JP7134973B2 - Ｄｙｒｋ１ａおよび／またはｄｙｒｋ１ｂキナーゼの阻害剤としてのキノリンの誘導体 - Google Patents

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Publication number

JP7134973B2

JP7134973B2 JP2019534721A JP2019534721A JP7134973B2 JP 7134973 B2 JP7134973 B2 JP 7134973B2 JP 2019534721 A JP2019534721 A JP 2019534721A JP 2019534721 A JP2019534721 A JP 2019534721A JP 7134973 B2 JP7134973 B2 JP 7134973B2

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JP

Japan

Prior art keywords

pyrrolo

pyridin

pyridine

methyl

carboxamide

Prior art date

2016-12-23

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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• 102100028554 Dual specificity tyrosine-phosphorylation-regulated kinase 1A Human genes 0.000 title description 33
• 101000838016 Homo sapiens Dual specificity tyrosine-phosphorylation-regulated kinase 1A Proteins 0.000 title description 33
• 102100033363 Dual specificity tyrosine-phosphorylation-regulated kinase 1B Human genes 0.000 title description 25
• 101000926738 Homo sapiens Dual specificity tyrosine-phosphorylation-regulated kinase 1B Proteins 0.000 title description 25
• 239000003112 inhibitor Substances 0.000 title description 6
• 150000003248 quinolines Chemical class 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims description 336
• 125000000623 heterocyclic group Chemical group 0.000 claims description 199
• 229910052799 carbon Inorganic materials 0.000 claims description 195
• 125000001424 substituent group Chemical group 0.000 claims description 185
• 125000005842 heteroatom Chemical group 0.000 claims description 136
• 229910052736 halogen Inorganic materials 0.000 claims description 108
• 150000002367 halogens Chemical class 0.000 claims description 108
• 125000002837 carbocyclic group Chemical group 0.000 claims description 107
• 229920006395 saturated elastomer Polymers 0.000 claims description 103
• -1 C 1 -C 6 -alkoxy Chemical group 0.000 claims description 102
• 229910052760 oxygen Inorganic materials 0.000 claims description 87
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 85
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 80
• 229910052739 hydrogen Inorganic materials 0.000 claims description 78
• 125000004122 cyclic group Chemical group 0.000 claims description 77
• 229910052757 nitrogen Inorganic materials 0.000 claims description 77
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 71
• 125000004434 sulfur atom Chemical group 0.000 claims description 68
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 60
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 60
• 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 51
• 150000001721 carbon Chemical group 0.000 claims description 50
• 125000006643 (C2-C6) haloalkenyl group Chemical group 0.000 claims description 44
• CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 43
• 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 42
• 125000004429 atom Chemical group 0.000 claims description 37
• 125000002619 bicyclic group Chemical group 0.000 claims description 31
• 125000006729 (C2-C5) alkenyl group Chemical group 0.000 claims description 30
• 125000006730 (C2-C5) alkynyl group Chemical group 0.000 claims description 30
• 125000004432 carbon atom Chemical group C* 0.000 claims description 25
