from the group consisting of NR R , aminoalkylenyl,
- R 23 24 more than one of R and R is hydroxy, amino, alkylamino, or dialkylamino at the same time;
- 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,
- 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;
- 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 ,
- 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
- W and W are independendy 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-
- W is optionally substituted with one or more of the group consisting of
- 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, 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, carb
- 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,
- 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 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 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, ring carbons and a nitrogen adjacent to the
- R 12 optionally substituted with R , a ring carbon three atoms from the point of
- 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, ring carbons and nitrogen adjacent to the
- R a ring carbon or nitrogen adjacent to the R position and two atoms from
- the point of attachment is optionally substituted with R , a ring carbon or
- R optionally substituted with R , a ring carbon or nitrogen three atoms from
- R , R , R , R , and R are independendy selected from the group consisting of hydrido, acetamido, haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl, amidino, guanidino, alkylenedioxy, 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 12 13 R , and R are substitutents for other than B;
- A is selected from the group consisting of single covalent bond and
- W is selected from the group
- 7 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; R and X are independently selected from the group consisting of hydrido, alkyl, cyano, halo, haloalkyl, haloalkoxy, amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio;
- W, X, Y, and Z are independendy selected from the group consisting of C(R 9 ), C(R 10 ), C(R 1 1 ), C(R 12 ), N, N(R 10 ), O, S and a covalent bond with the provisos that W, X, Y, and Z can be independently selected to be a covalent bond when one of W, X, Y, and Z is selected from the group consisting of N, N(R ), O, and S, no more than one of W, X, Y, and Z can be selected from the group consisting of O and S, and no more than three of
- 10 W, X, Y, and Z can be selected from the group consisting of N and N(R );
- R and R spacer pairs are independently optionally selected to be taken together to form a spacer pair wherein the spacer pair forms 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 from 5 through 8 contiguous members and a partially saturated heterocyclyl ring having from 5 through 8 contiguous members, wherein said spacer pair is optionally substituted with one or more of the group consisting of ⁇ R 9 , R ⁇ . 10 , permite RH , ⁇ R 2 , and , R, 13 ;
- 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-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3- cyclohexyl, 1,2-cyclopentyl, 13-cyclopentyl, 23-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-piperidinyl, 3,4- piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 23-pyrrolidinyl, 2,4- pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl,
- 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;
- R , R , R , and R are independently 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
- 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 , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino; 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 R " and R are independently selected from the group consisting of hydrido, alkyl, and haloalkyl;
- R R 38 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 ,
- 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, 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;
- R and X are independendy 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 , 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, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl, halo, haloalkyl, 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 than one is a covalent bond, K is C, no more than one of D , D , J , and J
- D , D , J , and J must be a covalent bond when two of D , D , J , and J
- 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
- 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 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
- 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; ⁇ is NH;
- R and X are independently 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
- 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, dialkyl amidosulfonyl, hydroxyalkyl, alkylenylamino, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl, halo, haloalkyl, 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
- 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, haloalkyl thio, 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
- 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 hydrido, C(NR )NR R , and N(R )C(NR )N(R )(R ), with
- 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 selected from the group consisting of C3-C7 cycloalkyl and C4
- 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, ring carbons and a nitrogen adjacent to the
- the point of attachment and adjacent to the R position is optionally
- R 12 33 and adjacent to the R position is optionally substituted with R , and a ring carbon four atoms from the point of attachment and adjacent to the R and
- R positions is optionally substituted with R ;
