JP6113828B2 - プロテインキナーゼc阻害剤およびその使用 - Google Patents
プロテインキナーゼc阻害剤およびその使用 Download PDFInfo
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- JP6113828B2 JP6113828B2 JP2015504725A JP2015504725A JP6113828B2 JP 6113828 B2 JP6113828 B2 JP 6113828B2 JP 2015504725 A JP2015504725 A JP 2015504725A JP 2015504725 A JP2015504725 A JP 2015504725A JP 6113828 B2 JP6113828 B2 JP 6113828B2
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- Prior art keywords
- compound
- amino
- ylamino
- fluoro
- tetrazol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 101710175516 14 kDa zinc-binding protein Proteins 0.000 title 1
- 229940123924 Protein kinase C inhibitor Drugs 0.000 title 1
- 239000003881 protein kinase C inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 680
- -1 amino, substituted amino Chemical group 0.000 claims description 374
- 125000001072 heteroaryl group Chemical group 0.000 claims description 271
- 125000000217 alkyl group Chemical group 0.000 claims description 261
- 229910052739 hydrogen Inorganic materials 0.000 claims description 234
- 239000001257 hydrogen Substances 0.000 claims description 233
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 225
- 125000004043 oxo group Chemical group O=* 0.000 claims description 217
- 125000003118 aryl group Chemical group 0.000 claims description 204
- 125000005309 thioalkoxy group Chemical group 0.000 claims description 181
- 229910052736 halogen Inorganic materials 0.000 claims description 177
- 150000002367 halogens Chemical class 0.000 claims description 177
- 125000003545 alkoxy group Chemical group 0.000 claims description 158
- 125000002252 acyl group Chemical group 0.000 claims description 157
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 155
- 125000000266 alpha-aminoacyl group Chemical group 0.000 claims description 152
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 143
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 135
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 131
- 125000004442 acylamino group Chemical group 0.000 claims description 113
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 106
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 103
- 125000003107 substituted aryl group Chemical group 0.000 claims description 94
- 150000003573 thiols Chemical class 0.000 claims description 92
- 150000001540 azides Chemical class 0.000 claims description 89
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 86
- 125000004423 acyloxy group Chemical group 0.000 claims description 85
- 125000004104 aryloxy group Chemical group 0.000 claims description 85
- 125000000033 alkoxyamino group Chemical group 0.000 claims description 83
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 claims description 83
- 125000005255 oxyaminoacyl group Chemical group 0.000 claims description 82
- 125000000304 alkynyl group Chemical group 0.000 claims description 81
- 125000003342 alkenyl group Chemical group 0.000 claims description 80
- YAAWASYJIRZXSZ-UHFFFAOYSA-N pyrimidine-2,4-diamine Chemical compound NC1=CC=NC(N)=N1 YAAWASYJIRZXSZ-UHFFFAOYSA-N 0.000 claims description 76
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 75
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 75
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 72
- 150000003839 salts Chemical class 0.000 claims description 65
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 63
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 61
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 58
- 238000000034 method Methods 0.000 claims description 58
- 239000000203 mixture Substances 0.000 claims description 33
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 30
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 29
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 28
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 26
- XVIAPHVAGFEFFN-UHFFFAOYSA-N pyrimidine-5-carbonitrile Chemical compound N#CC1=CN=CN=C1 XVIAPHVAGFEFFN-UHFFFAOYSA-N 0.000 claims description 22
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims description 20
- 108090000315 Protein Kinase C Proteins 0.000 claims description 18
- 102000003923 Protein Kinase C Human genes 0.000 claims description 18
