WO2000069826A1 - 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 cascade Download PDFInfo
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- WO2000069826A1 WO2000069826A1 PCT/US2000/008220 US0008220W WO0069826A1 WO 2000069826 A1 WO2000069826 A1 WO 2000069826A1 US 0008220 W US0008220 W US 0008220W WO 0069826 A1 WO0069826 A1 WO 0069826A1
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- Prior art keywords
- group
- hydrido
- carbon
- amino
- hydroxy
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- -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
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 2
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 claims 2
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- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
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- 229910001424 calcium ion Inorganic materials 0.000 description 1
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- 125000004966 cyanoalkyl group Chemical group 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
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- 208000009190 disseminated intravascular coagulation Diseases 0.000 description 1
- 230000002497 edematous effect Effects 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
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- 230000000302 ischemic effect Effects 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
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- 150000003904 phospholipids Chemical class 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.
- 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 , 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 ;
- 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
- 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 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 ;
- 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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Abstract
The invention relates to substituted polycyclic aryl and heteroaryl pyridone compounds having Formula (I) or a pharmaceutically acceptable salt thereof, wherein: a.o., Γ is selected from the group consisting of NH and NOH; useful as inhibitors of serine proteases of the coagulation cascade and compounds, compositions and methods for anticoagulant therapy for the treatment and prevention of a variety of thrombotic conditions including coronary artery and cerebrovascular diseases.
Description
Substituted Polycyclic Aryl and Heteroaryl Pyridones Useful for Selective Inhibition of the Coagulation Cascade
Field of the Invention 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.
Background of the Invention
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.
While clotting as a result of an injury to a blood vessel is a critical physiological process for mammals such as man, clotting can also lead to disease states. A pathological process called 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. When the thrombosis occurs in a coronary 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.
There have been several reports of non-peptidic and peptidic pyridone compounds that act as an inhibitor of a coagulation factor present in the coagulation cascade or clotting process. In PCT Patent Application WO 9847876, Van Boeckel et al. describe peptidic 6-alkylpyridones and 2- alkylpyrimidinones as anti-thrombotic compounds. In PCT Patent Application WO 98/16547, Zhu and Scarborough describe 3-(N-heterocyclylamino)^,5,6- substituted-pyridonylacetamides and 2,4-substituted-5-(N-heterocyclylamino)- pyrimidinonyl-acetamides containing amide substituents and having activity against mammalian factor Xa. In US Patent 5,656,645, Tamura et al. describe 4,5,6-substituted-3-aminopyridonyl-acetamides, 1 ,6-substituted-5- aminouracinylacetamides, and 2,4-substituted-5-aminopyrimidinonyl- acetamides containing amide substituents having a formyl function and having activity against thrombin. In US Patent 5,658,930, Tamura et al. again
describe 4,5,6-substituted-3-aminopyridonyl-acetamides, 1 ,6-substituted-5- aminouracinylacetamides, and 2,4-substituted-5-aminopyrimidinonyl- acetamides containing amide substituents having a formyl function and having activity against thrombin. In PCT Patent Applications 96/18644 and 97/46207, Tamura et al. further describe 4v5,6-substituted-3-aminopyridonylacetamides, 1,6-substituted- aminouracinyl-acetamides, and 2,4-substituted-5-amino- pyrimidinonylacetamides containing amide substituents having a formyl function and having activity against thrombin. In PCT Patent Application WO 98 09949, Suzuki et al. describe 2-heterocyclylacetamido derivatives of 1,2- diketones and report that they inhibit proteases, especially chymase inhibitors. In US Patent 5,668,289, Sanderson et al. describe 6-alkyl, 6-cycloalkyl, and 6-trifluoromethyl pyridones unsubstituted at the 4 and 5 positions and reported to inhibit thrombin. In PCT Patent Application WO 97/01338, Sanderson et al. describe 6-alkyl, 6-cycloalkyl, and 6-trifluoromethyl pyridones unsubstituted at the 4 and 5 positions and reported to inhibit thrombin. In US Patent
5,792,779, Sanderson et al. describe substituted 4,6-alkyl, 4,6-cycloalkyl, and 4,6-trifluoromethyl pyridones having utility as thrombin inhibitors. In PCT Patent Application WO 97/30708, Sanderson et al. describe additional substituted 4,6-alkyl, 4,6-cycloalkyl, and 4,6-trifluoromethyl pyridones having utility as thrombin inhibitors. In US Patent 5,869,487, Coburn et al. describe pyrido[3,4-B]pyrazines containing a fused 6-methylpyridone functionality and having utility as thrombin inhibitors. In PCT Patent Application WO 9831670, Sanderson et al. describe additional 4-substi.tuted 6-alkyl, 6-cycloalkyl, and 6- trifluoromethyl pyridones having utility as thrombin inhibitors. In PCT Patent Application WO 98/17274, Coburn et al. disclose substituted 3,4-diamino-6- methylpyridones having utility as human thrombin inhibitors. In PCT Patent Application WO 98/42342, Isaacs et al. describe additional 6-alkyl, cycloalkyl, and trifluoromethyl substituted pyridones and pyrazinones reported to inhibit human thrombin.
Summary of the Invention
It is an object of the present invention to provide compounds that are beneficial in anticoagulant therapy and that have a general structure:
It is another object of the present invention to provide methods for preventing and treating thrombotic conditions, such as coronary artery disease, cerebrovascular disease, and other coagulation related disorders. Such thrombotic conditions are prevented and treated by administering to a patient in need thereof an effective amount of compounds of Formula (I).
Various other objects and advantages of the present invention will become apparent from the following description of the invention.
Description of the Invention
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
wherein 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
4a 4b 39 40 5 14 15 consisting of R , R , R , R , R , R , and R to form a heterocyclyl ring having 5 through 8 contiguous members; B is formula (V):
1 2 1 2 1 wherein 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
1 1 2 1 2 1
K must be a covalent bond when two of D , D , J , J and K are O and S,
1 2 1 2 1 and no more than four of D , D , J , J and K are N with the proviso that
32 33 34 35 36
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;
R9 R10. R1 1. R12. R13. R16 R17. A18. R19. R32, R33. RM
35 36
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, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxy alkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxy alkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, alkoxyamino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfmylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, alkylenylamino, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboxy, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl ;
R
are independently 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 ;
T,32 _, r,33 r,33 J „34 34 _, „35 _, „35 J „36 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
32 33 33 34 34 35 35 consisting of spacer pairs R and R , R and R , R and R , and R
36 and R can be used at the same time;
9 10 10 11 11 12 12 13
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
13 and R can be used at the same time;
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 , τ,34 π35 _, 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
33 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 carbon atom at the point of attachment are optionally
9 13 9 substituted with R or R , a ring carbon or nitrogen adjacent to the R position and two atoms from the point of attachment is optionally substituted
10 13 with R , a ring carbon or nitrogen adjacent to the R position and two atoms
12 from the point of attachment is optionally substituted with R , a ring carbon
or nitrogen three atoms from the point of attachment and adjacent to the R
position is optionally substituted with R , a ring carbon or nitrogen three
12 atoms from the point of attachment and adjacent to the R position is
33 optionally substituted with R , and a ring carbon or nitrogen four atoms from
11 33 the point of attachment and adjacent to the R and R positions is optionally
su ib-sti •tuted j wi .tht R„34 ; A is selected from the group consisting of single covalent bond,
(W )rr-(CH(R15))pa and (CH(R15))pa-(W7)rr wherein rr is an integer
7 selected from 0 through 1, pa is an integer selected from 0 through 6, and W is selected from the group consisting of O, S, C(O), C(S), C(O)S, C(S)O,
C(O)N(R7), C(S)N(R?), (R?)NC(O), (R7)NC(S), S(O), S(O)2,
S(O)2N(R ), (R )NS(O)2, P(O)(R8), N(R?)P(O)(R8),
C(NR7)N(R7), (R?)NC(NR7), (R?)NC(NR7)NR7, and N(R7) with the proviso that no more than one of the group consisting of rr and pa can be 0 at the same time;
7 8
R and R are independently selected from the group consisting of hydrido, hydroxy, alkyl, acyl, aroyl, heteroaroyl, and alkoxyalkyl;
14 15 37 38
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; Ψ is selected from the group consisting of NR , O, C(O), C(S), S,
5 8 39 40
S(O), S(O)2, ON(R ), P(O)(R ), and CR R ;
R is selected from the group consisting of hydrido, hydroxy, amino, alkyl, alkoxy, alkoxyalkyl, haloalkyl, acyl, aroyl, and heteroaroyl;
39 40
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;
1 2 0
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;
X and R and R and R , with the proviso that no more than one of
the group consisting of spacer pair X and R and spacer pair R and R is be used at the same time, are optionally selected to be -W=X-Y=Z- wherein - W=X-Y=Z- forms a ring selected from the group consisting of a heteroaryl ring having from 5 through 6 contiguous members and an aryl;
W, X, Y, and Z are independently selected from the group consisting of C(R ), C(R10), C(R11), C(R12), N, N(R1°), 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
. . .„9 ,, 10 1 1 12 J T, 13 _, . . one or more of the group consisting of R , R , R , R , and R and with the proviso that no more than one of the group consisting of spacer pair X and R 1 and spacer pair R 1 and R ? is present at the same time;
Z is selected from the group consisting of covalent single bond,
41 42 41
(CR R )„ wherein q is an integer selected from 1 through 6, (CH(R ))σ-
.0 42 -(CH(R ))_ wherein g and p are integers independently selected from 0
through 3 and W is selected from the group consisting of O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R41), (R41)NC(O), C(S)N(R41),
(R41)NC(S), OC(O)N(R41), (R41)NC(O)O, SC(S)N(R41), (R4l)NC(S)S,
SC(O)N(R41), (R41)NC(O)S, OC(S)N(R41), (R41)NC(S)O,
42 41 41 42 42 41 N(R )C(O)N(R ), (R )NC(O)N(R ), N(R )C(S)N(R ),
41 42 41 41
(R )NC(S)N(R ), S(O), S(O)2, S(O)2N(R ), N(R )S(O)2, Se, Se(O),
Se(O)2, Se(O)2N(R41), N(R41)Se(O)2, P(O)(R8), N(R?)P(O)(R8),
8 7 41 41 28 29 41 22
P(O)(R )N(R ), N(R ), ON(R ), and SiR R , and (CH(R ))e-W -
42 (CH(R ))jj wherein e and h are integers independently selected from 0
22 41 42 through 2 and w is selected from the group consisting of CR =CR ,
41 42 CR R =C; vinylidene), ethynylidene (C=C; 1,2-ethynyl), 1,2-cyclopropyl,
1,2-cyclobutyl, 1,2-cyclohexyl, 1 -cyclohexyl, 1,2-cyclopentyl, 13- cyclopentyl, 23-mo holinyl, 2,4-morpholinyl, 2,6-morpholinyl, 3,4- morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 1 -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, 13- pyrrolidinyl, 23-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4- pyrrolidinyl, 23-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-
41 tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the provisos that R and
42 R are selected from other than halo and cyano when directly bonded to N and Z is directly bonded to the pyridone ring;
41 42
R and R are independently selected from the group consisting of amidino, hydroxyamino, hydrido, hydroxy, amino, halo, cyano, aryloxy, hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, alkoxy, alkyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkylalkoxy, alkoxyalkyl, heteroaryloxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl,
haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaralkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, alkyl sulfonyl, haloalkylsulfonyl, arylsulfonyl, arylsulfonylalkyl, aralkyl sulfonyl, cycloalkylsulfonyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfonyl, and aralkylsulfonylalkyl; Q is formula (II):
1 2 1 2 1 wherein 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
, L , ,-r 2 τl τ2 Λ τA . _ 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
1 1 2 1 2 1
K must be a covalent bond when two of D , D , J , J and K are O and S,
1 2 1 2 1 and no more than four of D , D , J , J and K are N, with the proviso that
9 10 11 12 13
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;
Q is optionally selected from formula (III):
3 4 3 4 wherein D , D , J , and J are independently selected from the group
3 4 3 4 consisting of C, N, O, and S, no more than one of D , D , J , and J is O, no
3 4 3 4 1 2 more than one of D , D , J , and J is S, and no more than three of D , D ,
J , and J 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;
4a 4b
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;
0 1 4a 4b 1
E is E , when K is (CR R )n, wherein E is selected from the group consisting of a covalent single bond, O, S, C(O), C(S), C(O)O, C(S)O,
C(O)S, C(S)S, C(O)N(R?), (R?)NC(O), C(S)N(R7), (R7)NC(S),
OC(O)N(R7), (R?)NC(O)O, SC(S)N(R?), (R?)NC(S)S, SC(O)N(R?),
(R7)NC(O)S, OC(S)N(R7), (R7)NC(S)O, N(R8)C(O)N(R7),
(R7)NC(O)N(R8), N(R8)C(S)N(R?), (R?)NC(S)N(R8), S(O), S(O)2,
S(O)2N(R7), N(R7)S(O)2, S(O)2N(R7)C(O), C(O)N(R7)S(O)2, P(O)(R8),
7 8 8 7 7 7 4a 4b N(R )P(O)(R ), P(O)(R )N(R ), N(R ), ON(R ), CR =CR ,
4a 4b ethynylidene (C=C; 1,2-ethynyl), and C=CR R ;
14 K is optionally (CH(R )):-T wherein j is selected from a integer from
0 through 2 and T is selected from the group consisting of single covalent
7 14 bond, O, S, and N(R ) with the proviso that (CH(R )): is bonded to the pyridone ring; o J2 14 2
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,
C(S)O, C(O)S, C(S)S, C(O)N(R?), (R7)NC(O), C(S)N(R7), (R7)NC(S),
(R7)NC(O)O, (R7)NC(S)S, (R7)NC(O)S, (R7)NC(S)O, N(R8)C(O)N(R7),
(R7)NC(O)N(R8), N(R8)C(S)N(R7), (R?)NC(S)N(R8), S(O), S(O)2,
S(O)2N(R7), N(R7)S(O)2, S(O)2N(H)C(O), C(O)N(H)S(O)2, P(O)(R8),
N(R7)P(O)(R8), P(O)(R8)N(R?), and N(R?);
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
7 7 1155
NN((RR )) wwiitthh tthhee pprroovviissoo tthhaatt RR iiss ootthheerr tthhaann hhyyddrrooxx)y, cyano, halo, amino, alkylamino, dialkylamino, and sulfhydryl when k is 1;
*3 1 c
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?),
(R7)NC(S), OC(O)N(R?), (R7)NC(O)O, SC(S)N(R7), (R?)NC(S)S,
SC(O)N(R?), (R7)NC(O)S, OC(S)N(R?), (R7)NC(S)O, N(R8)C(O)N(R?),
(R )NC(O)N(R8), N(R8)C(S)N(R?), (R?)NC(S)N(R8), S(O), S(O)2,
S(O)2N(R7), N(R7)S(O)2, P(O)(R8), N(R7)P(O)(R8), P(O)(R8)N(R?),
7 7 4a 4b
N(R ), ON(R ), CR =CR , ethynylidene (C≡C; 1,2-ethynyl), and
^„4a 4b C=CR R ;
Y° is formula (IV):
5 6 5 6 wherein 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
2 than one is a covalent bond, K is independently selected from the group
consisting of C and N , no more than one of D , D , J , and J is O, no more
than one of D , D , J , and J is S, one of D , D , J , and J must be a
5 6 5 6 covalent bond when two of D , D , J , and J are O and S, no more than
three of D , D , J , and J is N when K is N , and no more than four of
5 6 5 6 2 16 17
D , D , J , and J are N when K is carbon with the provisos that R , 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;
16 17
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;
Λb . , . . ,.^20 21
Q is selected from the group consisting of NR R ,
+ 20 21 22 NR R R , oxy, alkyl, aminoalkylenyl, alkylamino, dialkylamino,
dialkylsulfoniumalkyl, acylamino and Q , wherein Q is hydrido and R ,
21 22
R , and R are independently selected from the group consisting of hydrido, amino, alkyl, hydroxy, alkoxy, aminoalkylenyl, alkylamino, dialkylamino, and
20 21 22 hydroxyalkyl with the provisos that no more than one of R , R , and R is hydroxy, alkoxy, alkylamino, amino, and dialkylamino at the same time and
20 21 22 that R , R , and R must be other than be hydroxy, alkoxy, alkylamino,
2 + amino, and dialkylamino when K is N ;
20 21 20 22 21 22
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
20 21 20 22 one of the group consisting of spacer pairs R and R , R and R , and
21 22
R and R is used at the same time;
Q is optionally selected from the group consisting of
N(R )SO2N(R )(R ), N(R )C(O)OR , N(R )C(O)SR ,
N(R )C(S)OR and N(R )C(S)SR with the proviso that no more than one
, 23 24 26 of R , R , and R is hydroxy, alkoxy, alkylamino, amino, and
23 24 26 dialkylamino when two of the group consisting of R , R , and R are bonded to the same atom; Q is optionally selected from the group consisting of
25 23 24 dialkylsulfonium, trialkylphosphonium, C(NR )NR R ,
26 25 23 24 26 23 24
N(R )C(NR )N(R )(R ), N(R )C(O)N(R )(R ),
N(R26)C(S)N(R23)(R24), C(NR25)OR5,
C(O)N(R26)C(NR25)N(R23)(R24), C(S)N(R26)C(NR25)N(R23)(R24),
N(R )N(R )C(NR )N(R )(R ), ON(R )C(NR )N(R )(R ),
26 26 23 24 25 5 23 24
N(R )N(R )SO2N(R )(R ), C(NR )SR , C(O)NR R , and
23 24 23 24 26
C(O)NR R with the provisos that no more than one of R , R , and R can be hydroxy, alkoxy, alkylaminol, amino, or dialkylamino when two of the
23 24 26 group consisting of R , R , and R are bonded to the same atom and that b said Q group is bonded directiy to a carbon atom;
23 24 25 26
R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, aminoalkylenyl, alkylamino, dialkylamino, amino, and hydroxyalkyl;
23 24
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,
37 38 ft (CR R )b"( )az wherein az is an integer selected from 0 through 1, b is an integer selected from 1 through 4, 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(R14),
(R14)NC(O), C(S)N(R14), (R14)NC(S), OC(O)N(R14), SC(S)N(R14),
SC(O)N(R14), OC(S)N(R14), N(R15)C(O)N(R14), (R14)NC(O)N(R15),
N(R15)C(S)N(R14), (R14)NC(S)N(R15), S(O), S(O)2, S(O)2N(R14),
N(R14)S(O)2, P(O)(R8), N(R?)P(O)(R8), P(O)(R8)N(R7), N(R14),
ON(R ), (CH(R 4))c-W1-(CH(R15))d wherein c and d are integers
independently selected from 1 through 4, 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(R14),
(R14)NC(O), C(S)N(R14), (R14)NC(S), OC(O)N(R14), (R14)NC(O)O,
SC(S)N(R14), (R14)NC(S)S, SC(O)N(R14), (R14)NC(O)S, OC(S)N(R14),
(R14)NC(S)O, N(R15)C(O)N(R14), (R14)NC(O)N(R15),
N(R15)C(S)N(R14), (R14)NC(S)N(R15), S(O), S(O)2, S(O)2N(R14),
N(R14)S(O)2, P(O)(R8), N(R7)P(O)(R8), P(O)(R8)N(R?), N(R14),
ON(R ), and (CH(R14))e-W22-(CH(R15))h wherein e and h are integers
independently selected from 0 through 2 and W is selected from the group
41 42 41 42 consisting of CR =CR , CR R =C; vinylidene), ethynylidene (GsC;
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-moφholinyl, 3,4-morpholinyl, 3,5-moφholinyl, 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-tetrahydrofuranyl, 2,4- tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and3,4-tetrahydrofuranyl, with the
14 15 provisos that R and R are selected from other than halo and cyano when
37 38 14 14 directly bonded to N and that (CR R )b, (CH(R ))c, (CH(R ))e and are bonded to E ;
0 b ss ss
Y is optionally Q -Q wherein Q is selected from the group
37 38 consisting of (CR R )f wherein f is an integer selected from 1 through 6,
(CH(R ))C-W -(CH(R ))d wherein c and d are integers independendy
selected from 1 through 4, and 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(R14), (R14)NC(O), C(S)N(R14), (R14)NC(S),
OC(O)N(R14), (R14)NC(O)O, SC(S)N(R14), (RM)NC(S)S, SC(O)N(R14),
(R14)NC(O)S, OC(S)N(R14), (R14)NC(S)O, N(R15)C(O)N(R14),
(R14)NC(O)N(R15), N(R15)C(S)N(R14), (R14)NC(S)N(R15), S(O),
S(O)2, S(O)2N(R14), N(R14)S(O)2, P(O)(R8), N(R?)P(O)(R8),
P(O)(R8)N(R7), N(R14), ON(R14), and (CH(R14))e-W2-(CH(R15))h
wherein e and h are integers independendy selected from 0 through 2 and w2
4a 4b is selected from the group consisting of CR =CR , ethynylidene (C≡C; 1 ,2-
4a 4b 14 15 ethynyl), and C=CR R with the provisos that R and R are selected
37 from other than halo and cyano when directly bonded to N and that (CR
38 14 14 o
R )f, (CH(R ))c, and (CH(R ))e are bonded to E ;
Y° is optiionally Qb-Qsss wherein QSSS is (C^R38)),.^, r is an
integer selected from 1 through 3, 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-moφholinyl, 2,5-moφholinyl, 2,6-moφholinyl, 3,4- moφholinyl, 3,5-moφholinyl, 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, 2,5- piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 3,5-piperidinyl, 3,6-piperidinyl, 1,2-pyrrolidinyl, 13-pyrrolidinyl, 23-ρyrrolidinyl, 2,4-pyrrolidinyl, 2,5- pyrrolidinyl, 3,4-pyrrolidinyl, 2H-2,3-pyranyl, 2H-2,4-pyranyl, 2H-2,5- pyranyl, 4H-23-pyranyl, 4H-2,4-pyranyl, 4H-2,5-pyranyl, 2H-pyran-2-one- 3,4-yl, 2H-ρyran-2-one-4,5-yl, 4H-pyran-4-one-2,3-yl, 23- tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, 3,4- tetrahydrofuranyl, 23-tetrahydropyranyl, 2,4-tetrahydropyranyl, 2,5- tetrahydropyranyl, 2,6-tetrahydropyranyl, 3,4-tetrahydropyranyl, and 3,5- tetrahydropyranyl, and each carbon and hyrido containing nitrogen member of the ring of the W"^ other than the points of attachment is optionally substituted
, ^ „ 10 11 J T, 12 . , , with one or more of the group consisting of R , R , R , and R , with the
proviso that (CH(R ))r is bonded to E and Q is bonded to lowest numbered
substituent position of each W ;
Y° is optionally Qb-Qsssr wherein QSSSr is (CH(R38))r-W4, r is an
4 integer selected from 1 through 3 , W is selected from the group consisting of
1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl, 1,2- cyclopentyl, 13-cyclopentyl, 23-moφholinyl, 2,4-moφholinyl, 2,5- moφholinyl, 2,6-moφholinyl, 3,4-moφholinyl, 3,5-moφholinyl, 1,2- piperazinyl, 1,3-piperazinyl, 1,4-piperazinyl, 23-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 1,4-piperidinyl, 2,3- piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 3,5-piperidinyl, 3,6-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 23- pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2H-23- pyranyl, 2H-2,4-ρyranyl, 2H-2,5-pyranyl, 4H-2,3-pyranyl, 4H-2,4-pyranyl, 4H-2,5-pyranyl, 2H-pyran-2-one-3,4-yl, 2H-pyran-2-one-4,5-yl, 4H-pyran- 4-one-2,3-yl, 23-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-
tetrahydrofuranyl, 3,4-tetrahydrofuranyl, 23-tetrahydropyranyl, 2,4- tetrahydropyranyl, 2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl, 3,4- tetrahydropyranyl, and 3,5-tetrahydropyranyl, and each carbon and hydrido
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
and Q is bonded to highest number substituent position of each W ;
Y° is optionally Qb-Qssss wherein QSSSS is (CH(R38))r-W5, r is an
integer selected from 1 through 3, ^ 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, 7- benzothiophenyl, 2,7-imidazo(l,2-a)pyridinyl, 3,4- imidazo(l,2-a)pyridinyl, 3,5-imidazo(l,2-a)pyridinyl, 3,6-imidazo(l,2- a)pyridinyl, 3,7-imidazo(l,2-a)pyridinyl, 2,4-indolyl, 2,5-indolyl, 2,6- indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6-indolyl, 3,7-indolyl, 1,4- isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl, 2,5-isoindolyl, 2,6- isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl, 3,4-indazolyl, 3,5-indazolyl, 3,6- indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5-benzoxazolyl, 2,6- benzoxazolyl, 2,7-benzoxazolyl, 3,4-benzisoxazolyl, 3,5-benzisoxazolyl, 3,6- benzisoxazolyl, 3,7-benzisoxazolyl, 1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl, 1 ,7-naphthyl, 1 ,8-naphthyl, 2,4-naphthyl, 2,5-naphthyl, 2,6-naphthyl, 2,7- naphthyl, 2,8-naphthyl, 2,4-quinolinyl, 2,5-quinolinyl, 2,6-quinolinyl, 2,7- quinolinyl, 2,8-quinolinyl, 3,4-quinolinyl, 3,5-quinolinyl, 3,6-quinolinyl, 3,7- quinolinyl, 3,8-quinolinyl, 4,5-quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl, 4,8- quinolinyl, 1,4-isoquinolinyl, 1,5-isoquinolinyl, 1,6-isoquinolinyl, 1,7- isoquinolinyl, 1,8-isoquinolinyl, 3,4-isoquinolinyl, 3,5-isoquinolinyl, 3,6- isoquinolinyl, 3,7-isoquinolinyl, 3,8-isoquinolinyl, 4,5-isoquinolinyl, 4,6- isoquinolinyl, 4,7-isoquinolinyl, 4,8-isoquinolinyl, 3,4-cinnolinyl, 3,5-
cinnolinyl, 3,6-cinnolinyl, 3,7-cinnolinyl, 3,8-cinnolinyl, 4,5-cinnolinyl, 4,6- cinnolinyl, 4,7-cinnolinyl, and 4,8-cinnolinyl, and each carbon and hydrido containing nitrogen member of the ring of the W"^ other than the points of attachment is optionally substituted with one or more of the group consisting of R , R , R , and R , with the proviso that Q is bonded to lowest number
substituent position of each W"^ and that (CH(R ))r is bonded to E ;
Y° is optionally Qb-Qssssr wherein QSSSSr is (CH(R38))r-W6, r is an
integer selected from 1 through 3, 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-imidazo(l,2-a)pyridinyl, 3,4- imidazo(l,2-a)pyridinyl, 3,5-imidazo(l,2-a)pyridinyl, 3,6-imidazo(l,2- a)pyridinyl, 3,7-imidazo(l,2-a)pyridinyl, 2,4-indolyl, 2,5-indolyl, 2,6- indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6-indolyl, 3,7-indolyl, 1,4- isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl, 2,5-isoindolyl, 2,6- isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl, 3,4-indazolyl, 3,5-indazolyl, 3,6- indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5-benzoxazolyl, 2,6- benzoxazolyl, 2,7-benzoxazolyl, 3,4-benzisoxazolyl, 3,5-benzisoxazolyl, 3,6- benzisoxazolyl, 3,7-benzisoxazolyl, 1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl, 1,7-naphthyl, 1,8-naphthyl, 2,4-naphthyl, 2,5-naphthyl, 2,6-naphthyl, 2,7- naphthyl, 2,8-naphthyl, 2,4-quinolinyl, 2,5-quinolinyl, 2,6-quinolinyl, 2,7- quinolinyl, 2,8-quinolinyl, 3,4-quinolinyl, 3,5-quinolinyl, 3,6-quinoIinyl, 3,7- quinolinyl, 3,8-quinolinyl, 4,5-quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl, 4,8- quinolinyl, 1,4-isoquinolinyl, 1,5-isoquinolinyl, 1,6-isoquinolinyl, 1,7- isoquinolinyl, 1,8-isoquinoIinyl, 3,4-isoquinolinyl, 3,5-isoquinolinyl, 3,6- isoquinolinyl, 3,7-isoquinolinyl, 3,8-isoquinolinyl, 4,5-isoquinolinyl, 4,6- isoquinolinyl, 4,7-isoquinolinyl, 4,8-isoquinolinyl, 3,4-cinnolinyl, 3,5- cinnolinyl, 3,6-cinnolinyl, 3,7-cinnolinyl, 3,8-cinnolinyl, 4,5-cinnolinyl, 4,6-
cinnolinyl, 4,7-cinnolinyl, and 4,8-cinnolinyl, and each carbon and hydrido containing nitrogen member of the ring of the W other than the points of attachment is optionally substituted with one or more of the group consisting of R , R , R , and R , with the proviso that Q is bonded to highest number
substituent position of each W and that (CH(R ))r is bonded to E .
In another embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof,
J is selected from the group consisting of O and S; B is formula (V):
1 2 1 2 1 wherein 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
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
1 1 2 1 2 1 K must be a covalent bond when two of D ,D ,J ,J andK are O and S,
1 2 1 2 1 and no more than four of D , D , J , J and K are N;
R ,R ,R ,R ,R ,R ,K ,R ,R ,R ,K ,K ,
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, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxy alkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, alkoxyamino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkyl sulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclyl sulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, alkylenylamino, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboxy, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl ;
τ R, l6 , R r, 19 , R r,32 , πR33 , R r,34 , TR35 , and Λ R „36 are i .nd Jepend Jend ,y opti .onal „ly
Q with the proviso that no more than one of R and R is Q at the same
time and that Q is Q ;
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 J 36 R , R , and R ; B is optionally selected from the group consisting of C3-C12 cycloalkyl, C5-C10 cycloalkenyl, and C4-C9 saturated heterocyclyl, wherein
33 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 carbon atom at the
9 13 point of attachment are optionally substituted with R or R , a ring carbon or
9 nitrogen adjacent to the R position and two atoms from the point of attachment
10 is optionally substituted with R , a ring carbon or nitrogen adjacent to the
13 R position and two atoms from the point of attachment is optionally
12 substituted with R , a ring carbon or nitrogen three atoms from the point of
attachment and adjacent to the R position is optionally substituted with R , a ring carbon or nitrogen three atoms from the point of attachment and adjacent
12 33 to the R position is optionally substituted with R , and a ring carbon or
nitrogen four atoms from the point of attachment and adjacent to the R and
33 34 R positions is optionally substituted with R ;
A is selected from the group consisting of single covalent bond, (W )rr-(CH(R1 ))pa and (CH(R15))pa-(W7)rr wherein rr is an integer
7 selected from 0 through 1, pa is an integer selected from 0 through 6, and W
7 7 is selected from the group consisting of O, S, C(O), C(O)N(R ), C(S)N(R ),
7 7 7 (R )NC(O), (R )NC(S), and N(R ) with the proviso that no more than one of the group consisting of rr and pa can be 0 at the same time;
7 8
R and R are independently selected from the group consisting of hydrido, hydroxy, alkyl, and alkoxyalkyl;
14 15 37 38
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;
Ψ is selected from the group consisting of NR , C(O), and S(O)2;
5 . R is selected from the group consisting of hydrido, hydroxy, alkyl, and alkoxy;
39 40
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;
X and R and R and R , with the proviso that no more than one of
the group consisting of spacer pair X and R and spacer pair R and R is be used at the same time, are optionally selected to be -W=X-Y=Z- wherein -
W=X-Y=Z- forms a ring selected from the group consisting of a heteroaryl ring having from 5 through 6 contiguous members and an aryl;
W, X, Y, and Z are independently selected from the group consisting of C(R ), C(R ), C(RH), C(R12), N, N(R10), 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
10 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
. . ,. „9 τ, 10 „ H „ 12 J T_ 13 J . u one or more of the group consisting of R , R , R , R , and R and with the proviso that no more than one of the group consisting of spacer pair X and
R 1 and spacer pair R 1 and KΛ 7 is present at the same time; R 2 is Z 0 -Q; Z is selected from the group consisting of covalent single bond,
41 42 41
(CR R )„ wherein q is an integer selected from 1 through 3, (CH(R ))σ-
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),
41 41 41 22 42
S(O)2, N(R ), and ON(R ), and (CH(R ))e-W^ -(CH(R ))h wherein e
and h are integers independently selected from 0 through 2 and W is selected
41 42 from the group consisting of CR =CR , 1,2-cyclopropyl, 1,2-cyclobutyl,
1,2-cyclohexyl, 1,3-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-
moφholinyl, 2,4-moφholinyl, 2,6-moφholinyl, 3,4-moφholinyl, 3,5- moφholinyl, 1,2-piperazinyl, 13 -piperazinyl, 2,3-piperazinyl, 2,6- piperazinyl, 1,2-piperidinyl, 13-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrτolidinyl, 23- pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 23- tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and 3,4- tetrahydrofuranyl, with the proviso that Z is directly bonded to the pyridone πng;
41 42
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):
1 2 1 2 1 wherein 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
1 1 2 1 2 1
K must be a covalent bond when two of D , D , J , J and K are O and S,
1 2 1 2 1 and no more than four of D , D , J , J and K is N, with the proviso that
9 10 11 12 13 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;
4a 4b
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,
C(O), C(S), C(O)N(R7), (R7)NC(O), S(O)2, (R?)NS(O)2, and S(O)2N(R );
Y° is formula (IV):
5 6 5 6 wherein 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
2 5 6 5 6 than one is a covalent bond, K is C, no more than one of D , D , J , and J
• ^ , ,-^5 ^6 5 , 6 . _ » — 5 _6 τ5 , τ6 is O, no more than one of D , D , J , and J is S, one of D , D , J , and J
5 6 5 6 must be a covalent bond when two of D , D , J , and J are O and S, and no
more than four of D , D , J , and J are N when K is carbon with the
provisos that R , R , R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; h 20 1
Q is selected from the group consisting of NR R ,
+ 20 21 22 be be 20
NR R R , aminoalkylenyl, and Q , wherein Q is hydrido and R ,
21 22 .
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
C(NR25)NR23R24 N(R26)C(NR25)N(R23)(R24),
C(O)N(R26)C(NR25)N(R23)(R24), N(R26)N(R26)C(NR25)N(R23)(R24),
and ON(R )C(NR )N(R )(R ) with the provisos that no more than one
23 24 26 of R , R , and R is hydroxy, alkylamino, am o, or dialkylamino when
23 24 26 two of the group consisting of R , R , and R are bonded to the same atom;
23 24 25 26 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,
(CR R )b"(W az wherein az is an integer selected from 0 through 1, b is an integer selected from 1 through 5, and is selected from the group consisting of O, C(O), S(O), S(O)2, S(O)2N(R14), N(Rl4)S(O)2, and
N(R ), (CH(R! ))c-W1-(CH(R15))d wherein c and d are integers
independently selected from 1 through 4 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(R14),
(R14)NC(O), C(S)N(R14), (R14)NC(S), OC(O)N(R14), (R14)NC(O)O,
SC(S)N(R14), (R14)NC(S)S, SC(O)N(R14), (R14)NC(O)S, OC(S)N(R14),
(R14)NC(S)O, N(R15)C(O)N(R14), (R14)NC(O)N(R15),
N(RI5)C(S)N(R14), (R14)NC(S)N(R15), S(O), S(O)2, S(O)2N(R14),
N(R14)S(O)2, P(O)(R8), N(R7)P(O)(R8), P(O)(R8)N(R?), N(R14),
ON(R ), and (CH(R14))e-W22-(CH(R15))h wherein e and h are integers
independently selected from 0 through 2 and W^ is selected from the group
41 42 41 42 consisting of CR =CR , CR R =C; vinylidene), ethynylidene (C≡C; 1,2-ethynyl), 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 13- cyclohexyl, 1,2-cyclopentyl, 13-cyclopentyl, 2,3- oφholinyl, 2,4- moφholinyl, 2,6-moφholinyl, 3,4-moφholinyl, 3,5-moφholinyl, 1,2- piperazinyl, 13-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 13-piperidinyl, 23-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4- piperidinyl, 1,2-pyrrolidinyl, 13-pyrrolidinyl, 23-pyrrolidinyl, 2,4- pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4- tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the
14 15 provisos that R and R are selected from other than halo and cyano when
37 38 14 14 direcdy bonded to N and that (CR R )b, (CH(R ))c, and (CH(R ))e are bonded to E ;
.0 . b ss ss i is optionally Q -Q wherein Q is selected from the group
37 38 consisting of (CR R )f wherein f is an integer selected from 1 through 4,
(CH(R ))C-W -(CH(R ))cj wherein c and d are integers independendy
selected from 1 through 2, and W is selected from the group consisting of W
14 is selected from the group consisting of O, S, C(O), C(O)N(R ),
(R14)NC(O), N(R15)C(O)N(R14), (R14)NC(O)N(R15), N(RM), ON(R14),
14 2 15 and (CH(R ))e-WX(CH(R ))^ wherein e and h are integers independently
selected from 0 through 2 and W^ is selected from the group consisting of
4a 4b 4a 4b
CR =CR , ethynylidene (C≡C; 1,2-ethynyl), and C=CR R with the
14 15 provisos that R and R are selected from other than halo when directly
*i T ^ O Λ Λ Λ Λ bonded to N and that (CR R )f, (CH(R ))c, and (CH(R ))e are bonded to E°;
Y° is optionally Qb-Qsss wherein QSSS is (CrKR38)),.^, r is a ; n
integer selected from 1 through 2, ^ is selected from the group consisting of
1,1-cyclopropyl, 1,2-cyclopropyl, 1,1-cyclo butyl, 1,2-cyclobutyl, 1,2- cyclohexyl, 13-cyclohexyl, 1,4-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-moφholinyl, 2,4-moφholinyl, 2,5-moφholinyl, 2,6-moφholinyl, 3,4- moφholinyl, 3,5-moφholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 1,4- piperazinyl, 23-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 1,4-piperidinyl, 23-piperidinyl, 2,4-piperidinyl, 2,5- piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 3,5-piperidinyl, 3,6-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 23-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5- pyrrolidinyl, 3,4-pyrrolidinyl, 2H-23-ρyranyl, 2H-2,4-pyranyl, 2H-2,5- pyranyl, 4H-2,3-pyranyl, 4H-2,4-pyranyl, 4H-2,5-pyranyl, 2H-pyran-2-one- 3,4-yl, 2H-pyran-2-one-4,5-yl, 4H-pyran-4-one-2,3-yl, 23- tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, 3,4- tetrahydrofuranyl, 23-tetrahydropyranyl, 2,4-tetrahydropyranyl, 2.5- tetrahydropyranyl, 2,6-tetrahydropyranyl, 3,4-tetrahydropyranyl, and 3,5- tetrahydropyranyl, and each carbon and hyrido 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 o .f r R,9 , T RΪ 10 , « RH , and J T R, 1 , wi •th L th.e
proviso that (CH(R ))r is bonded to E and Q is bonded to lowest numbered
substituent position of each W3; r° • 4 . Y is
)r-W , πs an
4 integer selected from 1 through 2, W is selected from the group consisting of
1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl, 1,2- cyclopentyl, 1,3-cyclopentyl, 23-moφholinyl, 2,4-moφholinyl, 2,5-
moφholinyl, 2,6-moφholinyl, 3,4-moφholinyl, 3,5-moφholinyl, 1,2- piperazinyl, 13-piperazinyl, 1,4-piperazinyl, 23-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 1,4-piperidinyl, 2,3- piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 3,5-piperidinyl, 3,6-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 23- pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2H-23- pyranyl, 2H-2,4-pyranyl, 2H-2,5-pyranyl, 4H-2,3-pyranyl, 4H-2,4-pyranyl, 4H-2,5-pyranyl, 2H-pyran-2-one-3,4-yl, 2H-pyran-2-one-4,5-yl, 4H-pyran- 4-one-23-yl, 23-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5- tetrahydrofuranyl, 3,4-tetrahydrofuranyl, 23-cetrahydropyranyl, 2,4- tetrahydropyranyl, 2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl, 3,4- tetrahydropyranyl, and 3,5-tetrahydropyranyl, and each carbon and hyrido
. . . 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 Qb-Qssss wherein QSSSS is (CH(R38))r-W5, r is an
integer selected from 1 through 2, 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-benzothioρhenyl, 2,7- benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6- benzothiophenyl, 3,7-benzothiophenyl, 2,7-imidazo( l,2-a)pyridinyl, 3,4- imidazo( 1 ,2-a)pyridinyl, 3 ,5-imidazo( 1 ,2-a)pyridinyl, 3,6-imidazo( 1 ,2- a)pyridinyl, 3,7-imidazo(l,2~a)pyridinyl, 2,4-indolyl, 2,5-indolyl, 2,6- indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6-indolyl, 3,7-indolyl, 1,4- isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl, 2,5-isoindolyl, 2,6- isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl, 3,4-indazolyl, 3,5-indazolyl, 3,6- indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5-benzoxazolyl, 2,6- benzoxazolyl, 2,7-benzoxazolyl, 3,4-benzisoxazolyl, 3,5-benzisoxazolyl, 3,6-
benzisoxazolyl, 3,7-benzisoxazolyl, 1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl, 1,7-naphthyl, 1,8-naphthyl, 2,4-naphthyl, 2,5-naphthyl, 2,6-naphthyl, 2,7- naphthyl, 2,8-naphthyl, 2,4-quinolinyl, 2,5-quinolinyl, 2,6-quinolinyl, 2,7- quinolinyl, 2,8-quinolinyl, 3,4-quinolinyl, 3,5-quinolinyl, 3,6-quinolinyl, 3,7- quinolinyl, 3,8-quinolinyl, 4,5-quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl, 4,8- quinolinyl, 1,4-isoquinolinyl, 1,5-isoquinolinyl, 1,6-isoquinolinyl, 1,7- isoquinolinyl, 1,8-isoquinolinyl, 3,4-isoquinolinyl, 3,5-isoquinolinyl, 3,6- isoquinolinyl, 3,7-isoquinolinyI, 3,8-isoquinolinyl, 4,5-isoquinolinyl, 4,6- isoquinolinyl, 4,7-isoquinolinyl, 4,8-isoquinolinyl, 3,4-cinnolinyl, 3,5- cinnolinyl, 3,6-cinnolinyl, 3,7-cinnolinyl, 3,8-cinnolinyl, 4,5-cinnolinyl, 4,6- cinnolinyl, 4,7-cinnolinyl, and 4,8-cinnolinyl, and each carbon and hyrido containing nitrogen member of the ring of the W"^ other than the points of attachment is optionally substituted with one or more of the group consisting of
R , R , R , and R , with the proviso that Q is bonded to lowest number
substituent position of each W and that (CH(R ))r is bonded to E ; v° • *• π ^ ssssr , . „ssssr . //^,ττ/rι38 6 . Y is optionally Q -Q wherein Q is (CH(R ))r-W , r is an
integer selected from 1 through 2, 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-imidazo(l,2-a)pyridinyl, 3,4- imidazo(l,2-a)pyridinyl, 3,5-imidazo(l,2-a)pyridinyl, 3,6-imidazo(l,2- a)pyridinyl, 3,7-imidazo(l,2-a)pyridinyl, 2,4-indolyl, 2,5-indolyl, 2,6- indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6-indolyl, 3,7-indolyl, 1,4- isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl, 2,5-isoindolyl, 2,6- isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl, 3,4-indazolyl, 3,5-indazolyl, 3,6- indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5-benzoxazolyl, 2,6- benzoxazolyl, 2,7-benzoxazoIyl, 3,4-benzisoxazolyl, 3,5-benzisoxazolyl, 3,6- benzisoxazolyl, 3,7-benzisoxazolyl, 1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl,
1,7-naphthyl, 1,8-naρhthyl, 2,4-naphthyl, 2,5-naphthyl, 2,6-naphthyl, 2,7- naphthyl, 2,8-naphthyl, 2,4-quinoIinyI, 2,5-quinolinyl, 2,6-quinolinyl, 2,7- quinolinyl, 2,8-quinolinyl, 3,4-quinolinyl, 3,5-quinolinyl, 3,6-quinolinyl, 3,7- quinolinyl, 3,8-quinolinyl, 4,5-quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl, 4,8- quinolinyl, 1,4-isoquinolinyl, 1,5-isoquinolinyl, 1 ,6-isoquinolinyl, 1,7- isoquinolinyl, 1,8-isoquinolinyl, 3,4-isoquinolinyl, 3,5-isoquinolinyl, 3,6- isoquinolinyl, 3,7-isoquinolinyl, 3,8-isoquinolinyl, 4,5-isoquinolinyl, 4,6- isoquinolinyl, 4,7-isoquinolinyl, 4,8-isoquinolinyl, 3,4-cinnolinyl, 3,5- cinnolinyl, 3,6-cinnolinyl, 3,7-cinnolinyl, 3,8-cinnolinyl, 4,5-cinnolinyl, 4,6- cinnolinyl, 4,7-cinnolinyl, and 4,8-cinnolinyl, and each carbon and hyrido
6 containing nitrogen member of the ring of the W other than the points of attachment is optionally substituted with one or more of the group consisting of R , R , R , and R , with the proviso that Q is bonded to highest number
substituent position of each W and that (CH(R ))r is bonded to E .
