EA022325B1 - Производные индолина как ингибиторы perk - Google Patents

Info

Publication number

EA022325B1

EA022325B1 EA201290952A EA201290952A EA022325B1 EA 022325 B1 EA022325 B1 EA 022325B1 EA 201290952 A EA201290952 A EA 201290952A EA 201290952 A EA201290952 A EA 201290952A EA 022325 B1 EA022325 B1 EA 022325B1

Authority

EA

Eurasian Patent Office

Prior art keywords

dihydro

indol

amine

acetyl

pyrimidin

Prior art date

2010-03-25

Links

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• 239000003112 inhibitor Substances 0.000 title abstract description 15
• 125000003387 indolinyl group Chemical class N1(CCC2=CC=CC=C12)* 0.000 title abstract 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 115
• 238000000034 method Methods 0.000 claims abstract description 38
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 23
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 19
• 201000011510 cancer Diseases 0.000 claims abstract description 17
• 201000010099 disease Diseases 0.000 claims abstract description 16
• 230000000694 effects Effects 0.000 claims abstract description 10
• 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 9
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
• 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 8
• 230000002401 inhibitory effect Effects 0.000 claims abstract description 8
• 201000001320 Atherosclerosis Diseases 0.000 claims abstract description 7
• 208000023105 Huntington disease Diseases 0.000 claims abstract description 7
• 208000018737 Parkinson disease Diseases 0.000 claims abstract description 7
• 208000006011 Stroke Diseases 0.000 claims abstract description 7
• 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims abstract description 7
• 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims abstract description 7
• 206010003119 arrhythmia Diseases 0.000 claims abstract description 7
• 230000006793 arrhythmia Effects 0.000 claims abstract description 7
• 208000010125 myocardial infarction Diseases 0.000 claims abstract description 7
• -1 phenylacetyl Chemical group 0.000 claims description 624
• OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 claims description 588
• 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 63
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 45
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 41
• 150000003839 salts Chemical class 0.000 claims description 31
• NUKYPUAOHBNCPY-UHFFFAOYSA-N 4-aminopyridine Chemical compound NC1=CC=NC=C1 NUKYPUAOHBNCPY-UHFFFAOYSA-N 0.000 claims description 27
• 229960004979 fampridine Drugs 0.000 claims description 26
• 238000001914 filtration Methods 0.000 claims description 26
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 25
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 24
• 108090000623 proteins and genes Proteins 0.000 claims description 20
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 17
• 102000004169 proteins and genes Human genes 0.000 claims description 17
• 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 16
• GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 16
• WNWVKZTYMQWFHE-UHFFFAOYSA-N 4-ethylmorpholine Chemical group [CH2]CN1CCOCC1 WNWVKZTYMQWFHE-UHFFFAOYSA-N 0.000 claims description 14
• 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 12
• 230000004044 response Effects 0.000 claims description 11
• 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 10
• 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 10
• 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 claims description 10
• 206010064930 age-related macular degeneration Diseases 0.000 claims description 10
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
• 108091000080 Phosphotransferase Proteins 0.000 claims description 9
• 102000020233 phosphotransferase Human genes 0.000 claims description 9
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 8
• 208000002780 macular degeneration Diseases 0.000 claims description 8
• 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 8
• XSKKJZREOBORCM-UHFFFAOYSA-N 1-[5-(4-aminofuro[3,2-c]pyridin-3-yl)-2,3-dihydroindol-1-yl]-2-(2,5-difluorophenyl)ethanone Chemical compound C1=2C(N)=NC=CC=2OC=C1C(C=C1CC2)=CC=C1N2C(=O)CC1=CC(F)=CC=C1F XSKKJZREOBORCM-UHFFFAOYSA-N 0.000 claims description 7
• 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 7
• 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 7
• 241000282412 Homo Species 0.000 claims description 6
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• FYILOGFFIMZZHN-UHFFFAOYSA-N 1-[5-(3-amino-1h-pyrazolo[3,4-c]pyridin-4-yl)-2,3-dihydroindol-1-yl]-2-(3-methylphenyl)ethanone Chemical compound CC1=CC=CC(CC(=O)N2C3=CC=C(C=C3CC2)C=2C=3C(N)=NNC=3C=NC=2)=C1 FYILOGFFIMZZHN-UHFFFAOYSA-N 0.000 claims description 5
• DYBQYHYWCJCVLA-UHFFFAOYSA-N 1-[5-(3-amino-1h-pyrazolo[3,4-c]pyridin-4-yl)-2,3-dihydroindol-1-yl]-2-[3-(trifluoromethyl)phenyl]ethanone Chemical compound C=12C(N)=NNC2=CN=CC=1C(C=C1CC2)=CC=C1N2C(=O)CC1=CC=CC(C(F)(F)F)=C1 DYBQYHYWCJCVLA-UHFFFAOYSA-N 0.000 claims description 5
• VNDDOAWIHYNTOI-UHFFFAOYSA-N 1-[5-(4-amino-7-pyridin-3-ylthieno[3,2-c]pyridin-3-yl)-2,3-dihydroindol-1-yl]-2-phenylethanone Chemical compound C1=2SC=C(C=3C=C4CCN(C4=CC=3)C(=O)CC=3C=CC=CC=3)C=2C(N)=NC=C1C1=CC=CN=C1 VNDDOAWIHYNTOI-UHFFFAOYSA-N 0.000 claims description 5
• YDRLBYPQASBCQA-UHFFFAOYSA-N 1-[5-(4-aminothieno[3,2-c]pyridin-3-yl)-2,3-dihydroindol-1-yl]-2-(2,5-difluorophenyl)ethanone Chemical compound C1=2C(N)=NC=CC=2SC=C1C(C=C1CC2)=CC=C1N2C(=O)CC1=CC(F)=CC=C1F YDRLBYPQASBCQA-UHFFFAOYSA-N 0.000 claims description 5
• RYVFTJZSAOBQNH-UHFFFAOYSA-N 1-[5-(4-aminothieno[3,2-c]pyridin-3-yl)-2,3-dihydroindol-1-yl]-2-(2-methoxyphenyl)ethanone Chemical compound COC1=CC=CC=C1CC(=O)N1C2=CC=C(C=3C4=C(N)N=CC=C4SC=3)C=C2CC1 RYVFTJZSAOBQNH-UHFFFAOYSA-N 0.000 claims description 5
• YQMAMHOIVLBXCV-UHFFFAOYSA-N 1-[5-(4-aminothieno[3,2-c]pyridin-3-yl)-2,3-dihydroindol-1-yl]-2-(3-methoxyphenyl)ethanone Chemical compound COC1=CC=CC(CC(=O)N2C3=CC=C(C=C3CC2)C=2C3=C(N)N=CC=C3SC=2)=C1 YQMAMHOIVLBXCV-UHFFFAOYSA-N 0.000 claims description 5