- 201000010099 disease Diseases 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 229910052717 sulfur Inorganic materials 0.000 claims description 17
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 15
- 208000035475 disorder Diseases 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 10
- 239000003937 drug carrier Substances 0.000 claims description 7
- 238000011282 treatment Methods 0.000 claims description 7
- PWDDRWHQJQYYAK-MSOLQXFVSA-N 3-[4-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-2-(tetrazol-1-yl)phenoxy]propan-1-ol Chemical compound N([C@H]1CC(N2CCC[C@H]2C1)(C)C)C(C(=CN=1)F)=NC=1NC(C=1)=CC=C(OCCCO)C=1N1C=NN=N1 PWDDRWHQJQYYAK-MSOLQXFVSA-N 0.000 claims description 6
- XHCBBQOBCSQZKL-UHFFFAOYSA-N 7-[[2-[4-cyclopropyl-2-fluoro-5-(4-methyl-5-oxotetrazol-1-yl)anilino]-5-fluoropyrimidin-4-yl]amino]-5,5-dimethyl-1,2,6,7,8,8a-hexahydroindolizin-3-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(NC3CC(C)(C)N4C(=O)CCC4C3)C(F)=CN=2)=C(F)C=C1C1CC1 XHCBBQOBCSQZKL-UHFFFAOYSA-N 0.000 claims description 6
- 150000003840 hydrochlorides Chemical class 0.000 claims description 6
- VXTYPJFMGAKVJO-UHFFFAOYSA-N 1-[5-[[4-[(5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl)amino]-5-fluoropyrimidin-2-yl]amino]-2-(oxan-4-yloxy)phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(NC3CC(C)(C)N4CCCC4C3)C(F)=CN=2)=CC=C1OC1CCOCC1 VXTYPJFMGAKVJO-UHFFFAOYSA-N 0.000 claims description 5
- ZQACGONEYXBNEW-KGLIPLIRSA-N O1CC(=O)NC2=C1C=CC=C2NC1=NC=C(F)C(N[C@H]2CC(N3CCC[C@H]3C2)(C)C)=N1 Chemical compound O1CC(=O)NC2=C1C=CC=C2NC1=NC=C(F)C(N[C@H]2CC(N3CCC[C@H]3C2)(C)C)=N1 ZQACGONEYXBNEW-KGLIPLIRSA-N 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 230000001404 mediated effect Effects 0.000 claims description 5
- MCOMGGLTFKWEOA-UHFFFAOYSA-N oxazepin-4-ol Chemical compound O1N=CC(=CC=C1)O MCOMGGLTFKWEOA-UHFFFAOYSA-N 0.000 claims description 5
- HIJUKDHGAOXGAM-UHFFFAOYSA-N 1-[5-[[4-[(5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl)amino]-5-fluoropyrimidin-2-yl]amino]-2-(oxetan-3-yloxy)phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(NC3CC(C)(C)N4CCCC4C3)C(F)=CN=2)=CC=C1OC1COC1 HIJUKDHGAOXGAM-UHFFFAOYSA-N 0.000 claims description 4
- LDUSGAYKQIOKIX-CTWPCTMYSA-N 1-[5-[[4-[(5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl)amino]-5-fluoropyrimidin-2-yl]amino]-2-[(3r)-oxolan-3-yl]oxyphenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(NC3CC(C)(C)N4CCCC4C3)C(F)=CN=2)=CC=C1O[C@H]1COCC1 LDUSGAYKQIOKIX-CTWPCTMYSA-N 0.000 claims description 4
- LDUSGAYKQIOKIX-ACBHZAAOSA-N 1-[5-[[4-[(5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl)amino]-5-fluoropyrimidin-2-yl]amino]-2-[(3s)-oxolan-3-yl]oxyphenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(NC3CC(C)(C)N4CCCC4C3)C(F)=CN=2)=CC=C1O[C@@H]1COCC1 LDUSGAYKQIOKIX-ACBHZAAOSA-N 0.000 claims description 4
- MRJRFBFEOKPCKB-CABCVRRESA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-2-(2-aminoethoxy)-4-fluorophenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)=C(F)C=C1OCCN MRJRFBFEOKPCKB-CABCVRRESA-N 0.000 claims description 4
- VNLANJHTNDZABY-CVEARBPZSA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-2-methoxyphenyl]-4-methyltetrazol-5-one Chemical compound COC1=CC=C(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)C=C1N1N=NN(C)C1=O VNLANJHTNDZABY-CVEARBPZSA-N 0.000 claims description 4
- SITBLSOUBBQNAT-SJORKVTESA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-2-methylphenyl]-4-methyltetrazol-5-one Chemical compound CC1=CC=C(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)C=C1N1N=NN(C)C1=O SITBLSOUBBQNAT-SJORKVTESA-N 0.000 claims description 4
- VBVITBNLMMIWGW-JAIYHHTPSA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-4-fluoro-2-(2-hydroxypropoxy)phenyl]-4-methyltetrazol-5-one Chemical compound CC(O)COC1=CC(F)=C(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)C=C1N1N=NN(C)C1=O VBVITBNLMMIWGW-JAIYHHTPSA-N 0.000 claims description 4
- HIDRHKGFFJSWEF-MOPGFXCFSA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-4-fluoro-2-(oxan-4-ylmethoxy)phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)=C(F)C=C1OCC1CCOCC1 HIDRHKGFFJSWEF-MOPGFXCFSA-N 0.000 claims description 4
- DAJYCZLHWNYIPA-SJORKVTESA-N 2-[1-[3-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]phenyl]tetrazol-5-yl]sulfanylethanol Chemical compound N([C@H]1CC(N2CCC[C@H]2C1)(C)C)C(C(=CN=1)F)=NC=1NC(C=1)=CC=CC=1N1N=NN=C1SCCO DAJYCZLHWNYIPA-SJORKVTESA-N 0.000 claims description 4
