CA2912986A1 - Pyrazolo-pyrrolidin-4-one derivatives as bet inhibitors and their use in the treatment of disease - Google Patents

Info

Publication number

CA2912986A1

CA2912986A1 CA2912986A CA2912986A CA2912986A1 CA 2912986 A1 CA2912986 A1 CA 2912986A1 CA 2912986 A CA2912986 A CA 2912986A CA 2912986 A CA2912986 A CA 2912986A CA 2912986 A1 CA2912986 A1 CA 2912986A1

Authority

CA

Canada

Prior art keywords

methyl

pyrazol

triazolo

dihydropyrrolo

pyridin

Prior art date

2013-05-28

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.)

Abandoned

Links

• Espacenet
• Global Dossier
• CIPO
• Discuss

• 238000011282 treatment Methods 0.000 title claims description 20
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title description 48
• 201000010099 disease Diseases 0.000 title description 34
• 239000003112 inhibitor Substances 0.000 title description 15
• 150000001875 compounds Chemical class 0.000 claims abstract description 195
• 238000000034 method Methods 0.000 claims abstract description 60
• 150000003839 salts Chemical class 0.000 claims abstract description 60
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 18
• 238000004519 manufacturing process Methods 0.000 claims abstract description 7
• 239000013543 active substance Substances 0.000 claims abstract description 3
• SEMXWBFSIDIGPO-UHFFFAOYSA-N 1,5-dihydropyrazol-4-one Chemical compound O=C1CNN=C1 SEMXWBFSIDIGPO-UHFFFAOYSA-N 0.000 claims description 97
• 239000003814 drug Substances 0.000 claims description 30
• 206010028980 Neoplasm Diseases 0.000 claims description 26
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 26
• 201000011510 cancer Diseases 0.000 claims description 19
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 17
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
• 239000003937 drug carrier Substances 0.000 claims description 7
• 125000001153 fluoro group Chemical group F* 0.000 claims description 6
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
• 125000005843 halogen group Chemical group 0.000 claims description 3
• 230000004952 protein activity Effects 0.000 claims description 3
• 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 2
• ZBIYSSHSZQVNSP-UHFFFAOYSA-N 6-(4-chlorophenyl)-3-cyclopropyl-5-[3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl]-1-methyl-6h-pyrrolo[3,4-c]pyrazol-4-one Chemical compound C=1N2C(C(F)F)=NN=C2C(C)=CC=1N(C1=O)C(C=2C=CC(Cl)=CC=2)C(N(N=2)C)=C1C=2C1CC1 ZBIYSSHSZQVNSP-UHFFFAOYSA-N 0.000 claims 3