In a preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, J is O; B is the Formula:
9 10 11 12 13 R , R , R , R , and R are optionally selected from the group
9 10 11 consisting of heteroaryl and heterocyclyl with the proviso that R , R , R , r R , and , R, 13 are su Lbsti .tutents f ,or oth , er th , an „ B; τ R, 6 , πRl9 , rR,32 , TR, 3 , R 34 , R 35 , and R 36 are i .nd _,epend _,entl ,y opti .onal „ly
Q with the proviso that no more than one of R and R is Q at the same
time and that Q is Q ;
B is optionally, with the proviso that R 1 and R 7 are selected from the group consisting of a spacer pair and -W=X-Y=Z-, Formula (V):
1 2 1 2 1 wherein 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
1 1 2 1 2 1
K must be a covalent bond when two of D , D , J , J and K are O and S,
1 2 1 2 1 and no more than four of D , D , J , J and K are N;
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 ,
„34 35 J 36 R , R , and R ;
B is selected from the group consisting of C3-C12 cycloalkyl and C4
33 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, ring carbons and a nitrogen adjacent to the
9 13 carbon at the point of attachment are optionally substituted with R or R , a
9 ring carbon or nitrogen adjacent to the R position and two atoms from the
10 point of attachment is optionally substituted with R , a ring carbon or
13 nitrogen adjacent to the R position and two atoms from the point of
12 attachment is optionally substituted with R , a ring carbon or nitrogen three
10 atoms from the point of attachment and adjacent to the R position is
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
33 substituted with R , and a ring carbon or nitrogen four atoms from the point
11 33 of attachment and adjacent to the R and R positions is optionally u • , - ^34 substituted with R ;
B is optionally, with the proviso that R 1 and R 2 are selected from the group consisting of a spacer pair and -W=X-Y=Z-, a C5-C9 saturated
33 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, ring carbons and nitrogen adjacent to the
9 carbon atom at the point of attachment are optionally substituted with R or
13 9 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
13 nitrogen adjacent to the R position and two atoms from the point of
12 attachment is optionally substituted with R , a ring carbon or nitrogen three
atoms from the point of attachment and adjacent to the R position is
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
33 subsututed with R , and a ring carbon or nitrogen four atoms from the point
11 33 of attachment and adjacent to the R and R positions is optionally
,. • , - , ^34 substituted with R ; A is selected from the group consisting of single covalent bond,
(W )rτ-(CH(R1 ))pa and (CH(R15))pa-(W7)rr wherein rr is an integer
7 selected from 0 through 1, pa is an integer selected from 0 through 6, and W
7 7 is selected from the group consisting of O, S, C(O), (R )NC(O), (R )NC(S),
7 and N(R ) with the proviso that no more than one of the group consisting of rr and pa is 0 at the same time;
7 . R is selected from the group consisting of hydrido, hydroxy, and alkyl;
15 . R is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl;
Ψ 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;
X and R and R and R , with the proviso that no more than one of
the group consisting of spacer pair X and R and spacer pair R and R is be used at the same time, are optionally selected to be -W=X-Y=Z- wherein - W=X-Y=Z- forms a ring selected from the group consisting of a heteroaryl ring having from 5 through 6 contiguous members and an aryl;
W, X, Y, and Z are independendy selected from the group consisting of C(R9), C(R10), C(RU), C(R12), N, N(R10), 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 );
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, r, 10 „ 11 „ 12 , „ 13 _, . L one or more of the group consisting of R , R , R , R , and R and with the proviso that no more than one of the group consisting of spacer pair X and
R 1 and spacer pair R 1 and R 2 is present at the same time;
R2 is Z°-Q;
Z is selected from the group consisting of covalent single bond,
41 42 41
(CR R )Q wherein q is an integer selected from 1 through 3, (CH(R ))σ- fi 42 -(CH(R ))p wherein g and p are integers independendy selected from 0 through 3 and W is selected from the group consisting of O, S, C(O), S(O),
41 41 41 22 42 N(R ), and ON(R ), and (CH(R ))e-W -(CH(R ))h wherein e and h
are integers independently selected from 0 through 1 and W^ is selected from
41 42 the group consisting of CR =CR , 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2- cyclohexyl, 13-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 23- moφholinyl, 2,4-moφholinyl, 2,6-moφholinyl, 3,4-moφholinyl, 3,5- moφholinyl, 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, 23- tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and 3,4- tetrahydrofuranyl, with the proviso that Z is directly bonded to the pyridone πng;
41 42
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):
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
1 1 2 1 2 1 K must be a covalent bond when two of D , D , J , J and K are O and S,
1 2 1 2 1 and no more than four of D , D , J , J and K are N, with the proviso that
9 10 11 12 13
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;
4a 4b
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
7 group consisting of a covalent single bond, C(O), C(S), C(O)N(R ),
(R )NC(O), S(O)2, (R7)NS(O)2, and S(O)2N(R?); Y° is formula (IV):
5 6 5 6 wherein 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
• <-\ , -T-.5 ,- 6 5 , 6 . _ ^ ^5 _ 6 5 τ6 is O, no more than one of D , D , J , and J is S, one of D , D , J , and J
must be a covalent bond when two of
are O and S, and no
5 6 5 6 16 17 more than four of D , D , J , and J are N with the proviso that R , 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;
^ . , , . . . xm 20τ,21 . „ , ,
Q is selected from the group consisting of NR R , aminoalkylenyl,
Q wherein Q is hydrido, N(R )C(NR )N(R )(R ), and
25 23 24 20 21
C(NR )NR R , with the provisos that no more than one of R and R is hydroxy, amino, alkylamino, or dialkylamino at the same time and that no
23 24 more than one of R and R is hydroxy, amino, alkylamino, or dialkylamino at the same time;
20 21 23 24 25 26 R , R , R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, aminoalkylenyl, amino, dialkylamino, alkylamino, and hydroxyalkyl; s Q is selected from the group consisting of a single covalent bond,
37 38 (CR R )(j wherein b is an integer selected from 1 through 4, and
(CH(R ))C-W -(CH(R ))^ wherein c and d are integers independendy
selected from 1 through 3 and W is selected from the group consisting of
C(O)N(R14), (R14)NC(O), S(O), S(O)2, S(O)2N(R14), N(R14)S(O)2, and
14 14
N(R ), with the provisos that R is selected from other than halo when
directly bonded to N and that (CR R , and (CH(R ))c are bonded to E ;
14 . R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
37 38
R and R are independently selected from the group consisting of hydrido, alkyl, and haloalkyl;
38 . R is optionally selected from the group consisting of aroyl and heteroaroyl;
Y° is optionally Qb-Qss wherein QSS is (CH(R14))e-W2-(CH(R15))h,
wherein e and h are integers independendy selected from 1 through 2 and W^
4a 4b 14 o is CR =CR with the proviso that (CH(R ))e is bonded to E ;
0 . b ssss b
Y is optionally selected from the group consisting of Q -Q and Q -
QSSSSr wherein QSSSS is (CH(R38))r-W5 and QSSSSr is (CH(R38))r-W6 r is an
integer selected from 1 through 2, and 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-benzothiophenyl, 3,7-benzothiophenyl, 2,7- imidazo(l,2-a)pyridinyl, 3,4-imidazo(l,2-a)pyridinyl, 3,5-imidazo(l,2- a)pyridinyl, 3,6-imidazo(l,2-a)pyridinyl, 3,7-imidazo(l,2-a)pyridinyl, 2,4- indolyl, 2,5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6- indolyl, 3,7-indolyl, 1,4-isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4-
isoindolyl, 2,5-isoindolyl, 2,6-isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl, 3,4- indazolyl, 3,5-indazolyl, 3,6-indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5- benzoxazolyl, 2,6-benzoxazolyl, 2,7-benzoxazolyl, 3,4-benzisoxazolyl, 3,5- benzisoxazolyl, 3,6-benzisoxazolyl, 3,7-benzisoxazolyl, 1,4-naphthyl, 1,5- naphthyl, 1,6-naphthyl, 1,7-naρhthyl, 1,8-naphthyl, 2,4-naphthyl, 2,5- naphthyl, 2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl, 2,4-quinolinyl, 2,5- quinolinyl, 2,6-quinolinyl, 2,7-quinolinyl, 2,8-quinolinyl, 3,4-quinolinyl, 3,5- quinolinyl, 3,6-quinolinyl, 3,7-quinolinyl, 3,8-quinolinyl, 4,5-quinolinyl, 4,6- quinolinyl, 4,7-quinolinyl, 4,8-quinolinyl, 1,4-isoquinolinyl, 1,5- isoquinolinyl, 1,6-isoquinolinyl, 1,7-isoquinolinyl, 1,8-isoquinolinyl, 3,4- isoquinolinyl, 3,5-isoquinolinyl, 3,6-isoquinolinyl, 3,7-isoquinolinyl, 3,8- isoquinolinyl, 4,5-isoquinolinyl, 4,6-isoquinolinyl, 4,7-isoquinolinyl, 4,8- isoquinolinyl, 3,4-cinnolinyl, 3,5-cinnolinyl, 3,6-cinnolinyl, 3,7-cinnolinyl, 3,8-cinnolinyl, 4,5-cinnolinyl, 4,6-cinnolinyl, 4,7-cinnolinyl, and 4,8- cinnolinyl, and each carbon and hyrido containing nitrogen member of the ring
5 6 5 of the W and of the ring of the W , other than the points of attachment of W
and W , is optionally substituted with one or more of the group consisting of
R , R , R , and R , with the provisos that Q is bonded to lowest
number substituent position of each WX Q is bonded to highest number
6 38 o substituent position of each W , and (CH(R ))r is bonded to E .
In a more preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, 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, carboxy, carboxamido, cyano, and Q ;
B is optionally, with the proviso that R 1 and R 2 are selected from the group consisting of a spacer pair and -W=X-Y=Z-, Formula (V):
1 2 1 2 1 wherein 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
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
1 1 2 1 2 1
K must be a covalent bond when two of D , D , J , J and K are O and S,
1 2 1 2 1 and no more than four of D , D , J , J and K are N;
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 ,
34 35 J 36 R , R , and R ;
B is selected from the group consisting of C3-C12 cycloalkyl and C4
33 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, ring carbons and a nitrogen adjacent to the
9 13 carbon at the point of attachment are optionally substituted with R or R , a
9 πng carbon or nitrogen adjacent to the R position and two atoms from the
point of attachment is optinally substituted with R , a ring carbon or nitrogen
13 adjacent to the R position and two atoms from the point of attachment are
12 optionally substituted with R , a ring carbon three atoms from the point of
attachment and adjacent to the R position is optionally substituted with R ,
12 a πng carbon three atoms from the point of attachment and adjacent to the R
33 position is optionally substituted with R , and a ring carbon four atoms from
11 33 the point of attachment and adjacent to the R and R positions is optionally
L • , - ^34 substituted with R ;
1 o
B is optionally, with the proviso that R and R are selected from the group consisting of a spacer pair and -W=X-Y=Z-, a C5-C9 saturated
33 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, ring carbons and nitrogen adjacent to the
9 carbon atom at the point of attachment are optionally substituted with R or
13 9
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
13 nitrogen adjacent to the R position and two atoms from the point of
12 attachment is optionally substituted with R , a ring carbon or nitrogen three
atoms from the point of attachment and adjacent to the R position is
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
33 substituted with R , and a ring carbon or nitrogen four atoms from the point
11 33 of attachment and adjacent to the R and R positions is optionally
34 substituted with R ;
„9 10 1 1 12 , 13 . J , , ,
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;
9 10 11 12 13
R , R , R , R , and R are optionally selected from the group
9 10 11 consisting of heteroaryl and heterocyclyl with the proviso that R , R , R ,
12 13 R , and R are substitutents for other than B;
A is selected from the group consisting of single covalent bond and
15 7
(CH(R ))pa-(W )rr wherein rr is an integer selected from 0 through 1, pa is
7 an integer selected from 0 through 3, and W is selected from the group
consisting of O, S, C(O), (R )NC(O), (R?)NC(S), and N(R?);
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; Ψ 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;
1 2
R and R is optionally selected to be -W=X-Y=Z- wherein -W=X- Y=Z- forms a ring selected from the group consisting of a heteroaryl ring having from 5 through 6 contiguous members and an aryl;
W, X, Y, and Z are independendy selected from the group consisting of C(R9), C(R10), C(R1 1), C(R12), N, N(R10), 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 );
1 2
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 ^ R9 , R τ. 10 , „ RH , τ R 2 , and , R, 13 ;
R2 is Z°-Q;
Z is selected from the group consisting of covalent single bond and
41 42 41
(CR R )q wherein q is an integer selected from 1 through 2, (CH(R ))σ- fi 42
W -(CH(R ))_ wherein g and p are integers independently selected from 0 o 41 through 3 and W is selected from the group consisting of O, S, and N(R ),
41 22 42 and (CH(R ))e- W -(CH(R ))^ wherein e and h are integers independendy
selected from 0 through 1 and W"^ is selected from the group consisting of
41 42 CR =CR , 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3- cyclohexyl, 1,2-cyclopentyl, 13-cyclopentyl, 23-moφholinyl, 2,4- moφholinyl, 2,6-moφholinyl, 3,4-moφholinyl, 3,5-moφholinyl, 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, 23-tetrahydrofuranyl, 2,4- tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and 3, 4- tetrahydrofuranyl, with the proviso that Z is direcdy bonded to the pyridone ring;
41 42
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
9 by R , the other carbon adjacent to the carbon at the point of attachment is
13 9 optionally substituted by R , a carbon adjacent to R and two atoms from the
10 carbon at the point of attachment is optionally substituted by R , a carbon
13 adjacent to R and two atoms from the carbon at the point of attachment is
12 10 12 optionally substituted by R , and any carbon adjacent to both R and R is
optionally substituted by R ;
4a 4a
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,
C(O)N(H), (H)NC(O), (R7)NS(O)2, and S(O)2N(R?);
Y° is formula (IV):
is O, no more than one of D , D , J , and J is S, one of D , D , J , and J
must be a covalent bond when two of D , D , J , and J are O and S, and no
more than four of D , D , J , and J are N, with the provisos that R , 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;
16 17 18 19
R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, 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
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
hydrido, N(R26)C(NR25)N(R23)(R24), and C(NR25)NR23R24, with the
20 21 provisos that no more than one of R and R is hydroxy, amino, alkylamino, or
23 24 dialkylamino at the same time and that no more than one of R and R is hydroxy, amino, alkylamino, or dialkylamino at the same time;
20 21 23 24 25 26
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,
37 38 (CR R )b wherein b is an integer selected from 1 through 4, and
(CH(R ))C-W -(CH(R ))j wherein c and d are integers independendy
selected from 1 through 3 and W is selected from the group consisting of
C(O)N(R14), (R14)NC(O), S(O), S(O)2, S(O)2N(R14), N(RM)S(O)2, and
14 14 N(R ), with the provisos that R is selected from other than halo when
■T7 *5 O 1 Λ directly bonded to N and that (CR R , and (CH(R ))c are bonded to E ;
14 R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
37 38 R R" and R are independently selected from the group consisting of hydrido, alkyl, and haloalkyl;
38 . R R38 is optionally selected from the group consisting of aroyl and heteroaroyl;
Y° is optionally Qb-Qss wherein QSS is (CH(R14))e-W2-(CH(R15))h,
wherein e and h are integers independendy selected from 1 through 2 and W^
is CR =CH with the proviso that (CH(R ))e is bonded to E°.
In an even more preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, J is O; B is the Formula:
„32 33 34 35 , „36 . , J , ,
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
.15,
(CH(R ))pa-(W . )rτ wherein rr is an integer selected from 0 through 1 , pa is
an integer selected from 0 through 3, and W is selected from the group
7 7 consisting of (R )NC(O) and N(R );
7 R is selected from the group consisting of hydrido, hydroxy and alkyl;
15 R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
Ψ 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;
R2 is Z°-Q;
Z is selected from the group consisting of a covalent single bond, O,
S, NH, and CH2;
Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted
9 by R , the other carbon adjacent to the carbon at the point of attachment is
13 9 optionally substituted by R , a carbon adjacent to R and two atoms from the
carbon at the point of attachment is optionally substituted by R , a carbon
13 adjacent to R and two atoms from the carbon at the point of attachment is
12 10 12 optionally substituted by R , and any carbon adjacent to both R and R is
optionally substituted by R ;
9 11 13
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 CH2;
E° is C(O)N(H);
Y° is formula (IV):
5 6 5 6 wherein 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
is optionally O, no more than one of D , D , J , and J is optionally S, one of
5 6 5 6 5 6 5 τ6
D , D , J , and J must be a covalent bond when two of D , D , J , and J
are O and S, and no more than four of D , D , J , and J are N;
16 17 18 19
R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
R and R are optionally Q with the proviso that no more than one of
R and R is Q at the same time and that Q is Q ;
Q is selected from the group consisting of NR R , Q wherein Q is
25 23 24 20 hydrido, and C(NR )NR R , with the provisos that no more than one of R
21 23 24 and R is hydroxy at the same time and that no more than one of R and R is hydroxy at the same time;
20 21 23 24 25
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,
CH2, and CH2CH2.
In another even more preferred embodiment of compounds of Formula
I or a pharmaceutically acceptable salt thereof,
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,3 π33 „34 35 J T,36 consisting of R , R , R , R , and R ;
32 33 34 35 36 R , R , R , R , and R are independendy selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q ;
A is selected from the group consisting of single covalent bond and
15 7
(CH(R ))pa-(W )rr wherein rr is an integer selected from 0 through 1, pa is
7 an integer selected from 0 through 3, and W is selected from the group
7 7 consisting of (R )NC(O) and N(R );
7 . R is selected from the group consisting of hydrido, hydroxy and alkyl;
15 . R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
Ψ 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;
R2 is Z°-Q;
Z is selected from the group consisting of covalent single bond, O, S,
NH, and CH2;
Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted
9 by R , the other carbon adjacent to the carbon at the point of attachment is
13 9 optionally substituted by R , a carbon adjacent to R and two atoms from the
carbon at the point of attachment is optionally substituted by R , a carbon
13 adjacent to R and two atoms from the carbon at the point of attachment is
12 10 12 optionally substituted by R , and any carbon adjacent to both R and R is
optionally substituted by R ;
9 11 13
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 CH2;
E° is C(O)N(H);
Y° is formula (IV):
5 6 5 6 wherein 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
2 5 6 5 6 than one is a covalent bond, K is C, no more than one of D , D , J , and J
• r . ,- τ^5 _6 τ5 , τ6 . ^ τ-, _ 6 5 , τ6 is O, no more than one of D , D , J , and J is S, one of D , D , J , and J
5 6 5 6 must be a covalent bond when two of D , D , J , and J are O and S, and no
more than four of D , D , J , and J are N, with the provisos that R , 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;
16 17 18 19
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
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 hydrido, C(NR )NR R , and N(R )C(NR )N(R )(R ), with
20 21 the provisos that no more than one of R and R is hydroxy at the same time
23 24 and that no more than one of R and R is hydroxy at the same time;
20 21 23 24 25 26 R , 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,
CH2, and CH2CH2.
In still another even more preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, J is O;
B is selected from the group consisting of C3-C7 cycloalkyl and C4
33 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, ring carbons and a nitrogen adjacent to the
9 13 carbon at the point of attachment are optionally substituted with R or R , a
9 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
13 nitrogen adjacent to the R position and two atoms from the point of
12 attachment is optionally substituted with R , a ring carbon three atoms from
the point of attachment and adjacent to the R position is optionally
substituted with R , a ring carbon three atoms from the point of attachment
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
33 34
R positions is optionally substituted with R ;
9 11 13
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;
10 12
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;
33 34 . .
R and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q ;
A is selected from the group consisting of single covalent bond and
15 7 (CH(R ))pa-(W )rr wherein rr is an integer selected from 0 through 1 , pa is
7 an integer selected from 0 through 3, and W is selected from the group
7 7 consisting of (R )NC(O) and N(R );
7 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;
Ψ 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; R2 is Z°-Q;
Ε is selected from the group consisting of covalent single bond, O, S,
NH, and CH2;
Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted
9 by R , the other carbon adjacent to the carbon at the point of attachment is
13 9 optionally substituted by R , a carbon adjacent to R and two atoms from the
carbon at the point of attachment is optionally substituted by R , a carbon
13 adjacent to R and two atoms from the carbon at the point of attachment is
12 10 12 optionally substituted by R , and any carbon adjacent to both R and R is
optionally substituted by R ;
K is CH2;
E° is C(O)N(H);
Y° is formula (IV):
2 5 6 5 6 than one is a covalent bond, K is C, no more than one of D , D , J , and J
is O, no more than one of D , D , J , and J is S, one of D , D , J , and J
must be a covalent bond when two of D , D , J , and
are O and S, and no
more than four of D , D , J , and J are N, with the provisos that R , 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;
16 17 18 19 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 ;
25 23 24 20 hydrido, and C(NR )NR R , with the provisos that no more than one of R
21 23 24 . and R is hydroxy at the same time and that no more than one of R and R is hydroxy at the same time;
20 21 23 24 25
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,
CH2, and CH2CH2.
In a further even more preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, J is O; B is the Formula (V):
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
1 1 2 1 2 1 K must be a covalent bond when two of D , D , J , J and K are O and S,
1 2 1 2 1 and no more than four of D , D , J , J and K are N;
32 33 34 35 36
R , R , R , R , and R are independendy selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q ;
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 „33 34 35 _, „36 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
33 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
9 carbon atom at the point of attachment are optionally substituted with R or
13 9
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
13 nitrogen adjacent to the R position and two atoms from the point of
12 attachment is optionally substituted with R , a ring carbon or nitrogen three
atoms from the point of attachment and adjacent to the R position is
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
33 substituted with R , and a ring carbon or nitrogen four atoms from the point
11 33 of attachment and adjacent to the R and R positions is optionally
substituted with R ;
9 10 11 12 13
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 consisting of single covalent bond and
15 7
(CH(R ))pa-(W )rr wherein rr is an integer selected from 0 through 1, pa is
7 an integer selected from 0 through 3, and W is selected from the group
7 7 consisting of (R )NC(O) and N(R );
7 . R is selected from the group consisting of hydrido, hydroxy and alkyl;
15 R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
Ψ is NH;
X is selected from the group consisting of hydrido, alkyl, cyano, halo, haloalkyl, haloalkoxy, amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio; R l and R2 are taken together to be - W=X-Y=Z- wherein -W=X-Y=Z- forms a ring selected from the group consisting of a heteroaryl ring having from 5 through 6 contiguous members and an aryl;
W, X, Y, and Z are independently selected from the group consisting of C(R9), C(R10), C(RJ C(R12), N, N(R10), 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(R10);
1 2
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
9 10 11 12 13 consisting of R , R , R , R , and R ;
K is CH2;
E° is C(O)N(H);
Y° is formula (IV)
5 6 5 6 wherein 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
2 5 6 5 6 than one is a covalent bond, K is C, no more than one of D , D , J , and J
is O, no more than one of D , D , J , and J is S, one of D , D , J , and J
must be a covalent bond when two of D ,
are O and S, and no
more than four of D , D , J , and J are N, with the provisos that R , 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;
16 17 18 19
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
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
hydrido,
with the
, 20 21 . L J „ , • provisos that no more than one of R and R is hydroxy, amino, alkylamino, or
23 24 dialkylamino at the same time and that no more than one of R and R is hydroxy, amino, alkylamino, or dialkylamino at the same time;
20 21 23 24 25 26
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,
CH2, and CH2CH2.
In a most preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, J is O; B is the Formula:
, cyano, and Q ;
A is selected from the group consisting of single covalent bond and
15 7
(CH(R ))pa-(W )rr wherein rr is an integer selected from 0 through 1, pa is
7 7 an integer selected from 0 through 3, and W is N(R );
7 R is selected from the group consisting of hydrido and alkyl;
R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
Ψ is 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;
R2 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
9 by R , the other carbon adjacent to the carbon at the point of attachment is
13 9 optionally substituted by R , a carbon adjacent to R and two atoms from the
10 carbon at the point of attachment is optionally substituted by R , a carbon
13 adjacent to R and two atoms from the carbon at the point of attachment is
12 10 12 optionally substituted by R , and any carbon adjacent to both R and R is
optionally substituted by R ;
9 11 13
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 amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxyamido, and cyano;
K is CH2;
E° is C(O)N(H);
Y° is formula (IV):
. 5 6 5 6 wherein 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
2 5 6 5 τ6 than one is a covalent bond, K is C, no more than one of D , D , J , and J (L ^ ft ^ ft is O, no more than one of D , D , J , and J is S, one of D , D , J , and J
must be a covalent bond when two of D , D , J , and J are O and S, and no
more than four of 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
„ 16 , „ 19 . Λb , . , Λb . Λbe
R and R is Q at the same time and that Q is Q ;
I Λ 91
Q is selected from the group consisting of NR R , Q wherein Q is
25 23 24 hydrido, and C(NR )NR R ;
20 21 23 24 25 R , R , R , R , and R are independently selected from the group consisting of hydrido and alkyl;
QS is CH2.
In another most preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, J is O;
B is optionally selected from the group consisting of hydrido, C2-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group
32 33 34 35 36 consisting of R , R , R , R , and R ;
32 33 34 35 36
R , R , R , R , and R are independendy selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q ;
A is selected from the group consisting of single covalent bond and
15 7
(CH(R ))pa-(W )n wherein rr is an integer selected from 0 through 1, pa is
7 7 an integer selected from 0 through 3, and W is N(R );
7 R is selected from the group consisting of hydrido and alkyl;
R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
Ψ 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;
R2 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
9 by R , the other carbon adjacent to the carbon at the point of attachment is
13 9 optionally substituted by R , a carbon adjacent to R and two atoms from the
carbon at the point of attachment is optionally substituted by R , a carbon
13 adjacent to R and two atoms from the carbon at the point of attachment is
12 10 12 optionally substituted by R , and any carbon adjacent to both R and R is
optionally substituted by R ;
9 11 13
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;
K is CH2;
E° is C(O)N(H);
Y° isfoπnula (IV):
5 6 5 6 wherein 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
2 5 6 5 6 than one is a covalent bond, K is C, no more than one of D , D , J , and J
• , ,-^5 _6 r5 , ,6 . _. ,-τ^5 _6 ,5 , ¥6 is O, no more than one of D , D , J , and J is S, one of D , D , J , and J
must be a covalent bond when two of D , D , J , and J are O and S, and no
more than four of D , D , J , and J are N, with the provisos that R , 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;
16 17 18 19
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
hydrido, N(R26)C(NR25)N(R23)(R24), and C(NR25)NR23R24;
20 21 23 24 25 26
R , R , R , R , R , and R are independently selected from the group consisting of hydrido and alkyl; QS is CH2.
In still another most preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, J is O; B is selected from the group consisting of C3-C7 cycloalkyl and C4
33 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, ring carbons and nitrogens adjacent to the
9 13 carbon at the point of attachment are optionally substituted with R or R , a
9 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
13 nitrogen adjacent to the R position and two atoms from the point of
12 attachment is optionally substituted with R , a ring carbon three atoms from
the point of attachment and adjacent to the R position is optionally
substituted with R , a ring carbon three atoms from the point of attachment
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
33 34
R positions is optionally substituted with R ;
9 11 13
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;
33 34 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;
33 b R is optionally Q ;
A is selected from the group consisting of single covalent bond and
15 7
(CH(R ))pa-(W )π wherein rr is an integer selected from 0 through 1, pa is
7 7 an integer selected from 0 through 3, and W is N(R );
7 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;
Ψ 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;
R2 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
9 by R , the other carbon adjacent to the carbon at the point of attachment is
13 9 optionally substituted by R , a carbon adjacent to R and two atoms from the
carbon at the point of attachment is optionally substituted by R , a carbon
13 adjacent to R and two atoms from the carbon at the point of attachment is
12 10 12 optionally substituted by R , and any carbon adjacent to both R and R is
optionally substituted by R ;
K is CH2; E° is C(O)N(H);
Y° is formula (IV):
5 6 5 6 wherein 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
is O, no more than one of D , D , J , and J is S, one of D , D , J , and J
must be a covalent bond when two of D , D , J , and J are O and S, and no
more than four of D , D , J , and J are N, with the provisos that R , 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;
16 17 18 19
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
25 23 24 hydrido, and C(NR )NR R ;
20 21 23 24 25
R , R , R , R , and R are independently selected from the group consisting of hydrido and alkyl;
QS is CH2. In a further most preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, J is O; B is the Formula (V):
1 2 1 2 1 wherein 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
1 1 2 1 2 1
K must be a covalent bond when two of D , D , J , J and K are O and S,
1 2 1 2 1 and no more than four of D , D , J , J and K are N;
32 33 34 35 36
R , R , R , R , and R are independendy selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q ; B is optionally selected from the group consisting of hydrido, C2-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group
32 33 34 35 36 consisting of R , R , R , R , and R ; B is selected from the group consisting of C3-C7 cycloalkyl and C4-C6 saturated heterocyclyl, wherein each ring carbon is optionally substituted with
33 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
9 carbon atom at the point of attachment are optionally substituted with R or
13 9
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
13 nitrogen adjacent to the R position and two atoms from the point of
12 attachment is optionally substituted with R , a ring carbon or nitrogen three
atoms from the point of attachment and adjacent to the R position is
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
33 substituted with R , and a ring carbon or nitrogen four atoms from the point
11 33 of attachment and adjacent to the R and R positions is optionally
, - , ^34 substituted with R ;
9 11 13 R , R , and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; R and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxyamido, and cyano;
A is selected from the group consisting of single covalent bond and
15 7
(CH(R ))pa-(W )rτ wherein rr is an integer selected from 0 through 1 , pa is
7 7 an integer selected from 0 through 3, and W is N(R );
7 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;
Ψ is NH;
X is selected from the group consisting of hydrido, alkyl, cyano, halo, haloalkyl, haloalkoxy, amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio;
R1 and R2 are taken together to be -W=X-Y=Z- wherein -W=X-Y=Z- forms a ring selected from the group consisting of a heteroaryl ring having 6 contiguous members and an aryl;
W, X, Y, and Z are independently selected from the group consisting
9 10 11 12 of C(R ), C(R ), C(R ), C(R ), and N;
K is CH2;
E° is C(O)N(H); Y° is foπnula (IV):
5 6 5 6 wherein 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
2 5 6 5 6 than one is a covalent bond, K is C, no more than one of D , D , J , and J
is O, no more than one of D , D , J , and J is S, one of D , D , J , and J
must be a covalent bond when two of D , D , J , and J are O and S, and no
more than four of D , D , J , and J are N, with the provisos that R , 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
hydrido, N(R26)C(NR25)N(R23)(R24), and C(NR25)NR23R24;
„20 21 23 24 25 26
R , R , R , R , R , and R are independendy selected from the group consisting of hydrido and alkyl;
QS is CH2.
In a preferred specific embodiment of Formula I, compounds have the Formula I-S:
32 33 34 35 36
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-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N- dimethylamidosulfonyl, acetyl, propanoyl, trifluoroacetyl, pentafluoropropanoyl, hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1 -hydroxyethyl, 2,2,2-trifluoro- 1 -trifiuoromethyl- 1- hydroxy ethyl, carboxymethyl, methoxy carbonyl, ethoxy carbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and Q ;
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-3-butenyl, 1-hexyl, 2- hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, l-methyl-2-pentenyl, l-methyl-3-pentenyl, l-methyl-4-pentenyl, 1- methyl-2-pentynyl, l-methyl-3-pentynyl, 3-hexyl, l-ethyl-2-butenyI, 1-ethyl- 3-butenyl, l-propyl-2-propenyl, l-ethyl-2-butynyl, 1-heptyl, 2-heptenyl, 3- heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 2-heptynyl, 3-heptynyl, 4- heptynyl, 5-heptynyl, 2-heptyl, l-methyl-2-hexenyl, 1 -methyl -3-hexenyl, 1- methyl-4-hexenyl, 1 -methyl -5-hexenyl, l-methyl-2-hexynyl, l-methyl-3- hexynyl, 1-methyl^-hexynyl, 3-heptyl, l-ethyl-2-pentenyl, l-ethyl-3- pentenyl, l-ethyl-4-pentenyl, l-butyl-2-propenyl, l-ethyl-2-pentynyl, 1-ethyl- 3-pentynyl, 1-octyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7- octenyl, 2-octynyl, 3-octynyl, 4-octynyl, 5-octynyl, 6-octynyl, 2-octyl, 1- methyl-2-heptenyl, l-methyl-3-heptenyl, l-methyl-4-heptenyl, l-methyl-5- heptenyl, l-methyl-6-heptenyl, l-methyl-2-heptynyl, l-methyl-3-heptynyl, 1- methyl-4-heptenyl, 1 -methyl -5-heptenyl, l-methyl-6-heptenyl, l-methyl-2- heptenyl, l-methyl-3-heptynyl, l-methyl-4-heptynyl, 1 -methyl -5-heptynyl, 3-
octyl, 1 -ethyl -2-hexenyl, l-ethyl-3-hexenyl, l-ethyl-4-hexenyl, l-ethyl-2- hexynyl, l-ethyl-3-hexynyl, l-ethyl-4-hexynyl, l-ethyl-5-hexenyl, l-pentyl-2- propenyl, 4-octyl, l-propyl-2-pentenyl, l-propyl-3-pentenyl, l-propyl-4- pentenyl, l-butyl-2-butenyl, l-propyl-2-pentynyl, l-propyl-3-pentynyl, 1- butyl -2-butynyl, l-butyl-3-butenyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6- pentafluorohexyl, and 3,33- rifluoropropyl, wherein each member of group B is optionally substituted at any carbon up to and including 5 atoms from the
32 point of attachment of B to A with one or more of the group consisting of R ,
„33 34 35 J 36 R , R , R , and R ;
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
33 cyclooctyl, wherein each ring carbon is optionally substituted with R , ring carbons or a nitrogen adjacent to the carbon atom at the point of attachment are
9 13 optionally substituted with R or R , a ring carbon or a nitrogen adjacent to
9 the R position and two atoms from the point of attachment is optionally
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
9 10 11 12 13
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 , 1,1 ,2,2-tetrafluoroethoxy , fluoro, chloro, bromo, methanesulfonamido, amidosulfonyl, N-
methylamidosulfonyl, N,N-dimethylamidosulfonyl, acetyl, propanoyl, trifluoroacetyl, pentafluoropropanoyl, hydroxymethyl, 1 -hydroxyethyl, 2- hydroxyethyl, 2,2,2-trifluoro- 1 -hydroxyethyl, 2,2,2-trifluoro- 1- trifluoromethyl-1-hydroxyethyl, carboxymethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N- dimethylamidocarbonyl, and cyano;
A is selected from the group consisting of single covalent bond, O, S,
NH, N(CH3), N(OH), C(O), CH2, CH3CH, CF3CH, NHC(O),
N(CH3)C(O), C(O)NH, C(O)N(CH3), CF3CC(O), C(O)CCH3, C(O)CCF3,
CH2C(O), (O)CCH2, CH2CH2, CH2CH2CH2, CH3CHCH2, CF3CHCH2,
CH3CC(O)CH2, CF3CC(O)CH2, CH2C(O)CCH3, CH2C(O)CCF3,
CH2CH2C(O), and CH2(O)CCH2;
A is optionally selected from the group consisting of CH2N(CH3),
CH2N(CH2CH3), CH2CH2N(CH3), and CH2CH2N(CH2CH3) with the proviso that B is hydrido;
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;
R2 is Z°-Q; Z is selected from the group consisting of covalent single bond, O, S,
NH, CH2, CH2CH2, CH(OH), CH(NH2), CH2CH(OH), CH2CHNH2,
CH(OH)CH2, and CH(NH2)CH2;
Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3- pyrazolyl, 4-pyrazolyl, 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-pyrimidinyl, 5- pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 13,5-triazin-2-yl, l,2,4-triazin-3- yl, l,2,4-triazin-5-yl, l,2,4-triazin-6-yl, l,2,3-triazin-4-yl, and 1,23-triazin- 5-yl, wherein a carbon adjacent to the carbon at the point of attachment is
9 optionally substituted by R , the other carbon adjacent to the carbon at the
13 9 point of attachment is optionally substituted by R , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by R , a carbon adjacent to R and two atoms from the carbon at
12 the point of attachment is optionally substituted by R , and any carbon
10 12 11 adjacent to both R and R is optionally substituted by R ;
4a 4a
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)2N(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-pentafluoropropyl, trifluoromethoxy, 1,1,2,2- tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N- methylamidosulfonyl, N,N-dimethylamidosulfonyl, acetyl, propanoyl, trifluoroacetyl, pentafluoropropanoyl, hydroxymethyl, 1 -hydroxyethyl, 2- hydroxyethyl, 2,2,2-trifluoro- 1 -hydroxyethyl, and cyano;
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 ;
Qbe is hydrido, C(NR25)NR23R24 and N(R26)C(NR25)N(R23)(R24), with
the proviso that no more than one of R and R is hydroxy, N- methylamino, and N ,N-dimethylamino at the same time and that no more than
23 24 one of R and R is hydroxy, N-methylamino, and N,N-dimethylamino at the same time;
„20 21 „23 24 „25 J „26 . Λ J , t Λ C
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, CH2, CH2CH2, CH3CH, CF3CH, CH3CHCH2, CF3CHCH2,
CH2(CH3)CH, CH=CH, CF=CH, C(CH3)=CH, CH=CHCH2, CF=CHCH2,
C(CH3)=CHCH2, CH2CH=CH, CH2CF=CH, CH2C(CH3)=CH,
CH2CH=CHCH2, CH2CF=CHCH2, CH2C(CH3)=CHCH2,
CH2CH=CHCH2CH2, CH2CF=CHCH2CH2, and CH2C(CH3)=CHCH2CH2.
In a more preferred specific embodiment of Formula I, compounds have the Formula I-MPS wherein B is an aromatic:
( I-MPS wherein B is aromatic ) or a pharmaceutically acceptable salt thereof, wherein; B is the Formula:
32 33 34 35 36
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, hydroxymethyl, 1- hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1 -hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl,
N,N-dimethylamidocarbonyl, cyano, and Q ;
A is selected from the group consisting of single covalent bond, NH, N(CH3), N(OH), CH2, CH3CH, CF3CH, NHC(O), N(CH3)C(O),
C(O)NH, C(O)N(CH3), CH2CH2, CH2CH2CH2, CH3CHCH2, and
CF3CHCH2;
R 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; R2 is Z°-Q;
Z is selected from the group consisting of covalent single bond, O, S,
NH, and CH2;
Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3- pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 13,5-triazin-2-yl, wherein a carbon adjacent
9 to the carbon at the point of attachment is optionally substituted by R , the other carbon adjacent to the carbon at the point of attachment is optionally
13 9 substituted by R , a carbon adjacent to R and two atoms from the carbon at
the point of attachment is optionally substituted by R , a carbon adjacent to
13 R and two atoms from the carbon at the point of attachment is optionally
12 10 12 substituted by R , and any carbon adjacent to both R and R is optionally
substituted by R ;
9 11 13 R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino,
N,N-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, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2- hydroxyethyl, 2,2,2-trifluoro- 1-hydroxyethyl, amidocarbonyl, N- methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
R and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl, 1- aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N- dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, fluoro, chloro, bromo, and cyano;
L. Λ i l* .
Q is selected from the group consisting of NR R , Q wherein Q is
25 23 24 , ,„20 hydrido, and C(NR )NR R , with the provisos that no more than one of R
21 23 24 . and R is hydroxy at the same time and that no more than one of R and R is hydroxy at the same time;
20 21 23 24 25 „
R , R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy; s Q is selected from the group consisting of a single covalent bond, CH2, and CH2CH2.
In another more preferred specific embodiment of Formula I, compounds have the Formula I-MPS wherein B is a non-cyclic substituent:
B is selected from the group consisting of hydrido, ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, 2-butynyl, sec- butyl, tert-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-ρentenyl, 3-pentenyl, 4-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl, l-methyI-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-methy 1-3 -butynyl, 3-methylbutyl, 3- methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4- hexenyl, 5-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, l-methyl-2- pentenyl, 1 -methyl -3-pentenyl, l-methyl-4-pentenyl, l-methyl-2-pentynyl, 1- methyl-3-pentynyl, 3-hexyl, l-ethyl-2-butenyl, l-ethyl-3-butenyl, l-propyl-2- propenyl, l-ethyl-2-butynyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5- heptenyl, 6-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2- heptyl, l-methyl-2-hexenyl, l-methyl-3-hexenyl, l-methyl-4-hexenyl, 1- methyl-5-hexenyl, l-methyl-2-hexynyl, l-methyl-3-hexynyl, l-methyl-4- hexynyl, 3-heptyl, l-ethyl-2-pentenyl, l-ethyl-3-pentenyl, 1 -ethyl -4-pentenyl, l-butyl-2-propenyl, l-ethyl-2-pentynyl, l-ethyl-3-pentynyl, 2,2,2- trifluoroethyl, 2,2-difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4- trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl, and 333-trifluoropropyl, wherein each member of group B is optionally substituted at any carbon up to and including 5 atoms from the point of attachment of B to A with one or more
• • „32 „33 34 35 36 of the group consis ng of R , R , R , R , and R ;
32 33 34 36 R , R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino,
acetamido, trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, 2,2333-pentafluoropropyl, trifluoromethoxy, 1,1,2,2- tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N- methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1- hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl,
N,N-dimethylamidocarbonyl, cyano, and Q ;
A is selected from the group consisting of single covalent bond, NH, N(CH3), N(OH), CH2, CH3CH, CF3CH, NHC(O), N(CH3)C(O),
C(O)NH, C(O)N(CH3), CH2CH2, CH2CH2CH2, CH3CHCH2, and
CF3CHCH2;
A is optionally selected from the group consisting of CH2N(CH3),
CH2N(CH2CH3), CH2CH2N(CH3), and CH2CH2N(CH2CH3) with the proviso that B is hydrido;
R and X° are independendy selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1- aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, methoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo;
R2 is Z°-Q;
Z is selected from the group consisting of covalent single bond, O, S, NH, and CH2;
Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3- pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,
3-pyridazinyl, 4-pyridazinyl, and 13,5-triazin-2-yl, wherein a carbon adjacent
9 to the carbon at the point of attachment is optionally substituted by R , the other carbon adjacent to the carbon at the point of attachment is optionally
13 9 substituted by R , a carbon adjacent to R and two atoms from the carbon at
the point of attachment is optionally substituted by R , a carbon adjacent to
13 R and two atoms from the carbon at the point of attachment is optionally
12 10 12 substituted by R , and any carbon adjacent to both R and R is optionally
substituted by R ;
9 11 13
R , R , and R are independendy selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,333- pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2- hydroxyethyl, 2,2,2-trifluoro- 1-hydroxyethyl, amidocarbonyl, N- methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
R and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl, 1- aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N- dimediylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2- trifluoro- 1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N- methylamidocarbonyl, N,N-dimethylamidocarbonyl, fluoro, chloro, bromo, and cyano;
Q is selected from the group consisting of NR R , Q , wherein Q
25 93 94 96 95 93 24 is hydrido, C(NR )NR R , and N(R )C(NR )N(R )(R ), with the
20 21 provisos that no more than one of R and R is hydroxy at the same time and
23 24 that no more than one of R and R is hydroxy at the same time;
20 21 23 24 25 26
R , R , R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy; s Q is selected from the group consisting of a single covalent bond,
CH2, and CH2CH2.
In still another more preferred specific embodiment of Formula I, compounds have the Formula I-MPS wherein B is a non-aromatic cyclic substituent:
33 . cycloheptyl , wherein each ring carbon is optionally substituted with R , ring carbons or a nitrogen adjacent to the carbon atom at the point of attachment is
9 13 optionally substituted with R or R , a ring carbon or nitrogen adjacent to the
9
R position and two atoms from the point of attachment is optionally
subsututed with R , and a πng carbon or nitrogen adjacent to the R position and two atoms from the point of attachment is optionally substituted with R ;
9 11 13
R , R , and R are independendy selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,333- pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2- hydroxyethyl, 2,2,2-trifluoro- 1-hydroxyethyl, amidocarbonyl, N- methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
10 12
R and R are independendy selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl, 1- aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N- dimediylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2- trifluoro- 1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N- methylamidocarbonyl, N,N-dimethylamidocarbonyl, fluoro, chloro, bromo, and cyano;
33 R are independently selected from the group consisting of hydπdo, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2333-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N- dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl,
amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and Qb;
A is selected from the group consisting of single covalent bond, NH, N(CH3), N(OH), CH2, CH3CH, CF3CH, NHC(O), N(CH3)C(O),
C(O)NH, C(O)N(CH3), CH2CH2, CH2CH2CH2, CH3CHCH2, and
CF3CHCH2;
R and X° are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1- aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, methoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo;
R2 is Z°-Q; Z is selected from the group consisting of covalent single bond, O, S,
NH, and CH2;
Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3- pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 13,5-triazin-2-yl, wherein a carbon adjacent
9 to the carbon at the point of attachment is optionally substituted by R , the other carbon adjacent to the carbon at the point of attachment is optionally
13 9 substituted by R , a carbon adjacent to R and two atoms from the carbon at
the point of attachment is optionally substituted by R , a carbon adjacent to
13 R and two atoms from the carbon at the point of attachment is optionally
12 10 12 substituted by R , and any carbon adjacent to both R and R is optionally
substi •tuted J L by R ;
Q is selected from the group consisting of NR R , Q wherein Q is
25 23 24 20 hydrido, and C(NR )NR R , with the provisos that no more than one of R
21 23 24 and R is hydroxy at the same time and that no more than one of R and R is hydroxy at the same time;
20 21 23 24 25
R , R , R , R , and R are independendy selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy; s Q is selected from the group consisting of a single covalent bond,
CH2, and CH2CH2.
In a further even more prefeπed embodiment of compounds of Formula I, compounds have the Formula I-FARMPS wherein there are two fused aromatic rings:
( I-FARMPS ) or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3- pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and l,3,5-triazin-2-yl, wherein a carbon adjacent
32 to the carbon at the point of attachment is optionally substituted by R , the other carbon adjacent to the carbon at the point of attachment is optionally
36 32 substituted by R , a carbon adjacent to R and two atoms from the carbon at
33 the point of attachment is optionally substituted by R , a carbon adjacent to
36
R and two atoms from the carbon at the point of attachment is optionally
35 33 35 substituted by R , and any carbon adjacent to both R and R is optionally
34 substituted by R ;
32 33 34 35 36
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, trifluoromethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, 2,2,333-pentafluoropropyl, trifluoromethoxy, 1,1,2,2- tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N- methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1- hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl,
N,N-dimethylamidocarbonyl, cyano, and Q ;
B is selected from the group consisting of hydrido, ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, 2-butynyl, sec- butyl, tert-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl, l-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-methyi-3-butynyl, 3-methylbutyl, 3- methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4- hexenyl, 5-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, l-methyl-2- pentenyl, l-methyl-3-pentenyl, l-methyl-4-pentenyl, 1 -methyl -2-pentynyl, 1- methyl-3-pentynyl, 3-hexyl, l-ethyl-2-butenyl, l-ethyl-3-butenyl, l-propyl-2- propenyl, l-ethyl-2-butynyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5- heptenyl, 6-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2- heptyl, l-methyl-2-hexenyl, l-methyl-3 -hexenyl, l-methyl-4-hexenyl, 1- methyl-5-hexenyl, l-methyl-2-hexynyl, l-methyl-3-hexynyl, l-methyl-4- hexynyl, 3-heptyl, l-ethyl-2-pentenyl, l-ethyl-3-pentenyl, l-ethyl-4-pentenyl,
l-butyl-2-propenyl, l-ethyl-2-pentynyl, 1 -ethyl -3-pentynyl, 2,2,2- trifluoroethyl, 2,2-difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4- trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl, and 333-trifluoropropyl, wherein each member of group B is optionally substituted at any carbon up to and including 5 atoms from the point of attachment of B to A with one or more
32 33 34 35 36 of the group consisting of R , R , R , R , and R ;
B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, thiaetan-3- yl, cyclopentyl, cyclohexyl, norbornyl, 7-oxabicyclo[2.2.1]heptan-2-yl, bicyclo[3.1.0]hexan-6-yl, cycloheptyl, 2-morpholinyl, 3-morpholinyl, 4- morpholinyl, 1 -piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3- piperidinyl, 4-piperidinyl, 1-pyrrolidinyl, 2-pyrroIidinyl, 3-pyrrolidinyl, 2- dioxanyl, 4H-2-pyranyl, 4H-3-pyranyl, 4H-4-pyranyl, 4H-pyran-4-one-2-yl, 4H-pyran-4-one-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2- tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 2- tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each ring carbon is
33 optionally substituted with R , a ring carbon and nitrogen atoms adjacent to
9 the carbon atom at the point of attachment is optionally substituted with R or
13 9
R , a ring carbon or nitrogen atom adjacent to the R position and two atoms
10 from the point of attachment is optionally substituted with R , and a πng
13 , carbon or nitrogen atom adjacent to the R position and two atoms from the
12 point of attachment is optionally substituted with R ;
9 11
R and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,333- pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-
hydroxyethyl, 2,2,2-trifluoro- 1-hydroxyethyl, amidocarbonyl, N- methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
R and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl, 1- aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N- dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, fluoro, chloro, bromo, and cyano;
A is selected from the group consisting of single covalent bond, NH,
N(CH3), N(OH), CH2, CH3CH, CF3CH, NHC(O), N(CH3)C(O),
C(O)NH, C(O)N(CH3), CH2CH2, CH2CH2CH2, CH3CHCH2, and
CF3CHCH2;
A is optionally selected from the group consisting of CH2N(CH3),
CH2N(CH2CH3), CH2CH2N(CH3), and CH2CH2N(CH2CH3) with the proviso that B is hydrido; X° is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1-aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, methoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2- tetrafluoroethoxy, fluoro, chloro, and bromo;
W, X, Y, and Z are independently selected from the group consisting of CH, N, CF, CC1, C-CN, C-CH3, C-CH2CH3, C-NH2, C-CH2NH2, C-CH2NHCH3, C-NHCH3, C-N(CH3)2, C-CH(NH2)CH3, C-CH2CH2NH2, C-NHOCH3, C-NHOCH2CH3, C-C(NH)NH2, C-C(NOH)NH2, C-OH, C-CH2OH, C-CH2CH2OH, C-CH(OH)CH3,
C-OCH3, C-OCH2CH3, C-CO2H, C-CO2CH3, C-C(O)NH2. C-C(O)NHCH3, C-C(O)NH(CH3)2, C-CH2CO2H, C-SO2NH2, C-SO2NHCH3, C-NH(O)CCH3, and C-NH(O)CCF3;
, 90 91
Q is selected from the group consisting of NR R , Q , wherein Q
25 93 24 26 95 23 24 is hydrido, C(NR )NR R , and N(R )C(NR )N(R )(R ), with the
20 21 provisos that no more than one of R and R is hydroxy at the same time and
23 24 that no more than one of R and R is hydroxy at the same time;
20 21 23 24 25 26
R , R , R , R , R , and R are independendy selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy; s Q is selected from the group consisting of a single covalent bond,
CH2, and CH2CH2.