- 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, dialkyl amidosulfonyl, hydroxyalkyl, alkylenylamino, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl, halo, haloalkyl, and cyano;
- 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
- R and X are independendy 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;
- ⁇ 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
- 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
- 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, 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 ;
- 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 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 the Formula (V):
- 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
- 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 ;
- 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 ,32 mecanic33 34 35 _, whatsoever36 consisting of R , R , R , R , and R ; B is selected from the group consisting of C3-C7 cycloalkyl and C4-C6 saturated heterocyclyl, wherein each ring carbon is optionally substituted with
- A is optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbons and nitrogen adjacent to the
- R a ring carbon or nitrogen adjacent to the R position and two atoms from
- the point of attachment is optionally substituted with R , a ring carbon or
- R optionally substituted with R , a ring carbon or nitrogen three atoms from
- R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl, amidino, guanidino, alkylenedioxy, haloalkylthio, heteroaryl, heterocyclyl, 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;
- A is selected from the group consist
- 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
- W, X, Y, and Z are independently selected from the group consisting of C(R 9 ), C(R 10 ), C(R J C(R 12 ), N, N(R 10 ), O, S and a covalent bond with the provisos that W, X, Y, and Z can be independendy selected to be a covalent bond when one of W, X, Y, and Z is selected from the group consisting of N, N(R ), O, and S, no more than one of W, X, Y, and Z is optionally selected from the group consisting of O and S, and no more than three of W, X, Y, and Z can be selected from the group consisting of N and N(R 10 );
- R and R spacer pair is optionally selected to be taken together to form a spacer pair wherein the spacer pair forms 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 from 5 through 8 contiguous members and a partially saturated heterocyclyl ring having from 5 through 8 contiguous members, wherein said spacer pair is optionally substituted with one or more of the group
- E° is C(O)N(H);
- 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, 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
- 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 , R , R , and R are independendy selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino; s Q is selected from the group consisting of a single covalent bond,
- J is O;
- B is the Formula:
- 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,
- 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;
- ⁇ H
- R and X are independendy 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 independendy selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulf
- 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 (L ⁇ f t ⁇ f t is O, no more than one of D , D , J , and J is S, one of D , D , J , and J
- D , D , J , and J are N;
- 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
- 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;
- R and X are independendy 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 independendy 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
- K is C, no more than one of D , D , J , and J
- R 18 19 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, 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 , 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 selected from the group consisting of C3-C7 cycloalkyl and C4
- 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, ring carbons and nitrogens adjacent to the
- the point of attachment and adjacent to the R position is optionally
- R positions is optionally substituted with R ;
- R , R , and R are independendy 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;
- R and R are independently selected from the group consisting of hydrido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, and cyano;
- 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, hydroxy and alkyl
- R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
- ⁇ is NH
- R and X are independendy 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
- 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;
- 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
- R , 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 the Formula (V):
- 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 than one is a covalent bond, no more than one of D , D , J , J and K is O, 1 2 1 2 1 1 2 1 2 no more than one of D , D , J , J and K is S, one of D , D , J , J and
- 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 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 ;
- 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
- B is selected from the group consisting of C3-C7 cycloalkyl and C4-C6 saturated heterocyclyl, wherein each ring carbon is optionally substituted with
- A is optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbons and nitrogen adjacent to the
- R a ring carbon or nitrogen adjacent to the R position and two atoms from
- the point of attachment is optionally substituted with R , a ring carbon or
- R optionally substituted with R , a ring carbon or nitrogen three atoms from 12 the point of attachment and adjacent to the R position is optionally