• YIEAFENYFHZFJZ-UHFFFAOYSA-N 1-[5-(4-aminothieno[3,2-c]pyridin-3-yl)-2,3-dihydroindol-1-yl]-2-[3-(trifluoromethyl)phenyl]ethanone Chemical compound C1=2C(N)=NC=CC=2SC=C1C(C=C1CC2)=CC=C1N2C(=O)CC1=CC=CC(C(F)(F)F)=C1 YIEAFENYFHZFJZ-UHFFFAOYSA-N 0.000 claims description 5
• GIDAHXRLHKZRNS-UHFFFAOYSA-N 1-[5-(4-aminothieno[3,2-c]pyridin-3-yl)-2,3-dihydroindol-1-yl]-2-naphthalen-1-ylethanone Chemical compound C1=CC=C2C(CC(=O)N3C4=CC=C(C=C4CC3)C3=CSC=4C=CN=C(C3=4)N)=CC=CC2=C1 GIDAHXRLHKZRNS-UHFFFAOYSA-N 0.000 claims description 5
• ODYPJFBAIADVRN-UHFFFAOYSA-N 1-[5-[4-amino-7-[3-[(dimethylamino)methyl]phenyl]thieno[3,2-c]pyridin-3-yl]-2,3-dihydroindol-1-yl]-2-phenylethanone Chemical compound CN(C)CC1=CC=CC(C=2C=3SC=C(C=3C(N)=NC=2)C=2C=C3CCN(C3=CC=2)C(=O)CC=2C=CC=CC=2)=C1 ODYPJFBAIADVRN-UHFFFAOYSA-N 0.000 claims description 5
• 208000030533 eye disease Diseases 0.000 claims description 5
• LTBUGKMPWQPUFH-UHFFFAOYSA-N 1-[5-(3-amino-1-methylindazol-4-yl)-2,3-dihydroindol-1-yl]-2-(3-methylphenyl)ethanone Chemical compound CC1=CC=CC(CC(=O)N2C3=CC=C(C=C3CC2)C=2C=3C(N)=NN(C)C=3C=CC=2)=C1 LTBUGKMPWQPUFH-UHFFFAOYSA-N 0.000 claims description 4
• XXIKKKQUZADDJI-UHFFFAOYSA-N 1-[5-(3-amino-1-methylpyrazolo[3,4-c]pyridin-4-yl)-2,3-dihydroindol-1-yl]-2-[3-(trifluoromethyl)phenyl]ethanone Chemical compound C1=NC=C2N(C)N=C(N)C2=C1C(C=C1CC2)=CC=C1N2C(=O)CC1=CC=CC(C(F)(F)F)=C1 XXIKKKQUZADDJI-UHFFFAOYSA-N 0.000 claims description 4
• LCRXWSJBFYHPTM-UHFFFAOYSA-N 1-[5-(4-amino-7-piperidin-4-ylthieno[3,2-c]pyridin-3-yl)-2,3-dihydroindol-1-yl]-2-phenylethanone Chemical compound C1=2SC=C(C=3C=C4CCN(C4=CC=3)C(=O)CC=3C=CC=CC=3)C=2C(N)=NC=C1C1CCNCC1 LCRXWSJBFYHPTM-UHFFFAOYSA-N 0.000 claims description 4
• YGJZRPGTTACELL-UHFFFAOYSA-N 1-[5-(4-aminothieno[3,2-c]pyridin-3-yl)-2,3-dihydroindol-1-yl]-2-(2,3-difluorophenyl)ethanone Chemical compound C1=2C(N)=NC=CC=2SC=C1C(C=C1CC2)=CC=C1N2C(=O)CC1=CC=CC(F)=C1F YGJZRPGTTACELL-UHFFFAOYSA-N 0.000 claims description 4
• HLXXZZJOWXVYFE-UHFFFAOYSA-N 1-[5-(4-aminothieno[3,2-c]pyridin-3-yl)-2,3-dihydroindol-1-yl]-2-(2-chlorophenyl)ethanone Chemical compound C1=2C(N)=NC=CC=2SC=C1C(C=C1CC2)=CC=C1N2C(=O)CC1=CC=CC=C1Cl HLXXZZJOWXVYFE-UHFFFAOYSA-N 0.000 claims description 4
• ADXYXPNGWRZFOH-UHFFFAOYSA-N 1-[5-(4-aminothieno[3,2-c]pyridin-3-yl)-2,3-dihydroindol-1-yl]-2-(3-fluoro-2-methylphenyl)ethanone Chemical compound CC1=C(F)C=CC=C1CC(=O)N1C2=CC=C(C=3C4=C(N)N=CC=C4SC=3)C=C2CC1 ADXYXPNGWRZFOH-UHFFFAOYSA-N 0.000 claims description 4
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• 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 4
• DVZUNDFNVGOMIR-UHFFFAOYSA-N 1-[5-(3-amino-1-methylindazol-4-yl)-2,3-dihydroindol-1-yl]-2-(2,5-difluorophenyl)ethanone Chemical compound C1=CC=C2N(C)N=C(N)C2=C1C(C=C1CC2)=CC=C1N2C(=O)CC1=CC(F)=CC=C1F DVZUNDFNVGOMIR-UHFFFAOYSA-N 0.000 claims description 3
• VFMMINQECOXKJE-UHFFFAOYSA-N 1-[5-(4-amino-7-chlorofuro[3,2-c]pyridin-3-yl)-2,3-dihydroindol-1-yl]-2-(2,5-difluorophenyl)ethanone Chemical compound C1=2C(N)=NC=C(Cl)C=2OC=C1C(C=C1CC2)=CC=C1N2C(=O)CC1=CC(F)=CC=C1F VFMMINQECOXKJE-UHFFFAOYSA-N 0.000 claims description 3
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