The more preferred specific embodiment (I-MPS) and (I-FARMPS) compounds of the present invention having the Formula:
Y is selected from the group of formulas consisting of:
102
16 _ 17 18 .19
R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, methyl sulfmyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2333-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1- hydroxyethyl, 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 .
In a most preferred specific embodiment of Formula I, compounds have the Formula I-EMPS wherein B is an aromatic:
( I-EMPS wherein B is aromatic ) or a pharmaceutically acceptable salt thereof, wherein; B is the Formula:
32 33 34 35 36
R , R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, carboxy, cyano, and Q ;
A is selected from the group consisting of single covalent bond, NH,
N(CH3), CH2, CH3CH, and CH2CH2;
X° is selected from the group consisting of hydrido, hydroxy, amino, amidino, aminomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and fluoro;
R is selected from the group consisting of hydrido, hydroxy, amino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, methylthio, trifluoromethoxy, fluoro, and chloro;
R2 is Z°-Q;
Z is a covalent single bond;
Q is selected from the group consisting of phenyl, 2-thienyl, 2-furyl, 2- pyrrolyl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl, and 3-pyridyl, wherein a carbon adjacent to the carbon at the point of attachment is optionally
9 substituted by R , the other carbon adjacent to the carbon at the point of
13 9 attachment is optionally substituted by R , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by
R , a carbon adjacent to R and two atoms from the carbon at the point of
12 attachment is optionally substituted by R , and any carbon adjacent to both
10 12 11
R and R is optionally substituted by R ;
9 11 13
R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, and cyano;
10 12 R and R are independently selected from the group consisting of hydrido, amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2- hydroxyethyl, carboxy, carboxymethyl, amino, acetamido, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl, N- methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, N,N- dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, and cyano;
Λb . 20 21
Q is selected from the group consisting of NR R and
25 23 24 b
C(NR )NR R , with the proviso that said Q group is bonded directly to a carbon atom;
20 21 23 24 25 R , R , R . R , and R are independently selected from the group consisting of hydrido, methyl, and ethyl;
QS is CH2.
In another most preferred specific embodiment of Formula I, compounds have the Formula I-EMPS wherein B is a non-cyclic substituent:
B is selected from the group consisting of hydrido, ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 2-butynyl, sec-butyl, tert- butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 2- pentynyl, 3-pentynyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 2-methyl-2-butenyl, 3-methylbutyl, 3-methyl-2-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, l-methyl-2-pentenyl, l-methyl-3- pentenyl, l-methyl-2-pentynyl, l-methyl-3-pentynyl, 3-hexyl, l-ethyl-2- butenyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, l-methyl-2-hexenyl, 1-methyl- 3-hexenyl, l-methyl-4-hexenyl, l-methyl-2-hexynyl, l-methyl-3-hexynyl, 1- methyl- -hexynyl, 3-heptyl, l-ethyl-2-pentenyl, l-ethyl-3-ρentenyl, l-ethyl-2- pentynyl, l-ethyl-3-pentynyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl, 4- trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6- pentafluorohexyl, and 333-trifluoropropyl, wherein each member of group B is optionally substituted at any carbon up to and including 5 atoms from the
32 point of attachment of B to A with one or more of the group consisting of R ,
33 34 35 36 R , R , R , and R ;
32 33 34 35 36
R , R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, carboxy, cyano, and Q ;
A is selected from the group consisting of single covalent bond, NH, N(CH3), CH2, CH3CH, and CH2CH2;
A is optionally selected from the group consisting of CH2N(CH3),
CH2N(CH2CH3), CH2CH2N(CH3), and CH2CH2N(CH2CH3) with the proviso that B is hydrido;
X° is selected from the group consisting of hydrido, hydroxy, amino, amidino, aminomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and fluoro;
R is selected from the group consisting of hydrido, hydroxy, amino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, methylthio, trifluoromethoxy, fluoro, and chloro;
R2 is Z°-Q;
Z is a covalent single bond;
Q is selected from the group consisting of phenyl, 2-thienyl, 2-furyl, 2- pyrrolyl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl, and 3-pyridyl, wherein a carbon adjacent to the carbon at the point of attachment is optionally
9 substituted by R , the other carbon adjacent to the carbon at the point of
13 9 attachment is optionally substituted by R , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by R , a carbon adjacent to R and two atoms from the carbon at the point of
12 attachment is optionally substituted by R , and any carbon adjacent to both π Rl° and J T R 2 i-s optional „ly su ,bsti •tuted , , by τ R. 1 ;
9 11 13
R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, and cyano;
10 12
R and R are independently selected from the group consisting of hydrido, amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2- hydroxyethyl, carboxy, carboxymethyl, amino, acetamido, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl, N- methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, N,N- dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, and cyano; h 20 21
Q is selected from the group consisting of NR R ,
C(NR
with the proviso that
said Q group is bonded direcdy to a carbon atom;
20 21 23 24 25 26
R , R , R , R , R , and R are independendy selected from the group consisting of hydrido, methyl, and ethyl;
QS is CH2.
In still another most preferred specific embodiment of Formula I, compounds have the Formula I-EMPS wherein B is a non-aromatic cyclic substituent:
B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, oxetan-3-yl, azetidin-3-yl, thiaetan-3-yl, cyclopentyl, and
• _. r,33 . cyclohexyl, wherein each ring carbon is optionally substituted with R , πng carbons or a nitrogen adjacent to the carbon atom at the point of attachment is
9 13 optionally substituted with R or R , a ring carbon or nitrogen adjacent to the
9
R position and two atoms from the point of attachment is optionally
10 13 substituted with R , and a ring carbon or nitrogen adjacent to the R position and two atoms from the point of attachment is optionally substituted
. L n 12 with R ;
33 R are independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, carboxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, cyano, and Q ;
A is selected from the group consisting of single covalent bond, NH,
N(CH3), CH2, CH3CH, and CH2CH2;
X° is selected from the group consisting of hydrido, hydroxy, amino, amidino, aminomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and fluoro;
R is selected from the group consisting of hydrido, hydroxy, amino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, methylthio, trifluoromethoxy, fluoro, and chloro;
R2 is Z°-Q; Z is a covalent single bond;
Q is selected from the group consisting of phenyl, 2-thienyl, 2-furyl, 2- pyrrolyl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl, and 3-pyridyl, wherein a carbon adjacent to the carbon at the point of attachment is optionally
9 substituted by R , the other carbon adjacent to the carbon at the point of
13 9 attachment is optionally substituted by R , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by
R , a carbon adjacent to R and two atoms from the carbon at the point of
12 attachment is optionally substituted by R , and any carbon adjacent to both
10 12 11
R and R is optionally substituted by R ;
9 11 13
R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, and cyano;
10 12
R and R are independently selected from the group consisting of hydrido, amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2- hydroxyethyl, carboxy, carboxymethyl, amino, acetamido, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl, N- methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, N,N- dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, and cyano; . r ^ m2Dn2l
Q is selected from the group consisting of NR R and
25 23 24 b
C(NR )NR R , with the proviso that said Q group is bonded directly to a carbon atom;
20 21 23 24 25
R , R , R , R , and R are independently selected from the group consisting of hydrido, methyl, and ethyl;
QS is CH2.
In a further most preferred embodiment of compounds of Formula I, compounds have the Formula I-FARMPS wherein there are two fused aromatic rings:
B is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3- pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, and 5-isoxazolyl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted
32 by R , the other carbon adjacent to the carbon at the point of attachment is
36 32 optionally substituted by R , a carbon adjacent to R and two atoms from
33 the carbon at the point of attachment is optionally substituted by R , a carbon
36 adjacent to R and two atoms from the carbon at the point of attachment is
35 33 35 optionally substituted by R , and any carbon adjacent to both R and R is
34 optionally substituted by R ;
32 33 34 35 36
R , R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, carboxy, cyano, and Q ;
B is selected from the group consisting of hydrido, ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 2-butynyl, sec-butyl, tert- butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 2- pentynyl, 3-pentynyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 2-methyl-2-butenyl,
3-methylbutyl, 3-methyl-2-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, l-methyl-2-pentenyl, l-methyl-3- pentenyl, l-methyl-2-pentynyl, l-methyl-3-pentynyl, 3-hexyl, l-ethyl-2- butenyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, l-methyl-2-hexenyl, 1-methyl- 3-hexenyl, l-methyl^-hexenyl, l-methyl-2-hexynyl, l-methyl-3-hexynyl, 1- methyM-hexynyl, 3-heptyl, l-ethyl-2-pentenyl, l-ethyl-3-pentenyl, l-ethyl-2- pentynyl, l-ethyl-3-pentynyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl, 4- trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6- pentafluorohexyl, and 3,33-trifluoropropyl, wherein each member of group B is optionally substituted at any carbon up to and including 5 atoms from the
32 point of attachment of B to A with one or more of the group consisting of R ,
33 34 35 J 36 R , R , R , and R ;
B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, oxetan-3-yl, azetidin-3-yl, thiaetan-3-yl, cyclopentyl, cyclohexyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-tetrahydrofuranyl, 3- tetrahydrofuranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each
33 ring carbon is optionally substituted with R , a ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment is optionally
9 13 9 substituted with R or R , a ring carbon or nitrogen atom adjacent to the R position and two atoms from the point of attachment is optionally substituted
10 13 with R , and a ring carbon or nitrogen atom adjacent to the R position and
12 two atoms from the point of attachment is optionally substituted with R ;
9 11 13
R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, and cyano;
R and R are independently selected from the group consisting of hydrido, amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2- hydroxyethyl, carboxy, carboxymethyl, amino, acetamido, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl, N- methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, N,N- dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, and cyano; A is selected from the group consisting of single covalent bond, NH,
N(CH3), CH2, CH3CH, and CH2CH2;
A is optionally selected from the group consisting of CH2N(CH3),
CH2N(CH2CH3), CH2CH2N(CH3), and CH2CH2N(CH2CH3) with the proviso that B is hydrido;
X° is selected from the group consisting of hydrido, hydroxy, amino, amidino, aminomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and fluoro;
W and Z are independendy selected from the group consisting of CH, N, CF, CC1, C-CN, C-NH2, C-CH2NH2, C-NHCH3, C-OH, C-CH2OH, C-
CO2H, and C-C(O)NH2;
X and Y are independently selected from the group consisting of CH, N, CF, C-CN, C-CH3, C-NH2, C-CH2NH2, C-CH2NHCH3, C-NHCH3,
C-CH(NH2)CH3, C-CH2CH2NH2, C-NHOCH3, C-C(NH)NH2,
C-C(NOH)NH2, C-OH, C-CH2OH, C-CH2CH2OH, C-CH(OH)CH3,
C-OCH3, C-CO2H, C-C(O)NH2, C-C(O)NHCH3, C-CH2CO2H, and
C-SO2NH2; Q is selected from the group consisting of NR R ,
C(NR )NR R , and N(R )C(NR )N(R )(R ), with the proviso that b said Q group is bonded directly to a carbon atom;
20 21 23 24 25 26
R , R , R , R , R , and R are independendy selected from the group consisting of hydrido, methyl, and ethyl;
QS is CH2.
The most preferred specific embodiment (I-EMPS) compounds of the present invention having the Formula:
The compounds of this invention can be used in anticoagulant therapy for the treatment and prevention of a variety of thrombotic conditions including coronary artery and cerebrovascular disease. The compounds of this invention can be used to inhibit serine protease associated with the coagulation cascade and factors II, VII, VIII, IX, X, XI, or XII. The compounds of the invention can inhibit the formation of blood platelet aggregates, inhibit the formation of fibrin, inhibit thrombus formation, and inhibiting embolus formation in a mammal, in blood, in blood products, and in mammalian organs. The compounds also can be used 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 in a mammal. The compounds can also be used in prophylactic treatment of subjects who are at risk of developing such disorders. The compounds can be used to lower the risk of atherosclerosis. The compounds of Formula (I) would also be useful in prevention of cerebral vascular accident (CVA) or stroke. Besides being useful for human treatment, these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
In yet another embodiment of the present invention, the novel compounds are selected from the compounds set forth in Examples 1 through Example 28 and Example Table 1.
The use of generic terms in the description of the compounds are herein defined for clarity.
Standard single letter elemental symbols are used to represent specific types of atoms unless otherwise defined. The symbol '"C" represents a carbon atom.
The symbol "O" represents an oxygen atom. The symbol "N" represents a nitrogen atom. The symbol "P' represents a phosphorus atom. The symbol "S" represents a sulfur atom. The symbol "H" represents a hydrido atom. Double letter elemental symbols are used as defined for the elements of the periodical table (i.e., CI represents chlorine, Se represents selenium, etc.).
As utilized herein, the term "alkyl", either alone or within other terms such as "haloalkyl" and "alkylthio", means an acyclic alkyl radical containing from 1 to about 10, preferably from 3 to about 8 carbon atoms and more preferably 3 to about 6 carbon atoms. Said alkyl radicals may be optionally substituted with groups as defined below. Examples of such radicals include methyl, ethyl, chloroethyl, hydroxyethyl, n-propyl, oxopropyl, isopropyl, n-butyl, cyanobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, aminopentyl, iso-amyl, hexyl, octyl and the like.
The term "alkenyl" refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains at least one double bond. Such alkenyl radicals contain from about 2 to about 10 carbon atoms, preferably from about 3 to about 8 carbon atoms and more preferably 3 to about 6 carbon atoms. Said alkenyl radicals may be optionally substituted with groups as defined below. Examples of suitable alkenyl radicals include propenyl, 2-chloropropenyl, buten-1-yl, isobutenyl, penten-1-yl, 2- 2-methylbuten-l-yl, 3-methylbuten-l-yl, hexen-1-yl, 3-hydroxyhexen-l-yl, hepten-1-yl, and octen-1-yl, and the like.
The term "alkynyl" refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains one or more triple bonds, such radicals containing about 2 to about 10 carbon atoms, preferably having from about 3 to about 8 carbon atoms and more preferably having 3 to about 6 carbon atoms. Said alkynyl radicals may be optionally substituted with groups as defined below. Examples of suitable alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, ρentyn-2-yl, 4- methoxypentyn-2-yl, 3-methylbutyn-l-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3- yl, 33-dimethylbutyn-l-yI radicals and the like.
The term "hydrido" denotes a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a "hydroxyl" radical, one hydrido radical may be attached to a carbon atom to form a "methine" radical -CH=, or two hydrido radicals may be attached to a carbon atom to form a "methylene" (-CH2-) radical.
The term "carbon" radical denotes a carbon atom without any covalent bonds and capable of forming four covalent bonds.
The term "cyano" radical denotes a carbon radical having three of four covalent bonds shared by a nitrogen atom. The term "hydroxyalkyl" embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with a hydroxyl as defined above. Specifically embraced are monohydroxyalkyl, dihydroxyalkyl and polyhydroxyalkyl radicals.
The term "alkanoyl" embraces radicals wherein one or more of the terminal alkyl carbon atoms are substituted with one or more carbonyl radicals as defined below. Specifically embraced are monocarbonylalkyl and dicarbonylalkyl radicals. Examples of monocarbonylalkyl radicals include formyl, acetyl, and pentanoyl. Examples of dicarbonylalkyl radicals include oxalyl, maionyl, and succinyl. The term "alkylene" radical denotes linear or branched radicals having from 1 to about 10 carbon atoms and having attachment points for two or more covalent bonds. Examples of such radicals are methylene, ethylene, methylethylene, and isopropylidene.
The term "alkenylene" radical denotes linear or branched radicals having from 2 to about 10 carbon atoms, at least one double bond, and having attachment points for two or more covalent bonds. Examples of such radicals are 1 ,1-vinylidene (CH2=C), 1 ,2-vinylidene (-CH=CH-), and 1 ,4-butadienyl (-CH=CH-CH=CH-).
The term "halo" means halogens such as fluorine, chlorine, bromine or iodine atoms.
The term "haloalkyl" embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have either a bromo, chloro or a fluoro atom within the radical. Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred haloalkyl radicals are "lower haloalkyl" radicals having one to about six carbon atoms. Examples of such haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,
dichloromethyl, trichloromethyl, trifluoroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
The term "hydroxyhaloalkyl" embraces radicals wherein any one or more of the haloalkyl carbon atoms is substituted with hydroxy as defined above. Examples of "hydroxyhaloalkyl" radicals include hexafluorohydroxypropy 1.
The term "haloalkylene radical" denotes alkylene radicals wherein any one or more of the alkylene carbon atoms is substituted with halo as defined above. Dihalo alkylene radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkylene radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred haloalkylene radicals are "lower haloalkylene" radicals having one to about six carbon atoms. Examples of "haloalkylene" radicals include difluoromethylene, tetrafluoroethylene, tetrachloroethylene, alkyl substituted monofluoromethylene, and aryl substituted trifluoromethylene.
The term "haloalkenyl" denotes linear or branched radicals having from 1 to about 10 carbon atoms and having one or more double bonds wherein any one or more of the alkenyl carbon atoms is substituted with halo as defined above. Dihaloalkenyl radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkenyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. The terms "alkoxy" and "alkoxyalkyl" embrace linear or branched oxy- containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy radical. The term "alkoxyalkyl" also embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. More preferred alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy, isopropoxy and terr-butoxy alkyls. The "alkoxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" and "haloalkoxyalkyl" radicals. Examples of such haloalkoxy radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy,
trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy. Examples of such haloalkoxyalkyl radicals include fluoromethoxymethyl, chloromethoxyethyl, trifluoromethoxymethyl, difluoromethoxyethyl, and trifluoroethoxymethyl. The terms "alkenyloxy" and "alkenyloxyalkyl" embrace linear or branched oxy-containing radicals each having alkenyl portions of two to about ten carbon atoms, such as ethenyloxy or propenyloxy radical. The term "alkenyloxyalkyl" also embraces alkenyl radicals having one or more alkenyloxy radicals attached to the alkyl radical, that is, to form monoalkenyloxyalkyl and dialkenyloxyalkyl radicals. More preferred alkenyloxy radicals are "lower alkenyloxy" radicals having two to six carbon atoms. Examples of such radicals include ethenyloxy, propenyloxy, butenyloxy, and isopropenyloxy alkyls. The "alkenyloxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkenyloxy" radicals. Examples of such radicals include trifluoroethenyloxy, fluoroethenyloxy, difluoroethenyhloxy, and fluoropropenyloxy.
The term "haloalkoxyalkyl" also embraces alkyl radicals having one or more haloalkoxy radicals attached to the alkyl radical, that is, to form monohaloalkoxyalkyl and dihaloalkoxyalkyl radicals. The term "haloalkenyloxy" also embraces oxygen radicals having one or more haloalkenyloxy radicals attached to the oxygen radical, that is, to form monohaloalkenyloxy and dihaloalkenyloxy radicals. The term "haloalkenyloxyalkyl" also embraces alkyl radicals having one or more haloalkenyloxy radicals attached to the alkyl radical, that is, to form monohaloalkenyloxyalkyl and dihaloalkenyloxyalkyl radicals.
The term "alkylenedioxy" radicals denotes alkylene radicals having at least two oxygens bonded to a single alkylene group. Examples of "alkylenedioxy" radicals include methylenedioxy, ethylenedioxy, alkyl substituted methylenedioxy, and aryl substituted methylenedioxy. The term "haloalkylenedioxy" radicals denotes haloalkylene radicals having at least two oxy groups bonded to a single haloalkyl group. Examples of "haloalkylenedioxy" radicals include difluoromethylenedioxy, tetrafluoroethylenedioxy, tetrachloroethylenedioxy, alkylsubstituted monofluoromethylenedioxy, and arylsubstituted monofluoromethylenedioxy.
The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused. The term "fused" means that a second ring is present (ie, attached or formed) by having two adjacent atoms in common (ie, shared) with the first ring. The term "fused" is equivalent to the term "condensed". The term "aryl" embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.
The term "perhaloaryl" embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl wherein the aryl radical is substituted with 3 or more halo radicals as defined below.
The term "heterocyclyl" embraces saturated and partially saturated heteroatom-containing ring-shaped radicals having from 4 through 15 ring members, herein referred to as "C4-C15 heterocyclyl" selected from carbon, nitrogen, sulfur and oxygen, wherein at least one ring atom is a heteroatom. Heterocyclyl radicals may contain one, two or three rings wherein such rings may be attached in a pendant manner or may be fused. Examples of saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl, etc.]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl, etc.]. Examples of partially saturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. Non-limiting examples of heterocyclic radicals include 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, 1,3- dioxolanyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, and the like.
The term "heteroaryl" embraces fully unsaturated heteroatom-containing ring-shaped aromatic radicals having from 5 through 15 ring members selected from carbon, nitrogen, sulfur and oxygen, wherein at least one ring atom is a heteroatom. Heteroaryl radicals may contain one, two or three rings wherein such rings may be attached in a pendant manner or may be fused. Examples of "heteroaryl" radicals, include unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl,
pyridazinyl, triazolyl [e.g., 4H-l,2,4-triazolyl, lH-l,23-triazolyl, 2H-1,2,3- triazolyl, etc.] tetrazolyl [e.g. lH-tetrazolyl, 2H-tetrazolyl, etc.], etc.; unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [l,5-b]pyridazinyl, etc.], etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 13,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4- thiadiazolyl, 13,4- thiadiazolyl, 1,2,5-thiadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl, etc.] and the like. The term also embraces radicals where heterocyclic radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like. Said "heterocyclyl" group may have 1 to 3 substituents as defined below. Preferred heterocyclic radicals include five to twelve membered fused or unfused radicals. Non-limiting examples of heteroaryl radicals include pyrrolyl, pyridinyl, pyridyloxy, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrazolyl, 2- imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,23-triazolyl, 1,3,4-thiadiazolyl, pyrazinyl, piperazinyl, 13,5-triazinyl, 13,5-trithianyl, benzo(b)thiophenyl, benzimidazoyl, quinolinyl, tetraazolyl, and the like.
The term "sulfonyl", whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals -SO2-. "Alkylsulfonyl", embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. "Alkylsulfonylalkyl", embraces alkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. "Haloalkylsulfonyl", embraces
haloalkyl radicals attached to a sulfonyl radical, where haloalkyl is defined as above. "Haloalkylsulfonylalkyl", embraces haloalkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. The term "aminosulfonyl" denotes an amino radical attached to a sulfonyl radical. The term "sulfmyl", whether used alone or linked to other terms such as alkylsulfinyl, denotes respectively divalent radicals -S(O)-. "Alkylsulfinyl", embraces alkyl radicals attached to a sulfinyl radical, where alkyl is defined as above. "Alkylsulfinylalkyl", embraces alkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above. "Haloalkylsulfinyl", embraces haloalkyl radicals attached to a sulfinyl radical, where haloalkyl is defined as above. "Haloalkylsulfinylalkyl", embraces haloalkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above.
The term "aralkyl" embraces aryl-substituted alkyl radicals. Preferable aralkyl radicals are "lower aralkyl" radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl. The terms benzyl and phenylmethyl are interchangeable.
The term "heteroaralkyl" embraces heteroaryl-substituted alkyl radicals wherein the heteroaralkyl radical may be additionally substituted with three or more substituents as defined above for aralkyl radicals. The term
"perhaloaralkyl" embraces aryl-substituted alkyl radicals wherein the aralkyl radical is substituted with three or more halo radicals as defined above.
The teim "aralkylsulfinyl", embraces aralkyl radicals attached to a sulfinyl radical, where aralkyl is defined as above. "Aralkylsulfinylalkyl", embraces aralkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above.
The term "aralkylsulfonyl", embraces aralkyl radicals attached to a sulfonyl radical, where aralkyl is defined as above. "Aralkylsulfonylalkyl", embraces aralkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
The term "cycloalkyl" embraces radicals having three to 15 carbon atoms. More preferred cycloalkyl radicals are "lower cycloalkyl" radicals having three to seven carbon atoms. Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term cycloalkyl embraces radicals having seven to 15 carbon atoms and having two
to four rings. Examples incude radicals such as norbornyl (i.e., bicyclo[2.2.1]heptyl) and adamantyl. The term "cycloalkylalkyl" embraces cycloalkyl-substituted alkyl radicals. Preferable cycloalkylalkyl radicals are "lower cycloalkylalkyl" radicals having cycloalkyl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include cyclohexylhexyl. The term "cycloalkenyl" embraces radicals having three to ten carbon atoms and one or more carbon-carbon double bonds. Preferred cycloalkenyl radicals are "lower cycloalkenyl" radicals having three to seven carbon atoms. Examples include radicals such as cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. The term "halocycloalkyl" embraces radicals wherein any one or more of the cycloalkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohalocycloalkyl, dihalocycloalkyl and polyhalocycloalkyl radicals. A monohalocycloalkyl radical, for one example, may have either a bromo, chloro or a fluoro atom within the radical. Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhalocycloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred halocycloalkyl radicals are "lower halocycloalkyl" radicals having three to about eight carbon atoms. Examples of such halocycloalkyl radicals include fluorocyclopropyl, difluorocyclobutyl, trifluorocyclopentyl, tetrafluorocyclohexyl, and dichlorocyclopropyl. The term "halocycloalkenyl" embraces radicals wherein any one or more of the cycloalkenyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohalocycloalkenyl, dihalocycloalkenyl and polyhalocycloalkenyl radicals.
The term "cycloalkoxy" embraces cycloalkyl radicals attached to an oxy radical. Examples of such radicals includes cyclohexoxy and cyclopentoxy. The term "cycloalkoxyalkyl" also embraces alkyl radicals having one or more cycloalkoxy radicals attached to the alkyl radical, that is, to form monocycloalkoxyalkyl and dicycloalkoxyalkyl radicals. Examples of such radicals include cyclohexoxyethyl. The "cycloalkoxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "halocycloalkoxy" and "halocycloalkoxyalkyl" radicals.
The term "cycloalkylalkoxy" embraces cycloalkyl radicals attached to an alkoxy radical. Examples of such radicals includes cyclohexylmethoxy and cyclopentylmethoxy.
The term "cycloalkenyloxy" embraces cycloalkenyl radicals attached to an oxy radical. Examples of such radicals includes cyclohexenyloxy and cyclopentenyloxy. The term "cycloalkenyloxyalkyl" also embraces alkyl radicals having one or more cycloalkenyloxy radicals attached to the alkyl radical, that is, to form monocycloalkenyloxyalkyl and dicycloalkenyloxyalkyl radicals. Examples of such radicals include cyclohexenyloxyethyl. The "cycloalkenyloxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "halocycloalkenyloxy" and "halocycloalkenyloxyalkyl" radicals.
The term "cycloalkylenedioxy" radicals denotes cycloalkylene radicals having at least two oxygens bonded to a single cycloalkylene group. Examples of "alkylenedioxy" radicals include 1,2-dioxycyclohexylene.
The term "cycloalkylsulfinyl", embraces cycloalkyl radicals attached to a sulfinyl radical, where cycloalkyl is defined as above. "Cycloalkylsulfinylalkyl", embraces cycloalkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above. The term "Cycloalkylsulfonyl", embraces cycloalkyl radicals attached to a sulfonyl radical, where cycloalkyl is defined as above. "Cycloalkylsulfonylalkyl", embraces cycloalkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
The term "cycloalkylalkanoyl" embraces radicals wherein one or more of the cycloalkyl carbon atoms are substituted with one or more carbonyl radicals as defined below. Specifically embraced are monocarbonylcycloalkyl and dicarbonylcycloalkyl radicals. Examples of monocarbonylcycloalkyl radicals include cyclohexylcarbonyl, cyclohexylacetyl, and cyclopentylcarbonyl. Examples of dicarbonylcycloalkyl radicals include 1,2- dicarbonylcyclohexane. The term "alkylthio" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom.
More preferred alkylthio radicals are "lower alkylthio" radicals having one to six carbon atoms. An example of "lower alkylthio" is methylthio (CH3-S-).
The "alkylthio" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkylthio" radicals.
Examples of such radicals include fluoromethylthio, chloromethylthio, trifluoromethylthio, difluoromethylthio, trifluoroethylthio, fluoroethylthio, tetrafluoroethylthio, pentafluoroethylthio, and fluoropropylthio.
The term "alkyl aryl amino" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, and one aryl radical both attached to an amino radical. Examples include N-methyl-4-methoxyaniline, N-ethyl-4-methoxyaniline, and N-methyl-4-trifluoromethoxyaniline.
The terms alkylamino denotes "monoalkylamino" and "dialkylamino" containing one or two alkyl radicals, respectively, attached to an amino radical. The terms arylamino denotes "monoarylamino" and "diarylamino" containing one or two aryl radicals, respectively, attached to an amino radical.
Examples of such radicals include N-phenylamino and N-naphthylamino.
The term "aralkylamino", embraces aralkyl radicals attached to an amino radical, where aralkyl is defined as above. The term aralkylamino denotes "monoaralkylamino" and "diaralkylamino" containing one or two aralkyl radicals, respectively, attached to an amino radical. The term aralkylamino further denotes "monoaralkyl monoalkylamino" containing one aralkyl radical and one alkyl radical attached to an amino radical.
The term "arylsulfinyl" embraces radicals containing an aryl radical, as defined above, attached to a divalent S(O) atom. The term "arylsulfinylalkyl" denotes arylsulfinyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms.
The term "arylsulfonyl", embraces aryl radicals attached to a sulfonyl radical, where aryl is defined as above, "arylsulfonylalkyl", embraces arylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. The term "heteroarylsulfinyl" embraces radicals containing an heteroaryl radical, as defined above, attached to a divalent S(O) atom. The term "heteroarylsulfinylalkyl" denotes heteroarylsulfinyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms. The term "Heteroarylsulfonyl", embraces heteroaryl radicals attached to a sulfonyl radical, where heteroaryl is defined as above. "Heteroarylsulfonylalkyl", embraces heteroarylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
The term "aryloxy" embraces aryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include phenoxy, 4-chloro-3-
ethylphenoxy, 4-chloro-3-methylphenoxy, 3-chloro-4-ethylphenoxy, 3,4- dichlorophenoxy, 4-methylphenoxy, 3-trifluoromethoxyphenoxy, 3- trifluoromethylphenoxy, 4-fluorophenoxy, 3,4-dimethyIphenoxy, 5-bromo-2- fluorophenoxy, 4-bromo-3-fluorophenoxy, 4-fluoro-3-methylphenoxy, 5,6,7,8-tetrahydronaphthyloxy, 3-isopropylphenoxy, 3-cyclopropylphenoxy, 3-ethylphenoxy, 3-pentafluoroethylphenoxy , 3-( 1 , 1 ,2,2-tetrafluoroethoxy)- phenoxy, and 4-tert -butylphenoxy.
The term "aroyl" embraces aryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include benzoyl and toluoyl.
The term "aralkanoyl" embraces aralkyl radicals, as defined herein, attached to an carbonyl radical as defined above. Examples of such radicals include, for example, phenylacetyl.
The term "aralkoxy" embraces oxy-containing aralkyl radicals attached through an oxygen atom to other radicals. More preferred aralkoxy radicals are "lower aralkoxy" radicals having phenyl radicals attached to lower alkoxy radical as described above. Examples of such radicals include benzyloxy, 1- phenylethoxy, 3-trifluoromethoxybenzyloxy, 3-trifluoromethylbenzyloxy, 3,5- difluorobenyloxy, 3-bromobenzyloxy, 4-propylbenzyloxy, 2-fluoro-3- trifluoromethylbenzyloxy, and 2-phenylethoxy.
The term "aryloxyalkyl" embraces aryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenoxy methyl. The term "haloaryloxyalkyl" embraces aryloxyalkyl radicals, as defined above, wherein one to five halo radicals are attached to an aryloxy group. The term "heteroaroyl" embraces heteroaryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include furoyl and nicotinyl.
The term "heteroaralkanoyl" embraces heteroaralkyl radicals, as defined herein, attached to an carbonyl radical as defined above. Examples of such radicals include, for example, pyridylacetyl and furylbutyryl.
The term "heteroaralkoxy" embraces oxy-containing heteroaralkyl radicals attached through an oxygen atom to other radicals. More preferred heteroaralkoxy radicals are "lower heteroaralkoxy" radicals having heteroaryl radicals attached to lower alkoxy radical as described above.
The term "haloheteroaryloxyalky ' embraces heteroaryloxyalkyl radicals, as defined above, wherein one to four halo radicals are attached to an heteroaryloxy group.
The term "heteroarylamino" embraces heterocyclyl radicals, as defined above, attached to an amino group. Examples of such radicals include pyridylamino.
The term "heteroarylaminoalkyl" embraces heteroarylamino radicals, as defined above, attached to an alkyl group. Examples of such radicals include pyridylmethylamino. The term "heteroaryloxy" embraces heterocyclyl radicals, as defined above, attached to an oxy group. Examples of such radicals include 2- thiophenyloxy, 2-pyrimidyloxy, 2-ρyridyloxy, 3-pyridyloxy, and 4- pyridyloxy.
The term "heteroaryloxyalkyl" embraces heteroaryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include 2-pyridyloxymethyl, 3-pyridyloxyethyl, and 4-pyridyloxyrnethyl.
The term "arylthio" embraces aryl radicals, as defined above, attached to an sulfur atom. Examples of such radicals include phenylthio.
The term "arylthioalkyl" embraces arylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenylthiomethyl.
The term "alkylthioalkyl" embraces alkylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include methyl thiomethyl. The term "alkoxyalkyl" embraces alkoxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include methoxymethyl.
The term "carbonyl" denotes a carbon radical having two of the four covalent bonds shared with an oxygen atom. The term "carboxy" embraces a hydroxyl radical, as defined above, attached to one of two unshared bonds in a carbonyl group. The term "carboxamide" embraces amino, monoalkylamino, dialkylamino, monocycloalkylamino, alkylcycloalkylamino, and dicycloalkylamino radicals, attached to one of two unshared bonds in a carbonyl group. The term "carboxamidoalkyl" embraces carboxamide radicals, as defined above, attached to an alkyl group. The term "carboxyalkyl" embraces a carboxy radical, as defined above, attached to an alkyl group. The term "carboalkoxy" embraces alkoxy
radicals, as defined above, attached to one of two unshared bonds in a carbonyl group. The term "carboaralkoxy" embraces aralkoxy radicals, as defined above, attached to one of two unshared bonds in a carbonyl group. The term "monocarboalkoxyalkyl" embraces one carboalkoxy radical, as defined above, attached to an alkyl group. The term "dicarboalkoxyalkyl" embraces two carboalkoxy radicals, as defined above, attached to an alkylene group. The term "monocyanoalkyl" embraces one cyano radical, as defined above, attached to an alkyl group. The term "dicyanoalkylene" embraces two cyano radicals, as defined above, attached to an alkyl group. The term "carboalkoxycyanoalkyl" embraces one cyano radical, as defined above, attached to an carboalkoxyalkyl group. The term "acyl", alone or in combination, means a carbonyl or thionocarbonyl group bonded to a radical selected from, for example, hydrido, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkoxyalkyl, haloalkoxy, aryl, heterocyclyl, heteroaryl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, alkylthio, arylthio, amino, alkylamino, dialkylamino, aralkoxy, arylthio, and alkylthioalkyl. Examples of "acyl" are formyl, acetyl, benzoyl, trifluoroacetyl, phthaloyl, malonyl, nicotinyl, and the like. The term "haloalkanoyl" embraces one or more halo radicals, as defined herein, attached to an alkanoyl radical as defined above. Examples of such radicals include, for example, chloroacetyl, trifluoroacetyl, bromopropanoyl, and heptafluorobutanoyl .
The term "phosphono" embraces a pentavalent phosphorus attached with two covalent bonds to an oxygen radical. The term "dialkoxyphosphono" denotes two alkoxy radicals, as defined above, attached to a phosphono radical with two covalent bonds. The term "diaralkoxyphosphono" denotes two aralkoxy radicals, as defined above, attached to a phosphono radical with two covalent bonds. The term "dialkoxyphosphonoalkyl" denotes dialkoxyphosphono radicals, as defined above, attached to an alkyl radical. The term "diaralkoxyphosphonoalkyl" denotes diaralkoxyphosphono radicals, as defined above, attached to an alkyl radical. The term "amino" denotes a nitrogen atom containing two substituents such as hydrido, hydroxy or alkyl and having one covalent bond available for bonding to a single atom such as carbon. Examples of such amino radicals include, for example, -NH2, -NHCH3, -NHOH, and -NHOCH3. The term "imino" denotes a nitrogen atom containing one substituent such as hydrido, hydroxy or alkyl and having two covalent bonds available for bonding to a single atom such as carbon.
Examples of such imino radicals include, for example, =NH, =NCH3, =NOH,
and =NOCH3. The term "imino carbonyl" denotes a carbon radical having two of the four covalent bond sites shared with an imino group. Examples of such imino carbonyl radicals include, for example, C=NH, C=NCH3, C=NOH, and
C=NOCH3. The term '"amidino" embraces a substituted or unsubstituted amino group bonded to one of two available bonds of an iminocarbonyl radical. Examples of such amidino radicals include, for example, NH -C=NH, NH2-C=NCH3,
NH2-C=NOCH3 and CH3NH-C=NOH. The term "guanidino" denotes an amidino group bonded to an amino group as defined above where said amino group can be bonded to a third group. Examples of such guanidino radicals include, for example, NH2-C(NH)-NH-, NH2-C(NCH3)-NH-, NH2-
C(NOCH3)-NH-, and CH3NH-C(NOH)-NH-.
The term "sulfonium" denotes a positively charged trivalent sulfur atom where said sulfur is substituted with three carbon based groups such as alkyl, alkenyl, aralkyl, or aryl. The term "dialkyl sulfonium" denotes a sulfonium group where said sulfur is substituted with two alkyl groups. Examples of such dialkylsulfonium radicals include, for example, (CH3)2S -. The term "dialkyl sulfonium alkyl" denotes a dialkyl sulfonium group where said group is bonded to one bond of an alkylene group as defined above. Examples of such dialkylsulfoniumalkyl radicals include (CH3) S -CH2CH2-.
The term "phosphonium" denotes a positively charged tetravalent phosphorus atom where said phosphorus is substituted with four carbon based groups such as alkyl, alkenyl, aralkyl, or aryl. The term "trialkyl phosphonium" denotes a phosphonium group where said phosphorus is substituted with three alkyl groups. Examples of such trialkylphosphonium radicals include, for example,
(CH3)3P+.
Said "alkyl", "alkenyl", "alkynyl", "alkanoyl", "alkylene", "alkenylene", "hydroxyalkyl", "haloalkyl", "haloalkylene", "haloalkenyl", "alkoxy", "alkenyloxy", "alkenyloxyalkyl", "alkoxyalkyl", "aryl", "perhaloaryl",
"haloalkoxy", "haloalkoxyalkyl", "haloalkenyloxy", "haloalkenyloxyalkyl", "alkylenedioxy", "haloalkylenedioxy", "heterocyclyl", "heteroaryl", "hydroxyhaloalkyl", "alkylsulfonyl", "haloalkylsulfonyl", "alkylsulfonylalkyl", "haloalkylsulfonylalkyl", "alkylsulfinyl", "alkylsulfinylalkyl", "haloalkylsulfinylalkyl", "aralkyl", "heteroaralkyl", "perhaloaralkyl",
"aralkylsulfonyl", "aralkylsulfonylalkyl", "aralkylsulfinyl", "aralkylsulfinylalkyl", "cycloalkyl", "cycloalkylalkanoyl", "cycloalkylalkyl", "cycloalkenyl", "halocycloalkyl", "halocycloalkenyl", "cycloalkylsulfinyl", "cycloalkylsulfinylalkyl", "cycloalkylsulfonyl", "cycloalkylsulfonylalkyl", "cycloalkoxy", "cycloalkoxyalkyl", "cycloalkylalkoxy", "cycloalkenyloxy", "cycloalkenyloxyalkyl", "cycloalkylenedioxy", "halocycloalkoxy", "halocycloalkoxyalkyl", "halocycloalkenyloxy", "halocycloalkenyloxyalkyl", "alkylthio", "haloalkylthio", "alkylsulfinyl", "amino", "oxy", "thio", "alkylamino", "arylamino", "aralkylamino", "arylsulfinyl", "arylsulfinylalkyl", "arylsulfonyl", "arylsulfonylalkyl", "heteroarylsulfinyl", "heteroarylsulfinylalkyl", "heteroarylsulfonyl", "heteroarylsulfonylalkyl", "heteroarylamino", "heteroarylaminoalkyl", "heteroaryloxy", "heteroaryloxylalkyl", "aryloxy", "aroyl", "aralkanoyl", "aralkoxy", "aryloxyalkyl", "haloaryloxyalkyl", "heteroaroyl", "heteroaralkanoyl", "heteroaralkoxy", "heteroaralkoxyalkyl", "arylthio", "arylthioalkyl", "alkoxyalkyl", "acyl", "amidino", "guanidino",
"dialkylsulfonium", "trialkylphosphonium", and "dialkylsulfoniumalkyl" groups defined above may optionally have 1 or more non-hydrido substituents such as amidino, guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, heteroaryloxy, heteroaryloxylalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl,
alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diary lamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, aminoalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxy carbonyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl.
The term "spacer" can include a covalent bond and a linear moiety having a backbone of 1 to 7 contiguous atoms. The spacer may have 1 to 7 atoms of a univalent or multi-valent chain. Univalent chains may be constituted by a radical selected from =C(H)-, ^(R2*)-, -O-, -S-, -S(O)-, -S(O)2-,
-NH-, -N(R2a)-, -N=, -CH(OH)-, =C(OH)-, -CH(OR2&)-,
and
2a -C(O)- wherein R is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, perhaloaralkyl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, and heteroarylalkenyl. Multi-valent chains may consist of a strai ht chain of 1 or 2 or 3 or 4 or 5 or 6 or 7 atoms or a straight chain of 1 or 2 or 3 or 4 or 5 or 6 atoms with a side chain. The chain may be constituted of one or more radicals selected from: lower alkylene, lower alkenyl, -O-, -O-CH2-, -S-CH2-, -CH2CH2-, ethenyl,
-CH=CH(OH)-, -OCH2O-, -O(CH2)2O-, -NHCH2-, -OCH(R2a)O-,
-O(CH2CHR2a)O-, -OCF2O-, -O(CF2)2O-, -S-, -S(O)-, -S(O)2-, -N(H)-,
-N(H)O-, -NcΛo-, -N(R2a)-, -C(O)-, -C(O)NH-, -C(O)NR2a -, -N=,
-OCH2-, -SCH2-, S(O)CH2-, -CH2C(O)-, -CH(OH)-, =C(OH)-, -CH(OR2a)-,
2a 2a
=C(OR )-, S(O)2CH2-, and -NR CH2- and many other radicals defined above or generally known or ascertained by one of skill-in-the art. Side chains may include substituents such as 1 or more non-hydrido substituents such as amidino, guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, heteroaryloxy, heteroaryloxylalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, aminoalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy,
phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl.
Compounds of the present invention can exist in tautomeric, geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-geometric isomers, E- and Z-geometric isomers, R- and S- enantiomers, diastereomers, d-isomers, 1-isomers, the racemic mixtures thereof and other mixtures thereof, as falling within the scope of the invention. Pharmaceutically acceptable sales of such tautomeric, geometric or stereoisomeric forms are also included within the invention. The terms "cis" and "trans" denote a form of geometric isomerism in which two carbon atoms connected by a double bond will each have a hydrogen atom on the same side of the double bond ("cis") or on opposite sides of the double bond ("trans").
Some of the compounds described contain alkenyl groups, and are meant to include both cis and trans or "E" and "Z" geometric forms.
Some of the compounds described contain one or more stereocenters and are meant to include R, S, and mixtures of R and S forms for each stereocenter present.
Some of the compounds described herein may contain one or more ketonic or aldehydic carbonyl groups or combinations thereof alone or as part of a heterocyclic ring system. Such carbonyl groups may exist in part or principally in the "keto" form and in part or principally as one or more "enol" forms of each aldehyde and ketone group present. Compounds of the present invention having aldehydic or ketonic carbonyl groups are meant to include both "keto" and "enol" tautomeric forms.
Some of the compounds described herein may contain one or more amide carbonyl groups or combinations thereof alone or as part of a heterocyclic ring system. Such carbonyl groups may exist in part or principally in the "keto" form and in part or principally as one or more "enol" forms of each amide group present. Compounds of the present invention having amidic carbonyl groups are meant to include both "keto" and "enol" tautomeric forms. Said amide carbonyl groups may be both oxo (C=O) and thiono (C=S) in type.
Some of the compounds described herein may contain one or more imine or enamine groups or combinations thereof. Such groups may exist in part or principally in the "imine" form and in part or principally as one or more
"enamine" forms of each group present. Compounds of the present invention having said imine or enamine groups are meant to include both "imine" and "enamine" tautomeric forms.
The present invention also comprises a treatment and prophylaxis in anticoagulant therapy for the treatment and prevention of a variety of thrombotic conditions including coronary artery and cerebrovascular disease in a subject, comprising administering to the subject having such disorder a therapeutically-effective amount of a compound of Formula (I):
As a further embodiment, compounds of the present invention of Formula (I) or a pharmaceutically-acceptable salt thereof as defined above, comprise a treatment and prophylaxis of coronary artery disease, cerebrovascular disease and other coagulation cascade related disorders in a subject, comprising administering to the subject having such disorder a therapeutically-effective amount of compounds of formula (I) of the present invention or a pharmaceutically-acceptable salt thereof.
Compounds of the present invention of Formula (I) or a pharmaceutically-acceptable salt thereof can also be used whenever inhibition of blood coagulation is required such as to prevent coagulation of stored whole blood and to prevent coagulation in other biological samples for testing or storage. Thus coagulation inhibitors of the present inhibition can be added to or contacted with stored whole blood and any medium containing or suspected of containing plasma coagulation factors and in which it is desired that blood coagulation be inhibited, e.g. when contacting the mammal's blood with material selected from the group consisting of vascular grafts, stents, orthopedic prothesis, cardiac prosthesis, and extracorporeal circulation systems.
Compounds of Formula (I) are capable of inhibiting activity of serine proteases related to the coagulation cascade, and thus could be used in the manufacture of a medicament, a method for the prophylactic or therapeutic treatment of diseases mediated by coagulation cascade serine proteases, such as inhibiting the formation of blood platelet aggregates, inhibiting the formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation in a mammal, in blood, in blood products, and in mammalian organs. The compounds also can be used 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 in a mammal. The compounds also can be used to study the mechanism of action of coagulation cascade serine proteases to enable the design of better inhibitors and development of better assay methods. The compounds of Formula (I) would be also useful in prevention of cerebral vascular accident (CVA) or stroke.
Also included in the family of compounds of Formula (I) are the pharmaceutically-acceptable salts thereof. The term "pharmaceutically- acceptable salt" embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula (I) may be prepared from inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulf uric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucoronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethylsulfonic, benzenesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formula (I) include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N'-
dibenzylethyleneldiamine, choline, chloroprocaine, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procain. All of these salts may be prepared by conventional means from the corresponding compound of Formula (I) by reacting, for example, the appropriate acid or base with the compound of Formula (I).
The present invention also comprises a pharmaceutical composition comprising a therapeutically-effective amount of a compound of Formulas (I) in association with at least one pharmaceutically-acceptable carrier, adjuvant or diluent. Pharmaceutical compositions of the present invention can comprise the active compounds of Formula (I) in association with one or more non-toxic, pharmaceutically-acceptable carriers and/or diluents and or adjuvants (collectively referred to herein as "carrier" materials) and, if desired, other active ingredients. The active compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
The active compounds and composition may, for example, be administered orally, intravascularly, intraperitoneally, subcutaneously, intramuscularly, oculary, or topically. For treating ocular build up of fibrin, the compounds may be administered intraocularly or topically as well as orally or parenterally.
The compounds can be administered in the form of a depot injection or implant preparation which may be formulated in such a manner as to permit a sustained release of the active ingredient. The active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramusculary as depot injections or implants. Implants may employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic, silicone rubber or other silicon containing polymers.
The compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
The compounds may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds may also be coupled with soluble polymers as targetable drug
carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide- phenol, or ployethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphitpathic block copolymers of hydrogels. For oral administration, the pharmaceutical composition may be in the form of, for example, tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixers, tinctures, suspensions, liquids including syrups, and emulsions. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. The active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable carrier.