- FCECZAULLRIOJJ-UHFFFAOYSA-N 4-(1,2,3,5,6,7,8,8a-octahydroindolizin-7-yl)-1H-pyrimidine-2,4-diamine Chemical compound N1C(N)=NC=CC1(N)C1CC2CCCN2CC1 FCECZAULLRIOJJ-UHFFFAOYSA-N 0.000 claims description 4
- XMMQZBAIAYQGFP-UHFFFAOYSA-N 4-(5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1H-indolizin-7-yl)-1H-pyrimidine-2,4-diamine Chemical compound C1C2CCCN2C(C)(C)CC1C1(N)NC(N)=NC=C1 XMMQZBAIAYQGFP-UHFFFAOYSA-N 0.000 claims description 4
- OTPWEBUGLWNXLO-SOAGJPPSSA-N 5-[[4-[(5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl)amino]-5-fluoropyrimidin-2-yl]amino]-2-[(3r)-oxolan-3-yl]oxybenzonitrile Chemical compound C1C2CCCN2C(C)(C)CC1NC(C(=CN=1)F)=NC=1NC(C=C1C#N)=CC=C1O[C@@H]1CCOC1 OTPWEBUGLWNXLO-SOAGJPPSSA-N 0.000 claims description 4
- OTPWEBUGLWNXLO-MHJFOBGBSA-N 5-[[4-[(5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl)amino]-5-fluoropyrimidin-2-yl]amino]-2-[(3s)-oxolan-3-yl]oxybenzonitrile Chemical compound C1C2CCCN2C(C)(C)CC1NC(C(=CN=1)F)=NC=1NC(C=C1C#N)=CC=C1O[C@H]1CCOC1 OTPWEBUGLWNXLO-MHJFOBGBSA-N 0.000 claims description 4
- ICJQVSAYHUGWMQ-RJBLSPETSA-N 5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-2-(1,1,2,2-tetradeuterio-2-hydroxyethoxy)benzonitrile Chemical compound C1=C(C#N)C(OC([2H])([2H])C([2H])(O)[2H])=CC=C1NC1=NC=C(F)C(N[C@H]2CC(C)(C)N3CCC[C@H]3C2)=N1 ICJQVSAYHUGWMQ-RJBLSPETSA-N 0.000 claims description 4
- VWAMICUZLIDILJ-UHFFFAOYSA-N 5-fluoro-2-n-[4-fluoro-3-(5-methyltetrazol-1-yl)phenyl]-4-n-(5,5,8-trimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl)pyrimidine-2,4-diamine Chemical compound CC1C2CCCN2C(C)(C)CC1NC(C(=CN=1)F)=NC=1NC(C=1)=CC=C(F)C=1N1N=NN=C1C VWAMICUZLIDILJ-UHFFFAOYSA-N 0.000 claims description 4
- JKWWNCXYPDZBEU-OLZOCXBDSA-N 5-n-[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]-6-fluoro-2-n-methyl-1,3-benzoxazole-2,5-diamine Chemical compound C1[C@@H]2CCCN2C(C)(C)C[C@@H]1NC1=NC(NC=2C=C3N=C(OC3=CC=2F)NC)=NC=C1F JKWWNCXYPDZBEU-OLZOCXBDSA-N 0.000 claims description 4
- QMKSGJISSAPARY-JPDPOCBJSA-N COCC1(OC2=C(N3C1=NN=N3)C=C(C=C2)C1(NC=C(C(=N1)N[C@H]1CC(N2CCC[C@H]2C1)(C)C)F)N)COC Chemical compound COCC1(OC2=C(N3C1=NN=N3)C=C(C=C2)C1(NC=C(C(=N1)N[C@H]1CC(N2CCC[C@H]2C1)(C)C)F)N)COC QMKSGJISSAPARY-JPDPOCBJSA-N 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 230000002459 sustained effect Effects 0.000 claims description 4
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims description 3
- JFAIVAMGMCTLMH-CVEARBPZSA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-2-cyclopropyl-4-fluorophenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)=C(F)C=C1C1CC1 JFAIVAMGMCTLMH-CVEARBPZSA-N 0.000 claims description 3
- NZFDRBYUDMGIMU-SJORKVTESA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-2-methoxyphenyl]-4-(2-hydroxyethyl)tetrazol-5-one Chemical compound COC1=CC=C(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)C=C1N1N=NN(CCO)C1=O NZFDRBYUDMGIMU-SJORKVTESA-N 0.000 claims description 3
- WQRDIEJQTCEGHC-MSOLQXFVSA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-2-methylphenyl]-4-(2-hydroxyethyl)tetrazol-5-one Chemical compound CC1=CC=C(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)C=C1N1N=NN(CCO)C1=O WQRDIEJQTCEGHC-MSOLQXFVSA-N 0.000 claims description 3
- RSYAOTAOWSFUSI-CABCVRRESA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-4-fluoro-2-(2-hydroxyethoxy)phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)=C(F)C=C1OCCO RSYAOTAOWSFUSI-CABCVRRESA-N 0.000 claims description 3
- XPMFITJGZVFVNF-SJORKVTESA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-4-fluoro-2-(oxan-4-yloxy)phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)=C(F)C=C1OC1CCOCC1 XPMFITJGZVFVNF-SJORKVTESA-N 0.000 claims description 3
- WHKQTJGESNASRF-IXDOHACOSA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-4-fluoro-2-[(3r)-oxolan-3-yl]oxyphenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)=C(F)C=C1O[C@H]1COCC1 WHKQTJGESNASRF-IXDOHACOSA-N 0.000 claims description 3
- WHKQTJGESNASRF-IKGGRYGDSA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-4-fluoro-2-[(3s)-oxolan-3-yl]oxyphenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)=C(F)C=C1O[C@@H]1COCC1 WHKQTJGESNASRF-IKGGRYGDSA-N 0.000 claims description 3
