JP5905075B2 - ブロモドメイン阻害剤として有用なテトラヒドロキノリン誘導体 - Google Patents

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Publication number

JP5905075B2

JP5905075B2 JP2014505612A JP2014505612A JP5905075B2 JP 5905075 B2 JP5905075 B2 JP 5905075B2 JP 2014505612 A JP2014505612 A JP 2014505612A JP 2014505612 A JP2014505612 A JP 2014505612A JP 5905075 B2 JP5905075 B2 JP 5905075B2

Authority

JP

Japan

Prior art keywords

methyl

amino

acetyl

tetrahydroquinolin

mmol

Prior art date

2011-04-21

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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• 102000001805 Bromodomains Human genes 0.000 title description 37
• 108050009021 Bromodomains Proteins 0.000 title description 35
• 239000003112 inhibitor Substances 0.000 title description 18
• 125000000147 tetrahydroquinolinyl group Chemical class N1(CCCC2=CC=CC=C12)* 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims description 160
• 150000003839 salts Chemical class 0.000 claims description 103
• -1 (pyrimidin-2-ylamino) -1,2,3,4-tetrahydroquinolin-6-yl Chemical group 0.000 claims description 70
• 229920006395 saturated elastomer Polymers 0.000 claims description 43
• 239000008194 pharmaceutical composition Substances 0.000 claims description 30
• 238000011282 treatment Methods 0.000 claims description 30
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 27
• 239000003814 drug Substances 0.000 claims description 19
• KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 18
• 125000000217 alkyl group Chemical group 0.000 claims description 17
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 15
• IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 13
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 12
• 239000013543 active substance Substances 0.000 claims description 8
• 239000001257 hydrogen Substances 0.000 claims description 8
• 229910052739 hydrogen Inorganic materials 0.000 claims description 8
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
• IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 claims description 8
• 239000003085 diluting agent Substances 0.000 claims description 7
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
• 206010028980 Neoplasm Diseases 0.000 claims description 6
• 125000000623 heterocyclic group Chemical group 0.000 claims description 6
• 238000004519 manufacturing process Methods 0.000 claims description 6
• SYWATAHTVWWKEE-CCLHPLFOSA-N 2-[4-[(2s,4r)-1-acetyl-4-[(5-cyanopyridin-2-yl)amino]-2-methyl-3,4-dihydro-2h-quinolin-6-yl]phenyl]-n-[2-(dimethylamino)ethyl]acetamide Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1C=CC(CC(=O)NCCN(C)C)=CC=1)C(C)=O)C)C1=CC=C(C#N)C=N1 SYWATAHTVWWKEE-CCLHPLFOSA-N 0.000 claims description 5
• XZPYLOTVLUIJBU-QMHKHESXSA-N 6-[(2s,4r)-1-acetyl-4-[(5-cyanopyridin-2-yl)amino]-2-methyl-3,4-dihydro-2h-quinolin-6-yl]-n-(2-hydroxyethyl)pyridine-3-carboxamide Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1N=CC(=CC=1)C(=O)NCCO)C(C)=O)C)C1=CC=C(C#N)C=N1 XZPYLOTVLUIJBU-QMHKHESXSA-N 0.000 claims description 5
• OSDXAECFLKDYBD-AVRWGWEMSA-N 6-[(2s,4r)-1-acetyl-4-[(5-cyanopyridin-2-yl)amino]-2-methyl-3,4-dihydro-2h-quinolin-6-yl]-n-[2-(dimethylamino)ethyl]pyridine-3-carboxamide Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1N=CC(=CC=1)C(=O)NCCN(C)C)C(C)=O)C)C1=CC=C(C#N)C=N1 OSDXAECFLKDYBD-AVRWGWEMSA-N 0.000 claims description 5
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
• 238000002560 therapeutic procedure Methods 0.000 claims description 5
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 4
• 201000011510 cancer Diseases 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• QXMIGKMCEMWKOX-MHECFPHRSA-N 1-[(2s,4r)-2-methyl-4-[(5-methylpyrazin-2-yl)amino]-6-[5-(morpholine-4-carbonyl)pyridin-2-yl]-3,4-dihydro-2h-quinolin-1-yl]ethanone Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1N=CC(=CC=1)C(=O)N1CCOCC1)C(C)=O)C)C1=CN=C(C)C=N1 QXMIGKMCEMWKOX-MHECFPHRSA-N 0.000 claims description 3