The amount of therapeutically active compounds which are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the disease, the route and frequency of administration, and the particular compound employed, and thus may vary widely. The pharmaceutical compositions may contain active ingredients in the range of about 0.1 to 2000 mg, and preferably in the range of about 0.5 to 500 mg. A daily dose of about 0.01 to 100 mg/kg body weight, and preferably between about 0.5 and about 20 mg/kg body weight, may be appropriate. The daily dose can be administered in one to four doses per day. The compounds may be formulated in topical ointment or cream, or as a suppository, containing the active ingredients in a total amount of, for example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w. When formulated in an ointment, the active ingredients may be employed with either paraffinic or a water-miscible ointment base.
Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane- 13-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof. The topical formulation may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulf oxide and related analogs. The compounds of this invention can also be administered by a transdermal device. Preferably topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. In either case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent may also function as the membrane.
The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizers) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, among others. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic
alkyl esters such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters may be used. These may be used alone or in combination depending on the properties required. Alternatively, high melting point Iipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
For therapeutic purposes, the active compounds of the present invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
In practicing the methods of the present invention for the treatment and prevention of a variety of thrombotic conditions including coronary artery and cerebrovascular disease, the compounds and pharmaceutical compositions of the present invention are administered alone or in combination with one another, or in combination with other therapeutics or in vivo diagnostic agents. The coagulation cascade inhibitors of the present invention can also be co- administered with suitable anti-platelet agreggation agents, including, but not limited to ticlopidine or clopidrogel, fibrinogen receptor antagonists (e.g. to treat or prevent unstable angina or to prevent reocculsion after angioplasty and restenosis), anti-coagulants such as aspirin, warfarin or heparins, thrombolytic
agents such as plasminogen activators or streptokinase to achieve synergistic effects in the treatment of various pathologies, lipid lowering agents including antihypercholesterolemics (e.g. HMG CoA reductase inhibitors such as mevastatin, lovastatin, simvastatin, pravastatin, and fluvastatin, HMG CoA synthatase inhibitors, etc.), anti-diabetic drugs, or other cardiovascular agents (loop diuretics, thiazide type diuretics, nitrates, aldosterone antagonistics (i.e., spironolactone and epoxymexlerenone), angiotensin converting enzyme (e.g. ACE) inhibitors, angiotensin II receptor antagonists, beta-blockers, anπarrythmics, anti-hypertension agents, and calcium channel blockers) to treat or prevent atheriosclerosis. For example, patients suffering from coronary artery disease, and patients subjected to angioplasty procedures, would benefit from coadministration of fibrinogen receptor antagonists and coagulation cascade inhibitors of the present invention. Also, coagulation cascade inhibitors could enhance the efficiency of tissue plasminogen activator- mediated thrombolytic reperfusion.
Typical doses of coagulation cascade inhibitors of the present invention with other suitable anti-platelet agents, anticoagulation agents, cardiovascular therapeutic agents, or thrombolytic agents may be the same as those doses of coagulation cascade inhibitors administered without coadministration of additional anti-platelet agents, anticoagulation agents, cardiovascular therapeutic agents, or thrombolytic agents, or may be substantially less than those doses of coagulation cascade inhibitors administered without coadministration of additional anti-platelet agents, anticoagulation agents, cardiovascular therapeutic agents, or thrombolytic agents, depending on a patient' s therapeutic needs.
All mentioned references are incorporated by reference as if here written.
Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations. The following examples are provided to illustrate the present invention and are not intended to limit the scope thereof. Without further elaboration, it is believed that one skilled in the art can, using the preceding descriptions, utilize the present invention to its fullest extent. Therefore the following preferred specific embodiments are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way
whatsoever. Compounds containing multiple variations of the structural modifications illustrated in the schemes or the following Examples are also contemplated. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.
One skilled in the art may use these generic methods to prepare the following specific examples, which have been or may be properly characterized by 'H NMR, mass spectrometry, elemental composition, and similar procedures. These compounds also may be formed in vivo. The following examples contain detailed descriptions of the methods of preparation of compounds of Formula (I). These detailed descriptions fall within the scope and are presented for illustrative purposes only and are not intended as a restriction on the scope of the invention. All parts are by weight and temperatures are Degrees centigrade unless otherwise indicated. The following general synthetic sequences are useful in making the present invention. Abbreviations used in the schemes and tables include: "AA" represents amino acids, "AcCN" represents acetonitrile, "AcOH" represents acetic acid, "BINAF' represents 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl, "BnOH" represents benzyl alcohol, "BnCHO" represents 2-phenylethanal, " BnSO2Cl" represents benzylsulfonyl chloride, "Boc" represents tert- butyloxy carbonyl, "BOF' represents benzotriazol-1-yl-oxy-tris- (dimethylamino), "bu" represents butyl, "dba" represents dibenzylidene- acetone, "DCC" represents 13-dicyclohexylcarbodiimide, "DCM" represents dichloromethane or methylene chloride, "DIBAH" or "DIBAL" represents diisobutylaluminum hydride, "DMF" represents dimethylformamide, "DMSO" represents dimethylsulfoxide, "DPPA" represents diphenylphosphoryl azide", "EDC" represents l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, "Ex. No." represents Example Number, "Fmoc" represents 9- fluorenylmethoxy carbonyl, "HOBt" represents hydroxybenzoltriazole", "LDA" represents lithium dusopropylamide, "MW represents molecular weight,
"NMM" represents N-methylmorpholine, "Ph" represents phenyl or aryl, "PHTH" represents a phthaloyl group, "pnZ" represents 4-nitrobenzyloxy- carbonyl, "PTC" represents a phase transfer catalyst , "py" represents pyridine,
" RNH2" represents a primary organic amine, "SEM' represents 2- (trimethylsilyl)ethoxy-methyl chloride, "p-TsOH" represents
paratoluenesulfonic acid, "TBAF' represents tetrabutylammonium fluoride, "TBTU" represents 2-(lH-benzotriozole-l-yl)-l,133-tetramethyl uronium tetrafluoroborate, 'TEA" represents triethylamine, 'TFA" represents trifluoroacetic acid, "THF' represents tetrahydrofuran, "TMS" represents trimethylsilyl, "TMSCN" represents trimediylsilyl cyanide, and "Cbz" or "Z" represents benzyloxycarbonyl.
GENERAL SYNTHETIC PROCEDURES
ANP SPE IFIC EXA P S
The pyridone compounds of the present invention can be synthesized, for example, according to the following procedures and Schemes given below.
A pyridone having a fused aryl or heteroaryl group can be considered to be a quinolone. A generic quinolinone analogous structure to the basic pyridone ring type is shown in Figure 1. W, X, Y and Z are optionally selected from CH,
Figure 1. Quinolinone Analogues of Pyridones
N, CF, CC1, C-CN, C-CH3, C-CH2CH3, C-NH2, C-CH2NH2,
C-CH2NHCH3, C-NHCH3, C-N(CH3)2, C-CH(NH2)CH3, C-CH2CH2NH2, C-NHOCH3, C-NHOCH2CH3, C-C(NH)NH2,
C-C(NOH)NH2, C-OH, C-CH2OH, C-CH2CH2OH, C-CH(OH)CH3,
C-OCH3, C-OCH2CH3, C-CO2H, C-CO2CH3, C-C(O)NH2,
C-C(O)NHCH3, C-C(O)NH(CH3)2, C-CH2CO2H, C-SO2NH2,
C-SO2NHCH3, C-NH(O)CCH3, and C-NH(O)CCF3. Quinolones in which W of W-X=Y-Z is attached to the four and five positions of the pyridone instead of the
five and six positions can be prepared by comparable procedures. A general procedure for the preparation a wide variety of quinolone type 2-pyridones is summarized in Scheme 1 and Scheme 2. These procedures can accommodate the introduction of a wide range of substituents into the fused ring either as such, precursors groups for desired groups (for example, a nitro for subsequent conversion to an amino, an acetoxymethyl for subsequent hydrolysis to an hydroxymethyl or oxidation to an aldehyde or carboxylic acid, and the like) or using protected groups. The preparation of specific quinolinone analogues of a pyridone of this invention are exemplified as in Example 1 through Example 16.
Scheme 1 : General Quinoione Synthesis-I
EX- 1 A) 3-Nitro-lH-Quinolin-2-One (2.35 g, 12.37 mmole) in 50 ml anhydrous DMF was mixed with NaΗ 60% in mineral oil (0.59 g, 14.87 g), and the mixture was stirred for five minutes. To this mixture, 2-methyl-2-bromoacetate (2.27g, 14.84 mmole) was added dropwise. After stirring the reaction mixture for 2 hours at 20 °C, DMF was removed via vacuum rotary evaporation to lead to a yellow oil residue. The residue was triturated in water to yield a yellow solid that was washed with water and hexane. The yellow solid was re-crystallized in ethylacetate to yield a yellow needle crystal solid (138 g) as the expected product, methyl-(3-nitro-2-oxo-2H-quinoIin-l-yl)acetate. More product (1.20 g) was obtained from the mother liquor via silica gel flash chromatography to separate it from the O-alkylated side product (0.334 g). The desired product (EX- 1 A) yield was 80%. ΗPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50
°C): retention time 2.48 min, M+Η+ = 263.2 for formula C12H10N2O5. *H NMR
(400 MHz, CDC13): δ 3.80 (s, 3H), 5.17 (s, 2H), 7.19 (d, J = 8.4 Hz, 1H), 7.40
(t, J = 7.6 Hz, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 8.61 (s, 1H). 13C NMR (101 MHz, CDC13): 6 44.2, 52.9, 114.2, 117.1, 124.0, 131.7,
134.8, 137.9, 140.6, 154.0, 167.6.
EX- IB) Compound EX-1A (2.51 g, 9.58 mmole) was mixed with 10% Pd on activated carbon (0.51 g, 0.48 mmole) in 150 ml methanol. The mixture was stirred under H, that was introduced through a rubber balloon for 2 hours. The reaction mixture was filtered, and the methanol was removed to yield a white crystalline solid (2.06 g, y = 93%) as methyl-(3-amino-2-oxo-2H-quinolin-l- yl)acetate (3). ΗPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @
50 °C): retention time 2.12 min, M+Η+ = 233.1 for formula C12H12N2θ3.
Compound 3 (2.04 g, 8.79 mmole) and pyridine (3.55 ml, 43.95 mmole) were dissolved in 200 ml acetonitrile. This mixture was cooled down to -10 °C with a water-acetone-dry ice mixture bath. To this mixture, a-tolunesulfonyl chloride (4.19 g, 21.98 mmole) dissolved in 10 ml acetonitrile was added dropwise quickly. The reaction mixture was stirred for 2.5 hours from -10 °C to 0 °C. During the reaction, the product as a white solid precipitated from the solution. The pure product, methyl-(3-benzylsulfonylamido-2-oxo-2H-quinolin-l-yl)acetate (EX- IB) (2.92 g) was obtained by filtration and washing it with acetonitrile. More product (0.34 g) was obtained by working up the filtrate and subjecting it to a Biotage-40 silica gel column chromatography using 25% ethylacetate in hexane as the elute. ΗPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50
°C): retention time 3.52 min, M+Na+ = 408.9 for formula C19Η18N2O5SNa. Η
NMR (400 MHz, CDC13): δ 3.81 (s, 3H), 4.42 (s, 2H), 5.14 (s, 2H), 7.09 (d, J
= 8.8 Hz, 1H), 7.27 (m, 5H), 7.48 (t, J = 7.6 Hz, 2H), 7.61 (d, J = 10 Hz, 1H), 8.61 (s, 1H). 13C NMR (101 MHz, CDCl3): δ 44.5, 52.8, 58.5, 113.3, 119.5,
120.4, 123.5, 127.2, 127.8, 128.7, 128.8, 129.0, 129.2, 130.8, 135.2, 157.3, 167.9.
EX-1C) Compound EX-IB (3.19 g, 8.26 mmole) was dissolved in 50 ml THF, 30 ml MeOH and 50 ml 1 M UOH. The mixture was stirred at 20 °C for one hour. The mixture was concentrated to remove the organic solvents. The remaining aqueous solution was acidified to pH = 1 with IM HCI, and a solid precipitated from the solution. The solid was purified by filtration, washing with IM HCI and water, and drying via vacuum to give a white solid as the pure product (3-benzylsulfonylamino-2-oxo-2H-quinolin-l-yl)acetic acid (EX-1C) (2.98 g, yield of 97%). ΗPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @
50 °C): retention time 3.09 min, M+Na+ = 395.2 for formula C18Η16N2O5SNa. lH NMR (400 MHz, CDC13): δ 4.54 (s, 2H), 5.13 (s, 2H), 7.15 (t, J = 87.2 Hz,
1H), 7.23 (m, 3H), 7.33 (m, 3H), 7.50 (t, J = 7.6 Hz, 2H), 7.59 (s, 1H).
EX- ID) Compound EX-1C (0.209 g, 0.56 mmol), EDC (0.140 g, 0.73 mmol) and HOBt (0.112 g, 0.73 mmol) were mixed in 1.5 ml DMF, and the mixture was stirred at 20 °C for 10 minutes. To this mixture was added the premixed solution of (4S)-(9Cl)-N-[[[4-amino-5-hydroxy-5-(2- thiazolyl)pentyl]amino]iminomethyl]-4-methoxy-23,6-
trimethylbenzenesulfonamide HCI salt (0.387 g, 0.73 mmol), diisopropylethylamine (0.65 ml, 3.93 mmol) in 1.5 ml DMF. The combined reaction mixture was stirred for 45 minutes at 20 °C. The reaction mixture was partitioned between ethylacetate and saturated ammonium chloride aqueous solution. The organic phase was washed with saturated aqueous potassium carbonate and ammonium chloride solution, dried over Na2SO4 After removing the ethylacetate, the residue was subjected to a Biotage silica gel column chromatography to yield a white solid as the product N-[2(S)-l(R,S)-2-[l- hydroxy-l-(2-thiazolyl)]-5-[[(4-methoxy-23,6-trimethyl)sulfonylamino]- iminomethyl]aminopentyl]-[3-benzylsulfonylamino-2-oxo-2H-quinolin-l- yOacetamide (EX- ID) (0.347 g, y = 76%). ΗPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 °C): retention time 3.75 min, M+Η+ = 810.3 for formula C37H43N7OgS3. Since the compound is a mixture of two diastereomers,
1 13 the H NMR and C NMR was complex. EX- IE) Compound EX- ID (0.32 g, 0.395 mmol) was mixed with 1,3- dihydro-l-hydroxy-33-bis(trifluoromethyl)-l-oxide-l,2-benziodoxole (0.238 g, 0.593 mmole) in 5 ml acetonitrile. The mixture was stirred at 20 °C for 2 hours. It was then mixed with 30 ml IM NaHSO3 aqueous solution. The combined solution was extracted with ethylacetate, and the organic phase was washed with saturated NaHCO3 aqueous solution and dried over Na>SO4. After removing the ethylacetate, the remaining residue was subjected to a silica gel flash column chromatography using 30% ethylacetate in hexane as elute to yield a white solid as the product N-[[2(S)- 2-[l-Oxo-l-(2-thiazolyl)]-5-[[[(4-methoxy-23,6- trimethyl)sulfonylanτino]inιinomethyl]amino]pentyl]-(3-benzylsulfonylamino-2- oxo-2H-quinolin-l-yl)acetamide (EX- IE) (0.296 g, 93%). ΗPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 °C): retention time 4.07 min,
M+Η+ = 808.2 for formula C37H41 N7OgS3 l H NMR (400 MHz, acetone-dg): δ
1.71 (b, 4H), 2.07 (s, 3H), 2.59 (s, 3H), 2.64 (s, 3H), 3.24 (m, 2H), 3.80 (s, 3H), 4.62 (s, 2H), 5.17 (d, J = -16.4 Hz, IH), 5.22(d, J = 16.4Hz, IH), 5.62 (m, IH), 6.47 (b, 2H), 6.64(s, IH), 7.24 (m, 4H), 7.36 (m, 3H), 7.44 (m, 2H),
7.59 (t, J = 7.2 Hz, 2H), 7.95 (b, IH), 8.08 (m, 3H). 13C NMR (101 MHz,
CDC13): δ 12.0, 15.6, 18.6, 24.2, 41.1, 46.6, 55.8, 55.9, 58.5, 66.1, 1 12.3, 120.3, 121.2, 123.8, 124.8, 128.5, 129.1 , 129.2, 129.3, 129.6, 129.7, 129.9,
123.0, 131.9, 135.8, 136.7, 137.0, 139.0, 146.1, 157.4, 158.0, 158.8, 165.6, 167.7, 192.0.
Compound EX- IE (0.240 g, 0.296 mmol) was treated with thioanisole (0.220 g, 1.78 mmol) and 8 ml trifluoroacetic acid for 5 hours. After removing the TFA, the residue was triturated in diethylether twice and ethylacetate once to give a white amorphous solid as the product N-[[2(S)- 2-[l-Oxo-l-(2-thiazolyl)]-5- [(amino)iminomethyl)amino] pentyl]-(3-benzylsulfonylamino-2-oxo-2H-quinolin- l-yl)acetamide trifluoroacetic acid salt (0.183 g, yield of 87%). ΗPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 °C): retention time 3.07 min,
M+Η+ = 596.2 for formula C27H29N7O5S2. H NMR (400 MHz, DMSO-d6): 6
1.58 (bm, 2H), 1.67 (bm, IH), 1.90 (b, IH), 3.10 (bm, 2H), 4.60 (s, 2H), 3.80 (s, 3H), 4.62 (s, 2H), 5.01 (d, J = -17.2 Hz, IH), 5.11 (d, J = -17.2 Hz, IH), 5.38 (m, IH), 6.80-7.70 (m, 15H), 8.14(s, IH), 8.23 (s, IH), 8.88 (b, IH),
9.99 (d, J = 8.0 Hz, IH). 13C NMR (101 MHz, DMSO-d6): δ 25.3, 28.0, 44.9,
48.6, 54.4, 58.0, 114.2, 119.7, 121.9, 124.8, 126.1, 128.2, 128.3, 128.7, 131.0, 135.9, 137.1, 138.7, 144.7, 145.4, 156.6, 157.4, 164.4, 166.8, 191.4.
Example 2
M+Η+ = 638.3 for formula C34H3 ,N5O6S. LH NMR (400 MHz, CDC13): δ 4.38
(s, 2H), 4.50 (d, J = 6.0 Hz, 2H), 4.92 (s, 2H), 5.14 (s, 2H), 7.06 (t, J = 7.2 Hz, IH), 7.13 (t, J = 7.6 Hz, 2H), 7.15-7.24 (m, 6H), 7.30-7.40 (m, 6H), 7.45 (m, 3H), 7.52 (m, IH), 7.57 (d, J = 8.4 Hz, 2H), 8.65(b, IH), 9.09 (b, IH).
Compound EX-2 (0.118 g, 0.185 mmol), -toluenesulfonic acid mono hydrate (0.035 g, 0.185 mmol) and 10% Pd on activated carbon (0.029 g, 0.018 mmol) were mixed with 5 ml methanol. The mixture was stirred for 2 hours under an atmosphere of hydrogen that was introduced through a rubber balloon. After filtering off the catalyst and removing the methanol, the remaining residue was recrystallized in a solvent of 2: 1 ether to methanol to yield a white amorphous solid as the product, N-[[4-[(amino)iminomethyl]phenyl]methyl]-(3-benzylsulfonyl- amino-2-oxo-2H-quinolin-l-yl)acetamide j-toluenesulfonic acid salt, (0.080 g, yield = 64%). ΗPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @
50 °C): retention time 2.81 min, M+Η+ = 504.5 for formula C26H25N5O4S. l NMR (400 MHz, CD3OD): δ 2.36 (s, 3H), 4.52 (s, 2H), 4.57 (s, 2H), 5.15 (s, 2H), 7.18-7.32 (m, 7H), 7.36 (t, J = 7.2 Hz, 2H), 7.48-7.55 (m, 4H), 7.59 (s, IH), 7.70 (d, J = 8.0 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H).
Example 3
EX-3A) Methyl 2-[3-amino-2-oxo-2H-quinolin-l-yl]acetate, (9.1 g, 39.2 mmol) was mixed with Boc anhydride (9.41 g, 43.1 mmol), triethylamine (6 ml, 43.1 mmol) and DMAP (50 mg, 0.4 mmol) in 200 ml DCM. The reaction mixture was stiπed at 20 °C for 14 hours. The reaction solution was washed with IM citric acid solution twice, saturated sodium bicarbonate solution three times, saturated ammonium chloride once and it was dried over anhydrous MgSO4. After filtration and removing the solvent, the residue was treated with methanol. A white solid was precipitated. Filtration and washing with methanol, the pure product , EX- 3 , was obtained as a white powder (9.90 g, 87%). HPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 °C): retention time 2.85 min, M+H+ =
291.1 for formula C14H13N2O3. *H NMR (400 MHz, Methanol-d4): d 3.76 (s, 3H), 3.82 (s, 3H), 5.15 (s, 2H), 7.09 (d, J = 8.4 Hz, IH), 7.26 (t, J = 7.6 Hz, IH), 7.43 (t, J = 7.6 Hz, 2H), 7.61 (d, J = 7.6 Hz, IH), 7.96 (s, IH), 8.39 (s, IH). 13C NMR (101 MHz, Methanol-d4): d (ppm) 44.4, 52.5, 52.6, 113.1, 118.9, 121.0, 123.3, 127.4, 128.4, 128.5, 134.5, 153.9, 157.6, 168.1.
EX-3B) Compound EX-3A (1.09 g, 3.75 mmol) was mixed with KOH (5.2 g, 92.8 mmol) in 30 ml water and 30 ml methanol. After refluxing for three hours, the reaction solution was concentrated to 10 ml and acidified with concentrated HCI to pH = 2. After cooling down to 0 °C, the product was filtered out, washed with water and dried via vacuum. A yellow powder acid was obtained as the pure product (0.733 g, y = 90%). HPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 °C): retention time 1.60 min, M+H+ = 219.1 for formula C u H π N2Q3.
EX-3C) Compound EX-3B (0.296 g, 1.16 mmol) was treated with phenylacetaldehyde (0.21 g, 1.74 mmol) in 15 ml methanol for 10 minutes. To this mixture was added sodium cyanoborohydride (0.08 g, 1.28 mmol). After two hours, the reaction was completed. Methanol was removed under reduced pressure and the residue was mixed with water. The product 2-[3-(2-phenylethylamino)-2- oxo-2H-quinolin-l-yl]acetic acid (EX-3C) was obtained after filtration and washed with water as a white powder (0.225 g, 60%). HPLC-MS (0 to 95%
AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 °C): retention time 3.55 min,
M+H+ = 323.2 for formula C19H,9N2O3. lH NMR (400 MHz, Methanol-d4): d 2.97 (t, J = 7.2 Hz, 2H), 3.45 (t, J = 7.2 Hz, 2H), 5.02 (s, 2H), 6.65 (s, IH), 7.13-7.29 (m, 8H), 7.46 (d, J = 8.0 Hz, IH). 13C NMR (101 MHz, Methanol- d4): d (ppm) 35.9, 45.5, 46.6, 105.7, 115.1, 123.9, 124.5, 125.9, 127.0, 127.4, 129.6, 129.8, 133.9, 137.8, 140.8, 159.9, 173.1.
EX-3D) Compound EX-3D was synthesized in same way as described for compound EX-2A. It is a white powder. HPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 °C): retention time 3.65 min, M+H+ = 588.6 for formula C35H34N5O4. l H NMR (400 MHz, Methanol-d4): d 2.95 (t, J = 7.2 Hz,
2H), 3.43 (t, J = 7.2 Hz, 2H), 4.46 (s, 2H), 5.09 (s, 2H), 5.37 (s, 2H), 6.64 (s, IH), 7.13-7.29 (m, 9H), 7.38-7.41 (m, 3H), 7.47 (m, 4H), 7.70 (d, J = 8.4 Hz,
2H). l3C NMR (101 MHz, Methanol-d4): d (ppm) 35.8, 43.7, 45.4, 46.9, 70.6,
105.8, 114.9, 124.2, 124.6, 126.0, 127.2, 127.4, 129.1, 129.6, 129.7, 129.8,
129.9, 130.0, 133.8, 137.8, 140.7, 160.2, 170.3.
The product of Example 3 was synthesized in same way as described for compound of Example 2 as a /?-toluenesulfonic acid salt and an amorphous solid. HPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 °C): retention time 3.18 min, M+H+ = 454.1 for formula C27H28N5O2. *H NMR (400 MHz, Methanol-d4): d 2.32 (s, 3H), 3.03 (t, J = 7.2 Hz, 2H), 3.56 (t, J = 7.2 Hz,
2H), 4.48 (s, 2H), 5.14 (s, 2H), 7.19 (d, J = 8.0 Hz, 4H), 7.26-7.34 (m, 6H), 7.48 (d, J = 8.0 Hz, 2H), 7.55 (s, IH), 7.64 (d, J = 7.6 Hz, IH), 7.69 (t, J = 8 Hz, 4H), 8.72 (s, 2H), 9.18 (s, 2H). 13C NMR (101 MHz, Methanol-d4): d
(ppm) 21.3, 34.3, 43.7, 46.8, 59.6, 115.4, 122.0, 124.6, 126.9, 127.8, 128.2, 128.3, 129.0, 129.2, 129.5, 129.7, 129.8, 129.9, 130.3, 131.4, 137.4, 138.9, 141.8, 146.7, 159.5, 168.2, 168.3, 169.7.
Example 4
EX-4A) 2-[3-Amino-2-oxo-2H-quinolin-l-yl]acetic acid, (0.206 g, 0.81 mmol) was treated with benzenesulfonyl chloride (0.172 g, 0.97 mmol) in pyridine for one hour. After removing the pyridine, the residue was recrystallized in acetone to yield a white crystal solid as the product, 2-[3-benzenesulfonylamino-2- oxo-2H-quinolin-l-yl]acetic acid, (EX-4A)(0.117 g, y = 41% ). HPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 °C): retention time 2.85 min,
M+H+ = 359.2 for formula C17H ^N^S. 1H NMR (400 MHz, Acetone-d6): d
5.12 (s, 2H), 7.28 (t, J = 7.2 Hz, IH), 7.36 (d, J = 8.8 Hz, IH), 7.48-7.63 (m, 4H), 7.75 (dd, J = 8, 1.6 Hz, IH), 7.74 (s, IH), 8.00-8.03 (m, 2H). °C NMR
(101 MHz, Acetone-d6): d (ppm) 44.8, 115.0, 120.8, 120.9, 123.9, 127.8, 128.1, 129.4, 129.9, 130.1, 134.2, 136.7, 140.4, 158.2, 169.1.
EX-4B) Compound EX-4A was synthesized in same way as described for compound EX- 2 A giving a white powder. HPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 °C): retention time 3.23 min, M+H+ = 624.2 for formula C33H30N5O6S. Η NMR (400 MHz, Methanol-d4): d 4.45 (s, 2H), 5.06 (s, 2H), 5.38 (s, 2H), 7.24-7.60 (m, 14H), 7.71 (d, J = 8.0 Hz, 2H), 7.84 (s, IH), 7.94 (d, J = 7.2 Hz, 2H). °C NMR (101 MHz, Methanol-d4): d (ppm) 43.7, 47.0, 70.7, 115.3, 121.7, 122.5, 124.5, 127.3, 128.4, 129.1, 129.6, 129.7, 129.9, 130.0, 130.1, 130.2, 130.3, 134.4, 135.8, 137.2, 140.8, 147.7, 154.6, 159.3, 167.9, 169.8. Compound of this example was synthesized in same way as described for compound Example 2. It is an amorphous off-white solid and ap- toluenesulfonic acid salt. HPLC-MS (5 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 °C): retention time 2.02 min, M+H+ = 490.1 for formula
C25H24N5O4S. H NMR (400 MHz, Methanol-d4): d 2.34 (s, 3H), 4.46 (s, 2H), 5.06 (s, 2H), 7.20 (d, J = 8.0 Hz, IH), 7.24-7.29 (m, 2H), 7.46-7.51 (m, 6H), 7.55 (d, J = 7.2 Hz, IH), 7.62 (d, J = 8.0 Hz, IH), 7.71 (m, 4H), 7.86 (s, IH),
7.95 (d, J = 8.0 Hz, 2H). 13C NMR (101 MHz, Methanol-d4): d (ppm) 213,
43.6, 46.9, 115.1, 121.6, 122.4, 124.4, 126.8, 127.9, 128.2, 128.9, 129.0, 129.5, 129.7, 130.1, 130.2, 134.3, 137.0, 140.6, 146.6, 159.2, 169.5, 184.2.
EX-5 ) A solution of 2-amino pyridine (20.42 g, 217.0 mmol) in dichloromethane 500 mL was cooled to 0°C and treated with triethyl amine (36.29 mL, 260.4 mmol) and pivaloyl chloride (28.06 mL, 227.8 mmol). After 15
minutes, the reaction mixture was allowed to warm to room temperature and stir overnight. The reaction mixture was poured onto ice, and the organic layer was washed with saturated NaHCO3 (aq), and dried over Na2SO4. The volatile components were removed, and a brown oil was isolated. Crystallization with hexanes afforded 31 g of N-(pyrid-2-yl)-2,2-dimethylacetamide (EX-5 A)as white crystals in 80% yield. Reference: Turner, J. A. J. Org. Chem. 1983, 48, 3401. EX-SB) A solution of EX-5 A (2.00 g, 11.23 mmol) in THF (115 mL) at -78 C was treated with n-BuLi ( 14.1 mL, 28.10 mmol of a 2.0 M solution in hexanes). The reaction mixture was allowed to warm to 0 C and stir for 2h. The reaction mixture was again cooled to -78 C, and the mixture was quenched with DMF (2.18 mL, 28.10 mmol). The reaction mixture was allowed to warm to room temperature and to stir overnight. The reaction mixture was poured into a slurry of ice and 6N HCI, and the acidified mixture was stirred for 15 minutes. The organic layer was separated (discard), and the aqueous layer was neutralized with K^CC^ and extracted with ether (3 x 100 mL). The combined organic layers were washed with water, brine and dried over MgSO4. After filtration and evaporation of the volatiles, a yellow oil was isolated which solidified upon standing. 1.23 g (53%) of EX- 5B product was isolated. Reference: Turner, J. A. J. Org. Chem. 1990, 55, 4744. EX-5C) A mixture ofEX-5B (0.62 g, 3.01 mmol) and 3N HCI (30 mL) was refluxed overnight. After the reaction mixture was allowed to cool to room temperature, it was washed with ether (2 x 50 mL). The organic layer was discarded. The aqueous layer was neutralized with K2COj, and extracted with ether (4 x 50 mL). The combined ether layers were dried over K2COj, filtered, and concentrated to afford 2-aminopyridinecarboxaldehyde (EX-5C) as a yellow oil (036 g) which solidified upon standing. The crude material was used with any further purification. Reference: Moormann, A. E.; Yen, C. H.; Yu, S. Syn. Commun. 1987, 17, 1695.
EX-5D) A mixture of hippuric acid (0.54 g, 3.01 mmol) and acetic anhydride (30 mL) was heated to 80 °C. After 2h, the reaction mixture was homogeneous. The hot reaction mixture was treated with a solution of EX-5 C (037 g, 3.01 mmol) in acetic anhydride. After stirring the reaction mixture for an
additional 16 h, the reaction mixture became heterogeneous. The volatile components were removed in vacuo, and the precipitate was filtered. The filter cake was washed with ether (3 x 30 mL), and 0.36 g of 3-benzamido-2-oxo-2H-
1,8-naphthyridine (EX-5D) was isolated as tan colored powder in 45% yield: H NMR (300 MHz, tf-DMSO) d 12.77 (s, IH), 9.47 (s, IH), 8.72 (s, IH), 8.45 (d, J = 3.42 Hz, IH), 8.21-8.18 (m, IH), 7.95 (d, J = 7.6 Hz, 2H), 7.66-7.54 (m,
3H), 7.28 (dd, /j = 4.6 Hz, J2 = 4.8 Hz, IH); 13C NMR (75 MHz, CDC13) d
165.8, 159.4, 149.2, 146.6, 136.6, 134.3, 133.0, 130.3, 129.61 (2C), 129.58,
127.9, 120.2, 119.8, 115.7; HRMS (El) calcd for C^ jN^ 266.0930, found 266.0939.
EX-5E) A solution of EX-5D (0.072 g, 0.271 mmol) in DMF (5 mL) was cooled to 0 C, and NaH (60% dispersion in mineral oil, 0.013 g, 0.325 mmol) was slowly added. After five minutes, methyl bromoacetate was added dropwise via syringe. The reaction mixture was allowed to warm to room temperature, and it was stirred until no starting material remained by TLC. DMF was removed in vacuo which afforded a yellow residue. The residue was triturated in water and washed with water and hexanes to afford 0.062g of methyl 2-[3- benzamido-2-oxo-2H-l,8-naphthyridin-l-yl]acetate (EX-5E) in 68% yield: H
NMR (400 MHz, CDC13) d 9.30 (s, IH), 8.88 (s, IH), 8.45 (d, J= 4.6 Hz, IH), 7.95-7.91 (m, 3H), 7.56-7.46 (m, 3H), 7.23-7.20 (m, IH), 5.37 (s, 2H), 3.74 (s, 3H); 13C NMR (100 MHz, CDCl3) d 168.8, 166.1, 159.0, 148.0, 145.5, 136.5, 134.0, 132.6, 129.12, 129.11, 129.08, 128.8, 127.4, 119.8, 119.0, 116.7, 52.7, 43.2; HRMS (El) calcd for C18H15N3O4 338.1156, found 338.1141. EX-5F) A solution of EX-5E (0.053 g, 0.157 mmol) in THF and methanol (3:2, 5mL) was treated with 1.0 M LiOH (aq). The reaction mixture was stirred over night. The mixture was concentrated to remove the volatile components. The resulting aqueous solution was acidified with IN HCI, and a solid precipitated from the solution. After filtration, the filter cake was washed with IN HCI and water to afford 0.038 g of 2-[3-benzamido-2-oxo-2H-l,8- naphthyridin-l-yl]acetcc acid (EX- 5 F) as white solid in 74% yield: H NMR (400 MHz, -DMSO) d 13.10 (br s, 1H), 9.53 (s, lH), 8.78 (s, IH), 8.51-8.50
(m, IH), 8.26 (d, J= 7.8 Hz, IH), 7.93 (d, 7= 8.1 Hz, 2H), 7.62-7.51 (m, 3H),
7.36-7.32 (m, IH), 5.14 (s, 2H); 13C NMR (100 MHz, ci-DMSO) d 169.9,
166.0, 158.7, 148.8, 145.9, 137.5, 134.2, 133.0, 129.5 (2C), 128.8, 128.0
(2C), 120.4, 120.2, 116.2, 43.5; HRMS (El) calcd for C17H13N3O4324.1004, found 324.098.
EX-5G) A solution of EX-5F (0.099g, 0.30 mmol) in 3 mL of DMF was treated with N-hydroxybenzotriazole (0.054 g, 0.40 mmol), and l-[3- (dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.076 g, 0.40 mmol), and N,N-diisopropylethylamine (0.37 mL, 2,14 mmol). The resulting mixture was allowed to stir for 15 minutes at room temperature. The reaction mixture was then treated with 4-(N-Cbz-amidino)benzylamine (0.127 g, 0.40 mmol) as a solution in DMF (3 mL). The resulting reaction mixture was allowed to stir for 18 hours. The reaction mixture was partitioned between ethyl acetate and a saturated
NH4Cl(aq) solution. The separated organic layer was washed with saturated 2CQ (aq), saturated NH4C1 (aq), and brine. The organic solution was dried
(Na2SO4), filtered and concentrated. (EX-5G) was isolated as a white solid, and the crude product was used in the next step without further purification: HRMS (EL) calcd for C33H28N6O5 589.2178, found 589.2199.
A solution of Cbz-amidine (EX-5G) (0.090 g, 0.15 mmol) in 6 mL of methanol, and 1 mL of 4 N HCI in dioxane was treated with 25 mg of 10% Pd/C in one portion. The resulting reactin mixture was stirred under hydrogen gas (25 psi) for 18 hours. After filtration of the reaction mixture through a pad of Celite, the solvent was removed under reduced pressure. Slow addition of 1 M HCI precipitated pure product of the invention as a white solid: H NMR (400 MHz, d- DMSO) d 9.52 (s, IH), 9.24 (s, 2H), 8.91-8.83 (m, 2H), 8.77 (s, IH), 8.53- 8.52 (m, IH), 8.27 (d, 7 = 7.5 Hz, IH), 7.93 (d, J= 7.5 Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H), 7.63-7.61 (m, IH), 7.56-7.52 (m, 2H), 7.43 (d, J= 8.1 Hz, 2H), 7.37-7.34 (m, IH), 5.17 (s, 2H), 4.35 (d, J = 5.9 Hz, 2H); 13C NMR (100 MHz, d-OMSO) d 167.7, 166.0, 165.9, 159.0, 148.6, 146.4, 146.2, 137.4, 134.2, 133.1, 129.6, 128.9, 128.8, 127.93 (2C), 127.88 (2C), 127.0, 120.21, 120.16,
116.5, 72.9, 60.9, 44.8, 42.4; HRMS (El) calcd for C25H22N6O3 455.1832, found 455.1840.
Additional substituted N-[Substituted]-(3-benzylsulfonylamino-2-oxo-2H- quinolin-l-yl)acetamides can be prepared by one skilled in the art using methods similar to those above. These acetamides as shown in Example Table 1.
Example Tabl e 1 . N-[Substituted]-(3-benzylsulfonylamino-2-oxo-2H- quinolin- 1 -yl )acetamides .
Figure 2. General Structure of Pyridone Analogues
The general synthetic route is illustrated in Scheme 3 wherein substituents are as defined herein. These compounds are exemplified in Examples 17 through 23.
Scheme 3: General Synthesis of Pyridones
N-[[2(S)- 2-[ 1-hydroxy- l-(2-thiazolyl)]-5-[[[(4-methoxy-23,6- trimethyl)sulfonylamino] iminomethyl]amino]pentyl]-6-(2-phenylethyI)-2-o o-3- [[(phenylmethyl) sulfonyl]amino]- l(2H)-pyridineacetamide (0.084 g, 0.098 mmol) was treated with 13-dihydro-l-hydroxy-33-bis(trifluoromethyl)-l-oxide-l,2- benziodoxole (0.0588 g, 0.147 mmole) in 1 ml acetonitrile. Similar work-up procedure as in preparing EX- IE was used to yield the oxidation product. The oxidation product was treated with thioanisole (0.073 g, 0.59 mmol) and 3 ml trifluoroacetic acid for 6 hours. After removing the TFA, the residue was triturated in ether. It was purified by a preparative C-18 reverse HPLC column using a gradient that proceed from 5% to 95% acetonitrile in H-O in the presence of 0.1% TFA in 30 minutes to yield the product, N-[[2(S)- 2-[l-Otσ-l-(2-thiazolyl)]-5- [[[(amino)iminomethyl]amino] ρentyl]-6-(2-phenylethyl)-2-αtø-3- [[(phenylmethyl)sulfonyl]amino]- l(2H)-pyridineacetamide trifluoroacetic acid salt, as a white amorphous solid (0.0232 g, y = 31 %). ΗPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 °C): retention time 3.43 min, M+Η+ = 650.2 for formula C3 jH35N7O5S2.
Example 18
This compound, N-[[2(S)- 2-[l-Oxσ-l-(2-thiazolyI)]-5- [(amino)iminomethyl)-amino] pentyl ]-6-methyl-2-αrø-3-
[[(phenylmethyl)sulfonyl]amino]-l(2H)-pyridineacetamide trifluoroacetic acid salt, was prepared in a similar fashion as for Example 1. ΗPLC-MS (0 to 95% AcCN
/ 6 min @ 1.0 mL / Min @ 254 nm @ 50 °C): retention time 2.69 min, M+H+ = 560.3 for formula C24H29N7O5S2.
Example 19
The compound, N-[[4-(amino)iminomethyl]phenyl]methyl]- 6-(2- phenylethyl)-2-oxo-3-[[(phenylmethyl)sulfonyl]an ino]-l(2H)-pyridineacetamide -toluenesulfonic acid salt, was synthesized in a similar fashion as for Example 2 using 6-(2-phenylethyl)-2-σxσ-3-[[(phenylmethyl) sulfonyl]amino]- 1 (2H)- pyridineacetic acid as starting material. ΗPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 °C): retention time 3.23 min, M+Η+ = 558.5 for formula C30H31N5O4S. *H NMR (400 MHz, CD3OD): δ 2.36 (s, 3H), 2.92
(bm, 4H), 4.43 (s, 2H), 4.54 (s, 2H), 4.87 9s, 2H), 6.10 (d, J = 8.0 Hz, IH), 7.21 (m, 5H), 7.26-7.31 (m, 8H), 7.55 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 8.0 Hz, 2H).
Example 20
This compound, N-[[4[-(amino)iminomethyl]phenyl]methyl]- 6-methyl-2- σxo-3-[[(phenylmethyl)sulfonyl]amino]-l(2H)-pyridineacetamide J- toluenesulfonic acid salt, was synthesized in a similar fashion as for Example 2 using 6-methyl-2-σxø-3-[[(phenylmethyl)sulfonyl] amino]- l(2H)-pyridineacetic acid as starting material. ΗPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 °C): retention time 2.41 min, M+Η+ = 468.1 for formula
C23H25N5O4S. H NMR (400 MHz, CD3OD): δ 2.34 (s, 3H), 2.36 (s, 3H), 4.43 (s, 2H), 4.53 (s, 2H), 4.87 (s, 2H), 6.15 (d, J = 7.6 Hz, IH), 7.21-7.31
(m, 8H), 7.56 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.0 Hz, 2H), 7.72 (d, J = 8.0 Hz, 2H), 8.70 (b, IH), 9.19 (b, IH).
Example 21
This compound was synthesized in a similar fashion as for Example 2 using 6-(2-phenylethyl)-2-σxø-3-[[(phenylmethyl)sulfonyl] amino]- l(2H)- pyridineacetic acid as starting material and coupling it with 4-[l-(N,N-bis-Boc- amidino)piperidinyl]methylamine The coupling product was treated with 4N HCI in dioxane to generate the product. The compounds were purified by reverse phase C-18 HPLC to generate the final pure products. HPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 °C): retention time 3.10 min, M+H+ = 565.6 for formula C29H37N6O4S .
Example 22
This compound was synthesized in a similar fashion as for Example 2 using 6-methyl-2-σxσ-3-[[(phenylmethyl)sulfonyl] amino]- l(2H)-pyridineacetic acid as starting material and coupling it with 4-[l-(N,N-bis-Boc- amidino)piperidinyl]methylamine The coupling product was treated with 4N ΗC1 in dioxane to generate the product. The compounds were purified by reverse phase C-18 ΗPLC to generate the final pure products. ΗPLC-MS (0 to 95% AcCN / 6
min @ 1.0 mL / Min @ 254 nm @ 50 °C): retention time 2.42 min, M+H+ = 475.3 for formula C22H31N6O4S .
One subclass of pyridone analogs have a heteroaryl group substituting the pyridone ring at the 5 or 6 position. Scheme 4 illustrates a process to prepare heteroaryl substituted pyridones. The preparation procedure is exemplified in Example 23 for the preparation of a 6-substituted pyridyl group although it will be readily recognized that a wide variety of substituted pyridines and other 5 and 6 membered heteroaryl groups can be introduced using the procedure described below.
cheme 4: Preparation of Heteroaryl Pyridones
EX- 23 A) One equivalent of commercially available 4-acetylpyridine is treated with three equivalents N, N-dimethylformamide dimethyl acetal in refluxing acetonitrile for 12 hours. After removing the solvent and excess amount of N, N- dimethylformamide dimethyl acetal, the resulting yellow solid is dissolved in DMF.
To this solution is added one equivalent cyanoacetamide and two equivalents of sodium methoxide. The resulting mixture is heated at 100 °C for 5 hours. After cooling down, the reaction mixture is mixed with water and acidified with HCI to pH 5. The resulting yellow precipitate is filtered, washed with water and dried via vacuum to give the product EX-23A as a yellow solid.
EX-23B) Compound EX-23 is heated to reflux in one portion of 48% aqueous HBr and two portions of acetic acid for 12 hours. After the mixture is cooled down, mixed with water and adjusted the pH to 5, a light yellow precipitate is formed. The light yellow precipitate is filtered and washed with IN HCI and water, dried via vacuum to give the product EX-23B as an off-white solid.
EX-23C) Compound EX-23B is treated with 1.1 equivalent of DPPA, 1 equivalent triethylamine in dioxane at refluxing temperature for two hours. Five equivalents t-butanol is added into the mixture, and the mixture is then refluxed overnight. After removing the solvent, the remaining residue is worked up by standard aqueous work-up procedure. The residue is then purified by silica gel column chromatography to yield Compound EX-23C.
EX-23D) Compound EX-23C is mixed with one equivalent sodium hydride in DMF and one equivalent methyl bromoacetate subsequentiy. After stirring at ambient temperature for 12 hours, the reaction is worked up by standard procedure. The product EX-23D is purified by silica gel column chromatography.
EX-23E) Compound EX-23D is treated with 50% TFA in dichloromethane for 1 hour. After removing the solvent and TFA, the residue is redissolved in THF with one equivalent of triethylamine. To this solution is added one equivalent phenylacetaldehyde and two equivalents sodium triacetoxyborohydride. After stirring for 12 hours, the reaction is quenched with addition of aqueous ammonium chloride. Standard aqueous work-up and silica gel column chromatography yields the desired product EX-23E.
EX-23F) Compound EX-23E is treated with IM LiOH in 1: 1: 1 ratio of THF, methanol and water for half hour. After it is acidified with IN HCI, the organic solvent is removed and a precipitate will form. The precipitate is filtered, washed with water and dried by vacuum to give the desired product EX-23F. Compound EX-23F is treated with one equivalent EDC and HOBt in the presence of three equivalents diisopropylethylamine in DMF for 10 minutes. One equivalent of 4-a inomethylbenzamidine, which is protected with Cbz at the amidine, is then added into the reaction mixture. After stirring at ambient temperature for four hours, the reaction mixture is worked up by standard procedure and the product EX-23G is purified by silica gel column chromatography.
Compound EX-23G is dissolved in methanol in the presence of 5 equivalents of HCI and 5% equivalent of 10% Pd /C. The mixture is stirred under an atmosphere of hydrogen (ambient pressure) for five hours. After filtration and removing the solvent, Compound 23 is obtained as the pure product
In a related procedure, 5-substituted pyridones can be prepared as illustrated in Examples 24 and 25.
Example 24
EX-24A) 3-Nitro-2-hydroxylpyridine (49.5 g, 0.35 mol) and 10% Pd C (4.21 g, 4 mmol) in 500 ml ethanol was stirred under an atmosphere of hydrogen introduced via a balloon for 24 hours. After filtering through a pad of Celite 545 and removing the ethanol, a brown solid was obtained as the pure product, 3- aminopyrid-2-one, (38 g, 97%). HPLC-MS (0 to 30% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 °C): retention time 0.097 min, M+H+ = 111.1 for formula
C5H7N2O.
EX-24B) Compound EX-24A (27.25 g, 0.248 mol) was treated with Boc anhydride (59.47 g, 0.272 mol), triethylamine (52 ml, 0372 mol) and DMAP (1.5 g, 12.4 mmol) in 500 ml DCM for 4 hours. After an aqueous work-up and removing the solvent, the residue was passed through a short silica gel plug using 40% ethylacetate in hexane as eluent to yield the crude product (28 g, 56%0. Pure product, 3-(N-Boc-amino)pyrid-2-one, was obtained by recrystallization in acetone as a needle-like white crystalline solid. HPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 °C): retention time 239 min, M-Boc + H+ = 111.1 for formula C5H7N2O. *H NMR (400 MHz, CDC13): d 1.52 (s, 9H), 6.32 (t, J = 7.2 Hz, IH), 7.00 (dd, J = 6.4, 1.6 Hz, IH), 7.55 (s, IH), 8.10 (d, J = 6.4 Hz, IH), 12.86(b, IH). 13C NMR (101 MHz, CDC13): d 28.2, 80.8, 107.7, 121.8, 125.2, 129.7, 152.7, 158.8.