- BXGYYDRIMBPOMN-UHFFFAOYSA-N 2-(hydroxymethoxy)ethoxymethanol Chemical compound OCOCCOCO BXGYYDRIMBPOMN-UHFFFAOYSA-N 0.000 claims description 3
- NRIZOVPQKMPULJ-SJORKVTESA-N 3-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-chloropyrimidin-2-yl]amino]benzonitrile Chemical compound N([C@H]1CC(N2CCC[C@H]2C1)(C)C)C(C(=CN=1)Cl)=NC=1NC1=CC=CC(C#N)=C1 NRIZOVPQKMPULJ-SJORKVTESA-N 0.000 claims description 3
- IPDNXEBPZBRHFI-NXHRZFHOSA-N 4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-2-[2-fluoro-4-[(2r)-2-hydroxypropoxy]-5-(4-methyl-5-oxotetrazol-1-yl)anilino]pyrimidine-5-carbonitrile Chemical compound C[C@@H](O)COC1=CC(F)=C(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(C#N)=CN=2)C=C1N1N=NN(C)C1=O IPDNXEBPZBRHFI-NXHRZFHOSA-N 0.000 claims description 3
- METAQSSLDNXOEC-CVEARBPZSA-N 4-n-[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]-5-fluoro-2-n-(3,4,5-trimethoxyphenyl)pyrimidine-2,4-diamine Chemical class COC1=C(OC)C(OC)=CC(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)=C1 METAQSSLDNXOEC-CVEARBPZSA-N 0.000 claims description 3
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- CQWAILPSZVCBCM-XHSDSOJGSA-N 1-[5-[[4-[[(2s,7r,8ar)-2-fluoro-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-2-cyclopropyl-4-fluorophenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(N[C@H]3CC(C)(C)N4C[C@@H](F)C[C@H]4C3)C(F)=CN=2)=C(F)C=C1C1CC1 CQWAILPSZVCBCM-XHSDSOJGSA-N 0.000 claims description 2
- MRPPCAXBPQTACM-OLZOCXBDSA-N 1-[5-[[4-[[(7R,8aS)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1H-indolizin-7-yl]amino]-5-chloropyrimidin-2-yl]amino]-4-fluoro-2-hydroxyphenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(Cl)=CN=2)=C(F)C=C1O MRPPCAXBPQTACM-OLZOCXBDSA-N 0.000 claims description 2
- RSYAOTAOWSFUSI-JCGOAIGOSA-N 1-[5-[[4-[[(7R,8aS)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1H-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-4-fluoro-2-(1,1,2,2-tetradeuterio-2-hydroxyethoxy)phenyl]-4-methyltetrazol-5-one Chemical compound [2H]C([2H])(O)C([2H])([2H])Oc1cc(F)c(Nc2ncc(F)c(N[C@@H]3C[C@@H]4CCCN4C(C)(C)C3)n2)cc1-n1nnn(C)c1=O RSYAOTAOWSFUSI-JCGOAIGOSA-N 0.000 claims description 2
- YFDNDTKEMZBVNX-CVEARBPZSA-N 1-[5-[[4-[[(7R,8aS)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1H-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-4-fluoro-2-(2-methoxyethoxy)phenyl]-4-methyltetrazol-5-one Chemical compound COCCOC1=CC(F)=C(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)C=C1N1N=NN(C)C1=O YFDNDTKEMZBVNX-CVEARBPZSA-N 0.000 claims description 2
- XHWCBFSCZUJKQJ-KBZJNTCOSA-N 1-[5-[[4-[[(7S,8aS)-3,3-dimethyl-2,5,6,7,8,8a-hexahydro-1H-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-2-(1-deuterio-3-hydroxycyclobutyl)oxyphenyl]-4-methyltetrazol-5-one Chemical compound [2H]C1(CC(O)C1)Oc1ccc(Nc2ncc(F)c(N[C@H]3CCN4[C@@H](CCC4(C)C)C3)n2)cc1-n1nnn(C)c1=O XHWCBFSCZUJKQJ-KBZJNTCOSA-N 0.000 claims description 2
- KXTUEBXYMDBGJS-HUUCEWRRSA-N 1-[5-[[4-[[(7r,8ar)-2,2-difluoro-5,5-dimethyl-1,3,6,7,8,8a-hexahydroindolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-2-cyclopropyl-4-fluorophenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(N[C@H]3CC(C)(C)N4CC(F)(F)C[C@H]4C3)C(F)=CN=2)=C(F)C=C1C1CC1 KXTUEBXYMDBGJS-HUUCEWRRSA-N 0.000 claims description 2
- FPSFRDVHTGFKDS-CVEARBPZSA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-chloropyrimidin-2-yl]amino]-2-cyclopropyl-4-fluorophenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(Cl)=CN=2)=C(F)C=C1C1CC1 FPSFRDVHTGFKDS-CVEARBPZSA-N 0.000 claims description 2
- DHXBBYDGQZQXKU-CVEARBPZSA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-chloropyrimidin-2-yl]amino]-4-fluoro-2-(2-hydroxy-2-methylpropoxy)phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(Cl)=CN=2)=C(F)C=C1OCC(C)(C)O DHXBBYDGQZQXKU-CVEARBPZSA-N 0.000 claims description 2
- AWBHALPAYVXPAL-CABCVRRESA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-chloropyrimidin-2-yl]amino]-4-fluoro-2-(2-hydroxyethoxy)phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(Cl)=CN=2)=C(F)C=C1OCCO AWBHALPAYVXPAL-CABCVRRESA-N 0.000 claims description 2
- HTSLJDMDEMNGEP-XHSDSOJGSA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-chloropyrimidin-2-yl]amino]-4-fluoro-2-[(2s)-2-hydroxypropoxy]phenyl]-4-methyltetrazol-5-one Chemical compound C[C@H](O)COC1=CC(F)=C(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(Cl)=CN=2)C=C1N1N=NN(C)C1=O HTSLJDMDEMNGEP-XHSDSOJGSA-N 0.000 claims description 2