- 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
- 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, hydroxy and alkyl
- R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
- ⁇ is NH
- W, X, Y, and Z are independently selected from the group consisting of
- K is CH 2 ;
- E° is C(O)N(H); Y° is fo ⁇ nula (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
- 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, 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 , R , R , and R are independendy selected from the group consisting of hydrido and alkyl;
- Q S is CH 2 .
- R , R , R , R , and R are independendy selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, nitro, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, trifiuoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3- pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetra
- B is selected from the group consisting of hydrido, trimethylsilyl, ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, 2-butynyl, sec-butyl, tert-butyl, isobutyl, 2-methylpropenyI, 1-pentyl, 2- pentenyl, 3-pentenyl, 4-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl, 1-methyl- 2-butenyl, l-methyl-3-butenyl, l-methyl-2-butynyl, 3-pentyl, l-ethyl-2- propenyl, 2-methylbutyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 2-methyl-3-butynyl, 3-methylbutyl, 3-methyl-2-butenyl, 3-methyl-2-buteny
- B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, oxetan-2-yl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, thiaetan-2-yl, thiaetan-3-yl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, 3- trifluoromethylnorbornyl, bicyclo[3.1.0]hexan-6-yl, cycloheptyl, and
- each ring carbon is optionally substituted with R , ring carbons or a nitrogen adjacent to the carbon atom at the point of attachment are
- R substituted with R , and a ring carbon or a nitrogen adjacent to the R position and two atoms from the point of attachment is optionally substituted
- R , R , R , R , and R are independendy selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, nitro, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, trifiuoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2333 -pentafluoropropyl , trifl uoromethoxy
- A is selected from the group consisting of single covalent bond, O, S,
- A is optionally selected from the group consisting of CH 2 N(CH 3 ),
- R and X° are independently selected from the group consisting of hydrido, hydroxy, amino, thiol, amidino, hydroxyamino, aminomethyl, 1- aminoethyl, 2-aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, isopropyl, propyl, trifiuoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2333-pentafluoropropyl, methoxy, ethoxy, propoxy, hydroxymethyl, 1- hydroxyethyl, 2-hydroxyethyl, methoxyamino, ethoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo;
- 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 phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3- pyrazolyl, 4-pyrazolyl, l,2,4-triazol-3-yl, l,2,4-triazol-5-yl, 1,2,4-oxadiazol- 3-yI, l,2,4-oxadiazol-5-yl, 13,4-oxadiazol-3-yl, 13,4-oxadiazol-5-yl, 3- isothiazolyl, 5-isothiazolyl, 2-oxazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-
- K is CHR wherein R is selected from the group consisting of methyl, ethyl, propyl, isopropyl, hydroxymethyl, 1-hydroxyethyl, methoxymethyl, trifiuoromethyl, pentafluoroethyl, 2,2,2-trifluoromethyl, methylthiomethyl, and hydrido;
- E° is a covalent single bond, C(O)N(H), (H)NC(O), and S(O) 2 N(H);
- Y is selected from the group of formulas consisting of:
- R , R , R , and R are independendy selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N- N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifiuoromethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, 2,2,3 ,33-pent
- R and R are optionally Q with the proviso that no more than one o an is at t e same time an t at is ;
- 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 and R is hydroxy, N-methylamino, and N,N-dimethylamino at the same time;
- R , R , R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, hydroxy, 2- aminoethyl, 2-(N-methylamino)ethyl, and 2-(N,N-dimethylamino)ethyl;
- Q is selected from the group consisting of a single covalent bond, CH 2 , CH 2 CH 2 , CH 3 CH, CF 3 CH, CH 3 CHCH 2 , CF 3 CHCH 2 ,
- CH 2 CH CHCH 2
- CH 2 CF CHCH 2
- CH 2 C(CH 3 ) CHCH 2
- CH 2 CH CHCH 2 CH 2
- CH 2 CF CHCH 2 CH 2
- CH 2 C(CH 3 ) CHCH 2 CH 2 .
- compounds have the Formula I-MPS wherein B is an aromatic:
- R , R , R , R , and R are independendy selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifiuoromethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, 2,2,333-pentafluoropropyl, trifluoromethoxy, 1,1,2,2- tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N- methylamidosulfonyl, N,N-dimethylamidosulfonyl
- A is selected from the group consisting of single covalent bond, NH, N(CH 3 ), N(OH), CH 2 , CH 3 CH, CF 3 CH, NHC(O), N(CH 3 )C(O), C(O)NH, C(O)N(CH 3 ), CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 3 CHCH 2 , and
- R and X° are independendy selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1- aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, trifiuoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, methoxy, hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo;
- R 2 is Z°-Q;
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US13481199P | 1999-05-19 | 1999-05-19 | |
US134811P | 1999-05-19 | ||
PCT/US2000/008220 WO2000069826A1 (en) | 1999-05-19 | 2000-05-15 | Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade |
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EP (1) | EP1178964A1 (es) |