EX-24C) Compound EX-24B (13.58 g, 64.6 mmol) and N- iodosuccinimide (21.8 g, 97 mmol) in 250 ml dichloromethane was stirred at room temperature for 18 hours. After filtration to remove the by-product succinimide,
the solvent was removed under reduced pressure. The remaining residue was subjected to a silica gel flash chromatography to yield a brown solid as the product, 3-(N-Boc-amino)-5-iodopyrid-2-one, (173g, 80%). HPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 °C): retention time 3.22 min, M + Na+ = 359.0 for formula C10H13IN2O3Na.
EX-24D) Compound EX-24C (9.62 g, 28.6 mmol) was treated with sodium hydride (1.71 g, 42.9 mmol) 60% in mineral oil in 200 ml THF for 10 minutes. To this mixture was added methyl bromoacetate (4.33 ml, 45.8 mmol). The resulting structure was stirred at room temperature for 1 hour. After removing the THF, the residue was washed with hexanes to remove the mineral oil. It was then partitioned between ethylacetate and saturated aqueous ammonium chloride. The organic layer was washed with saturated aqueous ammonium chloride three times and dried over anhydrous MgSO4. After removing the solvent, a yellow amorphous solid was obtained as the product, methyl 2-[3-(N-Boc-amino)-5-iodo- 2-oxopyrid-2-yI]acetate, (11.1 g, 95%).
EX-24E) 3-Pyridyl boronic acid (2.0 g, 4.93 mmol) was suspended in 80 ml toluene and the mixture was degassed by bubbling nitrogen through for 10 minutes. Tetrakis-(triphenyl)phosphine Palladium (0.54 g, 0.46 mmol) was dissolved in a pre-degassed mixture of 20 ml toluene and 50 ml methanol. The catalyst solution was added to the boronic acid solution under nitrogen. To this resulting mixture was added compound EX-24D (3.80 g, 9.31 mmol) in 25 ml methanol followed with 22 ml 2M Na.CO3 solution. The reaction solution was heated to reflux for 2.5 hours. After it was cooled down to room temperature, it was mixed with 10 ml 2.5N NaOH and was stirred for an half hour. After removing all the solvent, the remaining residue was re-dissolved in methanol and the pH of the solution was adjusted to 6 with 1 N HCI. After removing all the solvent, the residue was absorbed on silica gel and subjected to silica gel flash chromatography using 5% methanol in DCM as the eluate. The pure product, methyl 2-[3-(N-Boc-amino)-5-(pyrid-3-yl)-2-oxopyrid-2-yl]acetate (EX-24E), was obtained as a white amorphous solid (1.01 g, 57%). HPLC-MS (5 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 °C): retention time 1.89 min,
M+H+ = 346.0 for formula C17H19N3O5. *H NMR (400 MHz, CDC13): d 1.53 (s, 9H), 4.82 (s, 2H), 7.62 (d, J = 2.4 Hz, IH), 7.87 (t, J = 6.0, IH), 8.36 (s, IH), 8.47 (d, J = 8.4 Hz, IH), 8.68 (d, J = 4.4 Hz, IH), 9.05 (s, IH). l3C NMR (101
MHz, CDCl3): d 28.0, 50.9, 81.6, 113.8, 117.3, 126.5, 128.9, 130.4, 136.4, 139.8, 140.4, 140.6, 152.7, 156.6, 169.0.
Starting with the intermediate EX-24E, the final inhibitor compound is synthesized in a similar fashion as described in other examples by procedures described above.
Example 25
EX-25A) 3-Nitrobenzeneboronic acid (1.41 g, 8.43 mmol) was suspended in 50 ml dioxane and the mixture was degassed with nitrogen. Tetrakis- (triphenyl)phosphine Palladium (0.406 g, 035 mmol) dissolved in 10 ml dioxane was added to the boronic acid solution under nitrogen. To this mixture was added compound EX-24D (2.87 g, 7.03 mmol) and 7 ml 2M potassium phosphate solution. The reaction mixture was heated to reflux for 3 hours. After removing the dioxane, the remaining residue was partitioned between ethylacetate and aqueous saturated ammonium chloride. The organic layer was washed with aqueous saturated ammonium chloride and dried over sodium sulfate. The pure product was isolated by a silica gel column flash chromatography to yield a yellow crystalline solid (1.13 g, 40%). The product, methyl 2-[3-(N-Boc-amino)-5-(3- nitrophenyl)-2-oxopyrid-2-yl]acetate, showed one peak on LC-MS. However, it is
1 13 a mixture of two isomers with a ratio of 2.8 to 1 based on H NMR and C NMR. One isomer has the nitro group at the same side of the Boc amino group, the other in the opposite direction. The NMR data only lists the dominant isomer here.
HPLC-MS (5 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 °C): retention time 3.74 min, M+Na+ = 4263 for formula C19H2ιN3O7Na. 'H NMR
(400 MHz, CDC13): d 1.50 (s, 9H), 3.82 (s, 3H), 4.80 (s, 2H), 7.20 (d, J = 2.4
Hz, IH), 7.56 (t, J = 8.0, IH), 7.66 (s, IH), 7.81 (d, J = 8.0 Hz, IH), 8.15 (d, J = 8.0 Hz, IH), 8.28 (d, J = 2.4 Hz, IH), 8.36 (s, IH).
Starting with the intermediate EX-25A, the final inhibitor compound is synthesized in a similar fashion as described in other examples by procedures described above.
Preparation of sulfonyl analogs of pyridones of the present invention in which a sulfonyl replaces the carbonyl group of the N-1 acetamide side chain can be accomplished by use of the general procedure in Scheme 3. Example 26, a specific example of a sulfonamide of the present invention, is synthesized as according to the general procedure shown in Scheme 5.
(21) Compound EX-26C can be prepared using same methods as described in Example 23 for compounds EX-23A, EX-23B, and EX-23C.
EX-26D) Compound EX-26C is treated with 1.1 equivalent NaH and 1.5 equivalents sodium bromomethanesulfonate in DMF overnight. The reaction is quenched by dilution with water and addition of IN HCI to adjust the reaction solution to a pH of 3 to precipitate the product. The crude product is obtained by filtration and washing with water and ether. The pure product EX-26D is further purified by recrystallization in ethanol.
EX-26E) Compound EX-26D is treated with 50% TFA in dichloromethane for 1 hour. After removing the solvent and TFA, the residue is redissolved in THF/Methanol with one equivalent of triethylamine. To this solution is added one equivalent phenylacetaldehyde and two equivalents sodium triacetoxyborohydride. After stirring for 12 hours, the reaction is quenched with addition of aqueous ammonium chloride. Standard aqueous work-up and silica gel column chromatography yields the desired product EX-26E.
EX-26F) Compound EX-26E is treated with one equivalent PC15 in toluene for an half hour. One equivalent of 4-aminomethylbenzamidine, which is protected with Cbz at the amidine, is then added into the reaction mixture followed with the addition of five equivalents pyridine. The mixture is allowed to be stirred for 12 hours. The reaction mixture is worked up by standard procedure and the product EX-26F is purified by silica gel column chromatography. Compound 26 is prepared from EX-26F using the procedure for compound 23 in Example 23.
Preparation of methylene analogs of pyridones of the present invention in which a methylene replaces the carbonyl group of the N-1 acetamide side chain can be accomplished by using the essential features of the general procedure in
Scheme 3. Example 27, a specific example of an ethyleneamine of the present invention, can be synthesized as shown specifically in Scheme 6.
Scheme 6: Preparation of Ethylene Pyridone Analogs
EX- 27 A) To a ether solution of pyridinylacetate ester with the B-A group added, diisobutylaluminum hydride (5 eq.) is added at -78 °C. After 30 minutes stirring, methanol is added to quench the reaction. The resulting mixture is poured into a saturated aqueous solution of Rochelle salt. The layers are separated, and the aqueous layer is extracted with ethyl ether. The combined extract is dried over MgSO4, and the solvent is evaporated to dryness. The remaining residue is subjected to a silica gel column chromatography to yield the pure product aldehyde (EX-27A).
EX-27B) Compound EX-27 A is mixed with one equivalent of Cbz protected 4-amidinobenzylamine and two equivalents sodium triacetoxyborohydride in THF. The reaction mixture is worked up according to the standard procedure. The product EX-27B is purified by silica gel column chromatography.
Compound EX-27B is first treated with 4N HCI in dioxane for 4 hours. After removing the dioxane, the residue is re-dissolved in methanol in the presence of 5 equivalents of HCI and 5% equivalent of 10 % Pd /C. The mixture is stirred under an atmosphere of hydrogen (ambient pressure) for five hours. After filtration and removing the solvent, the compound is obtained as the pure product.
Another subclass of pyridone analogs have the general structure as shown in Figure 3. Substituents are defined as disclosed herein. Z can be heteroatoms such as S, O, N, and others. The synthesis of this subclass of pyridone analogs is exemplified as in the synthesis of Example 28 as summarized in Scheme 7.
Figure 3
Scheme 7. Preparation of Z°-Q Analogs of Pyridones
EX- 28 ) Commercially available compound 2-amino-3-nitro-6- chloropyridine is reacted with one equivalent of phenylthiol in the presence of sodium carbonate in DMF at 80 °C. After the completion of the reaction, the reaction mixture is mixed with water. Filtration yields the crude product EX- 28 A that can be purified by recrystallization in methanol.
EX-28B) Compound EX-28A is dissolved in 12N r SO4 and the solution is treated with aqueous solution of NaNO, (3 eq.) firstly at 0 °C, then at 100 °C. Dilution with water precipitates the product. Filtration and washing with water and ether yields the crude product EX-23B that can be further purified by recrystallization in ethanol.
EX-28C) Compound EX-28B is mixed with one equivalent sodium hydride in DMF and one equivalent methyl bromoacetate subsequendy. After stirring at ambient temperature for 12 hours, the reaction is worked up by standard procedure. The product EX-28C is purified by silica gel column chromatography.
EX-28D) Compound EX-28C is dissolved in methanol in the presence of 5% equivalent of 10% Pd /C. The mixture is stirred under an atmosphere of hydrogen (ambient pressure) for an half hour. After filtration and removing the solvent, Compound EX-28D is obtained as the pure product
Example compound 8 can be prepared from EX-28D in a similar fashion as described in the preparation of compounds EX-23E, EX-23F, EX- 23G and 23.
Formula (I) compounds of this invention possessing hydroxyl, thiol, and amine functional groups can be converted to a wide variety derivatives. Alternatively, derivatized Formula (I) compounds can be obtained by first derivatizing one or more intermediates in the processes of preparation before
further transforming the derivatized intermediate to comounds of Formula (I). A hydroxyl group in the form of an alcohol or phenol can be readily converted to esters of carboxylic, sulfonic, carbamic, phosphonic, and phosphoric acids. Acylation to form a carboxylic acid ester is readily effected using a suitable acylating reagent such as an aliphatic acid anhydride or acid chloride. The corresponding aryl and heteroaryl acid anhydrides and acid chlorides can also be used. Such reactions are generally carried out using an amine catalyst such as pyridine in an inert solvent. SimUarly, carbamic acid esters (urethanes) can be obtained by reacting a hydroxyl group with isocyanates and carbamoyl chlorides. Sulfonate, phosphonate, and phosphate esters can be prepared using the corresponding acid chloride and similar reagents. Compounds of Formula (I) that have at least one thiol group present can be converted to the corresponding thioesters derivatives analogous to those of alcohols and phenols using the same reagents and comparable reaction conditions. Compounds of Formula (I) that have at least one primary or secondary amine group present can be converted to the corresponding amide derivatives. Amides of carboxylic acids can be prepared using the appropriate acid chloride or anhydrides with reaction conditions analogous to those used with alcohols and phenols. Ureas of the corresponding primary or secondary amine can be prepared using isocyanates direcdy and carbamoyl chlorides in the presence of an acid scavenger such as triethylamine or pyridine. Sulfonamides can be prepared from the corresponding sulfonyl chloride in the presence of aqueous sodium hydroxide or a tertiary amine. Suitable procedures and methods for preparing these derivatives can be found in House's Modern Synthetic Reactions, W. A. Benjamin, Inc., Shriner, Fuson, and Curtin in The Systematic Identification of Organic Compounds, 5th Edition, John Wiley & Sons, and Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, John Wiley & Sons. Reagents of a wide variety that can be used to derivatize hydroxyl, thiol, and amines of compounds of Formula (I) are available from commercial sources or the references cited above, which are incorporated herein by reference. Formula (I) compounds of this invention possessing hydroxyl, thiol, and amine functional groups can be alkylated to a wide variety of derivatives. Alternatively, alkylated Formula (I) compounds can be obtained by first alkylating one or more intermediates in the processes of preparation before further transforming the alkylated intermediate to comounds of Formula (I). A hydroxyl group of compounds of Formula (I) can be readily converted to ethers. Alkylation
to form an ether is readily effected using a suitable alkylating reagent such as an alkyl bromide, alkyl iodide or alkyl sulfonate. The corresponding aralkyl, heteroaralkyl, alkoxyalkyl, aralkyloxyalkyl, and heteroaralkyloxyalkyl bromides, iodides, and sulfonates can also be used. Such reactions are generally carried out using an alkoxide forming reagent such as sodium hydride, potassium t-butoxide, sodium amide, lithium amide, and n-butyl lithium using an inert polar solvent such as DMF, DMSO, THF, and similar, comparable solvents, amine catalyst such as pyridine in an inert solvent. Compounds of Formula (I) that have at least one thiol group present can be converted to the corresponding thioether derivatives analogous to those of alcohols and phenols using the same reagents and comparable reaction conditions. Compounds of Formula (I) that have at least one primary, secondary or tertiary amine group present can be converted to the corresponding secondary, tertiary or quaternary ammonium derivative. Quaternary ammonium derivatives can be prepared using the appropriate bromides, iodides, and sulfonates analogous to those used with alcohols and phenols. Conditions involve reaction of the amine by warming it with the alkylating reagent with a stoichiometric amount of the amine (i.e., one equivalent with a tertiary amine, two with a secondary, and three with a primary). With primary and secondary amines, two and one equivalents, respectively, of an acid scavenger are used concurrently. Secondary or tertiary amines can be prepared from the corresponding primary or secondary amine. A primary amine can be dialkylated by reductive amination using an aldehyde, such as formaldehyde, and sodium cyanoborohydride in the presence of glacial acetic acid. A primary amine can be monoalkylated by first mono- protecting the amine with a ready cleaved protecting group, such as trifluoroacetyl. An alkylating agent, such as dimethylsulfate, in the presence of a non-nucleophilic base, such as Barton's base (2-tert-butyl-l,133-tetramethylguanidine), gives the monomethylated protected amine. Removal of the protecting group using aqueous potassium hydroxide gives the desired monoalkylated amine. Additional suitable procedures and methods for preparing these derivatives can be found in House's Modern Synthetic Reactions, W. A. Benjamin, Inc., Shriner, Fuson, and Curtin in The Systematic Identification of Organic Compounds, 5th Edition, John Wiley & Sons, and Fieser and Fieser in Reagents for Organic Synthesis published by John Wiley & Sons. Perfluoroalkyl derivatives can be prepared as described by DesMarteau in J. Chem. Soc. Chem. Commun. 2241 (1998). Reagents of a wide variety that can be used to derivatize hydroxyl, thiol, and amines of compounds of
Formula (I) are available from commercial sources or the references cited above, which are incorporated herein by reference.
Assays for Biological Activity TF-VIIa Assay
In this assay 100 nM recombinant soluble tissue factor and 2nM recombinant human factor Vila are added to a 96-well assay plate containing 0.4 mM of the substrate, N-Methylsulfonyl-D-phe-gly-arg-p-nitroaniline and either inhibitor or buffer (5 mM CaCl2,50 mM Tris-HCl, pH 8.0, 100 mM NaCI, 0.1% BSA). The reaction, in a final volume of 100 ul is measured immediately at 405 nm to determine background absorbance. The plate is incubated at room temperature for 60 min, at which time the rate of hydrolysis of the substrate is measured by monitoring the reaction at 405 nm for the release of p-nitroaniline. Percent inhibition of TF-VIIa activity is calculated from OD^.,. value from the experimental and control sample.
Xa Assay
0.3 nM human factor Xa and 0.15 mM N-α-Benzyloxycarbonyl-D-arginyl-
L-glycyl-L-arginine-p-nitroaniline-dihydrochloride (S-2765) are added to a 96-well assay plate containing either inhibitor or buffer (50 mM Tris-HCl, pH 8.0, 100 mM NaCI, 0.1% BSA). The reaction, in a final volume of 100 ul is measured immediately at 405 nm to determine background absorbance. The plate is incubated at room temperature for 60 min, at which time the rate of hydrolysis of the substrate is measured by monitoring the reaction at 405 nm for the release of p- nitroaniline. Percent inhibition of Xa activity is calculated from OD^,,., value from the experimental and control sample.
Thrombin Assay 0.28 nM human thrombin and 0.06 mM H-D-Phenylalanyl-L-pipecolyl-L- arginine-p-nitroaniline dihydrochloride are added to a 96-well assay plate containing either inhibitor or buffer (50 mM Tris-HCl, pH 8.0, 100 mM NaCI, 0.1% BSA). The reaction, in a final volume of 100 ul is measured immediately at 405 nm to determine background absorbance. The plate is incubated at room temperature for 60 min, at which time the rate of hydrolysis of the substrate is measured by monitoring the reaction at 405 nm for the release of p-nitroaniline. Percent inhibition of thrombin activity is calculated from GD40Sam value from the experimental and control sample.
Trypsin Assay
5 ug/ml trypsin, type IX from porcine pancreas and 0.375 mM N-α-
Benzoyl-L-arginine-p-nitroanilide (L-BAPNA) are added to a 96-well assay plate containing either inhibitor or buffer (50 mM Tris-HCl, pH 8.0, 100 mM NaCI, 0.1% BSA). The reactions, in a final volume of 100 ul are measured immediately at 405 nm to determine background absorbance. The plate is incubated at room temperature for 60 min, at which time the rate of hydrolysis of the substrate is measured by monitoring the reaction at 405 nm for the release of p-nitroaniline. Percent inhibition of trypsin activity is calculated from OD^^ value from the experimental and control sample.
Recombinant soluble TF, consisting of amino acids 1-219 of the mature protein sequence was expressed in E. coli and purified using a Mono Q Sepharose FPLC. Recombinant human Vila was purchased from American Diagnostica, Greenwich CT and chromogenic substrate N-Methylsulfonyl-D- phe-gly-arg-p-nitroaniline was prepared by American Peptide Company, Inc., Sunnyvale, CA. Factor Xa was obtained from Enzyme Research Laboratories, South Bend IN, thrombin from Calbiochem, La Jolla, CA, and trypsin and L- BAPNA from Sigma, St. Louis MO. The chromogenic substrates S-2765 and S-2238 were purchased from Chromogenix, Sweden.
The biological activity of the compounds of Examples 1 through 22 as determined by the bioassay procedures is summarized in the Table 1.
Table 1. Inhibitory Activity of Pyridones toward Factor Xa, TF-VIIA, Thrombin II, and Trypsin II.
Claims
1. A compound having the Formula:
„9 10 1 1 12 13 32 33 „34 35 j n36 R , R , R , R , R , R , R , R , R , and R are independendy 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, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkanoyl, haloalkanoyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxyalkyl, carboxyalkyl, carboalkoxy, carboxy, carboxamido, carboxamidoalkyl, and cyano;
9 10 11 12 13
R , R , R , R , and R are optionally selected from the group
consisting of heteroaryl and heterocyclyl with the proviso that R , R , R ,
^ 12 13 , . , , Λ
R , and R are substitutents for other than B;
„ 16 19 32 „33 34 35 36 . ,
R , R , R , R , R , R , and R are independently 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 ;
B is optionally, with the proviso that R 1 and R 7 are selected from the group consisting of a spacer pair and -W=X-Y=Z-, Formula (V):
1 2 1 2 1 wherein D , D , J , J and are independendy 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 is S, one of D , D , J , J and
1 1 2 1 2 1
K must be a covalent bond when two of D , D , J , J and K are O and S,
1 2 1 2 1 and no more than four of D , D , J , J and K are N;
B is optionally selected from the group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B may be optionally substituted at any carbon up to and including 6 atoms from the point of
32 33 attachment of B to A with one or more of the group consisting of R , R , 3 n35 J „36 R , R , and R ;
B is selected from the group consisting of C3-C12 cycloalkyl and C4-
33 heterocyclyl, wherein each ring carbon may be optionally substituted with R , a ring carbon other than the ring carbon at the point of attachment of B to A may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbons and nitrogens adjacent to the carbon at the point of attachment may be optionally substituted
9 13 9 with R or R , a ring carbon or nitrogen adjacent to the R position and two
atoms from the point of attachment may be substituted with R , a ring carbon
13 or nitrogen adjacent to the R position and two atoms from the point of
12 attachment may be substituted with R , a ring carbon three atoms from the
10 point of attachment and adjacent to the R position may be substituted with
R , a ring carbon three atoms from the point of attachment and adjacent to
12 33 the R position may be substituted with R , and a ring carbon four atoms
11 33 from the point of attachment and adjacent to the R and R positions may be
34 substituted with R ;
B is optionally, with the proviso that R and R are selected from the group consisting of a spacer pair and -W=X-Y=Z-, a C5-C9 saturated
33 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, ring carbons and nitrogen adjacent to the
9 carbon atom at the point of attachment are optionally substituted with R or
13 9 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
nitrogen adjacent to the R13 position and two atoms from the point of
12 attachment is optionally substituted with R , a ring carbon or nitrogen three
atoms from the point of attachment and adjacent to the R position is
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
33 substituted with R , and a ring carbon or nitrogen four atoms from the point
11 33 of attachment and adjacent to the R and R positions is optionally
, • , T 3 substituted with R ; A is selected from the group consisting of single covalent bond,
7 15 15 7
(W )ff-(CH(R ))pa and (CH(R ))pa-(W )π wherein rr is an integer
7 selected from 0 through 1, pa is an integer selected from 0 through 6, and W
7 7 is selected from the group consisting of O, S, C(O), (R )NC(O), (R )NC(S),
7 and N(R ) with the proviso that no more than one of the group consisting of rr and pa is 0 at the same time;
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; Ψ 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;
X and R and R and R , with the proviso that no more than one of
the group consisting of spacer pair X and R and spacer pair R and R is be used at the same time, are optionally selected to be -W=X-Y=Z- wherein - W=X-Y=Z- forms a ring selected from the group consisting of a heteroaryl ring having from 5 through 6 contiguous members and an aryl;
W, X, Y, and Z are independendy selected from the group consisting of C(R9), C(R10), C(RU), C(R12), N, N(R10), O, S and a covalent bond with the provisos that one of W, X, Y, and Z is 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 is optionally selected from the group consisting of O and S, and no more than three of W, X, Y, and Z are optionally selected from the group consisting of N and N(R10);
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 one or more of the group consi •sti •ng o .f r R,9 , R ^ 10 , R T, 1 , r R.12 , and -. r R 3 and Λ wi •t th.
the proviso that no more than one of the group consisting of spacer pair X and
R 1 and spacer pair R 1 and R 2 is present at the same time;
R2 is Z°-Q; Z is selected from the group consisting of covalent single bond,
41 42 41
(CR R )q wherein q is an integer selected from 1 through 3, (CH(R ))σ-
,0 42
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),
41 41 41 22 42
N(R ), and ON(R ), and (CH(R ))e-W -(CH(R ))h wherein e and h
are integers independently selected from 0 through 1 and "^ is selected from
41 42 the group consisting of CR =CR , 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2- cyclohexyl, 13-cyclohexyI, 1,2-cyclopentyl, 13-cyclopentyl, 2,3- moφholinyl, 2,4-moφholinyl, 2,6- moφholinyl, 3,4-moφholinyl, 3,5- moφholinyl, 1,2-piperazinyl, 13-piperazinyl, 2,3-piperazinyl, 2,6- piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 23-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrτolidinyl, 23- pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 23- tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and 3,4- tetrahydrofuranyl, with the proviso that Z is directly bonded to the pyrazinone πng;
41 42
R and R are independendy 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):
1 2 1 2 1 wherein 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
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
1 1 2 1 2 1
K must be a covalent bond when two of D , D , J , J and are O and S,
1 2 1 2 1 and no more than four of D , D , J , J and K are N, with the proviso that n9 Λ0 11 „ 12 13
R , R , R , R , and R are each independendy selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
4a 4b K is (CR R )n wherein n is an integer selected from 1 through 2;
4a 4b
R and R are independendy selected from the group consisting of halo, hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl;
E is E , when K is (CR R )n, wherein E is selected from the
7 group consisting of a covalent single bond, C(O), C(S), C(O)N(R ),
(R?)NC(O), S(O)2, (R?)NS(O)2, and S(O)2N(R7); Y° is formula (IV):
5 6 5 6 wherein D , D , J , and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, K is C, no more than one of D , D , J , and J
is O, no more than one of D , D , J , and J is S, one of D , D , J , and J
must be a covalent bond when two of D , D , J , and J are O and S, and no
more than four of D , D , J , and J are N;
16 17 18 19
R , R , R , and R are independendy selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, nitro, alkoxyamino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, alkenyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkylamino, haloalkoxyalkyl, carboalkoxy, and cyano; b 20 21
Q is selected from the group consisting of NR R , aminoalkylenyl,
25 23 24 20 21
C(NR )NR R , with the provisos that no more than one of R and R is hydroxy, amino, alkylamino, or dialkylamino at the same time and that no
,. 23 24 more than one of R and R is hydroxy, amino, alkylamino, or dialkylamino at the same time;
20 21 23 24 25 26
R , R , R , R , R , and R are independendy selected from the group consisting of hydrido, alkyl, hydroxy, aminoalkylenyl, amino, dialkylamino, alkylamino, and hydroxyalkyl;
Q is selected from the group consisting of a single covalent bond,
37 38 (CR R )tø wherein b is an integer selected from 1 through 4, and
(CH(R ))C-W -(CH(R ))(j wherein c and d are integers independendy
selected from 1 through 3 and W is selected from the group consisting of
C(O)N(R14), (R14)NC(O), S(O), S(O)2, S(O)2N(R14), N(R14)S(O)2, and
14 14
N(R ), with the provisos that R is selected from other than halo when
directly bonded to N and that (CR R )b, and (CH(R ))c are bonded to E°;
14 R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
37 38 R R3 and R are independently selected from the group consisting of hydrido, alkyl, and haloalkyl;
38 R is optionally selected from the group consisting of aroyl and heteroaroyl;
Y° is optionally Qb-QSS wherein QSS is (CH(R14))e-W2-(CH(R15))h,
wherein e and h are integers independendy selected from 1 through 2 and 2
4a 4b 14 o is CR =CR with the proviso that (CH(R ))e is bonded to E ;
-0 b ssss b i is optionally selected from the group consisting of Q -Q and Q -
QSSSSr wherein Q5558 is (CH(R38))r-W5 and QSSSSr is (CH(R38))r-W6 r is an
integer selected from 1 through 2, and W~^ and W are independently selected from the group consisting of 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7- indenyl, 2,7-indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3,4-indenyl, 3,5- indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuranyl, 2,5-benzofuranyl, 2,6- 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- imidazo(l,2-a)pyridinyl, 3,4-imidazo(l,2-a)pyridinyl, 3,5-imidazo(l,2- a)pyridinyl, 3,6-imidazo(l,2-a)pyridinyl, 3,7-imidazo(l,2-a)pyridinyl, 2,4- indolyl, 2,5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6- indolyl, 3,7-indolyl, 1,4-isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4- isoindolyl, 2,5-isoindolyl, 2,6-isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl, 3,4- indazolyl, 3,5-indazolyl, 3,6-indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5- benzoxazolyl, 2,6-benzoxazolyl, 2,7-benzoxazolyl, 3,4-benzisoxazolyl, 3,5- benzisoxazolyl, 3,6-benzisoxazolyl, 3,7-benzisoxazolyl, 1,4-naphthyl, 1,5- naphthyl, 1,6-naphthyl, 1,7-naphthyl, 1,8-naphthyl, 2,4-naphthyl, 2,5- naphthyl, 2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl, 2,4-quinolinyl, 2,5- quinolinyl, 2,6-quinolinyl, 2,7-quinolinyl, 2,8-quinolinyl, 3,4-quinolinyl, 3,5- quinolinyl, 3,6-quinolinyl, 3,7-quinolinyl, 3,8-quinolinyl, 4,5-quinolinyl, 4,6- quinolinyl, 4,7-quinolinyl, 4,8-quinolinyl, 1,4-isoquinolinyl, 1,5- isoquinolinyl, 1,6-isoquinolinyl, 1,7-isoquinolinyl, 1,8-isoquinolinyl, 3,4- isoquinolinyl, 3,5-isoquinolinyl, 3,6-isoquinolinyl, 3,7-isoquinolinyl, 3,8- isoquinolinyl, 4,5-isoquinolinyl, 4,6-isoquinolinyl, 4,7-isoquinolinyl, 4,8-
isoquinolinyl, 3,4-cinnolinyl, 3-5-cinnolinyl, 3,6-cinnolinyl.3.7-cinnolinyl, 3,8-cirunolinyl, 4,5-cinnolinyl, 4,6-cranolinyl, 4,7-ciDnolinyl, and 4,8- cinnolinyl, and each carbon and hyrido containing nitrogen member of the ring of the W^ and of the ring of the W , other than the points of attachment of W and W , is optionally substituted with one or more of the group consisting of R , R , R , and R , with the provisos that Q is bonded to lowest number substituent position of each Q is bonded to highest number substituent position of each W . and (CH(R ))r is bonded to E .
2. The compound as recited in Qaim 1 having the Formula:
_32 Λ33 „34 _35 Λ 36 . . J ,
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, haloalkanoyl, nitro, lower alkylamino, alkylthio, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyalkyl, alkylamino, carboalkoxy, carboxy, carboxamido, cyano, and Q ;
1
B is optionally, with the proviso that R and R are selected from the group consisting of a spacer pair and -W=X-Y=Z-, Formula (V):
1 2 1 2 1 wherein 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
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
1 1 2 1 2 1
K must be a covalent bond when two of D , D , J , J and K are O and S,
1 2 1 2 1 and no more than four of D , D , J , J and K are N; 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 ,
34 35 J 36 R , R , and R ;
B is selected from the group consisting of C3-C12 cycloalkyl and C4-
33 heterocyclyl, wherein each ring carbon may be optionally substituted with R ,
a ring carbon other than the ring carbon at the point of attachment of B to A may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbons and nitrogens adjacent to the carbon at the point of attachment may be optionally substituted
9 13 9 with R or R , a ring carbon or nitrogen adjacent to the R position and two
atoms from the point of attachment may be substituted with R , a ring carbon
13 or nitrogen adjacent to the R position and two atoms from the point of
12 attachment may be substituted with R , a ring carbon three atoms from the
point of attachment and adjacent to the R position may be substituted with
R , a ring carbon three atoms from the point of attachment and adjacent to
12 33 the R position may be substituted with R , and a ring carbon four atoms
11 33 from the point of attachment and adjacent to the R and R positions may be
34 substituted with R ;
B is optionally, with the proviso that R 1 and R 7 are selected from the group consisting of a spacer pair and -W=X-Y=Z-, a C5-C9 saturated
33 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, ring carbons and nitrogen adjacent to the
9 carbon atom at the point of attachment are optionally substituted with R or
13 9
R , a ring carbon or nitrogen adjacent to the R position and two atoms from
10 the point of attachment is optionally substituted with R , a ring carbon or
13 nitrogen adjacent to the R position and two atoms from the point of
12 attachment is optionally substituted with R , a ring carbon or nitrogen three
atoms from the point of attachment and adjacent to the R position is
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
33 substituted with R , and a ring carbon or nitrogen four atoms from the point
11 33 of attachment and adjacent to the R and R positions is optionally
substituted with R ;
9 10 11 12 13
R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl, amidino, guanidino, alkylenedioxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfamido, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxamido, and cyano;
9 10 „ 11 X2 13 . „ , J
R , R , R , R , and R are optionally selected from the group
9 10 11 consisting of heteroaryl and heterocyclyl with the proviso that R , R , R ,
12 13
R , and R are substitutents for other than B;
A is selected from the group consisting of single covalent bond and
15 7
(CH(R ))pa-(W )rτ wherein rr is an integer selected from 0 through 1, pa is
7 an integer selected from 0 through 3, and W is selected from the group
consisting of O, S, C(O), (R?)NC(O), (R?)NC(S), and N(R?);
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;
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;
R 1 and R 2 are optionally selected to be -W=X-Y=Z- wherein -W=X-
Y=Z- forms a ring selected from the group consisting of a heteroaryl ring having from 5 through 6 contiguous members and an aryl;
W, X, Y, and Z are independendy selected from the group consisting of C(R9), C(R10), C(RU), C(R12), N, N(R10), O, S and a covalent bond with the provisos that one of W, X, Y, and Z is independently selected to be a covalent bond when one of W, X, Y, and Z is selected from the group
10 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 are optionally selected from the group consisting of N and N(R10);
1 o
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
■ • o 9 „ 10 „ 11 „ 12 J TΪ 13 of the group consisting of R , R , R , R , and R ;
R2 is Z°-Q;
Z is selected from the group consisting of covalent single bond and
41 42 41
(CR R )q wherein q is an integer selected from 1 through 2, (CH(R ))σ-
,0 42 w -(CH(R ))p wherein g and p are integers independendy selected from 0 o 41 through 3 and W is selected from the group consisting of O, S, and N(R ),
41 22 42 and (CH(R ))e-W^ -(CH(R ))^ wherein e and h are integers independently
selected from 0 through 1 and W^ is selected from the group consisting of
41 42 CR =CR , 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3- cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 23-moφholinyl, 2,4- moφholinyl, 2,6-moφholinyl, 3,4-moφholinyl, 3,5-moφholinyl, 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, 13-ρyrrolidinyl, 2,3-pyrrolidinyl, 2,4- pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 23 -tetrahydrofuranyl, 2,4- tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the proviso that Z is direcdy bonded to the pyrazinone ring;
41 42
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 2/ 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
9 by R , the other carbon adjacent to the carbon at the point of attachment is
13 9 optionally substituted by R , a carbon adjacent to R and two atoms from the
10 carbon at the point of attachment is optionally substituted by R , a carbon
13 adjacent to R and two atoms from the carbon at the point of attachment is
12 10 12 optionally substituted by R , and any carbon adjacent to both R and R is
optionally substituted by R ;
4a 4a
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, C(O)N(H), (H)NC(O), (R?)NS(O)2, and S(O)2N(R?);
Y° is formula (IV):
5 6 5 6 wherein 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
2 5 6 5 than one can be a covalent bond, K is C, no more than one of D , D , J ,
and J can be O, no more than one of D , D , J , and J can be S, one of D ,
D , J , and J must be a covalent bond when two of D , D , J , and J are O
and S, and no more than four of D , D , J , and J can be N, 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;
16 17 18 19
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
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
hydrido, N(R26)C(NR25)N(R23)(R24), and QNR^NR^R24, with the
20 21 provisos that no more than one of R and R is hydroxy, amino, alkylamino, or
23 24 dialkylamino at the same time and that no more than one of R and R is hydroxy, amino, alkylamino, or dialkylamino at the same time;
20 21 23 24 25 26
R , R , R , R , R , and R are independendy selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino; Q is selected from the group consisting of a single covalent bond,
37 38 (CR R )tø wherein b is an integer selected from 1 through 4, and
(CH(R ))C-W -(CH(R ))j wherein c and d are integers independendy
selected from 1 through 3 and W is selected from the group consisting of
C(O)N(R14), (R14)NC(O), S(O), S(O)2, S(O)2N(R14), N(R14)S(O)2, and
14 14 N(R ), with the provisos that R is selected from other than halo when
direcdy bonded to N and that (CR R )b, and (CH(R ))c are bonded to E°;
14 R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
37 38
R and R are independently selected from the group consisting of hydrido, alkyl, and haloalkyl;
38 . R is optionally selected from the group consisting of aroyl and heteroaroyl;
Y° is optionally Qb-QSS wherein QSS is (CH(R14))e-W2-(CH(R15))h,
wherein e and h are integers independently selected from 1 through 2 and w2
is CR =CH with the proviso that (CH(R ))e is bonded to E°.
3. The compound as recited in Claim 2 or a pharmaceutically acceptable salt thereof, wherein;
B is 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 attachment of B to A with one or more of the group consisting o xf-r R,32 , r R,33 , r R> 34 , R „35 , and J „ R36 ;
32 33 34 35 36
R , R , R , R , and R are independendy selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q ;
15 7
A is (CH(R ))pa-W wherein pa is an integer selected from 1 through
7 7 3 and W is selected from the group consisting of O, S, and N(R ) wherein
7 R is selected from the group consisting of hydrido and alkyl;
15 R is selected from the group consisting of hydrido, hydroxy, halo,
alkyl, and haloalkyl with the proviso that R is other than hydroxy and halo
15 7 when R is on the carbon bonded direcdy to W ;
R and X are independendy selected from the group consisting of hydrido, alkyl, cyano, halo, haloalkyl, haloalkoxy, amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio;
R 1 and R 2 are optionally selected to be -W=X-Y=Z- wherein -W=X- Y=Z- forms a ring selected from the group consisting of a heteroaryl ring having from 5 through 6 contiguous members and an aryl;
W, X, Y, and Z are independendy selected from the group consisting of C(R9), C(R10), C(Rπ), C(R12), N, N(R10), O, S and a covalent bond with the provisos that one of W, X, Y, and Z is independently selected to be a covalent bond when one of W, X, Y, and Z is selected from the group
10 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 are optionally selected from the group consisting of N and N(R10);
1 2
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
9 10 11 12 13 of the group consisting of R , R , R , R , and R ;
R2 is Z°-Q;
27 is selected from the group consisting of covalent single bond and
41 42 (CR R )q wherein q is an integer selected from 1 through 2;
41 42
R and R are independently selected from the group consisting of hydrido, hydroxy, and amino;
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
9 substituted by R , the other carbon adjacent to the carbon at the point of
13 9 attachment is optionally substituted by R , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by
10 13
R , a carbon adjacent to R and two atoms from the carbon at the point of
12 attachment is optionally substituted by R , and any carbon adjacent to both r O J n 12 . . „ u . J L π l l R and R is optionally substituted by R ;
9 10 11 12 13
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,
alkyl sulfami do, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxamido, and cyano;
4a 4a
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,
C(O)N(H), (H)NC(O), (R?)NS(O)2, and S(O)2N(R?);
Y° is formula (IV):
5 6 5 6 wherein 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
2 5 6 5 6 than one is a covalent bond, K is C, no more than one of D , D , J , and J
• ^ , r τ-,5 _ 6 ,5 , ,6 . _ ,- r~ 5 _ 6 τ5 τ6 is O, no more than one of D , D , J , and J is S, one of D , D , J , and J
must be a covalent bond when two of D , D , J , and J are O and S, and no
5 6 5 6 more than four of D , D , J , and J are N;
16 17 18 19
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, alkylamino, 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 ;
■ n o 1 K U
Q is selected from the group consisting of NR R , Q wherein Q is
hydrido, N(R26)C(NR25)N(R23)(R24), and C(NR25)NR23R24, with the
20 21 provisos that no more than one of R and R is hydroxy, amino, alkylamino, or
23 24 dialkylamino at the same time and that no more than one of R and R is hydroxy, amino, alkylamino, or dialkylamino at the same time;
20 21 23 24 25 26
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,
37 38 (CR R )h wherein b is an integer selected from 1 through 3, and
(CH(R ))C-W -(CH(R ))^ wherein c and d are integers independendy
selected from 1 through 2 and W is selected from the group consisting of
C(O)N(R14), (R14)NC(O), S(O), S(O)2, S(O)2N(R14), N(R14)S(O)2, and
14 14 N(R ), with the provisos that R is selected from other than halo when *"? O A direcdy bonded to N and that (CR R )b, and (CH(R ))c are bonded to E°;
14 R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
37 38
R R' and R are independently selected from the group consisting of hydrido, alkyl, and haloalkyl;
38 R R38 is optionally selected from the group consisting of aroyl and heteroaroyl;
Y° is optionally Qb-QSS wherein QSS is (CH(R14))e-W2-(CH(R15))h,
wherein e and h are integers independently selected from 1 through 2 and Vv
is CR =CH with the proviso that (CH(R )). is bonded to E°.
4. The compound as recited in Claim 3 having the Formula:
B is selected from the group consisting of hydrido, trialkylsilyl, C2-C4 alkyl, C3-C5 alkylenyl, C3-C4 alkenyl, C3-C4 alkynyl, and C2-C4 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 3 atoms from the point of attachment of B to A with one or more
32 33 34 of the group consisting of R , R , and R ;
32 33 34
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, and cyano;
15 7
A is (CH(R ))pa-N(R ) wherein pa is an integer selected from 1
7 through 2 and R is selected from the group consisting of hydrido and alkyl;
15 . R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
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;
1 7 R and R" are optionally selected to be -W=X-Y=Z- wherein -W=X-
Y=Z- forms a ring selected from the group consisting of a heteroaryl ring having from 5 through 6 contiguous members and an aryl;
W, X, Y, and Z are independently selected from the group consisting of C(R9), C(R10), C(RU), C(R12), N, N(R10), O, S and a covalent bond with the provisos that one of W, X, Y, and Z is independently selected to be a covalent bond when one of W, X, Y, and Z is selected from the group
10 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 are optionally selected from the group consisting of N and N(R );
R 1 and R 2 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
9 10 11 12 13 of the group consisting of R , R , R , R , and R ;
R2 is Z°-Q; Z is selected from the group consisting of covalent single bond and
CH2;
Q is selected from the group consisting of aryl and heteroaryl, wherein a carbon adjacent to the carbon at the point of attachment is optionally
9 substituted by R , the other carbon adjacent to the carbon at the point of
13 9 attachment is optionally substituted by R , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by
10 13
R , a carbon adjacent to R and two atoms from the carbon at the point of
12 attachment is optionally substituted by R , and any carbon adjacent to both
10 12 11 R and R is optionally substituted by R ;
9 11 13
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;
10 12
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;
Y° is formula (IV):
. 5 6 5 6 wherein D , D , J , and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, K is C, no more than one of D , D , J , and J
is O, no more than one of D , D , J , and J is S, one of D , D , J , and J
must be a covalent bond when two of D , D , J , and J are O and S, and no
more than four of D , D , J , and J are N;
16 17 18 19
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 ;
L 20 21 K Q is selected from the group consisting of NR R , Q wherein
Qbe is hydrido, C(NR25)NR23R24, and N(R26)C(NR25)N(R23)(R24), with τ,20 21 . L _, the provisos that no more than one of R and R is hydroxy at the same Ume
23 24 and that no more than one of R and R is hydroxy at the same time;
20 21 23 24 25 26
R , 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,
CH2, and CH2CH2.
5. The compound as recited in Claim 4 having the Formula or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of ethyl, 2-propenyl, 2- propynyl, propyl, isopropyl, trimethylene, tetramethylene, butyl, 2-butenyl, 3- butenyl, 2-butynyl, sec-butyl, tert-butyl, isobutyl, 2-methylpropenyl, 2,2,2- trifluoroethyl, 333-trifluoropropyl, and 2,2-difluoropropyl, wherein each member of group B is optionally substituted at any carbon up to and including 3 atoms from the point of attachment of B to A with one or more of the group
32 33 34 consisting of R , R , and R ;
32 33 34
R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1 - hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N- methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
A is selected from the group consisting of single covalent bond, NH, and N(CH3);
R and X° are independendy selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1- aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, methoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo; R2 is Z°-Q;
Z is selected from the group consisting of a covalent single bond and
CH-
Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-ρyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3- pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and l,3,5-triazin-2-yl, wherein a carbon adjacent
9 to the carbon at the point of attachment is optionally substituted by R , the other carbon adjacent to the carbon at the point of attachment is optionally
13 9 substituted by R , a carbon adjacent to R and two atoms from the carbon at
the point of attachment is optionally substituted by R , a carbon adjacent to
13 R and two atoms from the carbon at the point of attachment is optionally
substituted by R , and any carbon adjacent to both R and R is optionally
substituted by R ;
9 11 13 R , R , and R are independendy selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,333- pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2- hydroxyethyl, 2,2,2-trifluoro- 1-hydroxyethyl, amidocarbonyl, N- methylamidocarbonyl, N,N-dimethyIamidocarbonyl, and cyano;
10 12 R and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl, 1- aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N- dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2-2-trifluoro- 1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, fluoro, chloro, bromo, and cyano; Y is selected from the group consisting of: b s 16 17 18 19 1-Q -4-Q -2-R -3-R -5-R -6-R benzene,
2-Q -5-QS-6-R -4-R -2-R pyridine,
3-Qb-6-QS-2-R 16-5-R 18-4-R 19pyridine, 2-Qb^-QS-3-R 16-6-R 18pyrazine,
„ Λb ^ ^s „ 18 ^ 18 Λ 19 . _, . 3-Q -6-Q -2-R -5-R -4-R pyπdazine,
2-Q -5-QS-6-R -4-R pyrimidine, 5-Q -2-QS-3-R -6-R pyrimidine,
3-Qb-5-QS^-R16-2-R19thiophene, 2-Qb-5-QS-3-R16-4-R17thiophene,
3-Qb-5-QS-4-R16-2-R19furan, 2-Qb-5-QS-3-R16-4-R17furan,
3-Qb-5-QS-4-R16-2-R19pyπ-ole, 2-Qb-5-QS-3-R16-4-R17pyrrole,
4-Q -2-QS- R imidazole, 2-Q -4-QS-5-R imidazole,
3-Q -5-Q -4-R isoxazole, 5-Q -3-Q -4-R isoxazole, b s 16 b s 19
2-Q -5-Q -4-R pyrazole, 4-Q -2-Q -5-R thiazole, and
2-Q -5-QS-4-R thiazole;
16 17 18 19 R , R , R , and R are independendy selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2333-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1- hydroxyethyl, 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 ; h 00 21 K
Q is selected from the group consisting of NR R , Q wherein
Qbe is hydrido, C(NR25)NR23R24, and N(R26)C(NR25)N(R23)(R24), with
20 21 23 24 the provisos that no more than one of R , R , R , and R can be
20 21 23 24 hydroxy, when any two of the group consisting of R , R , R , and R
are bonded to the same atom and that said Q group is bonded directly to a carbon atom;
20 21 23 24 25 26
R , R , R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy; s Q is selected from the group consisting of a single covalent bond,
CH2, and CH2CH2.