• XMRBIQDRTZCVGG-OAQYLSRUSA-N (6r)-6-(4-chlorophenyl)-3-cyclopropyl-5-(3,7-dimethylbenzotriazol-5-yl)-1-methyl-6h-pyrrolo[3,4-c]pyrazol-4-one Chemical compound N=1N(C)C([C@H](N(C2=O)C=3C=C(C=4N=NN(C)C=4C=3)C)C=3C=CC(Cl)=CC=3)=C2C=1C1CC1 XMRBIQDRTZCVGG-OAQYLSRUSA-N 0.000 claims 1
• SCOGYYPZUPWMLU-JOCHJYFZSA-N (6r)-6-(4-chlorophenyl)-3-cyclopropyl-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1-(2-methoxyethyl)-6h-pyrrolo[3,4-c]pyrazol-4-one Chemical compound C=1([C@H](N(C(=O)C=11)C2=CN3C(C)=NN=C3C(C)=C2)C=2C=CC(Cl)=CC=2)N(CCOC)N=C1C1CC1 SCOGYYPZUPWMLU-JOCHJYFZSA-N 0.000 claims 1
• NCLGWTFZOQZNIS-WIYYLYMNSA-N (6r)-6-(4-chlorophenyl)-3-cyclopropyl-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1-[(2r)-3,3,3-trifluoro-2-hydroxypropyl]-6h-pyrrolo[3,4-c]pyrazol-4-one Chemical compound N=1N(C[C@@H](O)C(F)(F)F)C([C@H](N(C2=O)C=3C=C(C)C4=NN=C(N4C=3)C)C=3C=CC(Cl)=CC=3)=C2C=1C1CC1 NCLGWTFZOQZNIS-WIYYLYMNSA-N 0.000 claims 1
• NCLGWTFZOQZNIS-GHTZIAJQSA-N (6r)-6-(4-chlorophenyl)-3-cyclopropyl-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1-[(2s)-3,3,3-trifluoro-2-hydroxypropyl]-6h-pyrrolo[3,4-c]pyrazol-4-one Chemical compound N=1N(C[C@H](O)C(F)(F)F)C([C@H](N(C2=O)C=3C=C(C)C4=NN=C(N4C=3)C)C=3C=CC(Cl)=CC=3)=C2C=1C1CC1 NCLGWTFZOQZNIS-GHTZIAJQSA-N 0.000 claims 1
• AVVWKDYUXSFEJL-LJQANCHMSA-N (6r)-6-(4-chlorophenyl)-3-cyclopropyl-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1-methyl-6h-pyrrolo[3,4-c]pyrazol-4-one Chemical compound N=1N(C)C([C@H](N(C2=O)C=3C=C(C)C4=NN=C(N4N=3)C)C=3C=CC(Cl)=CC=3)=C2C=1C1CC1 AVVWKDYUXSFEJL-LJQANCHMSA-N 0.000 claims 1
• MVAYDDZVYGANLI-HXUWFJFHSA-N (6r)-6-(4-chlorophenyl)-3-cyclopropyl-5-(8-methoxy-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1-methyl-6h-pyrrolo[3,4-c]pyrazol-4-one Chemical compound N=1N(C)C([C@H](N(C2=O)C=3C=C(C4=NN=C(C)N4C=3)OC)C=3C=CC(Cl)=CC=3)=C2C=1C1CC1 MVAYDDZVYGANLI-HXUWFJFHSA-N 0.000 claims 1
• ZBIYSSHSZQVNSP-GOSISDBHSA-N (6r)-6-(4-chlorophenyl)-3-cyclopropyl-5-[3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl]-1-methyl-6h-pyrrolo[3,4-c]pyrazol-4-one Chemical compound N=1N(C)C([C@H](N(C2=O)C=3C=C(C4=NN=C(N4C=3)C(F)F)C)C=3C=CC(Cl)=CC=3)=C2C=1C1CC1 ZBIYSSHSZQVNSP-GOSISDBHSA-N 0.000 claims 1
• JBWFCYLPISSKIG-HXUWFJFHSA-N (6r)-6-(4-chlorophenyl)-3-cyclopropyl-5-[3-(fluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl]-1-methyl-6h-pyrrolo[3,4-c]pyrazol-4-one Chemical compound N=1N(C)C([C@H](N(C2=O)C=3C=C(C4=NN=C(CF)N4C=3)C)C=3C=CC(Cl)=CC=3)=C2C=1C1CC1 JBWFCYLPISSKIG-HXUWFJFHSA-N 0.000 claims 1