- UXXQMRDQKHHTEK-BBWFWOEESA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-chloropyrimidin-2-yl]amino]-4-fluoro-2-[(2s)-2-methoxypropoxy]phenyl]-4-methyltetrazol-5-one Chemical compound CO[C@@H](C)COC1=CC(F)=C(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(Cl)=CN=2)C=C1N1N=NN(C)C1=O UXXQMRDQKHHTEK-BBWFWOEESA-N 0.000 claims description 2
- IGAANKJZCYFVQM-DVKDBIPTSA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-2-(1,4-dioxan-2-ylmethoxy)-4-fluorophenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)=C(F)C=C1OCC1OCCOC1 IGAANKJZCYFVQM-DVKDBIPTSA-N 0.000 claims description 2
- AYKYNMLUJYMTOD-YSPPHNQVSA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-2-(2,3-dihydroxypropoxy)-4-fluorophenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)=C(F)C=C1OCC(O)CO AYKYNMLUJYMTOD-YSPPHNQVSA-N 0.000 claims description 2
- NIUNOKKILDDXJQ-SJORKVTESA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-2-(2-hydroxyethoxy)phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)=CC=C1OCCO NIUNOKKILDDXJQ-SJORKVTESA-N 0.000 claims description 2
- AYKYNMLUJYMTOD-OWCLPIDISA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-2-[(2r)-2,3-dihydroxypropoxy]-4-fluorophenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)=C(F)C=C1OC[C@H](O)CO AYKYNMLUJYMTOD-OWCLPIDISA-N 0.000 claims description 2
- JPJHGCNSYBGKQJ-MOPGFXCFSA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-2-[2-(diethylamino)ethoxy]-4-fluorophenyl]-4-methyltetrazol-5-one Chemical compound CCN(CC)CCOC1=CC(F)=C(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)C=C1N1N=NN(C)C1=O JPJHGCNSYBGKQJ-MOPGFXCFSA-N 0.000 claims description 2
- DBJAVKKLRILSIN-SJORKVTESA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-2-[2-(dimethylamino)ethoxy]-4-fluorophenyl]-4-methyltetrazol-5-one Chemical compound CN(C)CCOC1=CC(F)=C(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)C=C1N1N=NN(C)C1=O DBJAVKKLRILSIN-SJORKVTESA-N 0.000 claims description 2
- VIUMVNLYLZGPMY-RTWAWAEBSA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-2-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)=CC=C1N1CCN(C2COC2)CC1 VIUMVNLYLZGPMY-RTWAWAEBSA-N 0.000 claims description 2
- DIBPQHOPOFDJIP-OLZOCXBDSA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-2-bromo-4-fluorophenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)=C(F)C=C1Br DIBPQHOPOFDJIP-OLZOCXBDSA-N 0.000 claims description 2
- NMZYPNYNOCKYOS-CVEARBPZSA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-2-ethenyl-4-fluorophenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)=C(F)C=C1C=C NMZYPNYNOCKYOS-CVEARBPZSA-N 0.000 claims description 2
- QLFDTSGRRHTPAW-CVEARBPZSA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-2-ethyl-4-fluorophenyl]-4-methyltetrazol-5-one Chemical compound CCC1=CC(F)=C(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)C=C1N1N=NN(C)C1=O QLFDTSGRRHTPAW-CVEARBPZSA-N 0.000 claims description 2
- MKUXZIVTVWDJFC-CABCVRRESA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-2-methoxyphenyl]-2h-tetrazol-5-one Chemical compound COC1=CC=C(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)C=C1N1N=NNC1=O MKUXZIVTVWDJFC-CABCVRRESA-N 0.000 claims description 2
- IFXOWFMPASNIHV-MSOLQXFVSA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-2-methoxyphenyl]-4-(2-hydroxy-2-methylpropyl)tetrazol-5-one Chemical compound COC1=CC=C(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)C=C1N1N=NN(CC(C)(C)O)C1=O IFXOWFMPASNIHV-MSOLQXFVSA-N 0.000 claims description 2
- GAZDVEPTZVODIV-SJORKVTESA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-2-methoxyphenyl]-4-(oxetan-3-yl)tetrazol-5-one Chemical compound COC1=CC=C(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)C=C1N(C1=O)N=NN1C1COC1 GAZDVEPTZVODIV-SJORKVTESA-N 0.000 claims description 2
- MLBBRZXTASACOG-CVEARBPZSA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-2-methylphenyl]-2h-tetrazol-5-one Chemical compound CC1=CC=C(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)C=C1N1N=NNC1=O MLBBRZXTASACOG-CVEARBPZSA-N 0.000 claims description 2