• 239000008194 pharmaceutical composition Substances 0.000 claims description 25
• 125000004550 quinolin-6-yl group Chemical group N1=CC=CC2=CC(=CC=C12)* 0.000 claims description 25
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 23
• 125000000304 alkynyl group Chemical group 0.000 claims description 21
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 21
• 201000010099 disease Diseases 0.000 claims description 20
• 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 claims description 14
• 150000003839 salts Chemical class 0.000 claims description 14
• 208000030159 metabolic disease Diseases 0.000 claims description 13
• 208000023275 Autoimmune disease Diseases 0.000 claims description 12
• 150000001412 amines Chemical class 0.000 claims description 12
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 12
• 229910052717 sulfur Inorganic materials 0.000 claims description 12
• 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 10
• 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 10
• 208000027866 inflammatory disease Diseases 0.000 claims description 10
• 230000002062 proliferating effect Effects 0.000 claims description 10
• FUCNPHQCFFQGOC-UHFFFAOYSA-N N-methyl-3-(8-methyl-4-pyridin-3-ylquinolin-6-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide Chemical compound CNC(=O)C=1C=C2C(=NC=1)NC=C2C=1C=C2C(=CC=NC2=C(C=1)C)C=1C=NC=CC=1 FUCNPHQCFFQGOC-UHFFFAOYSA-N 0.000 claims description 9
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
• KPXJTZIQXSWGIT-UHFFFAOYSA-N 1-[4-[[3-amino-6-(1H-pyrrolo[2,3-b]pyridin-3-yl)quinolin-4-yl]amino]piperidin-1-yl]ethanone Chemical compound NC=1C=NC2=CC=C(C=C2C=1NC1CCN(CC1)C(C)=O)C1=CNC2=NC=CC=C21 KPXJTZIQXSWGIT-UHFFFAOYSA-N 0.000 claims description 7
• VLPWWNJRDTWOIZ-UHFFFAOYSA-N 3-(3-aminoquinolin-6-yl)-N-(pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide Chemical compound NC=1C=NC2=CC=C(C=C2C=1)C1=CNC2=NC=C(C=C21)C(=O)NCC=1C=NC=CC=1 VLPWWNJRDTWOIZ-UHFFFAOYSA-N 0.000 claims description 7
• XWIFBFUJGAWXHS-UHFFFAOYSA-N 3-(4-chloroquinolin-6-yl)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide Chemical compound ClC1=CC=NC2=CC=C(C=C12)C1=CNC2=NC=C(C=C21)C(=O)NC XWIFBFUJGAWXHS-UHFFFAOYSA-N 0.000 claims description 7
• PAMXGACATZRENQ-UHFFFAOYSA-N 3-(8-chloroquinolin-6-yl)-N-methyl-N-prop-2-enyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide Chemical compound ClC=1C=C(C=C2C=CC=NC=12)C1=CNC2=NC=C(C=C21)C(=O)N(CC=C)C PAMXGACATZRENQ-UHFFFAOYSA-N 0.000 claims description 7
• XLCGSUWTGKAGTE-UHFFFAOYSA-N 3-(8-fluoro-4-pyridin-3-ylquinolin-6-yl)-N-(pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide Chemical compound FC=1C=C(C=C2C(=CC=NC=12)C=1C=NC=CC=1)C1=CNC2=NC=C(C=C21)C(=O)NCC=1C=NC=CC=1 XLCGSUWTGKAGTE-UHFFFAOYSA-N 0.000 claims description 7
• DXKFAZQYMJDRSE-UHFFFAOYSA-N 3-(8-fluoroquinolin-6-yl)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide Chemical compound FC=1C=C(C=C2C=CC=NC=12)C1=CNC2=NC=C(C=C21)C(=O)NC DXKFAZQYMJDRSE-UHFFFAOYSA-N 0.000 claims description 7
• CJXCXSPUKJXTHK-UHFFFAOYSA-N 3-(8-fluoroquinolin-6-yl)-N-methyl-N-prop-2-enyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide Chemical compound FC=1C=C(C=C2C=CC=NC=12)C1=CNC2=NC=C(C=C21)C(=O)N(CC=C)C CJXCXSPUKJXTHK-UHFFFAOYSA-N 0.000 claims description 7