• XZYFNQNYLMTZIS-JOCHJYFZSA-N (6r)-6-(4-chlorophenyl)-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-(2-methoxypyridin-3-yl)-1-methyl-6h-pyrrolo[3,4-c]pyrazol-4-one Chemical compound COC1=NC=CC=C1C1=NN(C)C2=C1C(=O)N(C1=CN3C(C)=NN=C3C(C)=C1)[C@@H]2C1=CC=C(Cl)C=C1 XZYFNQNYLMTZIS-JOCHJYFZSA-N 0.000 claims 1
• FRDVUWTYVBTBSE-UHFFFAOYSA-N 5-(8-amino-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-6-(4-chlorophenyl)-3-cyclopropyl-1-methyl-6h-pyrrolo[3,4-c]pyrazol-4-one Chemical compound C=1N2C(C)=NN=C2C(N)=CC=1N(C1=O)C(C=2C=CC(Cl)=CC=2)C(N(N=2)C)=C1C=2C1CC1 FRDVUWTYVBTBSE-UHFFFAOYSA-N 0.000 claims 1
• ADWUQOKWKQHUJB-FTYDEUEMSA-N 5-[(2R,4E)-4-[amino(cyclopropyl)methylidene]-2-(4-chlorophenyl)-3-methylimino-5-oxopyrrolidin-1-yl]-1,3-dimethylpyridin-2-one Chemical compound CC1=CC(=CN(C1=O)C)N2[C@@H](C(=NC)/C(=C(/C3CC3)\N)/C2=O)C4=CC=C(C=C4)Cl ADWUQOKWKQHUJB-FTYDEUEMSA-N 0.000 claims 1
• XMRBIQDRTZCVGG-UHFFFAOYSA-N 6-(4-chlorophenyl)-3-cyclopropyl-5-(3,7-dimethylbenzotriazol-5-yl)-1-methyl-6h-pyrrolo[3,4-c]pyrazol-4-one Chemical compound C=1C=2N(C)N=NC=2C(C)=CC=1N(C1=O)C(C=2C=CC(Cl)=CC=2)C(N(N=2)C)=C1C=2C1CC1 XMRBIQDRTZCVGG-UHFFFAOYSA-N 0.000 claims 1
• YTFVGFPLAOYSNF-UHFFFAOYSA-N 6-(4-chlorophenyl)-3-cyclopropyl-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1-(2-methylpyrazol-3-yl)-6h-pyrrolo[3,4-c]pyrazol-4-one Chemical compound C=1N2C(C)=NN=C2C(C)=CC=1N(C1=O)C(C=2C=CC(Cl)=CC=2)C2=C1C(C1CC1)=NN2C1=CC=NN1C YTFVGFPLAOYSNF-UHFFFAOYSA-N 0.000 claims 1
• ZRAGYVAOZMZDPY-UHFFFAOYSA-N 6-(4-chlorophenyl)-3-cyclopropyl-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1-methyl-6h-pyrrolo[3,4-c]pyrazol-4-one Chemical compound C=1N2C(C)=NN=C2C(C)=CC=1N(C1=O)C(C=2C=CC(Cl)=CC=2)C(N(N=2)C)=C1C=2C1CC1 ZRAGYVAOZMZDPY-UHFFFAOYSA-N 0.000 claims 1
• MLMDKPAWBXFXNA-UHFFFAOYSA-N 6-(4-chlorophenyl)-3-cyclopropyl-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1-(2-methylpyrazol-3-yl)-6h-pyrrolo[3,4-c]pyrazol-4-one Chemical compound N=1N2C(C)=NN=C2C(C)=CC=1N(C1=O)C(C=2C=CC(Cl)=CC=2)C2=C1C(C1CC1)=NN2C1=CC=NN1C MLMDKPAWBXFXNA-UHFFFAOYSA-N 0.000 claims 1
• AVVWKDYUXSFEJL-UHFFFAOYSA-N 6-(4-chlorophenyl)-3-cyclopropyl-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1-methyl-6h-pyrrolo[3,4-c]pyrazol-4-one Chemical compound N=1N2C(C)=NN=C2C(C)=CC=1N(C1=O)C(C=2C=CC(Cl)=CC=2)C(N(N=2)C)=C1C=2C1CC1 AVVWKDYUXSFEJL-UHFFFAOYSA-N 0.000 claims 1