- VTTZBKSZYLYKMO-MOPGFXCFSA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-2-methylphenyl]-4-(2-hydroxy-2-methylpropyl)tetrazol-5-one Chemical compound CC1=CC=C(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)C=C1N1N=NN(CC(C)(C)O)C1=O VTTZBKSZYLYKMO-MOPGFXCFSA-N 0.000 claims description 2
- RJRYGUYWFUAVBS-MSOLQXFVSA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-2-methylphenyl]-4-(oxetan-3-yl)tetrazol-5-one Chemical compound CC1=CC=C(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)C=C1N(C1=O)N=NN1C1COC1 RJRYGUYWFUAVBS-MSOLQXFVSA-N 0.000 claims description 2
- VMAOEDCJABWXBK-DMJDIKPUSA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-4-fluoro-2-(1-hydroxyethyl)phenyl]-4-methyltetrazol-5-one Chemical compound CC(O)C1=CC(F)=C(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)C=C1N1N=NN(C)C1=O VMAOEDCJABWXBK-DMJDIKPUSA-N 0.000 claims description 2
- KEWWCXJSVKMSKB-CVEARBPZSA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-4-fluoro-2-(2-fluoro-2-methylpropoxy)phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)=C(F)C=C1OCC(C)(C)F KEWWCXJSVKMSKB-CVEARBPZSA-N 0.000 claims description 2
- COSMFIFRYYAXRF-CABCVRRESA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-4-fluoro-2-(2-fluoroethoxy)phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)=C(F)C=C1OCCF COSMFIFRYYAXRF-CABCVRRESA-N 0.000 claims description 2
- PPLQXWLAQKLJMY-CVEARBPZSA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-4-fluoro-2-(2-hydroxyethyl)phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)=C(F)C=C1CCO PPLQXWLAQKLJMY-CVEARBPZSA-N 0.000 claims description 2
- XEHHETQZLHRHFY-MOPGFXCFSA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-4-fluoro-2-(2-morpholin-4-ylethoxy)phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)=C(F)C=C1OCCN1CCOCC1 XEHHETQZLHRHFY-MOPGFXCFSA-N 0.000 claims description 2
- WSEGUELEIBKHRX-FKTKBCEVSA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-4-fluoro-2-(2-oxooxolan-3-yl)oxyphenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)=C(F)C=C1OC1C(=O)OCC1 WSEGUELEIBKHRX-FKTKBCEVSA-N 0.000 claims description 2
- DSJDTYYVDJDUBW-NTCUHZHNSA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-4-fluoro-2-(3,3,3-trifluoro-2-hydroxypropoxy)phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)=C(F)C=C1OCC(O)C(F)(F)F DSJDTYYVDJDUBW-NTCUHZHNSA-N 0.000 claims description 2
- XDMBZOIYMOYKSK-XNIRIUNOSA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-4-fluoro-2-(3-hydroxycyclobutyl)oxyphenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)=C(F)C=C1OC1CC(O)C1 XDMBZOIYMOYKSK-XNIRIUNOSA-N 0.000 claims description 2
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- CVBYXRJFBCJMHS-SJORKVTESA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-4-fluoro-2-(3-hydroxypropyl)phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)=C(F)C=C1CCCO CVBYXRJFBCJMHS-SJORKVTESA-N 0.000 claims description 2
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- SGAWXOINZRUAHZ-GARXDOFDSA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-4-fluoro-2-(oxetan-2-ylmethoxy)phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)=C(F)C=C1OCC1OCC1 SGAWXOINZRUAHZ-GARXDOFDSA-N 0.000 claims description 2
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- QIESGLGAMPXIEE-OAGGEKHMSA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-4-fluoro-2-[(2r)-1-hydroxypropan-2-yl]oxyphenyl]-4-methyltetrazol-5-one Chemical compound OC[C@@H](C)OC1=CC(F)=C(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)C=C1N1N=NN(C)C1=O QIESGLGAMPXIEE-OAGGEKHMSA-N 0.000 claims description 2
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- YTWWCSDRAJHZBV-XHSDSOJGSA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-4-fluoro-2-[(2s)-2-fluoropropoxy]phenyl]-4-methyltetrazol-5-one Chemical compound C[C@H](F)COC1=CC(F)=C(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)C=C1N1N=NN(C)C1=O YTWWCSDRAJHZBV-XHSDSOJGSA-N 0.000 claims description 2
- XQXKNFTVHWDBBI-BBWFWOEESA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-4-fluoro-2-[(2s)-2-methoxypropoxy]phenyl]-4-methyltetrazol-5-one Chemical compound CO[C@@H](C)COC1=CC(F)=C(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)C=C1N1N=NN(C)C1=O XQXKNFTVHWDBBI-BBWFWOEESA-N 0.000 claims description 2