• JADLORYTDWUCHF-UHFFFAOYSA-N 3-(8-methoxyquinolin-6-yl)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide Chemical compound COC=1C=C(C=C2C=CC=NC=12)C1=CNC2=NC=C(C=C21)C(=O)NC JADLORYTDWUCHF-UHFFFAOYSA-N 0.000 claims description 7
• LHSFFGVPEQSDGZ-RSAXXLAASA-N 3-[3-amino-4-[(3S)-3-aminopiperidin-1-yl]quinolin-6-yl]-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide hydrochloride Chemical compound Cl.CNC(=O)c1cnc2[nH]cc(-c3ccc4ncc(N)c(N5CCC[C@H](N)C5)c4c3)c2c1 LHSFFGVPEQSDGZ-RSAXXLAASA-N 0.000 claims description 7
• ZPGZLXRLMOJWRQ-VEIFNGETSA-N 3-[4-[(3R)-3-aminopiperidin-1-yl]-8-fluoroquinolin-6-yl]-N-(pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide hydrochloride Chemical compound Cl.N[C@@H]1CCCN(C1)c1ccnc2c(F)cc(cc12)-c1c[nH]c2ncc(cc12)C(=O)NCc1cccnc1 ZPGZLXRLMOJWRQ-VEIFNGETSA-N 0.000 claims description 7
• OWPVQRHXNGZRDY-XFULWGLBSA-N 3-[4-[(3R)-3-aminopiperidin-1-yl]-8-fluoroquinolin-6-yl]-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide hydrochloride Chemical compound Cl.CNC(=O)c1cnc2[nH]cc(-c3cc(F)c4nccc(N5CCC[C@@H](N)C5)c4c3)c2c1 OWPVQRHXNGZRDY-XFULWGLBSA-N 0.000 claims description 7
• HZLFXUUVVAHBBX-RSAXXLAASA-N 3-[4-[(3S)-3-aminopiperidin-1-yl]-3-nitroquinolin-6-yl]-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide hydrochloride Chemical compound Cl.CNC(=O)c1cnc2[nH]cc(-c3ccc4ncc(c(N5CCC[C@H](N)C5)c4c3)[N+]([O-])=O)c2c1 HZLFXUUVVAHBBX-RSAXXLAASA-N 0.000 claims description 7
• OWPVQRHXNGZRDY-RSAXXLAASA-N 3-[4-[(3S)-3-aminopiperidin-1-yl]-8-fluoroquinolin-6-yl]-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide hydrochloride Chemical compound Cl.CNC(=O)c1cnc2[nH]cc(-c3cc(F)c4nccc(N5CCC[C@H](N)C5)c4c3)c2c1 OWPVQRHXNGZRDY-RSAXXLAASA-N 0.000 claims description 7
• FHUVRSYVNUWBJU-UHFFFAOYSA-N 3-[4-[(4-aminocyclohexyl)amino]-3-(oxan-4-ylmethylamino)quinolin-6-yl]-N-(pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide hydrochloride Chemical compound Cl.NC1CCC(CC1)Nc1c(NCC2CCOCC2)cnc2ccc(cc12)-c1c[nH]c2ncc(cc12)C(=O)NCc1cccnc1 FHUVRSYVNUWBJU-UHFFFAOYSA-N 0.000 claims description 7
• HTRWKFBTQABGLJ-UHFFFAOYSA-N 3-[4-[(4-aminocyclohexyl)amino]-3-nitroquinolin-6-yl]-N-(pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide hydrochloride Chemical compound Cl.NC1CCC(CC1)Nc1c(cnc2ccc(cc12)-c1c[nH]c2ncc(cc12)C(=O)NCc1cccnc1)[N+]([O-])=O HTRWKFBTQABGLJ-UHFFFAOYSA-N 0.000 claims description 7
• ANBPRTXIECGGEM-UHFFFAOYSA-N 4-[(1-methylpiperidin-4-yl)amino]-6-(1H-pyrrolo[2,3-b]pyridin-3-yl)quinoline-3-carbonitrile Chemical compound CN1CCC(CC1)NC1=C(C=NC2=CC=C(C=C12)C1=CNC2=NC=CC=C21)C#N ANBPRTXIECGGEM-UHFFFAOYSA-N 0.000 claims description 7
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• WCGVAQKYQAEAIH-UHFFFAOYSA-N 8-methyl-4-pyridin-3-yl-6-(1H-pyrrolo[2,3-b]pyridin-3-yl)quinoline Chemical compound CC=1C=C(C=C2C(=CC=NC=12)C=1C=NC=CC=1)C1=CNC2=NC=CC=C21 WCGVAQKYQAEAIH-UHFFFAOYSA-N 0.000 claims description 7
• XKYCTSHCXRBBDN-UHFFFAOYSA-N N-(3-aminopropyl)-3-(8-fluoroquinolin-6-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide hydrochloride Chemical compound Cl.NCCCNC(=O)c1cnc2[nH]cc(-c3cc(F)c4ncccc4c3)c2c1 XKYCTSHCXRBBDN-UHFFFAOYSA-N 0.000 claims description 7
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