• FBLOSBSWOXHYPV-UHFFFAOYSA-N 6-(4-chlorophenyl)-3-cyclopropyl-5-[3-(difluoromethyl)-8-methoxy-[1,2,4]triazolo[4,3-a]pyridin-6-yl]-1-methyl-6h-pyrrolo[3,4-c]pyrazol-4-one Chemical compound C=1N2C(C(F)F)=NN=C2C(OC)=CC=1N(C1=O)C(C=2C=CC(Cl)=CC=2)C(N(N=2)C)=C1C=2C1CC1 FBLOSBSWOXHYPV-UHFFFAOYSA-N 0.000 claims 1
• KKQGFFSHWVTNMA-UHFFFAOYSA-N 6-(4-chlorophenyl)-3-cyclopropyl-5-[3-(fluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl]-1-(2-methoxyethyl)-6h-pyrrolo[3,4-c]pyrazol-4-one Chemical compound C1=2C(=O)N(C3=CN4C(CF)=NN=C4C(C)=C3)C(C=3C=CC(Cl)=CC=3)C=2N(CCOC)N=C1C1CC1 KKQGFFSHWVTNMA-UHFFFAOYSA-N 0.000 claims 1
• JBWFCYLPISSKIG-UHFFFAOYSA-N 6-(4-chlorophenyl)-3-cyclopropyl-5-[3-(fluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl]-1-methyl-6h-pyrrolo[3,4-c]pyrazol-4-one Chemical compound C=1N2C(CF)=NN=C2C(C)=CC=1N(C1=O)C(C=2C=CC(Cl)=CC=2)C(N(N=2)C)=C1C=2C1CC1 JBWFCYLPISSKIG-UHFFFAOYSA-N 0.000 claims 1
• HDHIHYNEQCFQNL-UHFFFAOYSA-N 6-(4-chlorophenyl)-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-(2-methoxypyridin-3-yl)-1,6-dihydropyrrolo[3,4-c]pyrazol-4-one Chemical compound COC1=NC=CC=C1C1=NNC2=C1C(=O)N(C1=CN3C(C)=NN=C3C(C)=C1)C2C1=CC=C(Cl)C=C1 HDHIHYNEQCFQNL-UHFFFAOYSA-N 0.000 claims 1
• XZYFNQNYLMTZIS-UHFFFAOYSA-N 6-(4-chlorophenyl)-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-(2-methoxypyridin-3-yl)-1-methyl-6h-pyrrolo[3,4-c]pyrazol-4-one Chemical compound COC1=NC=CC=C1C1=NN(C)C2=C1C(=O)N(C1=CN3C(C)=NN=C3C(C)=C1)C2C1=CC=C(Cl)C=C1 XZYFNQNYLMTZIS-UHFFFAOYSA-N 0.000 claims 1
• MDJXFKRWSHUIHK-YMOXTTMHSA-N COc1ncccc1C1NNC2C1C(=O)N([C@@H]2c1ccc(Cl)cc1)c1cc(C)c2nnc(C)n2c1 Chemical compound COc1ncccc1C1NNC2C1C(=O)N([C@@H]2c1ccc(Cl)cc1)c1cc(C)c2nnc(C)n2c1 MDJXFKRWSHUIHK-YMOXTTMHSA-N 0.000 claims 1
• GTLGKZJPNAWIBT-UHFFFAOYSA-N ethyl n-[6-[6-(4-chlorophenyl)-3-cyclopropyl-1-methyl-4-oxo-6h-pyrrolo[3,4-c]pyrazol-5-yl]-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-8-yl]carbamate Chemical compound C=1N2C(C)=NN=C2C(NC(=O)OCC)=CC=1N(C1=O)C(C=2C=CC(Cl)=CC=2)C(N(N=2)C)=C1C=2C1CC1 GTLGKZJPNAWIBT-UHFFFAOYSA-N 0.000 claims 1
• OYDMPDMTZYTSSQ-UHFFFAOYSA-N tert-butyl n-[6-[6-(4-chlorophenyl)-3-cyclopropyl-1-methyl-4-oxo-6h-pyrrolo[3,4-c]pyrazol-5-yl]-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-8-yl]carbamate Chemical compound C=1N2C(C)=NN=C2C(NC(=O)OC(C)(C)C)=CC=1N(C1=O)C(C=2C=CC(Cl)=CC=2)C(N(N=2)C)=C1C=2C1CC1 OYDMPDMTZYTSSQ-UHFFFAOYSA-N 0.000 claims 1
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