6. The compound as recited in Claim 4 having the Formula:
A is selected from the group consisting of CH2N(CH3),
CH2N(CH2CH3), CH2CH2N(CH3), and CH2CH2N(CH2CH3);
R and X° are independendy selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1- aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, methoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo;
R2 is Z°-Q;
Z; is selected from the group consisting of covalent single bond and
CH2;
Q is selected from the group consisting of phenyl, 2-thienyI, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3- pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 13,5-triazin-2-yl, wherein a carbon adjacent
9 to the carbon at the point of attachment is optionally substituted by R , the other carbon adjacent to the carbon at the point of attachment is optionally
13 9 substituted by R , a carbon adjacent to R and two atoms from the carbon at
10 the point of attachment is optionally substituted by R , a carbon adjacent to
13 R and two atoms from the carbon at the point of attachment is optionally
12 10 12 substituted by R , and any carbon adjacent to both R and R is optionally
su tb.sti •tuted . b..y τ R, H ;
9 11 13 R , R , and R are independendy selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,333- pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2- hydroxyethyl, 2,2,2-trifluoro- 1-hydroxyethyl, amidocarbonyl, N- methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
10 12 R and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl, 1- aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino,
methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N- dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-l-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, fluoro, chloro, bromo, and cyano;
Y is selected from the group consisting of: 1-Qb^-QS.2 .R16. 3.R17.5- 18.6-R19benzene,
2-Qb-5-QS-6-R17-4-R18-2-R19pyridine,
3-Qb-6-QS-2-R16-5-R18-4-R19pyridine, 2-Qb^l-QS-3-R16-6-R18pyrazine, > ^s ^ „ 18 ^ „ 18 Λ r, 19 ._, . 3-Q -6-Q -2-R -5-R -4-R pyridazine,
2-Q -5-QS-6-R -4-R pyrimidine, 5-Q -2-QS-3-R -6-R pyrimidine,
3.Q -5-QS-4-R -2-R thiophene, 2-Q -5-QS-3-R -4-R thiophene,
3-Qb-5-QS-4-R16-2-R19furan, 2-Qb-5-QS-3-R16-4-R17furan,
3-Qb-5-QS-4-R16-2-R19pyπOle, 2-Qb-5-QS-3-R16-4-R17pyrrole,
4-Q -2-QS-5-R imidazole, 2-Q -4-QS-5-R imidazole, b s 16 b s 16
3-Q -5-Q -4-R isoxazole, 5-Q -3-Q -4-R isoxazole, b s 16 b s 19
2-Q -5-Q -4-R pyrazole, 4-Q -2-Q -5-R thiazole, and
2-Q -5-QS-4-R thiazole;
„16 17 „ 18 19 . _, J , , Λ e
R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1- aminoethyl, 2-aminoethyl, N-N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2.2,333-pentafluoropropyl, trifluoromethoxy, 1,1,2,2- tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-
methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1- hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1-hydroxyethyl, and cyano;
Q is selected from the group consisting of NR R ,
C(NR25)NR23R24, and N(R26)C(NR25)N(R23)(R24), with the provisos
20 21 23 24 that no more than one of R , R , R , and R can be hydroxy, when any
20 21 23 24 two of the group consisting of R , R , R , and R are bonded to the
same atom and that said Q group is bonded direcdy to a carbon atom;
20 21 23 24 25 26
R , R , R , R , R , and R are independendy selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy; g
Q is selected from the group consisting of a single covalent bond, CH2, and CH2CH2.
7. The compound as recited in Claim 6 or a pharmaceutically acceptable salt thereof, wherein;
A is selected from the group consisting of CH2N(CH3),
CH2N(CH2CH3), CH2CH2N(CH3), and CH2CH2N(CH2CH3);
R and X° are independendy selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio, trifluoromethoxy, fluoro, and chloro;
R2 is Z°-Q;
Z is selected from the group consisting of covalent single bond and
CH2; Q is selected from the group consisting of 5-amino-3- amidocarbonylphenyl, 5-amino-2-fluorophenyl, 3-amino-5- hydroxymethylphenyl, Samino-3-methoxycarbonylphenyl, 3-amidinophenyl,
3-amino-2-methyl phenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, 3-carboxy-5-hydroxyphenyl, 3-carboxy-5- aminophenyl, 3-chlorophenyl, 2-chlorophenyl, 3-cyanophenyl, 3- dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 2-hydroxyphenyl, 3- hydroxyphenyl, 3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3- methoxyphenyl, 3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2- methylaminophenyl, 3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2- thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl;
Y is selected from the group consisting of: l-Qb^_QS-2-R16-3-R17-5-R18-6-R19benzene,
„ ^> ^s 17 „ „ 18 19 . J# 2-Q -5-Q -6-R -4-R -2-R pyπdine,
3-Qb-6-QS-2-R16-5-R18-4-R19pyridine,
3-Q -5-QS-4-R -2-R thiophene, and 2-Q -5-QS-3-R -4-R thiophene;
R and R are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, 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 ;
17 18
R and R are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano;
Q is selected from the group consisting of Q wherein Q is hydrido
25 23 24 and C(NR )NR R ;
23 24 25 R , R , and R are independently selected from the group consisting of hydrido and methyl;
QS is CH2.
8. A compound as recited in Claim 7 or a pharmaceutically acceptable salt thereof where said compound is selected from the group consisting of:
2-[l-[6-[3-aminophenyl]-4-chloro-N-[[4-iminomethylphenyI]methyl]- 3-[N^I-dimethylhydrazino]-2-oxo-l(2H)-pyridinyl]]acetamide;
2-[l-[6-[3-aminophenyl]-4-fluoro-3-rN-ethyl-N-methylhydrazino]-N- [[4-iminomethyiphenyl]methyl]-2-oxo-l(4H)-pyridinyl]]acetamide;
2-[l-[6-[3-aminophenyl]-3-[N,N-diethylhydrazino]-N-[[4- iminomethylphenyl]methyl]-2-oxo-l(4H)-pyridinyl]]acetamide;
2-[l-[6-[3-aminophenyl]-3-[N-(azetidin-l-yl)amino]^-fluoro-N-[[4- iminomethylphenyl]methyl]-2-oxo-l(4H)-pyridinyl]]acetamide;
2-[l-[6-[3-aminophenyl]-N-[[4-iminomethylphenyl]methyl]-3-[N,N- dimethylhydrazino]-2-oxo-l(2H)-pyridinyl]]acetamide;
2-[ 1 -[6-[3-aminophenyl]-4-fluoro-N- [[4-iminomethylphenyllmethyll- 3-[N,N-dimethylhydrazino]-2-oxo-l(2H)-pyridinyl]]acetamide;
9. The compound as recited in Claim 2 having the Formula:
32 33 34 35 36
R , R , R , R , and R are independendy selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q ;
A is selected from the group consisting of single covalent bond and
15 7
(CH(R ))pa-(W )rr wherein rr is an integer selected from 0 through 1, pa is
7 an integer selected from 0 through 3, and W is selected from the group
7 7 consisting of (R )NC(O) and N(R );
7 R is selected from the group consisting of hydrido, hydroxy and alkyl;
15 R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; 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;
R2 is Z°-Q; Z is selected from the group consisting of a covalent single bond, O,
S. NH, and CH2;
Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted
9 by R , the other carbon adjacent to the carbon at the point of attachment is
13 9 optionally substituted by R , a carbon adjacent to R and two atoms from the
carbon at the point of attachment is optionally substituted by R , a carbon
13 adjacent to R and two atoms from the carbon at the point of attachment is
12 10 12 optionally substituted by R , and any carbon adjacent to both R and R is
optionally substituted by R ;
9 11 13
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;
10 12
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; Y° is formula (IV):
is O, no more than one of D , D , J , and J is S, one of D , D , J , and J
must be a covalent bond when two of D , D , J , and J are O and S, and no
5 6 5 6 more than four of D , D , J , and J are N;
„16 17 18 19 . , ,
R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
R and R are optionally Q with the proviso that no more than one
of R and R is Q at the same time and that Q is Q ;
s se ecte rom t e group cons s ng of N R , where n is
25 23 24 20 hydrido, and C(NR )NR R , with the provisos that no more than one of R
21 23 24 and R is hydroxy at the same time and that no more than one of R and R is hydroxy at the same time;
20 21 23 24 25
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,
CH2, and CH2CH2.
10. The compound as recited in Claim 9 or a pharmaceutically acceptable salt thereof, wherein; B is the Formula:
„32 33 34 35 ,,36 . , , ,
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, trifluoromethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, 2,2333-pentafluoropropyl, trifluoromethoxy, 1,1,2,2- tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N- methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1- hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl,
N,N-dimethylamidocarbonyl, cyano, and Q ;
A is selected from the group consisting of single covalent bond, NH,
N(CH3), N(OH), CH2 CH3CH, CF3CH, NHC(O), N(CH3)C(O),
C(O)NH, C(O)N(CH3), CH2CH2, CH2CH2CH2, CH3CHCH2, and
CF3CHCH2;
R and X° are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1- aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, methoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo;
R2 is Z°-Q;
Z is selected from the group consisting of a covalent single bond, O,
S, NH, and CH2;
Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3- pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and l,3,5-triazin-2-yl, wherein a carbon adjacent
9 to the carbon at the point of attachment is optionally substituted by R , the other carbon adjacent to the carbon at the point of attachment is optionally
13 9 substituted by R , a carbon adjacent to R and two atoms from the carbon at
the point of attachment is optionally substituted by R , a carbon adjacent to
13 R and two atoms from the carbon at the point of attachment is optionally
12 10 12 substituted by R , and any carbon adjacent to both R and R is optionally
substituted by R ;
9 11 13 R , R , and R are independendy selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, NJM-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2333- pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2- hydroxyethyl, 2,2,2-trifluoro- 1-hydroxyethyl, amidocarbonyl, N- methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
10 12 R and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl, 1- aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino,
methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N- dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, fluoro, chloro, bromo, and cyano;
Y is selected from the group consisting of:
, > Λ s 16 „ „ 17 18 ^ 19,
1-Q -4-Q -2-R -3-R -5-R -6-R benzene,
2-Q -5-QS-6-R -4-R -2-R pyridine,
3-Qb-6-QS-2-R16-5-R18-4-R19pyridine, 2-Qb-4-QS-3-R16-6-R18pyrazine, 3- > . s „ „ 18 ^ „ 18 19 . , . Q -6-Q -2-R -5-R -4-R pyπdazme,
2-Q -5-QS-6-R -4-R pyrimidine, 5-Q -2-QS-3-R -6-R pyrimidine,
3-Qb-5-QS-4-Rl -2-R19thiophene, 2-Qb-5-QS-3-R16-4-R17thiophene,
3-Qb-5-QS-4-R16-2-R19furan, 2-Qb-5-QS-3-R16-4-R17furan,
3-Qb- QS-4-R16-2-R19pyrτole, 2-Qb-5-QS-3-R16-4-R17pyrrole, b s 19 b s 17 4-Q -2-Q -5-R imidazole, 2-Q -4-Q -5-R imidazole,
3-Q -5-Q -4-R isoxazole, 5-Q -3-Q -4-R isoxazole,
2-Q -5-QS-4-R pyrazole, 4-Q -2-QS-5-R thiazole, and b s 17 2-Q -5-Q -4-R thiazole;
16 17 18 19
R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2333-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo,
amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1- hydroxyethyl, 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 Q wherein Q is hydrido
25 23 24 23 24 and C(NR )NR R , with the proviso that no more than one of R and R is hydroxy at the same time;
23 24 25
R , R , and R are independendy selected from the group consisting of hydrido, methyl, ethyl, and hydroxy; s Q is selected from the group consisting of a single covalent bond, CH2 and CH2CH2.
11. The compound as recited in Claim 10 or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of 2-aminophenyl, 3- aminophenyl, 3-amidinophenyl, 4-amidinophenyl, 3-carboxyphenyl, 3- carboxy-5-hydroxy phenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4- dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 3- hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyaminophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, and 3- trifluoromethylphenyl ;
A is selected from the group consisting of CH2, CH CH, CF3CH,
NHC(O), CH2CH2,and CH2CH2CH2;
R and X are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio, trifluoromethoxy, fluoro, and chloro;
R2 is Z°-Q;
Z is selected from the group consisting of a covalent single bond, O,
S, NH, and CH2;
Q is selected from the group consisting of 5-amino-3- amidocarbonylphenyl, 5-amino-2-fluorophenyl, 3-amino-5- hydroxymethylphenyl, amino-3-methoxycarbonyI phenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl, 3-carboxy-5- hydroxyphenyl, 3-carboxymethyl-5-aminophenyl, 3-carboxymethyl-5- hydroxyphenyl, 3-carboxymethylphenyl, 3-chlorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 2,5-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3- methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3- methoxyaminophenyl, 3-methoxycarbonyl phenyl, 2-methylaminophenyl, 3- methylaminophenyl, 2-methyIphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl, 2- trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2- thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl; Y is selected from the group consisting of:
1-Q -4-Q -2-R -3-R -5-R -6-R benzene, > , ^s , „17 „ „18 Λ „19 . ,. 2-Q -5-Q -6-R -4-R -2-R pyπdine,
. > , ^ <, 16 18 Λ \9 . .. 3-Q -6-Q -2-R -5-R -4-R pyπdine,
3-Q -5-QS-4-R -2-R thiophene, and 2-Q -5-QS-3-R -4-R thiophene;
16 19
R and R are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, 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 ;
17 18
R and R are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano;
Q is selected from the group consisting of Q wherein Q is hydrido
25 23 24 and C(NR )NR R ;
23 24 25
R , R , and R are independently selected from the group consisting of hydrido and methyl; Qs is CH2.
12. The compound as recited in Claim 9 having the Formula:
32 33 34 35 36
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
15 7
(CH(R ))pa-(W )rr wherein π is an integer selected from 0 through 1, pa is
7 7 an integer selected from 0 through 3, and W is N(R );
7 . R is selected from the group consisting of hydrido and alkyl;
R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
R 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;
R2 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
9 by R , the other carbon adjacent to the carbon at the point of attachment is
13 9 optionally substituted by R , a carbon adjacent to R and two atoms from the
10 carbon at the point of attachment is optionally substituted by R , a carbon
13 adjacent to R and two atoms from the carbon at the point of attachment is
12 10 12 optionally substituted by R , and any carbon adjacent to both R and R is
optionally substituted by R ;
9 11 13
R , R , and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkylamidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano;
10 12
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, carboxyamido, carboxyalkyl, and cyano;
Y° is formula (IV):
. 5 6 5 6 wherein 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
2 5 6 5 6 than one is a covalent bond, is C, no more than one of D , D , J , and J
5 6 5 6 5 6 5 6 is O, no more than one of D , D , J , and J is S, one of D , D , J , and J
must be a covalent bond when two of D , D , J , and J are O and S, and no
more than four of D , D , J , and J are N;
16 17 18 19 R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; R and R are optionally Q with the proviso that no more than one of
R and R is Q at the same time and that Q is Q ;
is
25 23 24 hydrido, and C(NR )NR R ;
20 21 23 24 25
R , R , R , R , and R are independendy selected from the group consisting of hydrido and alkyl;
Qs is CH2.
13. The compound as recited in Qaim 12 or a pharmaceutically acceptable salt thereof, wherein;
B is the Formula:
32 33 34 35 36
R , R , R , R , and R are independendy selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, carboxy, cyano, and Q ;
A is selected from the group consisting of single covalent bond, NH,
N(CH3), CH2, CH3CH, and CH2CH2;
X is selected from the group consisting of hydrido, hydroxy, amino, amidino, aminomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and fluoro;
R is selected from the group consisting of hydrido, hydroxy, amino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, methylthio, trifluoromethoxy, fluoro, and chloro;
R is selected from the group consisting of phenyl, 2-thienyl, 2-furyl, 2-pyrrolyl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl, and 3-pyridyl, wherein a carbon adjacent to the carbon at the point of attachment is optionally
9 substituted by R , the other carbon adjacent to the carbon at the point of
13 9 attachment is optionally substituted by R , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by
10 13 R , a carbon adjacent to R and two atoms from the carbon at the point of
12 attachment is optionally substituted by R , and any carbon adjacent to both
10 12 . 11
R and R is optionally substituted by R ;
9 11 13
R , R , and R are independendy selected from the group consisting of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, and cyano;
10 12
R and R are independendy selected from the group consisting of hydrido, amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2- hydroxyethyl, carboxy, carboxymethyl, amino, acetamido, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl, N- methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, N,N- dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, and cyano;
Y is selected from the group consisting of: l-Qb -QS-2-R16-3-R17-5-R18-6-R19benzene,
2-Qb-5-QS-6-R17-4-R18-2-R19pyridine, 2-Qb-5-QS-3-R16-4-R17thiophene,
b s 16 18 19 b s 16 19
3-Q -6-Q -2-R -5-R -4-R pyridine, 3-Q -5-Q -4-R -2-R thiophene,
3-Qb-5-QS-4-R16-2-R19furan, 2-Qb-5-QS-3-R16-4-R17furan,
3-Qb-5-QS-4-R16-2-R19pyrrole, 2-Qb-5-QS-3-R16-4-R17pyrrole, b s 19 b s 17
4-Q -2-Q -5-R thiazole, and 2-Q -5-Q -4-R thiazole;
R , R , R , and R are independendy selected from the group consisting of hydrido, methyl, ethyl, amidino, guanidino, methoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethylthio, methylsulfinyl, methylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoromethoxy, fluoro, chloro, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, carboxy, and cyano.
Xb 20 21
Q is selected from the group consisting of NR R and
25 23 24 b
C(NR )NR R , with the proviso that said Q group is bonded directly to a carbon atom;
20 21 23 24 25 R , R , R , R , and R are independendy selected from the group consisting of hydrido, methyl, and ethyl;
Qs is CH2.
14. The compound as recited in Claim 13 or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of 2-aminophenyl, 3- aminophenyl, 3-amidinophenyl, 4-amidinophenyI, 3-carboxyphenyl, 3- carboxy-Shydroxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4- dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 3- hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyaminophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-methylphenyl, 4-methylphenyl, and phenyl;
A is selected from the group consisting of CH , CH CH, CF3CH,
NHC(O), CH2CH2,and CH2CH2CH2;
X° is selected from the group consisting of hydrido, hydroxy, amino, amidino, aminomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and fluoro;
R is selected from the group consisting of hydrido, hydroxy, amino, aminomethyl, cyano, methyl, trifluoromethyl, and fluoro;
2
R is selected from the group consisting of 5-amino-3- amidocarbonylphenyl, 5-amino-2-fluorophenyl, 3-amino-5- hydroxymethylphenyl, amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl, 3-carboxy-5- hydroxyphenyl, 3-carboxymethyl-5-aminophenyl, 3-carboxymethyl- hydroxyphenyl, 3-carboxymethylphenyl, 3-chlorophenyl, 2-chlorophenyl, 3- cyanophenyl, 3-dimethylaminophenyl, 2-fluorophenyl, 3-fluoroρhenyl, 2,5- difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3- methanesulfonylammophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3- methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl, 3- methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl, 2- trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2- thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl;
Y is selected from the group consisting of:
1-Q -4-Q -2-R -3-R -5-R -6-R benzene,
„ > - Λs , „ 17 Λ „ 18 ^ ^ 19 . ,. 2-Q ->Q -6-R -4-R -2-R pyπdine,
3-Qb-6-QS-2-R16-5-R18-4-R19pyridine,
3-Q -5-QS-4-R -2-R thiophene, and 2-Q -5-QS-3-R ^t-R thiophene;
16 19
R and R are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano;
R and R are optionally Q with the proviso that no more than one
_ _ 16 19 . b , , . _b . .-.be of R and R is Q at the same time and that Q is Q ;
17 18
R and R are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano;
Q is selected from the group consisting of Q wherein Q is hydrido
25 23 24 and C(NR )NR R ;
23 24 25
R , R , and R are independendy selected from the group consisting of hydrido and methyl;
QS is CH2.
15. The compound as recited in Claim 14 or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of 3-aminophenyl, 3- amidinophenyl, 4-amidinophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4- dichlorophenyl, 2-fluorophenyl, 4-methylphenyl, and phenyl;
A is selected from the group consisting of CH , NHC(O),
CH2CH2,and CH2CH2CH2;
X° is selected from the group consisting of hydrido, hydroxy, amino, amidino, aminomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and fluoro;
R is selected from the group consisting of hydrido, hydroxy, amino, aminomethyl, cyano, methyl, trifluoromethyl, and fluoro;
2
R is selected from the group consisting of 3-aminophenyl, benzyl, 3- chlorophenyl, 3-dimethylaminophenyl, 3-hydroxyphenyl, 3- methanesulfonylaminophenyl, 3-methylaminophenyl, 2-methy 1 phenyl, 3- methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-bromo-2-thienyl, 2- thienyl, and 3-thienyl;
Y is selected from the group consisting of 5-amidino-2-thienylmethyl, 4-amidinobenzyl, 2-fluoro-4-amidinobenzyl, and 3-fluoro-4-amdinobenzyl.
16. A compound as recited in Claim 9 where said compound is selected from the group having the Formula:
RΛ is 3-aminophenyl, B is 3-chlorophenyl, A is CH2CH2, Y" is 4-
amidinobenzyl, R is hydrido, and X° is hydrido;
2 0 1 R is 3-aminophenyl, B is phenyl, A is CH2, Y is 4-amidinobenzyl, R
is hydrido, and X° is hydrido;
R 2 is phenyl, B is 3-chlorophenyl, A is CH2CH2, Y 0 is 4-amidinobenzyl,
R is hydrido, and X° is hydrido;
2 0
R is 3-dimethylamιnophenyl, B is phenyl, A is CH2CH2, Y is 4-
amidinobenzyl, R is hydrido, and X° is hydrido;
2 0
R is 2-methylphenyl, B is phenyl, A is CH2CH2, Y is 4-amidinobenzyl,
R is hydrido, and X° is hydrido;
2 0
R is phenyl, B is 3-aminophenyl, A is C(O)NH, Y is 4-amidinobenzyl,
R is hydrido, and X° is hydrido;
2 0 1 R is phenyl, B is 3-amidinophenyl, A is CH2, Y is 4-amidinobenzyl, R
is hydrido, and X° is hydrido;
7 0
R is 3-(N-methylamino)phenyl, B is phenyl, A is CH2CH2, Y is 4-
amidinobenzyl, R is hydrido, and X° is hydrido;
2 o
R is 3-methylsulfonamidophenyl, B is phenyl, A is CH2CH2, Y is 4-
amidinobenzyl, R is hydrido, and X° is hydrido;
7 0 1 R is phenyl, B is 4-amidinophenyl, A is CH2, Y is 4-amidinobenzyl, R
is hydrido, and X° is hydrido;
2 0
R is 3-methylaminophenyl, B is phenyl, A is CH2CH , Y is 4-
amidinobenzyl, R is hydrido, and X° is hydrido; 0 1
R is phenyl, B is phenyl, A is CH2, Y is 4-amidinobenzyl, R is
hydrido, and X° is hydrido;
R2 is 3-methylphenyl, B is 4-phenyl, A is CH2CH2, Y° is 4-
amidinobenzyl, R is hydrido, and X° is hydrido;
2 0 .
R is 3-aminophenyl, B is 3-chlorophenyl, A is CH2CH2, Y is 4-
amidinobenzyl, R is hydrido, and X° is hydrido;
2 0 1 R is 3-aminophenyl, B is phenyl, A is CH2, Y is 4-amidinobenzyl, R
is hydrido, and X° is hydrido; 0
R is phenyl, B is 3-chlorophenyl, A is CH2CH2, Y is 4-amidinobenzyl,
R is hydroxy, and X° is fluoro;
2 0
R is 3-dimethylaminophenyl, B is phenyl, A is CH2CH2. Y is 4-
amidinobenzyl, R is hydroxy, and X° is fluoro;
2 0
R is 2-methylphenyl, B is phenyl, A is CH2CH2, Y is 4-amidinobenzyl,
R is hydroxy, and X° is fluoro;
2 0
R is phenyl, B is 3-aminophenyl, A is C(O)NH, Y is 4-amidinobenzyl,
R is hydroxy, and X° is fluoro;
7 0 1
R is phenyl, B is 3-amidinophenyl, A is CH2, Y is 4-amidinobenzyl, R
is hydroxy, and X° is fluoro;
7 0
R* is 3-(N-methylamino)phenyl, B is phenyl, A is CH2CH2, Y is 4-
amidinobenzyl, R is hydroxy, and X° is fluoro;
2 0 R is 3-methylsulfonamidophenyl, B is phenyl, A is CH2CH2, Y is 4-
amidinobenzyl, R is hydroxy, and X° is fluoro;
2 0 1
R is phenyl, B is 4-amidinophenyl, A is CH2, Y is 4-amidinobenzyl, R
is hydroxy, and X° is fluoro;
2 0
R is 3-methylaminophenyl, B is phenyl, A is CH2CH2, Y is 4-
amidinobenzyl, R is hydroxy, and X° is fluoro;
2 0 1
R is phenyl, B is phenyl, A is CH2, Y is 4-amidinobenzyl, R is
hydroxy, and X° is fluoro; 0
R is 3-methylphenyl, B is 4-phenyl, A is CH2CH2, Y is 4-
amidinobenzyl, R is hydroxy, and X° is fluoro;
2 o R is 3-aminophenyl, B is 3-chlorophenyl, A is CH2CH2, Y is 4-
amidinobenzyl, R is amino, and X° is hydrido;
2 0 1
R is 3-aminophenyl, B is phenyl, A is CH2, Y is 4-amidinobenzyl, R
is amino, and X° is hydrido;
2 0
R is phenyl, B is 3-chlorophenyl, A is CH2CH2, Y is 4-amidinobenzyl,
R is amino, and X° is hydrido;
2 0
R is 3-dimethylaminophenyl, B is phenyl, A is CH2CH2, Y is 4-
amidinobenzyl, R is amino, and X° is hydrido;
R 2 is 2-methylphenyl, B is phenyl, A is CH2CH2, Y 0 is 4-amidinobenzyl,
R1 is amino, and X° is hydrido;
2 0
R is phenyl, B is 3-aminophenyl, A is C(O)NH, Y is 4-amidinobenzyl,
R is amino, and X° is hydrido;
2 0 1
R is phenyl, B is 3-amidinophenyl, A is CH2, Y is 4-amidinobenzyl, R
is amino, and X° is hydrido;
2 0 R is 3-(N-methylamino)phenyl, B is phenyl, A is CH2CH2, Y is 4-
amidinobenzyl, R is amino, and X° is hydrido;
2 0
R is 3-methylsulfonamidophenyl, B is phenyl, A is CH2CH2, Y is 4-
amidinobenzyl, R is amino, and X° is hydrido;
2 0 1
R is phenyl, B is 4-amidinophenyl, A is CH2, Y is 4-amidinobenzyl, R
is amino, and X° is hydrido;
2 0
R is 3-methylaminophenyl, B is phenyl, A is CH2CH2, Y is 4-
amidinobenzyl, R is amino, and X° is hydrido;
2 0 1
R is phenyl, B is phenyl, A is CH2, Y is 4-amidinobenzyl, R is amino,
and X° is hydrido; R2 is 3-methylphenyl, B is 4-phenyl, A is CH2CH2, Y° is 4-
amidinobenzyl, R is amino, and X° is hydrido;
R 2 is 3-aminophenyl, B is 3-chlorophenyl, A is CH CH , Y 0 is 4-
amidinobenzyl, R is aminomethyl, and X° is hydrido;
2 0 1
R is 3-aminophenyl, B is phenyl, A is CH2, Y is 4-amidinobenzyl, R
is aminomethyl, and X° is hydrido;
2 0
R is phenyl, B is 3-chlorophenyl, A is CH2CH2, Y is 4-amidinobenzyl,
R is aminomethyl, and X° is hydrido;
2 0
R is 3-dimethylamιnophenyl, B is phenyl, A is CH2CH2, Y is 4-
amidinobenzyl, R is aminomethyl, and X° is hydrido;
7 0
R^ is 2-methylphenyl, B is phenyl, A is CH2CH2, Y is 4-amidinobenzyl,
R is aminomethyl, and X° is hydrido;
7 0
R is phenyl, B is 3-aminophenyl, A is C(O)NH, Y is 4-amidinobenzyl,
R is aminomethyl, and X° is hydrido;
7 0 1 R is phenyl, B is 3-amidinophenyl, A is CH2, Y is 4-amidinobenzyl, R
is aminomethyl, and X° is hydrido;
2 0 .
R is 3-(N-methylamino)phenyl, B is phenyl, A is CH2CH2, Y is 4-
amidinobenzyl, R is aminomethyl, and X° is hydrido;
2 0 .
R is 3-methylsulfonamidophenyl, B is phenyl, A is CH2CH , Y is 4-
amidinobenzyl, R is aminomethyl, and X° is hydrido;
2 0 1
R is phenyl, B is 4-amidinophenyl, A is CH2, Y is 4-amidinobenzyl, R
is aminomethyl, and X° is hydrido;
2 0 .
R is 3-methylaminophenyl, B is phenyl, A is CH2CH2, Y is 4-
amidinobenzyl, R is aminomethyl, and X° is hydrido;
2 0 1 R is phenyl, B is phenyl, A is CH2, Y is 4-amidinobenzyl, R is
aminomethyl, and X° is hydrido;
R2 is 3-methylphenyl, B is 4-phenyl. A is CH2CH2, Y° is 4-
amidinobenzyl, R is aminomethyl, and X° is hydrido.
17. The compound as recited in Claim 2 having the Formula:
B is selected from the group consisting of hydrido, C2-C8 alkyl, C3- C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group
32 33 34 35 36 consisting of R , R , R , R , and R ;
32 33 34 35 36
R , R , R , R , and R are independendy selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q ;
A is selected from the group consisting of single covalent bond and
15 7
(CH(R ))Pa"(W )rr wherein rr is an integer selected from 0 through 1 , pa is
7 an integer selected from 0 through 3, and W is selected from the group
7 7 consisting of (R )NC(O) and N(R );
7 R is selected from the group consisting of hydrido, hydroxy and alkyl;
R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
R 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;
R2 is Z°-Q;
Z is selected from the group consisting of a covalent single bond, O,
S, NH, and CH2; Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted
9 by R , the other carbon adjacent to the carbon at the point of attachment is
13 9 optionally substituted by R , a carbon adjacent to R and two atoms from the
carbon at the point of attachment is optionally substituted by R , a carbon
13 adjacent to R and two atoms from the carbon at the point of attachment is
12 10 12 optionally substituted by R , and any carbon adjacent to both R and R is
optionally substituted by R ;
9 11 13
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;
10 12
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;
Y° is formula (IV):
5 6 5 6 wherein D , D , J , and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, K is C, no more than one of D , D , J , and J
is O, no more than one of D , D , J , and J is S, one of D , D , J , and J
must be a covalent bond when two of D , D , J , and J are O and S, and no
5 6 5 6 more than four of D , D , J , and J are N;
16 17 18 19
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
, 01 OΛ Of 0^ 01 OΛ
Q is hydrido, C(NR )NR R , and N(R )C(NR )N(R )(R ), with
20 21 the provisos that no more than one of R and R is hydroxy at the same time
23 24 and that no more than one of R and R is hydroxy at the same time;
20 21 23 24 25 26
R , R , R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, and hydroxy;
Q is selected from the group consisting of a single covalent bond,
CH2, and CH2CH2.
18. The compound as recited in Qaim 17 or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of hydrido, ethyl, 2-propynyl, 2-propenyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, 2-butynyl, sec- butyl, tert-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl, l-methyl-2-butenyl, l-methyl-3- butenyl, l-methyl-2-butynyl, 3-pentyl, l-ethyl-2-propenyl, 2-methy lbutyl, 2- methyl-2-butenyl, 2-methyl-3-butenyl, 2-methyl-3-butynyl, 3-methylbutyl, 3- methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4- hexenyl, 5-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, l-methyl-2- pentenyl, l-methyl-3-pentenyl, l-methyl-4-pentenyl, 1 -methyl -2-pentynyl, 1- methyl-3-pentynyl, 3-hexyl, l-ethyl-2-butenyl, l-ethyl-3-butenyl, l-propyl-2- propenyl, l-ethyl-2-butynyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5- heptenyl, 6-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2- heptyl, l-methyl-2-hexenyl, l-methyl-3-hexenyl, 1 -methyl -4-hexenyl, 1- methyl-5-hexenyl, l-methyl-2-hexynyl, l-methyl-3-hexynyl, l-methyl-4- hexynyl, 3-heptyl, l-ethyl-2-pentenyl, l-ethyl-3-pentenyl, l-ethyl-4-pentenyl, l-butyl-2-propenyl, l-ethyl-2-pentynyl, 1 -ethyl -3-pentynyl, 2,2,2- trifluoroethyl, 2,2-difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4- trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl, and 333-trifluoropropyl, wherein each member of group B is optionally substituted at any carbon up to and including 5 atoms from the point of attachment of B to A with one or more of the group consisting o rf r R,32 , R r,33 , R r,34 , ^ R , and , r R,^ ;
32 33 34 35 36
R , R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino,
methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, 2,2333-pentafluoropropyl, trifluoromethoxy, 1,1,2,2- tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N- methylamidosulfonyl, N,N-dimethylamidosuIfonyl, hydroxymethyl, 1- hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-l-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl,
N,N-dimethylamidocarbonyl, cyano, and Q ;
A is selected from the group consisting of single covalent bond, NH,
N(CH3), N(OH), CH2, CH3CH, CF3CH, NHC(O), N(CH3)C(O),
C(O)NH, C(O)N(CH3), CH2CH2, CH2CH2CH2, CH3CHCH2, and
CF3CHCH2;
R and X° are independendy selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1- aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, methoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo;
R2 is Z°-Q; Z is selected from the group consisting of a covalent single bond, O,
S, NH, and CH2;
Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-ρyrrolyl, 2-imidazolyl, 4-imidazolyl, 3- pyrazolyi, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 13,5-triazin-2-yl, wherein a carbon adjacent
9 to the carbon at the point of attachment is optionally substituted by R , the other carbon adjacent to the carbon at the point of attachment is optionally
13 9 substituted by R , a carbon adjacent to R and two atoms from the carbon at
the point of attachment is optionally substituted by R , a carbon adjacent to
13 R and two atoms from the carbon at the point of attachment is optionally
12 10 12 substituted by R , and any carbon adjacent to both R and R is optionally
substituted by R ;
9 11 13 R , R , and R are independendy selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,333- pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, methanesulfonamido, amidosulfonyl, N-methyiamidosulfonyl, N,N-dimethylamidosuIfonyl, hydroxymethyl, 1-hydroxyethyl, 2- hydroxyethyl, 2,2,2-trifluoro- 1-hydroxyethyl, amidocarbonyl, N- methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano; R and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl, 1- aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N- dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, fluoro, chloro, bromo, and cyano; Y is selected from the group consisting of: l-Qb^.QS-2-R16-3-R17-5-R18-6-R19benzene,
2-Qb-5-QS-6-R17-4-R18-2-R19pyridine,
3-Qb-6-QS-2-R16-5-R18-4-R19pyridine, 2-Qb-4-QS-3-Rl6-6-R18pyrazine, 3- b s 18 18 19 Q -6-Q -2-R -5-R -4-R pyridazine,
2-Q -5-Q -6-R -4-R pyrimidine, 5-Q -2-QS-3-R -6-R pyrimidine,
3-Q -5-QS-4-R -2-R thiophene, 2-Q -5-QS-3-R -4-R thiophene,
3-Qb-5-QS-4-R16-2-R19furan, 2-Qb-5-QS-3-R16-4-R1?furan,
3-Qb-5-QS-4-R16-2-R19pyrrole, 2-Qb-5-QS-3-R16-4-R17pyrrole,
4-Q -2-QS-5-R imidazole, 2-Q -4-QS-5-R imidazole,
3-Q -5-Q -4-R isoxazole, 5-Q -3-QS-4-R isoxazole,
2-Qb-5-QS-4-R pyrazole, 4-Qb-2-QS-5-R19thiazole, and
2-Q -5-QS-4-R thiazole;
R , R , R , and R are independendy selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2333-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-l- hydroxyethyl, 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 ; h 00 01 K
Q is selected from the group consisting of NR R , Q , wherein Q
is hydrido, C(NR25)NR23R24, and N(R26)C(NR25)N(R23)(R24), with the
20 21 provisos that no more than one of R and R is hydroxy at the same time and
23 24 that no more than one of R and R is hydroxy at the same time;
20 21 23 24 25 26
R , R , R , R , R , and R are independendy selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy; s Q is selected from the group consisting of a single covalent bond,
CH2, and CH2CH2.
19. The compound as recited in Claim 18 or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of hydrido,ethyl, 2-propenyl,
2-propynyl, propyl, isopropyl, butyl, 2-butyl, (R)-2-butyl,(S)-2-butyl, tert- butyl, isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-trifluoroethyl, 6- amidocarbonylhexyl, 4-methyl-2-pentyl, 3-hydroxypropyl, 3-methoxy-2- propyl, 2-methoxyethyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2- dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2-hydroxyethyl, 2- amidinoethyl, 2-guanidinoethyl, 3-guanidinopropyl, 4-guanidinobutyl, 3- hydroxypropyl, 4-hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl, 3- methylbutyl, 2-methylbutyl, (S 2-methylbutyl, 3-aminopropyl, 2-hexyl, and 4-aminobutyl; A is selected from the group consisting of single covalent bond,CH ,
NHC(O), CH2CH2, CH2CH2CH2, and CH3CHCH2;
R and X° are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio, trifluoromethoxy, fluoro, and chloro;
R2 is Z°-Q;
27 is selected from the group consisting of a covalent single bond, O,
S, NH, and CH2;
Q is selected from the group consisting of 5-amino-3- amidocarbonylphenyl, amino-2-fluorophenyl, 3-amino-5- hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl, 3-carboxy- hydroxyphenyl, 3-carboxymethyl-5-aminophenyl, 3-carboxymethyl-5- hydroxyphenyl, 3-carboxymethylphenyl, 3-chlorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl, 2-fluorophenyl, 3 -fluorophenyl, 2,5-difluoroρhenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3- methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3- methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl, 3- methylaminophenyl, 2-methylphenyl, 3-methyl phenyl, 4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl, 2- trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2- thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl;
Y is selected from the group consisting of: l-Qb-4-QS-2-R16-3-R17-5-R18-6-R19benzene,
2-Qb-5-QS-6-R17-4-R18-2-R19pyridine,
„ Λ , Λs „ «16 ^ „18 Λ 19 . .. 3-Q -6-Q -2-R -5-R -4-R pyridine, b s 16 19 b s 16 17 3-Q -5-Q -4-R -2-R thiophene, and 2-Q -5-Q -3-R -4-R thiophene;
16 19
R and R are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, 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 ;
17 18
R and R are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano;
Q is selected from the group consisting of Q wherein Q is hydrido
25 23 24 and C(NR )NR R ;
.23 ^24 25
R , R , and R are independently selected from the group consisting of hydrido and methyl;
^s .
Q is CH2.
20. The compound as recited in Claim 17 having the Formula:
B is selected from the group consisting of hydrido, C2-C8 alkyl, C3- C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group
32 33 34 35 36 consisting of R , R , R , R , and R ;
32 33 34 35 36
R , R , R , R , and R are 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 oϊ single covalent bond and
15 7
(CH(R ))pa-(W )n wherein rr is an integer selected from 0 through 1, pa is
7 7 an integer selected from 0 through 3, and W is N(R );
7 R is selected from the group consisting of hydrido and alkyl;
R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
R 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;
R2 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
9 by R , the other carbon adjacent to the carbon at the point of attachment is
13 9 optionally substituted by R , a carbon adjacent to R and two atoms from the
carbon at the point of attachment is optionally substituted by R , a carbon
13 adjacent to R and two atoms from the carbon at the point of attachment is
opti •onal „ly substi •tuted . b..y π Rl , and _, any carbon adjacent to b _.oth . R,10 and J RΛ 12 i-s
optionally substituted by R ;
9 11 13
R , R , and R are independendy selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkylamidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano;
10 12
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, carboxyamido, carboxyalkyl, and cyano;
Y° is formula (IV):
5 6 5 6 wherein 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
is O, no more than one of D , D , J , and J is S, one of D , D , J , and J
5 6 5 6 must be a covalent bond when two of D , D , J , and J are O and S, and no
5 6 5 6 more than four of D , D , J , and J are N;
„16 17 18 19 . J ., , , „ ,
R , R , R , and R are independendy selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
R and R are optionally Q with the proviso that no more than one of
R and R is Q at the same time and that Q is Q ;
Q is selected from the group consisting of NR R , Q wherein Q is
hydrido, N(R26)C(NR25)N(R23)(R24), and C(NR25)NR23R24;
20 21 23 24 25 26
R , R , R , R , R , and R are independently selected from the group consisting of hydrido and alkyl;
QS is CH2.
21. The compound as recited in Claim 17 or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of hydrido, ethyl, 2-proρenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 2-butynyl, sec-butyl, tert- butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 2- pentynyl, 3-pentynyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 2-methyl-2-butenyl, 3-methylbutyl, 3-methyl-2-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, l-methyl-2-pentenyl, l-methyl-3- pentenyl, l-methyl-2-pentynyl, l-methyl-3-pentynyl, 3-hexyl, l-ethyl-2- butenyl, 1-heptyl, 2-heptenyl, 3-heρtenyl, 4-heptenyl, 5-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, l-methyl-2-hexenyl, 1-methyl- 3-hexenyl, 1-methyl^-hexenyl, l-methyl-2-hexynyl, 1 -methyl -3-hexynyl, 1- methyl -4-hexynyl, 3-heptyl, l-ethyl-2-pentenyl, l-ethyl-3-pentenyl, l-ethyl-2- pentynyl, l-ethyl-3-pentynyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl, 4- trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6- pentafluorohexyl, and 333-trifluoropropyl, wherein each member of group B is optionally substituted at any carbon up to and including 5 atoms from the
32 point of attachment of B to A with one or more of the group consisting of R ,
33 34 35 36
R , R , R , and R ;
32 33 34 35 36 R , R , R , R , and R are independendy selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, carboxy, cyano, and Q ;
A is selected from the group consisting of single covalent bond, NH,
N(CH3), CH2, CH3CH, and CH2CH2;
A is optionally selected from the group consisting of CH N(CH3),
CH2N(CH2CH3), CH2CH2N(CH3), and CH2CH2N(CH2CH3) with the proviso that B is hydrido;
X° is selected from the group consisting of hydrido, hydroxy, amino, amidino, aminomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and fluoro;
R is selected from the group consisting of hydrido, hydroxy, amino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, methylthio, trifluoromethoxy, fluoro, and chloro;
2
R is selected from the group consisting of phenyl, 2-thienyl, 2-furyl,
2-pyrrolyl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl, and 3-pyridyl, wherein a carbon adjacent to the carbon at the point of attachment is optionally
9 substituted by R , the other carbon adjacent to the carbon at the point of
13 9 attachment is optionally substituted by R , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by
R , a carbon adjacent to R and two atoms from the carbon at the point of
12 attachment is optionally substituted by R , and any carbon adjacent to both
10 12 11 R and R is optionally substituted by R ;
9 11 13
R , R , and R are independendy selected from the group consisting of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, and cyano;
10 12
R and R are independently selected from the group consisting of hydrido, amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2- hydroxyethyl, carboxy, carboxymethyl, amino, acetamido, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl, N- methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, N,N- dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, and cyano;
Y is selected from the group consisting of:
, Λb Λ Λs „ „16 „ „ 17 ^ 18 , „ 19u
1-Q -4-Q -2-R -3-R -5-R -6-R benzene,
2-Qb-5-QS-6-R 17^1-R l8-2-R 19pyridine, 2-Qb-5-QS-3-R 16-4-R 17thiophene,
3-Qb-6-QS-2-R16-5-R18-4-R19pyridine, 3-Qb-5-QS-4-R16-2-R19thiophene,
3-Qb-5-QS-4-Rl6-2-R19furan, 2-Qb-5-QS-3-R16-4-R17furan,
3-Q -5-QS^-R -2-R pyπole, 2-Q -5-QS-3-R -4-R pyrrole, b s 19 b s 17
4-Q -2-Q -5-R thiazole, and 2-Q -5-Q -4-R thiazole;
16 17 18 19
R , R , R , and R are independendy selected from the group consisting of hydrido, methyl, ethyl, amidino, guanidino, methoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethylthio, methylsulfinyl, methylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoromethoxy, fluoro, chloro, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, carboxy, and cyano. b 20 21
Q is selected from the group consisting of NR R ,
C
with the proviso that b said Q group is bonded direcdy to a carbon atom;
20 21 23 24 25 26
R , R , R , R , R , and R are independently selected from the group consisting of hydrido, methyl, and ethyl; s .
Q is CH2.
22. The compound as recited in Claim 21 or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of hydrido,ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butyl, (R)-2-butyl,(S)-2-butyl, tert- butyl, isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-trifluoroethyl, 6- amidocarbonylhexyl, 4-methyl-2-pentyl, 3-hydroxypropyl, 3-methoxy-2- propyl, 2-methoxy ethyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2- dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2-hydroxyethyl, 2-
amidinoethyl, 2-guanidinoethyl, 3-guanidinopropyl, 4-guanidinobutyl, 3- hydroxypropyl, 4-hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl, 3- methylbutyl, 2-methylbutyl, (S)-2-methylbutyl, 3-aminopropyl, 2-hexyl, and 4-aminobutyl; A is selected from the group consisting of single covalent bond, CH ,
CH3CH, and CH2CH2;
X° is selected from the group consisting of hydrido, hydroxy, amino, amidino, aminomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and fluoro; R is selected from the group consisting of hydrido, hydroxy, amino, aminomethyl, cyano, methyl, trifluoromethyl, and fluoro;
2 R is selected from the group consisting of 5-amino-3- amidocarbonylphenyl, 5-amino-2-fluorophenyl, 3-amino-5- hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyρhenyl, 3-carboxy-5-aminophenyl, 3-carboxy-5- hydroxyphenyl, 3-carboxymethyl-5-aminophenyl, 3-carboxymethyl-5- hydroxyphenyl, 3-carboxymethyl phenyl, 3-chlorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 2,5-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3- methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3- methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl, 3- methylaminophenyl, 2-methylphenyl, 3-methyl phenyl, 4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl, 2- trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2- thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl;
Y is selected from the group consisting of:
, J> . Λs „ 16 „ „ 17 e „ 18 , „ 19,
1-Q -4-Q -2-R -3-R -5-R -6-R benzene, b s 17 18 19 2-Q -5-Q -6-R -4-R -2-R pyridine, b s 16 18 19 3-Q -6-Q -2-R -5-R -4-R pyridine,
3-Q -5-QS-4-R -2-R thiophene, and 2-Q S-QS -3-R1 -4-R thiophene;
R and R are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, 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 ;
17 18
R and R are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano; b . be be
Q is selected from the group consisting of Q wherein Q is hydrido
25 23 24 and C(NR )NR R ;
23 24 25
R , R , and R are independendy selected from the group consisting of hydrido and methyl;
QS is CH2.
23. The compound as recited in Qaim 22 or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of hydrido,ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butyl, (R)-2-butyl,(S)-2-butyl, tert- butyl, isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-trifluoroethyl, 6- amidocarbonylhexyl, 4-methyl-2-pentyl, 3-hydroxypropyl, 3-methoxy-2- propyl, 2-methoxyethyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2- dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2-hydroxyethyl, 2- amidinoethyl, 2-guanidinoethyl, 3-guanidinopropyl, 4-guanidinobutyl, 3- hydroxypropyl, 4-hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl, 3- methylbutyl, 2-methylbutyl, (S)-2-methylbutyl, 3-aminopropyl, 2-hexyl, and 4-aminobutyl;
A is selected from the group consisting of single covalent bond, CH2,
CH3CH, and CH2CH2;
X° is selected from the group consisting of hydrido, hydroxy, amino, amidino, aminomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and fluoro;
R is selected from the group consisting of hydrido, hydroxy, amino, aminomethyl, cyano, methyl, trifluoromethyl, and fluoro;
2
R is selected from the group consisting of 5-amino-2-fluorophenyl, 3- amino- 2- methyl phenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl, 3- carboxyphenyl, 3-cyanophenyl, 3-methoxycarbonylphenyl, phenyl, and 3- pyridyl;
Y is selected from the group consisting of 5-amidino-2-thienylmethyl,
4-amidinobenzyl, 2-fluoro-4-amidinobenzyl, and 3-fluoro-4-amidinobenzyl.
24. A compound as recited in Claim 17 where said compound is selected from the group having the Formula:
R is 3-aminophenyl, B is 2,2,2-trifluoroethyl, A is single bond, Y is 4- amidinobenzyl, R is hydrido, and X° is hydrido;
R 2 is 3-aminophenyl, B is (S)-2-butyl, A is single bond, Y 0 is 4- amidinobenzyl, R is hydrido, and X° is hydrido;
2 0
R is 5-amino-2-fluorophenyl, B is isopropyl, A is single bond, Y is 4- amidinobenzyl, R is hydrido, and X° is hydrido;
2 0
R is 2-methyl-3-aminophenyl, B is isopropyl, A is single bond, Y is 4- amidinobenzyl, R is hydrido, and X° is hydrido;
R 2 is 3-aminophenyl, B is ethyl, A is single bond, Y 0 is 4-amidinobenzyl,
R1 is hydrido, and X° is hydrido;
R 2 is 3-aminophenyl, B is ethyl, A is single bond, Y 0 is 4-amidino-2- fluorobenzyl, R is hydrido, and X° is hydrido;
2 o R is 3-aminophenyl, B is 2-propenyl, A is single bond, Y is 4- amidinobenzyl, R is hydrido, and X° is hydrido;
2 0 . .