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- URMRVFQNASQIQK-MSOLQXFVSA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-4-fluoro-2-[2-(2-methoxyethoxy)ethoxy]phenyl]-4-methyltetrazol-5-one Chemical compound COCCOCCOC1=CC(F)=C(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)C=C1N1N=NN(C)C1=O URMRVFQNASQIQK-MSOLQXFVSA-N 0.000 claims description 2
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- NIAPQRFFZKSUBZ-CVEARBPZSA-N 1-[5-[[4-[[(7r,8as)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-4-fluoro-2-propan-2-yloxyphenyl]-4-methyltetrazol-5-one Chemical compound CC(C)OC1=CC(F)=C(NC=2N=C(N[C@H]3CC(C)(C)N4CCC[C@H]4C3)C(F)=CN=2)C=C1N1N=NN(C)C1=O NIAPQRFFZKSUBZ-CVEARBPZSA-N 0.000 claims description 2
- KXTUEBXYMDBGJS-LSDHHAIUSA-N 1-[5-[[4-[[(7s,8ar)-2,2-difluoro-5,5-dimethyl-1,3,6,7,8,8a-hexahydroindolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-2-cyclopropyl-4-fluorophenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(N[C@@H]3CC(C)(C)N4CC(F)(F)C[C@H]4C3)C(F)=CN=2)=C(F)C=C1C1CC1 KXTUEBXYMDBGJS-LSDHHAIUSA-N 0.000 claims description 2
- JFAIVAMGMCTLMH-JKSUJKDBSA-N 1-[5-[[4-[[(7s,8ar)-5,5-dimethyl-2,3,6,7,8,8a-hexahydro-1h-indolizin-7-yl]amino]-5-fluoropyrimidin-2-yl]amino]-2-cyclopropyl-4-fluorophenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(N[C@@H]3CC(C)(C)N4CCC[C@@H]4C3)C(F)=CN=2)=C(F)C=C1C1CC1 JFAIVAMGMCTLMH-JKSUJKDBSA-N 0.000 claims description 2
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- AOKKGXXYBPBKDR-UHFFFAOYSA-N 1-methyl-2h-tetrazol-5-one Chemical compound CN1N=NN=C1O AOKKGXXYBPBKDR-UHFFFAOYSA-N 0.000 claims description 2
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- FQMZXMVHHKXGTM-UHFFFAOYSA-N 2-(1-adamantyl)-n-[2-[2-(2-hydroxyethylamino)ethylamino]quinolin-5-yl]acetamide Chemical compound C1C(C2)CC(C3)CC2CC13CC(=O)NC1=CC=CC2=NC(NCCNCCO)=CC=C21 FQMZXMVHHKXGTM-UHFFFAOYSA-N 0.000 claims description 2
- QTMAZYGAVHCKKX-UHFFFAOYSA-N 2-[(4-amino-5-bromopyrrolo[2,3-d]pyrimidin-7-yl)methoxy]propane-1,3-diol Chemical compound NC1=NC=NC2=C1C(Br)=CN2COC(CO)CO QTMAZYGAVHCKKX-UHFFFAOYSA-N 0.000 claims description 2
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- PAYROHWFGZADBR-UHFFFAOYSA-N 2-[[4-amino-5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)pyrimidin-2-yl]amino]propane-1,3-diol Chemical compound C1=C(I)C(OC)=CC(C(C)C)=C1OC1=CN=C(NC(CO)CO)N=C1N PAYROHWFGZADBR-UHFFFAOYSA-N 0.000 claims description 2
- VVCMGAUPZIKYTH-VGHSCWAPSA-N 2-acetyloxybenzoic acid;[(2s,3r)-4-(dimethylamino)-3-methyl-1,2-diphenylbutan-2-yl] propanoate;1,3,7-trimethylpurine-2,6-dione Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O.CN1C(=O)N(C)C(=O)C2=C1N=CN2C.C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 VVCMGAUPZIKYTH-VGHSCWAPSA-N 0.000 claims description 2
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- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 claims description 2
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Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201261620232P | 2012-04-04 | 2012-04-04 | |
| US61/620,232 | 2012-04-04 | ||
| US201361783647P | 2013-03-14 | 2013-03-14 | |
| US61/783,647 | 2013-03-14 | ||
| PCT/US2013/035285 WO2013152198A1 (en) | 2012-04-04 | 2013-04-04 | Protein kinase c inhibitors and uses thereof |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2015519307A JP2015519307A (ja) | 2015-07-09 |
| JP2015519307A5 JP2015519307A5 (https=) | 2016-06-02 |
| JP6113828B2 true JP6113828B2 (ja) | 2017-04-12 |
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| Application Number | Title | Priority Date | Filing Date |
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| JP2015504725A Expired - Fee Related JP6113828B2 (ja) | 2012-04-04 | 2013-04-04 | プロテインキナーゼc阻害剤およびその使用 |
Country Status (6)
| Country | Link |
|---|---|
| US (3) | US9321763B2 (https=) |
| EP (1) | EP2833889B1 (https=) |
| JP (1) | JP6113828B2 (https=) |
| CA (1) | CA2867760C (https=) |
| ES (1) | ES2658395T3 (https=) |
| WO (1) | WO2013152198A1 (https=) |
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| ES2658395T3 (es) * | 2012-04-04 | 2018-03-09 | Rigel Pharmaceuticals, Inc. | Inhibidores de proteína cinasa C y usos de los mismos |
| DK3077397T3 (da) * | 2013-12-06 | 2019-12-16 | Vertex Pharma | 2-amino-6-fluor-n-[5-fluor-pyridin-3-yl]pyrazolo[1,5-a]pyrimidin-3-carboxamidforbindelse anvendelig som atr-kinase-inhibitor, dens fremstilling, forskellige faste former og radiomarkerede derivater deraf |