JP (1) | JP2002544260A (es) |
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CN (1) | CN1378534A (es) |
AR (1) | AR029635A1 (es) |
AU (1) | AU771928B2 (es) |
BR (1) | BR0011272A (es) |
CA (1) | CA2373509A1 (es) |
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EA (1) | EA005367B1 (es) |
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IL (1) | IL146244A0 (es) |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
US6867217B1 (en) | 1999-05-19 | 2005-03-15 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade |
US6716838B1 (en) | 1999-05-19 | 2004-04-06 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl uracils as anticoagulative agents |
US6458952B1 (en) | 1999-05-19 | 2002-10-01 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl uracils 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 |
US6664255B1 (en) | 1999-05-19 | 2003-12-16 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrazinones useful for selective inhibition of the coagulation cascade |
AU2001243598A1 (en) | 2000-03-13 | 2001-09-24 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted benzenes useful for selective inhibition of the coagulation cascade |
PT1268463E (pt) | 2000-04-05 | 2005-05-31 | Pharmacia Corp | 4-pironas substituidas com arilo e heteroarilo policiclicos uteis para a inibicao selectiva da cascata de coagulacao |
EP1268428A2 (en) | 2000-04-05 | 2003-01-02 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted 4-pyridones useful for selective inhibition of the coagulation cascade |
AU2001255399A1 (en) * | 2000-04-14 | 2001-10-30 | Corvas International, Inc. | Pyridine and pyrazine derivatives as thrombin inhibitors |
WO2001079155A2 (en) | 2000-04-17 | 2001-10-25 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted 1,4-quinones useful for selective inhibition of the coagulation cascade |
AU2001217827A1 (en) * | 2000-05-18 | 2001-11-26 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade |
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 (en) | 2000-11-20 | 2002-05-30 | Michael S. South | Substituted polycyclic aryl and heteroaryl pyridines useful for selective inhibition of the coagulation cascade |
PT1357111E (pt) | 2000-12-28 | 2009-10-20 | Shionogi & Co | Derivados de 2-piridona com afinidade para receptores de canabinóides do tipo 2 |
US6969715B2 (en) | 2001-10-03 | 2005-11-29 | Pharmacia Corporation | 6-membered heterocyclic compounds useful for selective inhibition of the coagulation cascade |
MXPA04003170A (es) | 2001-10-03 | 2004-07-08 | Pharmacia Corp | Compuestos policiclicos, sustituidos, provisto de 5 miembros, utiles para la inhibicion selectiva de la cascada de coagulacion. |
WO2003048127A1 (en) * | 2001-12-04 | 2003-06-12 | Corvas International, Inc. | Aromatic heterocyclic non-covalent inhibitors of urokinase and blood vessel formation |
TW200307667A (en) | 2002-05-06 | 2003-12-16 | Bristol Myers Squibb Co | Sulfonylaminovalerolactams and derivatives thereof as factor Xa inhibitors |
US8846935B2 (en) | 2010-05-07 | 2014-09-30 | Glaxosmithkline Llc | Indazoles |
TWI633089B (zh) * | 2013-03-28 | 2018-08-21 | 拜耳製藥股份有限公司 | 經取代的酮基吡啶衍生物 |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2224437A1 (en) * | 1995-06-27 | 1997-01-16 | Merck & Co., Inc. | Pyridinone-thrombin inhibitors |
AU720616B2 (en) * | 1996-02-22 | 2000-06-08 | Merck & Co., Inc. | Pyridinone thrombin inhibitors |
AU743544B2 (en) * | 1996-10-11 | 2002-01-31 | Millennium Pharmaceuticals, Inc. | Selective factor Xa inhibitors |
US5792779A (en) * | 1997-02-19 | 1998-08-11 | Merck & Co., Inc. | Pyridinone thrombin inhibitors |
CA2283704A1 (en) * | 1997-03-24 | 1998-10-01 | Merck & Co., Inc. | Thrombin inhibitors |
IL123986A (en) * | 1997-04-24 | 2011-10-31 | Organon Nv | Medicinal compounds |
WO1999000126A1 (en) * | 1997-06-26 | 1999-01-07 | Eli Lilly And Company | Antithrombotic agents |
JP2001514227A (ja) * | 1997-09-05 | 2001-09-11 | メルク エンド カムパニー インコーポレーテッド | ピラジノン系トロンビン阻害薬 |
TWI222441B (en) * | 1997-11-26 | 2004-10-21 | Dimensional Pharm Inc | Heteroaryl aminoguanidines and alkoxyguanidines and their use as protease inhibitors |
CA2343109A1 (en) * | 1998-09-28 | 2000-04-06 | Merck & Co., Inc. | Thrombin inhibitors |
AU747776B2 (en) * | 1998-10-30 | 2002-05-23 | Merck & Co., Inc. | Thrombin inhibitors |
CA2348530A1 (en) * | 1998-10-30 | 2000-05-11 | Merck & Co., Inc. | Thrombin inhibitors |
FR2786482B1 (fr) * | 1998-11-27 | 2002-08-09 | Synthelabo | Nouveaux derives de 2-pyridone, leur preparation et leur application en therapeutique |
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Title |
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See references of WO0069826A1 * |
Also Published As
Publication number | Publication date |
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IL146244A0 (en) | 2002-07-25 |
HUP0201996A3 (en) | 2002-12-28 |
ZA200400449B (en) | 2004-11-24 |
MY138303A (en) | 2009-05-29 |
JP2002544260A (ja) | 2002-12-24 |
KR20010113970A (ko) | 2001-12-28 |
AU4797300A (en) | 2000-12-05 |
SK15862001A3 (sk) | 2002-08-06 |
ZA200109340B (en) | 2004-05-26 |
BR0011272A (pt) | 2002-05-07 |
AR029635A1 (es) | 2003-07-10 |
CA2373509A1 (en) | 2000-11-23 |
EA200101213A1 (ru) | 2002-04-25 |
EA005367B1 (ru) | 2005-02-24 |
CN1378534A (zh) | 2002-11-06 |
UY26154A1 (es) | 2000-12-29 |
MXPA01011805A (es) | 2003-09-04 |
AU771928B2 (en) | 2004-04-08 |
NZ514875A (en) | 2004-10-29 |
NO20015606L (no) | 2002-01-21 |
CZ20014117A3 (cs) | 2002-05-15 |
WO2000069826A1 (en) | 2000-11-23 |
PL352403A1 (en) | 2003-08-25 |
HUP0201996A2 (en) | 2002-09-28 |
NO20015606D0 (no) | 2001-11-16 |
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