R is 3-aminophenyl, B is isopropyl, A is single bond, Y is 4-amidino-2- fluorobenzyl, R is hydrido, and X° is hydrido;
R 2 i •s 3-aminophenyl, B is isopropyl, A is single bond, Y 0 i .s 4- amidinobenzyl, R is hydrido, and X° is hydrido; 0
R is 3-aminophenyl, B is 2-butyl, A is single bond, Y is 4- amidinobenzyl, R is hydrido, and X° is hydrido;
2 0
R is 3-aminophenyl, B is (R)-2-butyl, A is single bond, Y is 4- amidinobenzyl, R is hydrido, and X° is hydrido;
2 0 R is 3-aminophenyl, B is 2-propynyl, A is single bond, Y is 4- amidinobenzyl, R is hydrido, and X° is hydrido; 0
R is 3-aminophenyl, B is 3-pentyl, A is single bond, Y is 4- amidinobenzyl, R is hydrido, and X° is hydrido;
2 0 1
R is 3-aminophenyl, B is hydrido, A is CH , Y is 4-amidinobenzyl, R
is hydrido, and X° is hydrido;
2 0 1
R is 3-aminophenyl, B is ethyl, A is CH2, Y is 4-amidinobenzyl, R is
hydrido, and X° is hydrido;
2 0
R is 3-aminophenyl, B is 2-methypropyl, A is single bond, Y is 4- amidinobenzyl, R is hydrido, and X° is hydrido;
R 7 is 3-aminophenyl, B is 2-propyl, A is CH3CH, Y 0 is 4-amidinobenzyl,
R is hydrido, and X° is hydrido;
R 2 is 3-aminophenyl, B is propyl, A is single bond, Y 0 is 4-amidino-2- fluorobenzyl, R is hydrido, and X° is hydrido;
2 • 0 .
R is 3-aminophenyl, B is 6-amidocarbonylhexyl, A is single bond, Y is
4-amidinobenzyl, R is hydrido, and X° is hydrido;
R 2 is 3-aminophenyl, B is tert-butyl, A is single bond, Y 0 is 4- amidinobenzyl, R is hydrido, and X° is hydrido;
R 2 is 3-aminophenyl, B is tert-butyl, A is single bond, Y 0 is 4- amidinobenzyl, R is hydrido, and X° is hydrido;
2 • 0 .
R is 3-aminophenyl, B is 3-hydroxypropyl, A is single bond, Y is 4- amidinobenzyl, R is hydrido, and X° is hydrido;
R 2 is 3-aminophenyl, B is 2-methy lpropyl, A is single bond, Y 0 is 4- amidino-2-fluorobenzyl, R is hydrido, and X° is hydrido; R 2 is 3-aminophenyl, B is butyl, A is single bond, Y 0 is 4-amidinobenzyl,
R is hydrido, and X° is hydrido;
R 2 is 3-ami •nophenyl, B is 3-methoxy-2-propyl, A is single bond, Y i .s 4- amidinobenzyl, R is hydrido, and X° is hydrido;
2 0 .
R is 3-aminophenyl, B is 3-methoxy-2-propyl, A is single bond, Y is 4- amidinobenzyl, R is hydrido, and X° is hydrido;
R 2 is 3-ami •nophenyl, B is 2-methoxy-2-ethyl, A is single bond, Y 0 is 4- amidinobenzyl, R is hydrido, and X° is hydrido;
R 2 is 3-aminophenyl, B is 2-propyl, A is single bond, Y 0 is 5-amidino-2- thienylmethyl, R is hydrido, and X° is hydrido;
2 0
R is 3-aminophenyl, B is 2-propyl, A is single bond, Y is 4-amidino-3- fluorobenzyl, R is hydrido, and X° is hydrido;
2 0
R is 3-carboxyphenyl, B is 2-propyl, A is single bond, Y is 4- amidinobenzyl, R is hydrido, and X° is hydrido; R 2 is 3-aminophenyl, B is 2-propyl, A is single bond, Y 0 is 4-amidino-3- fluorobenzyl, R is hydrido, and X° is hydrido;
2 0 .
R is 3-aminophenyl, B is 2,2,2-trifluoroethyl, A is single bond, Y is 4- amidinobenzyl, R is aminomethyl, and X° is hydrido;
2 0
R is 3-aminophenyl, B is (S)-2-butyl, A is single bond, Y is 4- amidinobenzyl, R is aminomethyl, and X° is hydrido;
R 2 i •s 5-amino-2-fluorophenyl, B is isopropyl, A is single bond, Y 0 is 4- amidinobenzyl, R is aminomethyl, and X° is hydrido;
2 0
R is 2-methyl-3-aminophenyl, B is isopropyl, A is single bond, Y is 4- amidinobenzyl, R is aminomethyl, and X° is hydrido; R 2 is 3-aminophenyl, B is ethyl, A is single bond, Y 0 is 4-amidinobenzyl,
R is aminomethyl, and X° is hydrido;
R 2 is 3-aminophenyl, B is ethyl, A is single bond, Y 0 is 4-amidιno-2- fluorobenzyl, R is aminomethyl, and X° is hydrido;
R 2 is 3-aminophenyl, B is 2-propenyl, A is single bond, Y 0 is 4- amidinobenzyl, R is aminomethyl, and X° is hydrido;
R 2 i •s 3-aminophenyl, B is isopropyl, A is single bond, Y 0 is 4-amidino-2- fluorobenzyl, R is aminomethyl, and X° is hydrido;
R 2 is 3-aminophenyl, B is isopropyl, A is single bond, Y 0 is 4- amidinobenzyl, R is aminomethyl, and X° is hydrido;
R 2 is 3-ami •nophenyl, B is 2-butyl, A is single bond, Y 0 is 4- amidinobenzyl, R is aminomethyl, and X° is hydrido;
2 0
R is 3-aminophenyl, B is (R)-2-butyl, A is single bond, Y is 4- amidinobenzyl, R is aminomethyl, and X° is hydrido;
2 0 R is 3-aminophenyl, B is 2-propynyl, A is single bond, Y is 4- amidinobenzyl, R is aminomethyl, and X° is hydrido;
R 2 is 3-aminophenyl, B is 3-pentyl, A is single bond, Y 0 is 4- amidinobenzyl, R is aminomethyl, and X° is hydrido;
2 0 1
R is 3-aminophenyl, B is hydrido, A is CH2, Y is 4-amidinobenzyl, R
is aminomethyl, and X° is hydrido;
2 0 1
R is 3-aminophenyl, B is ethyl, A is CH2, Y is 4-amidinobenzyl, R is
aminomethyl, and X° is hydrido;
2 0
R is 3-aminophenyl, B is 2-methypropyl, A is single bond, Y is 4- amidinobenzyl, R is aminomethyl, and X° is hydrido; R 2 is 3-aminophenyl, B is 2-propyl, A is CH3CH, Y 0 is 4-amidinobenzyl,
R is aminomethyl, and X° is hydrido;
R 2 is 3-aminophenyl, B is propyl, A is single bond, Y 0 is 4-amidino-2- fluorobenzyl, R is aminomethyl, and X° is hydrido;
2 0
R is 3-aminophenyl, B is 6-amidocarbonylhexyl, A is single bond, Y is 4-amidinobenzyl, R is aminomethyl, and X° is hydrido;
R 2 is 3-aminophenyl, B is tert-butyl, A is single bond, Y 0 is 4- amidinobenzyl, R is aminomethyl, and X° is hydrido;
R 2 is 3-aminophenyl, B is tert-butyl, A is single bond, Y 0 is 4- amidinobenzyl, R is aminomethyl, and X° is hydrido;
0
R is 3-aminophenyl, B is 3-hydroxypropyl, A is single bond, Y is 4- amidinobenzyl, R is aminomethyl, and X° is hydrido;
R 2 is 3-aminophenyl, B is 2-methy Ipropyl, A is single bond, Y 0 is 4- amidino-2-fluorobenzyl, R is aminomethyl, and X° is hydrido;
R 2 is 3-aminophenyl, B is butyl, A is single bond, Y 0 is 4-amidinobenzyl,
R is aminomethyl, and X° is hydrido;
R 2 is 3-aminophenyl, B is 3-methoxy-2-propyl, A is single bond, Y 0 is 4- amidinobenzyl, R is aminomethyl, and X° is hydrido;
R 2 is 3-aminophenyl, B is 3-methoxy-2-propyl, A is single bond, Y 0 is 4- amidinobenzyl, R is aminomethyl, and X° is hydrido;
2 0
R is 3-aminophenyl, B is 2-methoxy-2-ethyl, A is single bond, Y is 4- amidinobenzyl, R is aminomethyl, and X° is hydrido;
R 2 is 3-aminophenyl, B is 2-propyl, A is single bond, Y 0 is 5-amidino-2- thienylmethyl, R is aminomethyl, and X° is hydrido; R 2 is 3-aminophenyl, B is 2-propyl, A is single bond, Y 0 is 4-amidino-3- fluorobenzyl, R is aminomethyl, and X° is hydrido;
2 0
R is 3-carboxyphenyl, B is 2-propyl, A is single bond, Y is 4- amidinobenzyl, R is aminomethyl, and X° is hydrido;
R 2 is 3-aminophenyl, B is 2-propyl, A is single bond, Y 0 is 4-amidino-3- fluorobenzyl, R is aminomethyl, and X° is hydrido.
25. The compound as recited in Claim 2 having the Formula:
B is selected from the group consisting of C3-C7 cycloalkyl and C4 saturated heterocyclyl, wherein each ring carbon is optionally substituted with
33 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 carbon sand a nitrogen adjacent to
9 the carbon atom at the point of attachment is optionally substituted with R or
13 9
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
13 nitrogen adjacent to the R position and two atoms from the point of
12 attachment is optionally substituted with R , a ring carbon three atoms from
10 the point of attachment and adjacent to the R position is optionally
substituted with R , a ring carbon three atoms from the point of attachment
12 33 and adjacent to the R position is optionally substituted with R , and a πng
11 33 carbon atoms from the point of attachment and adjacent to the R and R
34 positions is optionally substituted with R ;
9 11 13
R , R , and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl,
amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano;
10 12
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;
33 34
R and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q ;
A is selected from the group consisting of single covalent bond and
15 7 (CH(R ))pa-(W )π wherein rr is an integer selected from 0 through 1, pa is
7 an integer selected from 0 through 3, and W is selected from the group
7 7 consisting of (R )NC(O) and N(R );
7 R is selected from the group consisting of hydrido, hydroxy and alkyl;
15 R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
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; R2 is Z°-Q;
Z is selected from the group consisting of a covalent single bond, O,
S, NH, and CH2;
Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted
9 by R , the other carbon adjacent to the carbon at the point of attachment is
13 9 optionally substituted by R , a carbon adjacent to R and two atoms from the
carbon at the point of attachment is optionally substituted by R , a carbon
13 adjacent to R and two atoms from the carbon at the point of attachment is
12 10 12 optionally substituted by R , and any carbon adjacent to both R and R is
optionally substituted by R ; Y° is formula (IV):
is O, no more than one of D , D , J , and J is S, one of D , D , J , and J
must be a covalent bond when two of D , D , J , and J are O and S, and no
more than four of D , D , J , and J are N;
_ 16 17 _ 18 19
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 e;
Q is selected from the group consisting of NR R , Q wherein Q is
25 23 24 20 hydrido, and C(NR )NR R , with the provisos that no more than one of R
21 23 24 and R is hydroxy at the same time and that no more than one of R and R is hydroxy at the same time;
20 21 23 24 25
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,
CH2, and CH2CH2.
26. The compound as recited in Claim 25 or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of cyclopropyl, cyclobutyl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, thiaetan-3-yl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[3.1.0]hexan-6-yl, and
33 cycloheptyl, wherein each ring carbon is optionally substituted with R , ring carbons and a nitrogen adjacent to the carbon atom at the point of attachment is
9 13 optionally substituted with R or R , a ring carbon or nitrogen adjacent to the
9 R position and two atoms from the point of attachment is optionally
10 13 substituted with R , and a ring carbon or nitrogen adjacent to the R position and two atoms from the point of attachment is optionally substituted
12 with R ;
9 11 13
R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,333- pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2- hydroxyethyl, 2,2,2-trifluoro- 1-hydroxyethyl, amidocarbonyl, N- methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
R and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl, 1- aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N- dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, fluoro, chloro, bromo, and cyano;
33 34
R and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, 2,2,3,33-pentafIuoropropyl, trifluoromethoxy, 1,1,2,2- tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N- methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1- hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl,
N,N-dimethylamidocarbonyl, cyano, and Q ;
A is selected from the group consisting of single covalent bond, NH, N(CH3), N(OH), CH2, CH3CH, CF3CH, NHC(O), N(CH3)C(O),
C(O)NH, C(O)N(CH3), CH2CH2, CH2CH2CH2, CH3CHCH2, and
CF3CHCH2;
R and X° are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1- aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, methoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo;
R2 is Z°-Q;
Z is selected from the group consisting of a covalent single bond, O,
S, NH, and CH2; Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl,
2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3- pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and l,3,5-triazin-2-yl, wherein a carbon adjacent
9 to the carbon at the point of attachment is optionally substituted by R , the other carbon adjacent to the carbon at the point of attachment is optionally
13 9 substituted by R , a carbon adjacent to R and two atoms from the carbon at
the point of attachment is optionally substituted by R , a carbon adjacent to
13 R and two atoms from the carbon at the point of attachment is optionally
12 10 12 substituted by R , and any carbon adjacent to both R and R is optionally
substituted by R ;
Y is selected from the group consisting of:
~b ~s „ „ 16 „ „ 17 ^ „ 18 ^ „ 19u 1-Q - Q -2-R -3-R -5-R -6-R benzene,
2_Qb-5-QS-6-R17-4-R18-2-R19pyridine,
3-Qb-6-QS-2-R16-5-R18-4-R19pyridine, 2-Qb-4-QS-3-R16-6-R18pyrazine, 3- > . s 18 18 Λ 19 . , . Q -6-Q -2-R -5-R -4-R pyπdazme, > r X . τ 1 Λ 18 . . ,. ^ J> „ Λs „ „ 16 , „ 19 . . „. 2-Q -5-Q -6-R -4-R pyπmidine, 5-Q -2-Q -3-R -6-R pyπmidine, b s 16 19 b s 16 17
3-Q -5-Q -4-R -2-R thiophene, 2-Q -5-Q -3-R -4-R thiophene,
3-Qb-5-QS-4-R16-2-R19furan, 2-Qb-5-QS-3-R16-4-R17furan,
3-Qb-5-QS-4-R16-2-R19pyrrole, 2-Qb-5-QS-3-R16-4-R17pyrrole,
4-Q -2-QS-5-R imidazole, 2-Q -4-QS-5-R imidazole, b s 16 b s 16 3-Q -5-Q -4-R isoxazole, 5-Q -3-Q -4-R isoxazole,
2-Q -5-QS-4-R pyrazole, 4-Q -2-QS-5-R thiazole, and
2-Q -5-QS-4-R thiazole;
16 17 „ 18 19 . Λ _, , ,
R , R , R , and R are independendy selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2333-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1- hydroxyethyl, 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 ;
b be be
Q is selected from the group consisting of Q wherein Q is hydrido
25 23 24 23 24 and C(NR )NR R , with the proviso that no more than one of R and R is hydroxy at the same time;
23 24 25
R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, and hydroxy;
Q is selected from the group consisting of a single covalent bond, CH2 and CH2CH2.
27. The compound as recited in Claim 26 or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-(2R)-bicyclo[2.2.1]-heptyl, oxetan-3- yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl,and bicyclo[3.1.0]hexan-6-yl;
A is selected from the group consisting of single covalent bond, CH2,
NHC(O), CH2CH2, and CH2CH2CH2;
R and X° are independendy selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio, trifluoromethoxy, fluoro, and chloro; R2 is Z°-Q; is selected from the group consisting of a covalent single bond, O,
S, NH, and CH2;
Q is selected from the group consisting of 5-amino-3- amidocarbonylphenyl, 5-amino-2-fluorophenyl, 3-amino- hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl, 3-carboxy-5- hydroxyphenyl, 3-carboxymethyl-5-aminophenyl, 3-carboxymethyl-5- hydroxyphenyl, 3-carboxymethylphenyl, 3-chlorophenyl, 2-chlorophenyl,
2,6-dichlorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 2,5-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3- methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3- methoxyaminophenyl, 3-methoxycarbonyl phenyl, 2-methylaminophenyl, 3- methylaminophenyl, 2-methylphenyl, 3-methyl phenyl, 4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl, 2- trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2- thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl;
Y is selected from the group consisting of: l-Qb^l-QS-2-R16-3-R17-5-R18-6-R19benzene, > ^ Λs 17 „ n18 Λ 19 . . 2-Q -5-Q -6-R -4-R -2-R pyπdine,
„ > , s ^ X6 18 Λ „ 19 . .. 3-Q -6-Q -2-R -5-R -4-R pyπdine, b s 16 19 b s 16 17
3-Q -5-Q -4-R -2-R thiophene, and 2-Q -5-Q -3-R -4-R thiophene;
16 19
R and R are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano;
R and R are optionally Q with the proviso that no more than one
16 , w- 19 . _.b ~b . Λ e of R and R is Q at the same time and that Q is Q ;
17 18
R and R are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano;
Q is selected from the group consisting of Q wherein Q is hydrido
25 23 24 and C(NR )NR R ;
23 24 25
R , R , and R are independently selected from the group consisting of hydrido and methyl; QS is CH2.
28. The compound as recited in Claim 25 having the Formula:
B is selected from the group consisting of C3-C7 cycloalkyl and C4 saturated heterocyclyl, wherein each ring carbon is optionally substituted with
33 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
9 the carbon atom at the point of attachment is optionally substituted with R or
13 9
R , a ring carbon or nitrogen adjacent to the R position and two atoms from
10 the point of attachment is optionally substituted with R , a ring carbon or
13 nitrogen adjacent to the R position and two atoms from the point of
12 attachment is optionally substituted with R , a ring carbon three atoms from
10 the point of attachment and adjacent to the R position is optionally
substituted with R , a ring carbon three atoms from the point of attachment
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
33 34
R positions is optionally substituted with R ;
9 11 13
R , R , and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl,
monoalkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano;
R and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxyamido, and cyano;
33 „34 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; τ,33 . „ h
R is optionally Q ; A is selected from the group consisting of single covalent bond and
15 7
(CH(R ))pa-(W )rr wherein rr is an integer selected from 0 through 1, pa is
7 7 an integer selected from 0 through 3, and W is N(R );
7 R is selected from the group consisting of hydrido and alkyl;
15 R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
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; R2 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
9 by R , the other carbon adjacent to the carbon at the point of attachment is
13 9 optionally substituted by R , a carbon adjacent to R and two atoms from the
carbon at the point of attachment is optionally substituted by R , a carbon
13 adjacent to R and two atoms from the carbon at the point of attachment is
12 10 12 optionally substituted by R , and any carbon adjacent to both R and R is
optionally substituted by R ;
9 11 13
R , R , and R are independendy selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkylamidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano;
10 12
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, arninoalkyl, halo, haloalkyl, carboalkoxy, carboxy, carboxyamido, carboxyalkyl, and cyano;
Y° is formula (IV):
5 6 5 6 wherein D , D , J , and J are independendy selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, K is C, no more than one of D , D , J , and J
5 6 5 6 5 6 5 6 is O, no more than one of D , D , J , and J is S, one of D , D , J , and J
must be a covalent bond when two of D , D , J , and J are O and S, and no
5 6 5 6 more than four of D , D , J , and J are N;
16 17 18 19
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
25 23 24 hydrido, and C(NR )NR R ;
„20 21 23 24 25
R , R , R , R , and R are independendy selected from the group consisting of hydrido and alkyl; QS is CH2.
29. The compound as recited in Claim 28 or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-(2R)-bicyclo[2.2.1]-heptyl, oxetan-3- yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, and bicyclo[3.1.0]hexan-6-yl,
33 wherein each ring carbon is optionally substituted with R , ring carbons and a nitrogen atoadjacent to the carbon atom at the point of attachment is optionally
9 13 9 substituted with R or R , a ring carbon or nitrogen adjacent to the R position and two atoms from the point of attachment is optionally substituted
with R , and a ring carbon or nitrogen adjacent to the R position and two
12 atoms from the point of attachment is optionally substituted with R ;
9 11 13
R , R , and R are independendy selected from the group consisting of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylarnidosulfonyl, hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, and cyano;
10 12
R and R are independently selected from the group consisting of hydrido, amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2- hydroxyethyl, carboxy, carboxymethyl, amino, acetamido, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl, N- methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, N,N- dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, and cyano;
33 R are independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, carboxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, cyano, and Q ;
A is selected from the group consisting of single covalent bond, NH,
N(CH3), CH2, CH3CH, CH2CH2, and CH2CH2CH2;
X° is selected from the group consisting of hydrido, hydroxy, amino, amidino, aminomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and fluoro;
R is selected from the group consisting of hydrido, hydroxy, amino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, methylthio, trifluoromethoxy, fluoro, and chloro;
2 R is selected from the group consisting of phenyl, 2-thienyl, 2-furyl, 2-pyrrolyl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl, and 3-pyridyl,
wherein a carbon adjacent to the carbon at the point of attachment is optionally
9 substituted by R , the other carbon adjacent to the carbon at the point of
13 9 attachment is optionally substituted by R , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by R , a carbon adjacent to R and two atoms from the carbon at the point of
12 attachment is optionally substituted by R , and any carbon adjacent to both
10 12 11
R and R is optionally substituted by R ;
Y is selected from the group consisting of: l_Qb- _QS-2-R16-3-R17-5-R18-6-R19benzene,
2-Q -5-QS-6-R -4-R -2-R pyridine, 2-Q -S-Q^-R^-ΦR1 thiophene,
3-Q -6-QS-2-R -5-R1 -4-R19pyridine, 3-Qb-5-QS-4-R16-2-R19thiophene,
3-Qb-5-QS-4-R16-2-R19furan, 2-Qb-5-QS-3-R16-4-R17furan,
3-Qb-5-QS-4-R16-2-R19pyrrole, 2-Qb-5-QS-3-R16-4-R17pyrrole,
4-Q -2-QS-5-R thiazole, and 2-Q -5-QS-4-R thiazole;
16 17 18 19 R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, amidino, guanidino, methoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethylthio, methylsulfinyl, methylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoromethoxy, fluoro, chloro, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, carboxy, and cyano.
Q is selected from the group consisting of NR R and
25 23 24 b
C(NR )NR R , with the proviso that said Q group is bonded directly to a carbon atom;
20 21 23 24 25
R , R , R , R , and R are independently selected from th group consisting of hydrido, methyl, and ethyl; QS is CH2.
30. The compound as recited in Claim 29 or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-(2R)-bicyclo[2.2.1]-heptyl, oxetan-3-yl, azetidin-1- yl, azetidin-2-yl,and azetidin-3-yl; A is selected from the group consisting of a single covalent bond,
CH2, NHC(O), CH2CH2 and CH2CH2CH2;
X° is selected from the group consisting of hydrido, hydroxy, amino, amidino, aminomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and fluoro; R is selected from the group consisting of hydrido, hydroxy, amino, aminomethyl, cyano, methyl, trifluoromethyl, and fluoro;
2 R is selected from the group consisting of 3-aminophenyl, 2,6- dichlorophenyl, 2-hydroxyphenyl, 5-amino-2-thienyl, and 3-thienyl;
Y is selected from the group consisting of: l-Qb-4-QS-2-R16-3-R17-5-R18-6-R19benzene,
3-Qb-5-QS-4-R16-2-R19thiophene, and 2-Qb-5-QS-3-R16-4-R17thiophene;
„ 16 19 . ., ., , , ., , , . .
R and R are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano; R and R are optionally Q with the proviso that no more than one
,.^ 16 , „ 19 . h , , , ^b . Λbe of R and R is Q at the same time and that Q is Q ;
17 18
R and R are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano;
b be e
Q is selected from the group consisting of Q wherein Q is hydrido
25 23 24 and C(NR )NR R ;
23 24 25
R , R , and R are independently selected from the group consisting of hydrido and methyl; QS is CH2.
31. The compound as recited in Claim 30 or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-(2R)-bicyclo[2.2.1]-heptyl, oxetan-3-yl, azetidin-1- yl, azetidin-2-yl,and azetidin-3-yl;
A is selected from the group consisting of a single covalent bond,
CH2, CH2CH2 and CH2CH2CH2;
X° is selected from the group consisting of hydrido, hydroxy, amino, amidino, aminomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and fluoro;
R is selected from the group consisting of hydrido, hydroxy, amino, aminomethyl, cyano, methyl, trifluoromethyl, and fluoro;
2
R is selected from the group consisting of 3-aminophenyl, 2,6- dichlorophenyl, 2-hydroxyhenyl, phenyl, 5-amino-2-thienyl, and 3-thienyl;
Y is selected from the group consisting of 5-amidino-2-thienylmethyl, 4-amidinobenzyl, 2-fluoro-4-amidinobenzyl, and 3-fluoro-4-amdinobenzyl.
32. A compound as recited in Claim 25 where said compound is selected from the group having the Formula:
2 0
R is 3-aminophenyl, B is cycylopropyl, A is single bond, Y is 4- amidinobenzyl, R is aminomethyl, and X° is hydrido; R 2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y 0 is 4-amidino-2- fluorobenzyl, R is aminomethyl, and X° is hydrido;
2 0
R is 3-aminophenyl, B is cyclobutyl, A is single bond, Y is 4- amidinobenzyl, R is aminomethyl, and X° is hydrido;
2 0 . .
R is 3-aminophenyl, B is cyclopropyl, A is single bond, Y is 4-amidιno- 2-fluorobenzyl, R is aminomethyl, and X° is hydrido;
R 2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y 0 is 4- amidinobenzyl, R is aminomethyl, and X° is hydrido;
R 2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y 0 is 4-amidino-3- fluorobenzyl, R is aminomethyl, and X° is hydrido;
R 2 i •s 3-aminophenyl, B is cyclopentyl, A is single bond, Y 0 is 4- amidinobenzyl, R is aminomethyl, and X° is hydrido;
2 0
R is 5-amino-2-thienyl, B is cyclobutyl, A is single bond, Y is 4- amidinobenzyl, R is aminomethyl, and X is hydrido;
2 0
R is 3-aminophenyl, B is cyclopropyl, A is CH2, Y is 4-amidinobenzyl,
R is aminomethyl, and X° is hydrido;
R2 is 3-aminophenyl, B is 2-(2R)-bicyclo[2.2.1]-heptyl, A is single bond,
Y is 4-amidinobenzyl, R is aminomethyl, and X° is hydrido; o . .
R is 3-aminophenyl, B is cyclopentyl, A is single bond, Y is 4-amidino-
2-fluorobenzyl, R is aminomethyl, and X° is hydrido;
7 0 R is 3-aminophenyl, B is cyclohexyl, A is CH2CH2, Y is 4-
amidinobenzyl, R is aminomethyl, and X° is hydrido;
7 0 .
R is 2-hydroxyphenyl, B is cyclobutyl, A is single bond, Y is 4- amidinobenzyl, R is aminomethyl, and X° is hydrido;
2 0 1
R is phenyl, B is cyclobutyl, A is single bond, Y is 4-amidinobenzyl, R is aminomethyl, and X° is hydrido;
R 2 is 3-thienyl, B is cyclobutyl, A is single bond, Y 0 is 4- amidinobenzyl, R is aminomethyl, and X° is hydrido;
R 7 is 2,6-dichlorophenyl, B is cyclobutyl, A is single bond, Y 0 is 4- amidinobenzyl, R is aminomethyl, and X° is hydrido;
2 0 R is 3-aminophenyl, B is cycylopropyl, A is single bond, Y is 4- amidinobenzyl, R is hydrido, and X° is hydroxymethyl;
R 7 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y 0 is 4-amιdino-2- fluorobenzyl, R is hydrido, and X° is hydroxymethyl;
2 0
R is 3-aminophenyl, B is cyclobutyl, A is single bond, Y is 4- amidinobenzyl, R is hydrido, and X° is hydroxymethyl;
2 0 . .
R is 3-aminophenyl, B is cyclopropyl, A is single bond, Y is 4-amidino-
2-fluorobenzyl, R is hydrido, and X° is hydroxymethyl;
R 2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y 0 is 4- amidinobenzyl, R is hydrido, and X° is hydroxymethyl;
7 0
R is 3-aminophenyl, B is cyclobutyl, A is single bond, Y is 4-amidιno-3- fluorobenzyl, R is hydrido, and X° is hydroxymethyl;
R 7 is 3-aminophenyl, B is cyclopentyl, A is single bond, Y 0 is 4- amidinobenzyl, R is hydrido, and X° is hydroxymethyl;
2 o R is 5-amino-2-thienyl, B is cyclobutyl, A is single bond, Y is 4- amidinobenzyl, R is hydrido, and X° is hydroxymethyl;
7 0
R is 3-aminophenyl, B is cyclopropyl, A is CH2, Y is 4-amidinobenzyl,
R is hydrido, and X° is hydroxymethyl;
2
R is 3-aminophenyl, B is 2-(2R)-bicyclo[2.2.1]-heptyl, A is single bond, Y is 4-amidinobenzyl, R is hydrido, and X° is hydroxymethyl; 0
R is 3-aminophenyl, B is cyclopentyl, A is single bond, Y is 4-amidιno-
2-fluorobenzyl, R is hydrido, and X° is hydroxymethyl;
2 o .
R is 3-aminophenyl, B is cyclohexyl, A is CH2CH2, Y is 4-
amidinobenzyl, R is hydrido, and X° is hydroxymethyl; R 7 is 2-hydroxyphenyl, B is cyclobutyl, A is single bond, Y 0 is 4- amidinobenzyl, R is hydrido, and X° is hydroxymethyl;
R 7 is phenyl, B is cyclobutyl, A is single bond, Y 0 is 4-amidinobenzyl, R 1
is hydrido, and X° is hydroxymethyl;
R 2 is 3-thienyl, B is cyclobutyl, A is single bond, Y 0 is 4- amidinobenzyl, R is hydrido, and X° is hydroxymethyl;
R 2 is 2,6-dichlorophenyl, B is cyclobutyl, A is single bond, Y 0 is 4- amidinobenzyl, R is hydrido, and X° is hydroxymethyl;
2 0
R is 3-aminophenyl, B is cycylopropyl, A is single bond, Y is 4- amidinobenzyl, R is hydroxymethyl, and X° is hydrido;
R 7 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y 0 is 4-amidino-2- fluorobenzyl, R is hydroxymethyl, and X° is hydrido;
2 0
R is 3-aminophenyl, B is cyclobutyl, A is single bond, Y is 4- amidinobenzyl, R is hydroxymethyl, and X° is hydrido;
2 o R is 3-aminophenyl, B is cyclopropyl, A is single bond, Y is 4-amidιno-
2-fluorobenzyl, R is hydroxymethyl, and X° is hydrido;
2 o
R is 3-aminophenyl, B is cyclobutyl, A is single bond, Y is 4- amidinobenzyl, R is hydroxymethyl, and X° is hydrido;
R 2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y 0 is 4-amidino-3- fluorobenzyl, R is hydroxymethyl, and X° is hydrido;
R 2 is 3-aminophenyl, B is cyclopentyl, A is single bond, Y 0 is 4- amidinobenzyl, R is hydroxymethyl, and X° is hydrido;
R 2 is 5-amιno-2-thienyl, B is cyclobutyl, A is single bond, Y 0 is 4- amidinobenzyl, R is hydroxymethyl, and X° is hydrido; R 2 is 3-aminophenyl, B is cyclopropyl, A is CH2, Y 0 is 4-amidinobenzyl,
R is hydroxymethyl, and X° is hydrido;
2 R is 3-aminophenyl, B is 2-(2R)-bicyclo[2.2.1]-heptyl, A is single bond,
Y is 4-amidinobenzyl, R is hydroxymethyl, and X° is hydrido;
R 2 is 3-aminophenyl, B is cyclopentyl, A is single bond, Y 0 is 4-amidmo- 2-fluorobenzyl, R is hydroxymethyl, and X° is hydrido;
R 2 is 3-aminophenyl, B is cyclohexyl, A is CH CH2, Y 0 is 4-
amidinobenzyl, R is hydroxymethyl, and X° is hydrido;
R 2 is 2-hydroxyphenyl, B is cyclobutyl, A is single bond, Y 0 is 4- amidinobenzyl, R is hydroxymethyl, and X° is hydrido;
2 0 1
R is phenyl, B is cyclobutyl, A is single bond, Y is 4-amidinobenzyl, R is hydroxymethyl, and X° is hydrido;
R 2 is 3-thienyl, B is cyclobutyl, A is single bond, Y 0 is 4- amidinobenzyl, R is hydroxymethyl, and X° is hydrido;
R 2 is 2,6-di -chlorophenyl, B is cyclobutyl, A is single bond, Y o is 4- amidinobenzyl, R is hydroxymethyl, and X° is hydrido.
33. The compound as recited in Claim 2 having the Formula:
1 2 1 2 1 wherein 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 is S, one of D , D , J , J and
1 1 2 1 2 1
K must be a covalent bond when two of D , D , J , J and are O and S,
1 2 1 2 1 and no more than four of D , D , J , J and K are N;
32 33 34 35 36
R , R , R , R , and R are independendy selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q ;
B is optionally selected from the group consisting of hydrido, C2-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group
32 33 34 35 36 consisting of R , R , R , R , and R ;
B is selected from the group consisting of C3-C7 cycloalkyl and C4-C6 saturated heterocyclyl, wherein each ring carbon is optionally substituted with
33 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
9 carbon atom at the point of attachment are optionally substituted with R or
13 9 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
nitrogen adjacent to the R position and two atoms from the point of
12 attachment is optionally substituted with R , a ring carbon or nitrogen three
atoms from the point of attachment and adjacent to the R position is
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
33 substituted with R , and a ring carbon or nitrogen four atoms from the point
11 33 of attachment and adjacent to the R and R positions is optionally
34 substituted with R ;
9 10 11 12 13
R , R , R , R , and R are independendy 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 consisting of single covalent bond and
15 7
(CH(R ))pa-(W )rr wherein rr is an integer selected from 0 through 1, pa is
7 an integer selected from 0 through 3, and W is selected from the group
7 7 consisting of (R )NC(O) and N(R );
7 R is selected from the group consisting of hydrido, hydroxy and alkyl;
15 R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
X is selected from the group consisting of hydrido, alkyl, cyano, halo, haloalkyl, haloalkoxy, amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio;
W, X, Y, and Z are independently selected from the group consisting of C(R9), C(R10), C(RU), C(R12), N, N(R10), O, S and a covalent bond with the provisos that one of W, X, Y, and Z is 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 is optionally selected from the group consisting of O and S, and no more than
three of W, X, Y, and Z are optionally selected from the group consisting of N and N(R10);
Y° is formula (IV):
5 6 5 6 wherein 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,
is O, no more than one of D , D , J , and J is S, one of D , D , J , and J
5 6 5 6 must be a covalent bond when two of D , D , J , and J are O and S, and no
more than four of D , D , J , and J are N, with the provisos that R , 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;
16 17 18 19
R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, 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
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
hydrido, N(R26)C(NR25)N(R23)(R24), and C(NR25)NR23R24, with the
20 21 provisos that no more than one of R and R is hydroxy, amino, alkylamino, or
23 24 dialkylamino at the same time and that no more than one of R and R is hydroxy, amino, alkylamino, or dialkylamino at the same time;
20 21 23 24 25 26
R , R , R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino;
Q is selected from the group consisting of a single covalent bond,
CH2, and CH2CH2.
34. The compound as recited in Claim 33 or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl,
2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3- pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,
3-pyridazinyl, 4-pyridazinyl, and 13,5-triazin-2-yl, wherein a carbon adjacent
32 to the carbon at the point of attachment is optionally substituted by R , the other carbon adjacent to the carbon at the point of attachment is optionally
36 32 substituted by R , a carbon adjacent to R and two atoms from the carbon at
33 the point of attachment is optionally substituted by R , a carbon adjacent to
36
R and two atoms from the carbon at the point of attachment is optionally
35 33 35 substituted by R , and any carbon adjacent to both R and R is optionally
34 substituted by R ;
32 33 34 35 36 R , R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy,
isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, 2,2333-pentafluoropropyl, trifluoromethoxy, 1,1,2,2- tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N- methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1- hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-l-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl,
N,N-dimethylamidocarbonyl, cyano, and Q ; B is optionally selected from the group consisting of hydrido, ethyl, 2- propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, 2- butynyl, sec-butyl, t -butyl, isobutyl, 2-methylpropenyl, 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-3-butenyl, 1-hexyl, 2- hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, l-methyl-2-pentenyl, l-methyl-3-pentenyI, l-methyl-4-pentenyl, 1- methyl-2-pentynyi, l-methyl-3 -pentynyl, 3-hexyl, l-ethyl-2-butenyl, 1-ethyl- 3-butenyl, l-propyl-2-propenyl, l-ethyl-2-butynyl, 1-heptyl, 2-heptenyl, 3- heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 2-heptynyl, 3-heptynyl, 4- heptynyl, 5-heptynyl, 2-heptyl, l-methyl-2-hexenyl, l-methyl-3-hexenyl, 1- methyI-4-hexenyl, 1 -methyl -5-hexenyl, l-methyl-2-hexynyl, l-methyl-3- hexynyl, l-methyI-4-hexynyl, 3-heptyl, l-ethyl-2-pentenyl, l-ethyl-3- pentenyl, 1-ethyl -4-pentenyl, l-butyl-2-propenyl, l-ethyl-2-pentynyl, 1-ethyl- 3-pentynyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl, 4-trifluoromethyl-5,5,5- trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl, and 333-trifluoropropyl, wherein each member of group B is optionally substituted at any carbon up to and including 5 atoms from the point of
32 33 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 cyclopropyl, cyclobutyl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, thiaetan-3- yl, cyclopentyl, cyclohexyl, norbornyl, 7-oxabicyclo[2.2.1]heptan-2-yl,
bicyclo[3.1.0]hexan-6-yl, cycloheptyl, 2-morpholinyl, 3-morpholinyl, 4- morpholinyl, 1 -piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3- piperidinyl, 4-piperidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2- dioxanyl, 4H-2-pyranyl, 4H-3-ρyranyl, 4H-4-pyranyl, 4H-pyran-4-one-2-yl, 4H-pyran-4-one-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2- tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 2- tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each ring carbon is
33 optionally substituted with R , a ring carbon and nitrogen atoms adjacent to
9 the carbon atom at the point of attachment is optionally substituted with R or
13 9 R , a πng carbon or nitrogen atom adjacent to the R position and two atoms
from the point of attachment is optionally substituted with R , and a ring
13 carbon or nitrogen atom adjacent to the R position and two atoms from the
12 point of attachment is optionally substituted with R ;
9 11
R and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,333- pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl,
N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2- hydroxyethyl, 2,2,2-trifluoro- 1-hydroxyethyl, amidocarbonyl, N- methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
Λ10 12 _, , , Λ r ■ ■ r
R and R are independently selected from the group consisting ot hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl, 1- aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, NJM- dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,
2,2,2-trifluoro- 1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, fluoro, chloro, bromo, and cyano;
A is selected from the group consisting of single covalent bond, NH, N(CH ),
N(OH), CH2, CH3CH, CF3CH, NHC(O), N(CH3)C(O), C(O)NH,
C(O)N(CH3), CH2CH2, CH2CH2CH2, CH3CHCH2, and CF3CHCH2;
A is optionally selected from the group consisting of CH N(CH3),
CH2N(CH2CH3), CH2CH2N(CH3), and CH2CH2N(CH2CH3) with the proviso that B is hydrido; X° is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1-aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, methoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2- tetrafluoroethoxy, fluoro, chloro, and bromo;
W, X, Y, and Z are independently selected from the group consisting of CH, N, CF, CC1, C-CN, C-CH3, C-CH2CH3, C-NH2, C-CH2NH2, C-CH2NHCH3, C-NHCH3, C-N(CH3)2, C-CH(NH2)CH3, C-CH2CH2NH2, C-NHOCH3, C-NHOCH2CH3, C-C(NH)NH2, C-C(NOH)NH2, C-OH, C-CH2OH, C-CH2CH2OH, C-CH(OH)CH3, C-OCH3, C-OCH2CH3, C-CO2H, C-CO2CH3, C-C(O)NH2, C-C(O)NHCH3, C-C(O)NH(CH3)2, C-CH2CO2H, C-SO2NH2, C-SO2NHCH3, C-NH(O)CCH3, and C-NH(O)CCF3;
Y is selected from the group consisting of:
Λb „ Λs , 16 „ 17 ^ „18 , „ 19L 1-Q -A-Q -2-R -3-R -5-R -6-R benzene,
2-Qb-5-QS-6-R17-4-R18-2-R19pyridine,
„ > , X> n 16 18 „ „ 19 . „ „ h s „ 16 , ,. 18 . „ 3-Q -6-Q -2-R -5-R -4-R pyπdine, 2-Q -4-Q -3-R -6-R pyrazine, 3- > , ^ ^ „ 18 18 Λ 19 . _, . Q -6-Q -2-R -5-R -4-R pyπdaz e,
,, > <■ Λs , „ 17 Λ n 18 . . .. „ „ <; 16 „ 19 .
2-Q -5-Q -6-R -4-R pyπmidine, 5-Q -2-Q -3-R -6-R pyπmidine,
3-Q -5-QS-4-R -2-R thiophene, 2-Q -5-QS-3-R -4-R thiophene, b s 16 19 b s 16 17 3-Q -5-Q -4-R -2-R furan, 2-Q -5-Q -3-R -4-R furan,
3-Qb-5-QS-4-R16-2-R19pyrrole, 2-Qb-5-QS-3-R16-4-R17pyrrole, b s 19 b s 17
4-Q -2-Q -5-R imidazole, 2-Q -4-Q -5-R imidazole, b s 16 b s 16
3-Q -5-Q -4-R isoxazole, 5-Q -3-Q -4-R isoxazole, b s 16 b s 19
2-Q -5-Q -4-R pyrazole, 4-Q -2-Q -5-R thiazole, and b s 17 2-Q -5-Q -4-R thiazole;
„ 16 17 „ 18 J T, 19 . _, J , ,
R , R , R , and R are independendy selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,23,33-ρentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1- hydroxyethyl, 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 ;
hydrido, C(NR25)NR23R24, and N(R26)C(NR25)N(R23)(R24), with the
20 21 provisos that no more than one of R and R is hydroxy at the same time and
23 24 that no more than one of R and R is hydroxy at the same time;
20 21 23 24 25 26
R , R , R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy; Q is selected from the group consisting of a single covalent bond,
CH2, and CH2CH2.
35. The compound as recited in Claim 34 or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of 2-aminophenyl, 3- aminophenyl, 3-amidinophenyl, 4-amidinophenyl, 3-carboxyphenyl, 3- carboxy-5-hydroxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4- dichlorophenyl, 2-fluorophenyl, 3 -fluorophenyl, 3,4-difluorophenyl, 3- hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyaminophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3- trifluoromethylphenyl, 2-imidazoyl, 2-pyridyl, 3-pyridyl, 5-chloro-3- trifluoromethyl-2-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, and 3- trifIuoromethyl-2-pyridy 1 ;
B is optionally selected from the group consisting of hydrido,ethyl, 2- propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butyl, (R)-2-butyl,(S)-2- butyl, tert-butyl, isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2- trifluoroethyl, 6-amidocarbonylhexyl, 4-methyl-2-pentyl, 3-hydroxypropyl, 3- methoxy-2-propyl, 2-methoxyethyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2- dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2-hydroxyethyl, 2- amidinoethyl, 2-guanidinoethyl, 3-guanidinopropyl, 4-guanidinobutyl, 3- hydroxypropyl, 4-hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl, 3- methylbutyl, 2-methylbutyl, (S)-2-methyl butyl, 3-aminopropyl, 2-hexyl, and 4-aminobutyl;
B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxalan-2-yl, 2-(2R)- bicyclo[2.2.1]-heptyl, 1-pyrrolidinyl, 1-piperidinyl, l,l-dioxothiolan-3-yl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, 7- oxabicyclo[2.2.1]heptan-2-yl, bicyclol3.1.0]hexan-6-yl, 2-morpholinyl, 3-
morpholinyl, 4-morpholinyl, 1 -piperazinyl, 2-piperazinyl, 1-piperidinyl, 2- piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3- pyrrolidinyl, 2-dioxanyl, 4H-2-pyranyl, 4H-3-pyranyl, 4H-4-pyranyl, 4H- pyran-4-one-2-yl, 4H-pyran-4-one-3-yl, 2-tetrahydrofuranyl, 3- tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4- tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl;
A is selected from the group consisting of single covalent bond, CH ,
NHC(O), CH2CH2, and CH2CH2CH2;
X° is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio, trifluoromethoxy, fluoro, and chloro;
W and Z are independently selected from the group consisting of CH,
N, CF, CCl, C-CN, C-NH2, C-CH2NH2, C-NHCH3, C-OH, C-CH2OH, C- CO2H, and C-C(O)NH2;
X and Y are independendy selected from the group consisting of CH, N, CF, C-CN, C-CH3, C-NH2, C-CH2NH2, C-CH2NHCH3, C-NHCH3, C-CH(NH2)CH3, C-CH2CH2NH2, C-NHOCH3, C-C(NH)NH2, C-C(NOH)NH2, C-OH, C-CH2OH, C-CH2CH2OH, C-CH(OH)CH3, C-OCH3, C-CO2H, C-C(O)NH2, C-C(O)NHCH3, C-CH2CO2H, and C-SO2NH2;
Y is selected from the group consisting of: l-Qb^_QS.2.R16.3. 17-5-R18-6-R19benzene,
2-Qb-5-QS-6-R17-4-R18-2-RI9pyridine,
-, > . ^s 16 18 Λ 19 . ,. 3-Q -6-Q -2-R -5-R -4-R pyπdine,
3-Q -5-QS-4-R -2-R thiophene, and 2-Q -5-QS-3-R -4-R thiophene;
R and R are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, 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 ;
17 18
R and R are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano; b be be
Q is selected from the group consisting of Q wherein Q is hydrido
25 23 24 and C(NR )NR R ;
„23 24 25
R , R , and R are independendy selected from the group consisting of hydrido and methyl;
QS is CH2.
36. The compound as recited in Claim 33 having the Formula:
1 2 1 2 1 wherein 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
1 1 2 1 2 1
K must be a covalent bond when two of D , D , J , J and K are O and S,
1 2 1 2 1 and no more than four of D , D , J , J and K are N;
32 33 34 35 36
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 ;
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 consisting of Rr 32 , R r,33 , T R.3 , R35 , and J r R,36 ;
B is optionally selected from the group consisting of C3-C7 cycloalkyl and C4-C6 saturated heterocyclyl, wherein each ring carbon is optionally
33 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 carbon atom at the point of attachment are optionally
9 13 9 substituted with R or 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 πng carbon or nitrogen adjacent to the R position and two atoms
12 from the point of attachment is optionally substituted with R , a ring carbon
10 or nitrogen three atoms from the point of attachment and adjacent to the R
position is optionally substituted with R , a ring carbon or nitrogen three
12 atoms from the point of attachment and adjacent to the R position is
33 optionally substituted with R , and a ring carbon or nitrogen four atoms from
11 33 the point of attachment and adjacent to the R and R positions is optionally
su Lbsti •tuted , wi-th^ R3 ;
9 11 13
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;
10 12
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;
A is selected from the group consisting of single covalent bond and
15 7
(CH(R ))pa-(W )rr wherein rr is an integer selected from 0 through 1, pa is
7 7 an integer selected from 0 through 3, and W is N(R );
7 R is selected from the group consisting of hydrido, hydroxy and alkyl;
15 R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
X is selected from the group consisting of hydrido, alkyl, cyano, halo, haloalkyl, haloalkoxy, amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio;
R1 and R2 are taken together to be -W=X-Y=Z- wherein -W=X-Y=Z- forms a ring selected from the group consisting of a heteroaryl ring having 6 contiguous members and an aryl;
W, X, Y, and Z are independendy selected from the group consisting
9 10 11 12 of C(R ), C(R ), C(R ), C(R ), and N;
Y° is formula (IV):
5 6 5 6 wherein 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
2 5 6 5 6 than one is a covalent bond, K is C, no more than one of D , D , J , and J
5 6 5 6 5 6 5 6 is O, no more than one of D , D , J , and J is S, one of D , D , J , and J
5 6 5 6 must be a covalent bond when two of D , D , J , and J are O and S, and no
5 6 5 6 16 17 more than four of D , D , J , and J are N, with the provisos that R , 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
hydrido, N(R26)C(NR25)N(R23)(R24), and C(NR25)NR23R24;
20 21 23 24 25 26 R , R , R , R , R , and R are independently selected from the group consisting of hydrido and alkyl;
QS is CH2.