| CN106456700B (zh) | 2014-01-29 | 2020-02-18 | 斯特拉斯堡大学 | 糖尿病治疗和预防的新靶标 |
| NZ715903A (en) | 2014-01-30 | 2017-06-30 | Signal Pharm Llc | Solid forms of 2-(tert-butylamino)-4-((1r,3r,4r)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their use |
| MX2016012574A (es) | 2014-03-28 | 2017-09-26 | Calitor Sciences Llc | Compuestos heteroarilo sustituidos y metodos de uso. |
| EP3206691B1 (en) | 2014-10-14 | 2018-09-19 | Sunshine Lake Pharma Co., Ltd. | Substituted heteroaryl compounds and methods of use |
| EP3319968A1 (en) | 2015-07-06 | 2018-05-16 | Rodin Therapeutics, Inc. | Heterobicyclic n-aminophenyl-amides as inhibitors of histone deacetylase |
| LT3319959T (lt) | 2015-07-06 | 2021-12-27 | Alkermes, Inc. | Histono deacetilazės hetero-halogeno inhibitoriai |
| WO2017044434A1 (en) | 2015-09-11 | 2017-03-16 | Sunshine Lake Pharma Co., Ltd. | Substituted heteroaryl compounds and methods of use |
| RS62959B1 (sr) | 2017-01-11 | 2022-03-31 | Alkermes Inc | Biciklični inhibitori histon-deacetilaze |
| EP3421485A1 (en) | 2017-06-30 | 2019-01-02 | Université de Strasbourg | Peptides for treatment and prevention of hyperglycaemia |
| US11225475B2 (en) | 2017-08-07 | 2022-01-18 | Alkermes, Inc. | Substituted pyridines as inhibitors of histone deacetylase |
| US10683297B2 (en) | 2017-11-19 | 2020-06-16 | Calitor Sciences, Llc | Substituted heteroaryl compounds and methods of use |
| JP2024513227A (ja) | 2021-04-05 | 2024-03-22 | ハリア・セラピューティクス・インコーポレイテッド | Nek7阻害剤 |
| US20250177382A1 (en) | 2021-04-22 | 2025-06-05 | Halia Therapeutics, Inc. | Nek7 inhibitors |
| WO2024122617A1 (ja) | 2022-12-08 | 2024-06-13 | 塩野義製薬株式会社 | セロトニン受容体結合活性を有する含窒素複素環および炭素環誘導体 |
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| US5843935A (en) | 1993-12-07 | 1998-12-01 | Eli Lilly And Company | Protein kinase C inhibitors |
| GB9523675D0 (en) | 1995-11-20 | 1996-01-24 | Celltech Therapeutics Ltd | Chemical compounds |
| TWI329105B (en) * | 2002-02-01 | 2010-08-21 | Rigel Pharmaceuticals Inc | 2,4-pyrimidinediamine compounds and their uses |
| US7144907B2 (en) | 2003-09-03 | 2006-12-05 | Array Biopharma Inc. | Heterocyclic inhibitors of MEK and methods of use thereof |
| NZ578876A (en) * | 2007-02-07 | 2012-12-21 | Pfizer | 3-amino-pyrrolo[3,4-c]pyrazole-5 (1h, 4h, 6h) carbaldehyde derivatives as pkc inhibitors |
| CA2693594A1 (en) | 2007-07-17 | 2009-01-22 | Rigel Pharmaceuticals, Inc. | Cyclic amine substituted pyrimidinediamines as pkc inhibitors |
| ES2555982T3 (es) | 2009-01-15 | 2016-01-12 | Rigel Pharmaceuticals, Inc. | Inhibidores de la proteína quinasa C y usos de los mismos |
| CA2749837C (en) * | 2009-01-21 | 2017-07-11 | Rigel Pharmaceuticals, Inc. | Derivatives of n2-(3-pyridil or phenyl)-n4-(4-piperidyl)-2,4-pyrimidinediamine useful in the treatment of inflammatory, autoimmune or proliferative diseases |
| US20110130415A1 (en) * | 2009-12-01 | 2011-06-02 | Rajinder Singh | Protein kinase c inhibitors and uses thereof |
| EP2595982B1 (en) | 2010-07-21 | 2018-06-13 | Rigel Pharmaceuticals, Inc. | Protein kinase c inhibitors and uses thereof |
| AU2011282742B2 (en) | 2010-07-28 | 2015-08-27 | Rigel Pharmaceuticals, Inc. | Compositions and methods for inhibition of the JAK pathway |
| ES2658395T3 (es) | 2012-04-04 | 2018-03-09 | Rigel Pharmaceuticals, Inc. | Inhibidores de proteína cinasa C y usos de los mismos |
| CA2904610A1 (en) * | 2013-03-14 | 2014-09-25 | Rigel Pharmaceuticals, Inc. | Protein kinase c inhibitors and uses thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2016519657A (ja) * | 2013-03-14 | 2016-07-07 | ライジェル ファーマシューティカルズ, インコーポレイテッド | プロテインキナーゼc阻害剤およびその使用 |
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| EP2833889A4 (en) | 2015-11-11 |
| US20130331374A1 (en) | 2013-12-12 |
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| US9682976B2 (en) | 2017-06-20 |
| EP2833889B1 (en) | 2017-11-01 |
| EP2833889A1 (en) | 2015-02-11 |
| CA2867760A1 (en) | 2013-10-10 |
| US9321763B2 (en) | 2016-04-26 |
| ES2658395T3 (es) | 2018-03-09 |
| WO2013152198A1 (en) | 2013-10-10 |
| JP2015519307A (ja) | 2015-07-09 |
| US20160257681A1 (en) | 2016-09-08 |
| US20180030050A1 (en) | 2018-02-01 |
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