37. The compound as recited in Claim 36 or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrroIyl, 2-imidazolyl, 4-imidazolyl, 3- pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, and 5-isoxazolyl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted
32 by R , the other carbon adjacent to the carbon at the point of attachment is
36 32 optionally substituted by R , a carbon adjacent to R and two atoms from
33 the carbon at the point of attachment is optionally substituted by R , a carbon
36 adjacent to R and two atoms from the carbon at the point of attachment is
35 33 35 optionally substituted by R , and any carbon adjacent to both R and R is
34 optionally substituted by R ;
are independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, carboxy, cyano, and Q ;
B is optionally selected from the group consisting of hydrido, ethyl, 2- propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 2-butynyl, sec- butyl, tert-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 2-methyl-2- butenyl, 3-methylbutyl, 3-methyl-2-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4- hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, l-methyl-2-ρentenyl, 1- methyl-3-pentenyl, l-methyl-2-pentynyl, l-methyl-3-pentynyl, 3-hexyl, 1- ethyl-2-butenyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 2- heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, l-methyl-2-hexenyl, l-methyl-3-hexenyl, l-methyl-4-hexenyl, 1 -methyl -2-hexynyl, l-methyl-3- hexynyl, 1 -methyl -4-hexynyl, 3-heptyl, l-ethyl-2-pentenyl, l-ethyl-3- pentenyl, l-ethyl-2-pentynyl, l-ethyl-3-pentynyl, 2,2,2-trifluoroethyl, 2,2- difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4- trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl, and 333-trifluoropropyl, wherein each member of group B is optionally substituted at any carbon up to and including 5 atoms from the point of attachment of B to A with one or more of the group consisting of r R>32 , T R,33 , R r.34 , r R,35 , and , R 6 ;
B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, oxetan-3-yl, azetidin-3-yl, thiaetan-3-yl, cyclopentyl, cyclohexyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-tetrahydrofuranyl, 3- tetrahydrofuranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each
33 ring carbon is optionally substituted with R , a ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment is optionally
9 13 9 substituted with R or R , a ring carbon or nitrogen atom adjacent to the R position and two atoms from the point of attachment is optionally substituted
with R , and a πng carbon or nitrogen atom adjacent to the R position and
12 two atoms from the point of attachment is optionally substituted with R ;
9 11 13
R , R , and R are independendy selected from the group consisting of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, and cyano;
10 12
R and R are independently selected from the group consisting of hydrido, amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2- hydroxyethyl, carboxy, carboxymethyl, amino, acetamido, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl, N- methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, N,N- dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, and cyano; A is selected from the group consisting of single covalent bond, NH,
N(CH3), CH2, CH3CH, and CH2CH2;
A is optionally selected from the group consisting of CH2N(CH3),
CH2N(CH2CH3), CH2CH2N(CH3), and CH2CH2N(CH2CH3) with the proviso that B is hydrido;
X° is selected from the group consisting of hydrido, hydroxy, amino, amidino, aminomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and fluoro;
W and Z are independently selected from the group consisting of CH, N, CF, CCl, C-CN, C-NH2, C-CH2NH2, C-NHCH3, C-OH, C-CH2OH, C-
CO2H, and C-C(O)NH2;
X and Y are independently selected from the group consisting of CH, N, CF, C-CN, C-CH3, C-NH2, C-CH2NH2, C-CH2NHCH3, C-NHCH3,
C-CH(NH2)CH3, C-CH2CH2NH2. C-NHOCH3, C-C(NH)NH2,
C-3202
C-C(NOH)NH2, C-OH, C-CH2OH, C-CH2CH2OH, C-CH(OH)CH3, C-OCH3, C-CO2H, C-C(O)NH2, C-C(O)NHCH3, C-CH2CO2H, and
C-SO2NH2; b 20 21
Q is selected from the group consisting of NR R ,
C(NR25)NR23R24, and N(R26)C(NR25)N(R23)(R24), with the proviso that b said Q group is bonded direcdy to a carbon atom;
20 21 23 24 25 26
R , R , R , R , R , and R are independently selected from the group consisting of hydrido, methyl, and ethyl; QS is CH2.
10
38. The compound as recited in Qaim 37 or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of 2-aminophenyl, 3- aminophenyl, 3-amidinophenyl, 4-amidinophenyl, 3-carboxyphenyl, 3-
15 carboxy-5-hydroxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4- dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 3- hydroxy phenyl, 4-hydroxyphenyl, 3-methoxyaminophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3- trifluoromethylphenyl, 2-imidazoyl, 2-pyridyl, 3-pyridyl, 5-chloro-3-
20 trifluoromethyl-2-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, and 3- trifluoromethy 1-2-pyridy 1 ;
B is optionally selected from the group consisting of hydrido,ethyl, 2- propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butyl, (R)-2-butyl,(S)-2- butyl, tert-butyl, isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-
25 trifluoroethyl, 6-amidocarbonylhexyl, 4-methyl-2-pentyl, 3-hydroxypropyl, 3- methoxy-2-propyl, 2-methoxy ethyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2- dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2-hydroxyethyl, 2- amidinoethyl, 2-guanidinoethyl, 3-guanidinopropyl, 4-guanidinobutyl, 3- hydroxypropyl, 4-hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl, 3-
30 methylbutyl, 2-methylbutyl, (S)-2-methylbutyl, 3-aminopropyl, 2-hexyl, and 4-aminobutyl;
B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxalan-2-yl, 2-(2R)-bicyclo[2.2.1]- heptyl, l,l-dioxothiolan-3-yl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, 1-pyrrolidinyl and 1-piperidinyl; A is selected from the group consisting of single covalent bond, CH ,
CH3CH, and CH2CH2;
X° is selected from the group consisting of hydrido, hydroxy, amino, amidino, aminomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and fluoro; W and Z are independendy selected from the group consisting of CH,
N, CF, CCl, C-CN, C-NH2, C-CH2NH2, C-OH, C-CH2OH, C-CO2H, and
C-C(O)NH2;
X and Y are independently selected from the group consisting of CH, N, CF, C-CN, C-NH2, C-CH2NH2, C-CH2CH2NH2, C-C(NH)NH2, C-C(NOH)NH2, C-OH, C-CH2OH, C-CH2CH2OH,
C-CO2H, C-C(O)NH2, and C-CH2CO2H; b 20 21
Q is selected from the group consisting of NR R ,
25 23 24 26 25 23 24
C(NR )NR R , and N(R )C(NR )N(R )(R ), with the proviso that b said Q group is bonded direcdy to a carbon atom;
20 21 23 24 25 26 R , R , R , R , R , and R are independendy selected from the group consisting of hydrido, methyl, and ethyl;
Qs is CH2.
39. The compound as recited in Claim 38 or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of 3-aminophenyl, 3- amidinophenyl, 4-amidinophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4- dichlorophenyl, 2-fluorophenyl, 4-methylphenyl, phenyl, 2-imidazoyl, 3- pyridyl, 4-pyridyl, and 3-trifluoromethyl-2-pyridyl;
B is optionally selected from the group consisting of hydrido.ethyl, 2- propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butyl, (R)-2-butyl,(S)-2- butyl, tert-butyl, isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2- trifluoroethyl, 6-amidocarbonylhexyl, 4-methyl-2-pentyl, 3-hydroxypropyl, 3- methoxy-2-propyl, 2-methoxy ethyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2- dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2-hydroxyethyl, 2- amidinoethyl, 2-guanidinoethyl, 3-guanidinopropyl, 4-guanidinobutyl, 3- hydroxypropyl, 4-hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl, 3- methylbutyl, 2-methylbutyl, (S)-2-methylbutyl, 3-aminopropyl, 2-hexyl, and 4-aminobutyl;
B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxalan-2-yl, 2-(2R)-bicyclo[2.2.1]- heptyl, l,l-dioxothiolan-3-yl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, andl-piperidinyl; A is selected from the group consisting of single covalent bond, CH ,
CH3CH, and CH2CH2;
X° is selected from the group consisting of hydrido, hydroxy, amino, amidino, aminomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and fluoro; W and Z are independendy selected from the group consisting of CH,
N, CF, CCl, C-CN, C-NH2, C-CH2NH2, C-OH, C-CH2OH, C-CO2H, and
C-C(O)NH2;
X and Y are independently selected from the group consisting of CH, N, CF, C-CN, C-NH2, C-CH2NH2, C-CH2CH2NH2, C-C(NH)NH2, C-C(NOH)NH2, C-OH, C-CH2OH, C-CH2CH2OH, C-CO2H, C-C(O)NH2, and C-CH2CO2H;
Y is selected from the group consisting of amidino-2-thienylmethyl, 4-amidinobenzyl, 2-fluoro-4-amidinobenzyl, and 3-fluoro-4-amidinobenzyl.
40. A compound as recited in Qaim 33 where said compound is selected from the group having the Formula:
or a pharmaceutically acceptable salt thereof, wherein:
B is 3-chlorophenyl, A is CH2CH2, Y is 4-amidinobenzyl, W is CH, X
is C-NH2, Y is C-CH2CO2H, Z is CH, and X° is hydrido;
B is phenyl, A is CH2, Y° is 4-amidinobenzyl, W is N, X is C-CH2NH2,
Y is C-CO2H, Z is CH, and X° is hydrido;
B is 3-chlorophenyl, A is CH2CH2, Y is 4-amidinobenzyl, W is C-OH,
X is C-CH2CH2NH2, Y is C-OH, Z is CH, and X° is hydrido;
B is 2-imidazoyl, A is CH2CH2CH2, Y is 4-amidinobenzyl, W is C-
NH2, X is C-CH2OH, Y is C- NH2, Z is CH, and X° is hydrido;
B is 2,2,2-trifluoroethyl, A is single bond, Y is 4-amidinobenzyl, W is CH, X is C-NH2, Y is C-CH2CO2H, Z is CH, and X° is hydrido;
B is (S)-2-butyl, A is single bond, Y is 4-amidinobenzyl, W is N, X is C- CH2NH2, Y is C-CO2H, Z is CH, and X° is hydrido; B is isopropyl, A is single bond, Y is 4-amidinobenzyl, W is C-OH, X is
C-CH2CH2NH2, Y is C-OH, Z is CH, and X° is hydrido;
B is isopropyl, A is single bond, Y is 4-amidinobenzyl, W is C-NH2, X
is C-CH2OH, Y is C- NH2, Z is CH, and X° is hydrido;
B is hydrido, A is CH2(CH3)N, Y° is 4-amidinobenzyl, W is CH, X is C-
NH2, Y is C-CH2CO2H, Z is CH, and X° is hydrido;
B is ethyl, A is single bond, Y is 4-amidinobenzyl, W is N, X is C- CH2NH2, Y is C-CO2H, Z is CH, and X° is hydrido; B is ethyl, A is single bond, Y is 4-amidino-2-fluorobenzyl, W is C-OH,
X is C-CH2CH2NH2, Y is C-OH, Z is CH, and X° is hydrido;
B is 2-propenyl, A is single bond, Y is 4-amidinobenzyl, W is C-NH2, X
is C-CH2OH, Y is C- NH2, Z is CH, and X° is hydrido;
B is isopropyl, A is single bond, Y is 4-amidino-2-fIuorobenzyl, W is CH, X is C-NH2, Y is C-CH2CO2H, Z is CH, and X° is hydrido;
B is isopropyl, A is single bond, Y is 4-amidinobenzyl, W is N, X is C-
CH2NH2, Y is C-CO2H, Z is CH, and X° is hydrido;
B is 2-butyl, A is single bond, Y is 4-amidinobenzyl, W is C-OH, X is C-CH2CH2NH2, Y is C-OH, Z is CH, and X° is hydrido;
B is (R)-2-butyl, A is single bond, Y is 4-amidinobenzyl, W is C-NH2,
X is C-CH2OH, Y is C- NH2, Z is CH, and X° is hydrido;
B is 2-propynyl, A is single bond, Y is 4-amidinobenzyl, W is CH, X is C-NH2, Y is C-CH2CO2H, Z is CH, and X° is hydrido;
B is hydrido, A is CH2, Y is 4-amidinobenzyl, W is N, X is C-
CH2NH2, Y is C-CO2H, Z is CH, and X° is hydrido;
B is cycylopropyl, A is single bond, Y is 4-amidinobenzyl, W is C-OH, X is C-CH2CH2NH2, Y is C-OH, Z is CH, and X° is hydrido;
B is cyclobutyl, A is single bond, Y is 4-amidino-2-fluorobenzyl, W is C- NH2, X is C-CH2OH, Y is C- NH2, Z is CH, and X° is hydrido;
B is cyclobutyl, A is single bond, Y is 4-amidinobenzyl, W is CH, X is C-NH2, Y is C-CH2CO2H, Z is CH, and X° is hydrido; B is cyclopropyl, A is single bond, Y is 4-amidino-2-fluorobenzyl, W is
N, X is C-CH2NH2, Y is C-CO2H, Z is CH, and X° is hydrido;
B is cyclobutyl, A is single bond, Y is 4-amidinobenzyl, W is C-OH, X is C-CH2CH2NH2, Y is C-OH, Z is CH, and X° is hydrido;
B is cyclobutyl, A is single bond, Y is 4-amidino-3-fluorobenzyl, W is C- NH2, X is C-CH2OH, Y is C- NH2, Z is CH, and X° is hydrido;
B is cyclopentyl, A is single bond, Y is 4-amidinobenzyl, W is CH, X is C-NH2, Y is C-CH2CO2H, Z is CH, and X° is hydrido;
B is cyclobutyl, A is single bond, Y is 4-amidinobenzyl, W is N, X is C- CH2NH2, Y is C-CO2H, Z is CH, and X° is hydrido;
B is cyclopropyl, A is CH2, Y is 4-amidinobenzyl, W is C-OH, X is C-
CH2CH2NH2, Y is C-OH, Z is CH, and X° is hydrido;
B is 2-(2R)-bicyclo[2.2.1]-heρtyl, A is single bond, Y° is 4- amidinobenzyl, W is C-NH2, X is C-CH2OH, Y is C- NH2, Z is CH, and X° is hydrido; B is cyclopentyl, A is single bond, Y is 4-amidino-2-fluorobenzyl, W is
CH, X is C-NH2, Y is C-CH2CO2H, Z is CH, and X° is hydrido;
B is cyclohexyl, A is CH2CH2, Y is 4-amidinobenzyl, W is N, X is
C-CH2NH2, Y is C-CO2H, Z is CH, and X° is hydrido;
B is 3-chlorophenyl, A is CH2CH2, Y is 4-amidinobenzyl, W is C-OH,
X is C-CH2CH2NH2, Y is C-OH, Z is CH, and X° is hydrido;
B is phenyl, A is CH2, Y is 4-amidinobenzyl, W is C-NH2, X is C-
CH2OH, Y is C- NH2, Z is CH, and X° is hydrido;
B is 3-chlorophenyl, A is CH2CH2, Y is 4-amidinobenzyl, W is CH, X
is C-NH2, Y is C-CH2CO2H, Z is CH, and X° is hydrido;
B is 2-imidazoyl, A is CH2CH2CH2, Y is 4-amidinobenzyl, W is N, X
is C-CH2NH2, Y is C-CO2H, Z is CH, and X° is hydrido;
B is 2,2,2-trifluoroethyl, A is single bond, Y is 4-amidinobenzyl, W is C- OH, X is C-CH2CH2NH2, Y is C-OH, Z is CH, and X° is hydrido;
B is (S)-2-butyl, A is single bond, Y is 4-amidinobenzyl, W is C-NH2,
X is C-CH2OH, Y is C- NH2, Z is CH, and X° is hydrido;
B is isopropyl, A is single bond, Y is 4-amidinobenzyl, W is CH, X is C- NH2, Y is C-CH2CO2H, Z is CH, and X° is hydrido; B is isopropyl, A is single bond, Y is 4-amidinobenzyl, W is N, X is C-
CH2NH2, Y is C-CO2H, Z is CH, and X° is hydrido;
B is hydrido, A is CH2(CH3)N, Y° is 4-amidinobenzyl, W is C-OH, X is
C-CH2CH2NH2, Y is C-OH, Z is CH, and X° is hydrido;
B is ethyl, A is single bond, Y is 4-amidinobenzyl, W is C-NH2, X is C-
CH2OH, Y is C- NH2, Z is CH, and X° is hydrido;
B is ethyl, A is single bond, Y is 4-amidino-2-fluorobenzyl, W is CH, X is C-NH2, Y is C-CH2CO2H, Z is CH, and X° is hydrido;
B is 2-propenyl, A is single bond, Y is 4-amidinobenzyl, W is N, X is C- CH2NH2, Y is C-CO2H, Z is CH, and X° is hydrido;
B is isopropyl, A is single bond, Y is 4-amidino-2-fluorobenzyl, W is C- OH, X is C-CH2CH2NH2, Y is C-OH, Z is CH, and X° is hydrido;
B is isopropyl, A is single bond, Y is 4-amidinobenzyl, W is C-NH2, X
is C-CH2OH, Y is C- NH2, Z is CH, and X° is hydrido;
B is 2-butyl, A is single bond, Y is 4-amidinobenzyl, W is CH, X is C- NH2, Y is C-CH2CO2H, Z is CH, and X° is hydrido;
B is (R)-2-butyl, A is single bond, Y is 4-amidinobenzyl, W is N, X is C-CH2NH2, Y is C-CO2H, Z is CH, and X° is hydrido;
B is 2-propynyl, A is single bond, Y is 4-amidinobenzyl, W is C- OH, X is C-CH2CH2NH2, Y is C-OH, Z is CH, and X° is hydrido;
B is hydrido, A is CH2, Y is 4-amidinobenzyl, W is C-NH2, X is C-
CH2OH, Y is C- NH2, Z is CH, and X° is hydrido; B is cycylopropyl, A is single bond, Y is 4-amidinobenzyl, W is CH, X is C-NH2, Y is C-CH2CO2H, Z is CH, and X° is hydrido;
B is cyclobutyl, A is single bond, Y is 4-amidino-2-fluorobenzyl, W is N, X is C-CH2NH2, Y is C-CO2H, Z is CH, and X° is hydrido;
B is cyclobutyl, A is single bond, Y is 4-amidinobenzyl, W is C-OH, X is C-CH2CH2NH2, Y is C-OH, Z is CH, and X° is hydrido;
B is cyclopropyl, A is single bond, Y is 4-amidino-2-fluorobenzyl, W is C-NH2, X is C-CH2OH, Y is C- NH2, Z is CH, and X° is hydrido;
B is cyclobutyl, A is single bond, Y is 4-amidinobenzyl, W is CH, X is C-NH2, Y is C-CH2CO2H. Z is CH, and X° is hydrido;
B is cyclobutyl, A is single bond, Y is 4-amidino-3-fluorobenzyl, W is N, X is C-CH2NH2, Y is C-CO2H, Z is CH. and X° is hydrido;
B is cyclopentyl, A is single bond, Y is 4-amidinobenzyl, W is C-OH, X is C-CH2CH2NH2, Y is C-OH, Z is CH, and X° is hydrido;
B is cyclobutyl, A is single bond, Y is 4-amidinobenzyl, W is C-NH2, X
is C-CH2OH, Y is C- NH2, Z is CH, and X° is hydrido;
B is cyclopropyl, A is CH2, Y is 4-amidinobenzyl, W is CH, X is C-
NH2, Y is C-CH2CO2H, Z is CH, and X° is hydrido;
B is 2-(2R)-bicyclo[2.2.1]-heptyl, A is single bond, Y° is 4- amidinobenzyl, W is N, X is C-CH2NH2, Y is C-CO2H, Z is CH, and X° is hydrido;
B is cyclopentyl, A is single bond, Y is 4-amidino-2-fluorobenzyl, W is
C-OH, X is C-CH2CH2NH2, Y is C-OH, Z is CH, and X° is hydrido;
B is cyclohexyl, A is CH2CH2, Y is 4-amidinobenzyl, W is C-NH2,
X is C-CH2OH, Y is C- NH2, Z is CH, and X° is hydrido.
41. The compound having the Formula:
32 33 34 35 36
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, haloalkanoyl, nitro, lower alkylamino, alkylthio, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyalkyl, alkylamino, carboalkoxy, carboxy, carboxamido, cyano, and Q ; 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 ,
34 35 J 36 R , R , and R ;
B is optionally selected from the group consisting of C3-C12 cycloalkyl and C4-C saturated heterocyclyl, wherein each ring carbon is
33 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 carbon atom at the point of attachment
9 13 are optionally substituted with R or R , a ring carbon or nitrogen adjacent to
9 the R position and two atoms from the point of attachment is optionally
10 13 substituted with R , a πng carbon or nitrogen adjacent to the R position
12 and two atoms from the point of attachment is optionally substituted with R ,
10 a ring carbon three atoms from the point of attachment and adjacent to the R
position is optionally substituted with R , a ring carbon three atoms from the
12 point of attachment and adjacent to the R position is optionally substituted
33 with R , and a ring carbon four atoms from the point of attachment and
11 33 34 adjacent to the R and R positions is optionally substituted with R ;
9 10 11 12 13
R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl, amidino, guanidino, alkylenedioxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfamido, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxamido, and cyano; A is selected from the group consisting of single covalent bond and
15 7
(CH(R ))pa-(W )π wherein rr is an integer selected from 0 through 1 , pa is
7 an integer selected from 0 through 3, and W is selected from the group
consisting of O, S, C(O), (R?)NC(O), (R7)NC(S), and N(R?);
7 R is selected from the group consisting of hydrido, hydroxy and alkyl;
15 R is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl:
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;
R2 is Z°-Q;
Z is selected from the group consisting of covalent single bond and
41 42 41
(CR R )q wherein q is an integer selected from 1 through 2, (CH(R ))σ- fi 42
W -(CH(R ))_ wherein g and p are integers independently selected from 0
through 3 and W is selected from the group consisting of O, S, and N(R ),
41 22 42 and (CH(R ))e-W -(CH(R ))^ wherein e and h are integers independently
selected from 0 through 1 and W^ is selected from the group consisting of
41 42 CR =CR , 1,2-cycloρroρyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3- cyclohexyl, 1,2-cyclopentyl, 13-cyclopentyl, 2,3-morpholinyl, 2,4- morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 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, 23-tetrahydrofuranyl, 2,4- tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the proviso that Z is direcdy bonded to the pyrazinone ring;
41 42
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
9 adjacent to the carbon at the point of attachment is optionally substituted by R , the other carbon adjacent to the carbon at the point of attachment is optionally
13 9 substituted by R , a carbon adjacent to R and two atoms from the carbon at
the point of attachment is optionally substituted by R , a carbon adjacent to
13 R and two atoms from the carbon at the point of attachment is optionally
substituted by R , and any carbon adjacent to both R and R is optionally
substituted by R ;
4a 4a
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,
C(O)N(H), (H)NC(O), (R?)NS(O)2, and S(O)2N(R?);
37 1R Q is (CR R )tø wherein b is an integer selected from 1 through 4,
37 R is selected from the group consisting of hydrido, alkyl, and haloalkyl, and
38 . R is selected from the group consisting of hydrido, alkyl, haloalkyl, aroyl, and heteroaroyl with the provisos that there is at least one aroyl or heteroaroyl substituent, that no more than one aroyl or heteroaroyl is bonded to
37 38 (CR R )tø at the same time, that said aroyl and said heteroaroyl are optionally substituted at from one through three of the ring carbons with a substituent selected from the group consisting of R , R , R , and R ,
37 38 that said aroyl and said heteroaroyl are bonded to the CR R that is direcdy bonded to E , that is no more than one alkyl or one haloalkyl is bonded to a
37 38 CR R at the same time, and that said alkyl and haloalkyl are bonded to a carbon other than the one bonding the aroyl or heteroaroyl;
16 17 18 19
R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
R, 16 and , r R, l9 are opti .ona „lly Q Λb wi .th , t ,he provi .so th , at no more than one
of R and R is Q at the same time and that Q is Q ;
* Λ i l— I*
Q is selected from the group consisting of NR R , Q wherein Q is
hydrido, N(R )C(NR )N(R )(R ), and C(NR )NR R , with the
20 21 provisos that no more than one of R and R is hydroxy, amino, alkylamino, or
23 24 dialkylamino at the same time and that no more than one of R and R is hydroxy, amino, alkylamino, or dialkylamino at the same time;
20 21 23 24 25 26
R , R , R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino.
42. The compound as recited in Claim 41 having the Formula:
32 33 34 35 J 36 . R , R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio,
ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, carboxy, cyano, and Q ;
B is optionally selected from the group consisting of hydrido, ethyl, 2- propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 2-butynyl, sec- butyl, tert-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 2-methyl-2- butenyl, 3-methylbutyl, 3-methyl -2-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4- hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, l-methyl-2-pentenyl, 1- methyl-3-pentenyl, l-methyl-2-pentynyl, l-methyl-3-pentynyl, 3-hexyl, 1- ethyl-2-butenyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 2- heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, l-methyl-2-hexenyl, l-methyl-3-hexenyl, 1 -methyl -4-hexenyl, 1 -methyl -2-hexynyl, l-methyl-3- hexynyl, l-methyl-4-hexynyl, 3-heptyl, l-ethyl-2-pentenyl, l-ethyI-3- pentenyl, 1-ethyl -2-pentynyl, l-ethyl-3-pentynyl, 2,2,2-trifluoroethyl, 2,2- difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4- trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl, and 333-trifluoropropyl, wherein each member of group B is optionally substituted at any carbon up to and including 5 atoms from the point of attachment of B to A with one or more • • . ^32 „33 34 35 Λ 36 of the group consisting of R , R , R , R , and R ;
B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-(2R)-bicyclo[2.2.1]- heptyl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, and bicyc!o[3.1.0]hexan-6-yl, wherein each ring carbon is optionally substituted
33 with R , ring carbons and anitrogen adjacent to the carbon atom at the point
9 13 of attachment is optionally substituted with R or R , a ring carbon or
9 nitrogen adjacent to the R position and two atoms from the point of attachment
10 is optionally substituted with R , and a ring carbon or nitrogen adjacent to the
13 R position and two atoms from the point of attachment is optionally
substituted , wi -th. τ R 2 ;
9 11 13
R , R , and R are independendy selected from the group consisting of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, and cyano;
10 12
R and R are independently selected from the group consisting of hydrido, amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2- hydroxyethyl, carboxy, carboxymethyl, amino, acetamido, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl, N- methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, N,N- dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, and cyano; A is selected from the group consisting of single covalent bond, NH, N(CH3), CH2, CH3CH, CH2CH2, and CH2CH2CH2;
R and X° are independendy selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1- aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, trifluoromethyl, 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 is selected from the group consisting of phenyl, 2-thienyl, 2-furyl,
2-pyrrolyl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl, and 3-pyridyl, wherein a carbon adjacent to the carbon at the point of attachment is optionally
9 substituted by R , the other carbon adjacent to the carbon at the point of
13 9 attachment is optionally substituted by R , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by
10 13
R , a carbon adjacent to R and two atoms from the carbon at the point of
12 attachment is optionally substituted by R , and any carbon adjacent to both
R and R is optionally substituted by R ;
..AT . „b ^s Y is Q -Q ; s Q is selected from the group consisting of:
37 37 38 C[R (benzoyl) CR R )b],
37 37 38
C[R (2-pyridylcarbonyl])](CR R )b],
37 37 38
C[R (3-pyridylcarbonyl])](CR R )b],
37 37 38
C[R (4-pyridylcarbonyl])](CR R )b],
37 37 38
C[R (2-thienylcarbonyl])](CR R )b],
37 37 38 C[R (3-thienylcarbonyl])](CR R )b],
37 37 38
C[R (2-thiazolylcarbonyl])](CR R )b],
37 37 38
C[R (4-tbiazolylcarbonyl])](CR R )b], and
37 37 38
C[R (5-thiazolylcarbonyl])](CR R ) ], wherein b is an integer selected
37 38 from 1 through 3, R and R are independently selected from the group consisting of hydrido, alkyl, and haloalkyl, with the provisos that said aroyl and said heteroaroyl are optionally substituted at from one through three of the
16 ring carbons with a substituent selected from the group consisting of R ,
17 18 19 17 18
R , R , and R with the proviso that R and R are optionally substituted at a carbon selected from other than the meta and para carbons relative to the carbonyl of the benzoyl substituent and the heteroaroyl substituent, that said benzoyl and said heteroaroyl are bonded to the carbon directly bonded to amide nitrogen of the l-(amidocarbonymethylene) group,
37 38 and that is no more than one alkyl or one haloalkyl is bonded to a CR R at the same time;
R , R , R , and R are independendy selected from the group consisting of hydrido, methyl, ethyl, amidino, guanidino, methoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethylthio, methylsulfinyl, methylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoromethoxy, fluoro, chloro, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, carboxy, and cyano; b 20 21
Q is selected from the group consisting of NR R and
25 23 24 b
C(NR )NR R , with the proviso that said Q group is bonded directly to a carbon atom;
20 21 23 24 25
R , R , R , R , and R are independendy selected from the group consisting of hydrido, methyl, and ethyl.
43. The compound as recited in Claim 42 or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of 2-aminophenyl, 3- aminophenyl, 3-amidinophenyl, 4-amidinophenyl, 3-carboxyphenyl, 3- carboxy-5-hydroxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4- dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 3- hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyaminophenyl, 3-methoxyphenyl, 4-methoxy phenyl, 3-methylphenyl, 4-methylphenyl, phenyl, and 3- trifluoromethylphenyl ;
B is optionally selected from the group consisting of hydrido,ethyl, 2- propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butyl, (R)-2-butyl,(S)-2- butyl, tert-butyl, isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2- trifluoroethyl, 6-amidocarbonylhexyl, 4-methyl-2-pentyl, 3-hydroxypropyl, 3- methoxy-2-propyl, 2-methoxy ethyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2- dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2-hydroxyethyl, 2- amidinoethyl, 2-guanidinoethyl, 3-guanidinopropyl, 4-guanidinobutyl, 3- hydroxypropyl, 4-hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl, 3- methylbutyl, 2-methylbutyl, (S)-2-methylbutyl, 3-aminopropyl, 2-hexyl, and 4-aminobutyl;
B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-(2R)-bicyclo[2.2.1]-heptyl, oxetan-3- yl, azetidin-1-yl, azetidin-2-yl, an d azetidin-3-yl;
A is selected from the group consisting of single covalent bond, CH ,
CH3CH, CH2CH2, and CH2CH2CH2;
R and X° are independendy selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio, trifluoromethoxy, fluoro, and chloro;
2 R is selected from the group consisting of 5-amino-3- amidocarbonylphenyl, 5-amino-2-fluorophenyl, 3-amino-5- hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl, 3-carboxy-5- hydroxyphenyl, 3-carboxymethyl-5-aminophenyl, 3-carboxymethyl-5- hydroxyphenyl, 3-carboxymethylphenyl, 3-chlorophenyl, 2-chlorophenyI, 2,6-dichlorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 2,5-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3- methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3- methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl, 3- methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl, 2- trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2- thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl; YAT is Qb-QS;
Q is selected from the group consisting of:
[CH(benzoyI)](CH2)b, [CH(2-pyridylcarbonyl)](CH2)b,
[CH(3-pyridylcarbonyl)](CH2)b, [CH(4-pyridylcarbonyl)](CH2)b,
[CH(2-thienylcarbonyl)](CH2)b,[CH(3-thienylcarbonyl)](CH2)b,
[CH(2-thiazolylcarbonyl)](CH2)b, [CH(4-thiazolylcarbonyl)](CH2)b,
and [CH(5-thiazolylcarbonyl)](CH2)b. wherein b is an integer selected from 1 through 3, with the provisos that said aroyl and said heteroaroyl are optionally substituted at from one through three of the ring carbons with a substituent selected from the group consisting of R , R , R , and R with the
17 18 proviso that R and R are optionally substituted at a carbon selected from other than the meta and para carbons relative to the carbonyl of the benzoyl substituent and the heteroaroyl substituent, and that said benzoyl and said heteroaroyl substituent are bonded to the carbon direcdy bonded to amide nitrogen of the l-(amidocarbony methylene) group;
16 19 R and R are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano;
17 18
R and R are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano; b 25 23 24 Q is C(NR )NR R ;
23 24 25
R , R , and R are independently selected from the group consisting of hydrido and methyl.
44. The compound as recited in Claim 43 or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of 3-aminophenyl, 3- amidinophenyl, 4-amidinophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4- dichlorophenyl, 2-fluorophenyl, 4-methylphenyl, and phenyl;
B is optionally selected from the group consisting of hydrido,ethyl, 2- propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butyl, (R)-2-butyl,(S)-2- butyl, tert-butyl, isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2- trifluoroethyl, 6-amidocarbonylhexyl, 4-methyl-2-pentyl, 3-hydroxypropyl, 3- methoxy-2-propyl, 2-methoxyethyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2- dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2-hydroxyethyl, 2- amidinoethyl, 2-guanidinoethyl, 3-guanidinopropyl, 4-guanidinobutyl, 3- hydroxypropyl, 4-hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl, 3-
methylbutyl, 2-methylbutyl, (S)-2-methylbutyl, 3-aminopropyl, 2-hexyl, and 4-aminobutyl;
B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-(2R)-bicyclo[2.2.1]-heptyl, oxetan-3- yl, azetidin-1-yl, azetidin-2-yl, and azetidin-3-yl;
A is selected from the group consisting of a single covalent bond,
CH2, CH2CH2 and CH2CH2CH2;
X° is selected from the group consisting of hydrido, hydroxy, amino, amidino, aminomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and fluoro;
R is selected from the group consisting of hydrido, hydroxy, amino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, methylthio, trifluoromethoxy, fluoro, and chloro;
2
R is selected from the group consisting of 3-aminophenyl, benzyl, 2,6-dichlorophenyl, 5-amino-2-thienyl, 5-amino-2-fluoroρhenyl, 3-amino-2- methylphenyl, 5-amino-2-methylthiophenyl, 3-carboxyphenyl, 3-cyanophenyl, 3-chlorophenyl, 2-hydroxyhenyl, 3-hydroxyphenyl, 3- methanesulfonylaminophenyl, 3-methoxycarbonylphenyl, 3- dimethylaminophenyl, 3-methylaminophenyl, 2-methylphenyl, 3- methylphenyl, phenyl, 3-pyridyl, 3-trifluoroacetamidophenyl, 3-bromo-2- thienyl, 2-thienyl, and 3-thienyl;
AT
Y is selected from the group consisting of Sguanidino-1-oxo- 1-(2- thiazolyl)-2-ρentyl, 5-guanidino-l-oxo-l-(4-thiazolyl)-2-pentyl, 5-guanidino- l-oxo-l-(Sthiazolyl)-2-pentyl, 5-guanidino- 1-oxo- l-( amino-2-thiazolyl)-2- pentyl, and 5-guanidino- l-oxo-l-phenyl-2-pentyl.
45. A compound as recited in Claim 41 where said compound is selected from the group having the Formula:
R is 3-aminophenyl, B is phenyl, A is CH2, Y' is 5-guanidino- 1 -oxo- 1-
(2-thiazolyl)-2-pentyl, R is hydroxymethyl, and X° is hydrido; R 2 is phenyl, B is phenyl, A is CH2CH2, Y" AT is 5-guanidino- 1 -oxo- 1-(2-
thiazolyl)-2-pentyl, R is hydroxymethyl, and X° is hydrido;
2 AT
R is benzyl, B is phenyl, A is CH2CH2, Y is 5-guanidino- 1 -oxo- 1 -(2-
thiazolyl)-2-pentyl, R is hydroxymethyl, and X° is hydrido;
2 AT
R is phenyl, B is phenyl, A is CH2CH2, Y is 5-guanidino- 1 -oxo- 1 -(2-
thiazolyl)-2-pentyl, R is hydroxymethyl, and X° is hydrido;
2 AT
R is benzyl, B is phenyl, A is CH2CH2, Y is 5-guanidino- l-oxo-l-(2-
thiazolyl)-2-pentyl, R is hydroxymethyl, and X° is hydrido;
7 \T
R is phenyl, B is phenyl, A is CH2CH2, Y' is 5-guanidino- 1 -oxo- 1 -(2-
thiazolyl)-2-pentyl, R is hydroxymethyl, and X° is hydrido;
2 ^T
R is 3-aminophenyl, B is phenyl, A is CH2, Y' is 5-guanidino- 1 -oxo- 1-
(2-thiazolyl)-2-pentyl, R is aminomethyl, and X° is fluoro;
2 T
R is phenyl, B is phenyl, A is CH2CH2, Y" is 5- guanidino- 1 -oxo- 1 -(2-
thiazolyl)-2-pentyl, R is aminomethyl, and X° is fluoro;
2 AT
R is benzyl, B is phenyl, A is CH2CH2, Y" is 5-guanidino- 1 -oxo- 1 -(2-
thiazolyl)-2-pentyl, R is aminomethyl, and X° is fluoro;
7 AT
R is phenyl, B is phenyl, A is CH2CH2, Y is 5-guanidino- 1 -oxo- 1 -(2-
thiazolyl)-2-pentyl, R is aminomethyl, and X° is fluoro;
2 AT
R is benzyl, B is phenyl, A is CH2CH2, Y is 5-guanidino- 1 -oxo- 1 -(2-
thiazolyl)-2-pentyl, R is aminomethyl, and X° is fluoro;
2 AT R is phenyl, B is phenyl, A is CH2CH2, Y is 5-guanidino-l-oxo-l-(2-
thiazolyl)-2-pentyl, R is aminomethyl, and X° is fluoro;
2 AT
R is 3-aminophenyl, B is phenyl, A is CH2, Y is 5-guanidino- 1 -oxo- 1-
(2-thiazolyl)-2-pentyl, R is fluoro, and X° is hydroxymethyl;
2 AT
R is phenyl, B is phenyl, A is CH2CH2, Y is 5-guanidino- 1 -oxo- 1 -(2-
thiazolyl)-2-pentyl, R is fluoro, and X° is hydroxymethyl;
2 AT
R is benzyl, B is phenyl, A is CH2CH , Y is 5-guanidino-l-oxo-l-(2-
thiazolyl)-2-pentyl, R is fluoro, and X° is hydroxymethyl;
2 AT
R is phenyl, B is phenyl, A is CH2CH2, Y is 5-guanidino- 1 -oxo- 1 -(2-
thiazolyl)-2-pentyl, R is fluoro, and X° is hydroxymethyl;
2 AT R is benzyl, B is phenyl, A is CH2CH2, Y is 5-guanidino- 1 -oxo- 1 -(2-
thiazolyl)-2-pentyl, R is fluoro, and X° is hydroxymethyl;
2 AT
R is phenyl, B is phenyl, A is CH2CH2, Y is 5-guanidino- 1 -oxo- 1 -(2-
thiazolyl)-2-pentyl, R is fluoro, and X° is hydroxymethyl;
2 AT
R is 3-aminophenyl, B is phenyl, A is CH2, Y is 5-guanidino- 1-oxo-l-
(2-thiazolyl)-2-pentyl, R is methoxy, and X° is aminomethyl;
R 2 is phenyl, B is phenyl, A is CH2CH2, Y AT is 5-guanidino- 1 -oxo- 1 -(2-
thiazolyl)-2-pentyl, R is methoxy, and X° is aminomethyl;
2 AT
R is benzyl, B is phenyl, A is CH2CH2, Y is 5-guanidino- 1-oxo-l -(2-
thiazolyl)-2-pentyl, R is methoxy, and X° is aminomethyl;
2 AT
R is phenyl, B is phenyl, A is CH2CH2, Y is 5-guanidino-l-oxo-l-(2-
thiazolyl)-2-pentyl, R is methoxy, and X° is aminomethyl;
2 AT
R is benzyl, B is phenyl, A is CH2CH2, Y is 5-guanidino- 1 -oxo- 1 -(2-
thiazolyl)-2-pentyl, R is methoxy, and X° is aminomethyl;
2 AT
R is phenyl, B is phenyl, A is CH2CH2, Y is 5-guanidino- 1 -oxo- 1 -(2-
thiazolyl)-2-pentyl, R is methoxy, and X° is aminomethyl.
46. A composition for inhibiting thrombotic conditions in blood comprising a compound of any one of Claims 8, 16, 24, 32, 40, and 45 and a pharmaceutically acceptable carrier.
47. A composition for inhibiting thrombotic conditions in blood comprising a compound of any one of Qaims 1 through 7, Claims 9 through 15, Claims 17 through 23, Claims 25 through 31, Qaims 33 through 39, and Qaims 41 through 44 and a pharmaceutically acceptable carrier.
48. A method for inhibiting thrombotic conditions in blood comprising adding to blood a therapeutically effective amount of a composition of any one of Claims 46 and 47.
49. A method for inhibiting formation of blood platelet aggregates in blood comprising adding to blood a therapeutically effective amount of a composition of any one of Claims 46 and 47.
50. A method for inhibiting thrombus formation in blood comprising adding to blood a therapeutically effective amount of a composition of any one of Claims 46 and 47.
51. A method for treating or preventing venuous thromboembolism and pulmonary embolism in a mammal comprising administering to the mammal a therapeutically effective amount of a composition of any one of Claims 46 and 47.
52. A method for treating or preventing deep vein thrombosis in a mammal comprising administering to the mammal a therapeutically effective amount of a composition of of any one of Claims 46 and 47.
53. A method for treating or preventing cardiogenic thromboembolism in a mammal comprising administering to the mammal a therapeutically effective amount of a composition of any one of Claims 46 and 47.
54. A method for treating or preventing thromboembolic stroke in humans and other mammals comprising administering to the mammal a therapeutically effective amount of a composition of any one of Claims 46 and 47.
55. A method for treating or preventing thrombosis associated with cancer and cancer chemotherapy in humans and other mammals comprising administering to the mammal a therapeutically effective amount of a composition of any one of Claims 46 and 47.
56. A method for treating or preventing unstable angina in humans and other mammals comprising administering to the mammal a therapeutically effective amount of a composition of any one of Claims 46 and 47.
57. A method for inhibiting thrombus formation in blood comprising adding to blood a therapeutically effective amount of a compound of any one of Qaims 1 through 45 with a therapeutically effective amount of fibrinogen receptor antagonist.
58. The use of a compound of any one of Claims 1 through 45, or a pharmaceutically acceptable salt thereof, in the manufacture of medicament for inhibiting thrombus formation, treating thrombus formation, or preventing thrombus formation in a mammal.
Priority Applications (13)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU47973/00A AU771928B2 (en) | 1999-05-19 | 2000-05-15 | Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade |
| NZ514875A NZ514875A (en) | 1999-05-19 | 2000-05-15 | Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade |
| EP00930092A EP1178964A1 (en) | 1999-05-19 | 2000-05-15 | Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade |
| JP2000618243A JP2002544260A (en) | 1999-05-19 | 2000-05-15 | Substituted polycyclic aryl or heteroaryl pyridones useful as selective inhibitors of the coagulation cascade |
| EA200101213A EA005367B1 (en) | 1999-05-19 | 2000-05-15 | Substituted pyridones, use thereof, composition and method for inhibiting thrombotic conditions and methods of prophylaxis and treatment |
| PL00352403A PL352403A1 (en) | 1999-05-19 | 2000-05-15 | Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of coagulation cascade |
| MXPA01011805A MXPA01011805A (en) | 1999-05-19 | 2000-05-15 | Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade. |
| IL14624400A IL146244A0 (en) | 1999-05-19 | 2000-05-15 | Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade |
| BR0011272-0A BR0011272A (en) | 1999-05-19 | 2000-05-15 | Substituted heteroaryl and polycyclic aryl pyridones useful for selective inhibition of the coagulation cascade |
| KR1020017014751A KR20010113970A (en) | 1999-05-19 | 2000-05-15 | Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade |
| SK1586-2001A SK15862001A3 (en) | 1999-05-19 | 2000-05-15 | Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade |
| CA002373509A CA2373509A1 (en) | 1999-05-19 | 2000-05-15 | Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade |
| NO20015606A NO20015606L (en) | 1999-05-19 | 2001-11-16 | Substituted polycyclic aryl and heteroaryl pyridones which can be used to selectively inhibit the coagulation cascade |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US13481199P | 1999-05-19 | 1999-05-19 | |
| US60/134,811 | 1999-05-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2000069826A1 true WO2000069826A1 (en) | 2000-11-23 |
Family
ID=22465131
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| 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 |
Country Status (21)
| Country | Link |
|---|---|
| EP (1) | EP1178964A1 (en) |
| JP (1) | JP2002544260A (en) |
| KR (1) | KR20010113970A (en) |
| CN (1) | CN1378534A (en) |
| AR (1) | AR029635A1 (en) |
| AU (1) | AU771928B2 (en) |
| BR (1) | BR0011272A (en) |
| CA (1) | CA2373509A1 (en) |
| CZ (1) | CZ20014117A3 (en) |
| EA (1) | EA005367B1 (en) |
| HU (1) | HUP0201996A3 (en) |
| IL (1) | IL146244A0 (en) |
| MX (1) | MXPA01011805A (en) |
| MY (1) | MY138303A (en) |
| NO (1) | NO20015606L (en) |
| NZ (1) | NZ514875A (en) |
| PL (1) | PL352403A1 (en) |
| SK (1) | SK15862001A3 (en) |
| UY (1) | UY26154A1 (en) |
| WO (1) | WO2000069826A1 (en) |
| ZA (2) | ZA200109340B (en) |
Cited By (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001079195A2 (en) * | 2000-04-14 | 2001-10-25 | Corvas International, Inc. | Pyridine and pyrazine derivatives as thrombin inhibitors |
| WO2001087842A1 (en) * | 2000-05-18 | 2001-11-22 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade |
| WO2002053543A1 (en) * | 2000-12-28 | 2002-07-11 | Shionogi & Co., Ltd. | Pyridone derivative having affinity for cannabinoid 2-type receptor |
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Also Published As
| Publication number | Publication date |
|---|---|
| AU4797300A (en) | 2000-12-05 |
| AU771928B2 (en) | 2004-04-08 |
| CA2373509A1 (en) | 2000-11-23 |
| CN1378534A (en) | 2002-11-06 |
| ZA200400449B (en) | 2004-11-24 |
| KR20010113970A (en) | 2001-12-28 |
| SK15862001A3 (en) | 2002-08-06 |
| ZA200109340B (en) | 2004-05-26 |
| PL352403A1 (en) | 2003-08-25 |
| EA005367B1 (en) | 2005-02-24 |
| HUP0201996A2 (en) | 2002-09-28 |
| MY138303A (en) | 2009-05-29 |
| AR029635A1 (en) | 2003-07-10 |
| MXPA01011805A (en) | 2003-09-04 |
| NO20015606D0 (en) | 2001-11-16 |
| CZ20014117A3 (en) | 2002-05-15 |
| NZ514875A (en) | 2004-10-29 |
| EP1178964A1 (en) | 2002-02-13 |
| BR0011272A (en) | 2002-05-07 |
| IL146244A0 (en) | 2002-07-25 |
| EA200101213A1 (en) | 2002-04-25 |
| HUP0201996A3 (en) | 2002-12-28 |
| JP2002544260A (en) | 2002-12-24 |
| NO20015606L (en) | 2002-01-21 |
| UY26154A1 (en) | 2000-12-29 |
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