• SMYFZSQJSUPJGR-MHECFPHRSA-N 1-[(2s,4r)-2-methyl-4-[(5-methylpyrazin-2-yl)amino]-6-[6-(morpholine-4-carbonyl)pyridin-3-yl]-3,4-dihydro-2h-quinolin-1-yl]ethanone Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1C=NC(=CC=1)C(=O)N1CCOCC1)C(C)=O)C)C1=CN=C(C)C=N1 SMYFZSQJSUPJGR-MHECFPHRSA-N 0.000 claims description 3
• CJDFFTPYOVZFLT-UQBPGWFLSA-N 1-[(2s,4r)-2-methyl-4-[(5-methylpyridin-2-yl)amino]-6-[5-(morpholine-4-carbonyl)pyridin-2-yl]-3,4-dihydro-2h-quinolin-1-yl]ethanone Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1N=CC(=CC=1)C(=O)N1CCOCC1)C(C)=O)C)C1=CC=C(C)C=N1 CJDFFTPYOVZFLT-UQBPGWFLSA-N 0.000 claims description 3
• KTYZUHKKGRQPKV-HFJWLAOPSA-N 1-[(2s,4r)-4-(3-chloroanilino)-2-methyl-6-[5-(morpholine-4-carbonyl)pyridin-2-yl]-3,4-dihydro-2h-quinolin-1-yl]ethanone Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1N=CC(=CC=1)C(=O)N1CCOCC1)C(C)=O)C)C1=CC=CC(Cl)=C1 KTYZUHKKGRQPKV-HFJWLAOPSA-N 0.000 claims description 3
• BMECLKDFZDYCGI-HFJWLAOPSA-N 1-[(2s,4r)-4-(4-chloroanilino)-2-methyl-6-[5-(morpholine-4-carbonyl)pyridin-2-yl]-3,4-dihydro-2h-quinolin-1-yl]ethanone Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1N=CC(=CC=1)C(=O)N1CCOCC1)C(C)=O)C)C1=CC=C(Cl)C=C1 BMECLKDFZDYCGI-HFJWLAOPSA-N 0.000 claims description 3
• PQJFTDQVYGKKQO-BXKMTCNYSA-N 1-[(2s,4r)-4-[(5-chloropyridin-2-yl)amino]-2-methyl-6-[5-(morpholine-4-carbonyl)pyridin-2-yl]-3,4-dihydro-2h-quinolin-1-yl]ethanone Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1N=CC(=CC=1)C(=O)N1CCOCC1)C(C)=O)C)C1=CC=C(Cl)C=N1 PQJFTDQVYGKKQO-BXKMTCNYSA-N 0.000 claims description 3
• FWKSNTUZWXUYAN-BXKMTCNYSA-N 1-[(2s,4r)-4-[(5-chloropyridin-2-yl)amino]-2-methyl-6-[6-(morpholine-4-carbonyl)pyridin-3-yl]-3,4-dihydro-2h-quinolin-1-yl]ethanone Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1C=NC(=CC=1)C(=O)N1CCOCC1)C(C)=O)C)C1=CC=C(Cl)C=N1 FWKSNTUZWXUYAN-BXKMTCNYSA-N 0.000 claims description 3
• YZWAJEXBFMCYOI-HFJWLAOPSA-N 2-[4-[(2s,4r)-1-acetyl-4-[(5-cyanopyridin-2-yl)amino]-2-methyl-3,4-dihydro-2h-quinolin-6-yl]phenyl]-n-(1,3-dihydroxypropan-2-yl)acetamide Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1C=CC(CC(=O)NC(CO)CO)=CC=1)C(C)=O)C)C1=CC=C(C#N)C=N1 YZWAJEXBFMCYOI-HFJWLAOPSA-N 0.000 claims description 3
• XFPGDISBPXOSQZ-AVRWGWEMSA-N 2-[4-[(2s,4r)-1-acetyl-4-[(5-cyanopyridin-2-yl)amino]-2-methyl-3,4-dihydro-2h-quinolin-6-yl]phenyl]-n-(2-hydroxyethyl)acetamide Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1C=CC(CC(=O)NCCO)=CC=1)C(C)=O)C)C1=CC=C(C#N)C=N1 XFPGDISBPXOSQZ-AVRWGWEMSA-N 0.000 claims description 3
• UBRUNBGXSXZHCM-AFMDSPMNSA-N 3-[4-[(2s,4r)-1-acetyl-4-[(5-cyanopyridin-2-yl)amino]-2-methyl-3,4-dihydro-2h-quinolin-6-yl]phenyl]-n-(2-hydroxyethyl)propanamide Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1C=CC(CCC(=O)NCCO)=CC=1)C(C)=O)C)C1=CC=C(C#N)C=N1 UBRUNBGXSXZHCM-AFMDSPMNSA-N 0.000 claims description 3
• DNOPNXBZQNDCPK-RBTNQOKQSA-N 3-[4-[(2s,4r)-1-acetyl-4-[(5-cyanopyridin-2-yl)amino]-2-methyl-3,4-dihydro-2h-quinolin-6-yl]phenyl]-n-[2-(dimethylamino)ethyl]propanamide Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1C=CC(CCC(=O)NCCN(C)C)=CC=1)C(C)=O)C)C1=CC=C(C#N)C=N1 DNOPNXBZQNDCPK-RBTNQOKQSA-N 0.000 claims description 3
• HXOMVXKQTUEMNP-BXKMTCNYSA-N 4-[(2s,4r)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-3,4-dihydro-2h-quinolin-6-yl]-n-(1,3-dihydroxypropan-2-yl)benzamide Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1C=CC(=CC=1)C(=O)NC(CO)CO)C(C)=O)C)C1=CC=CC=N1 HXOMVXKQTUEMNP-BXKMTCNYSA-N 0.000 claims description 3
• YRCXOAIUDLTPLT-SSOJOUAXSA-N 4-[(2s,4r)-1-acetyl-4-[(5-cyanopyridin-2-yl)amino]-2-methyl-3,4-dihydro-2h-quinolin-6-yl]-n-(1,3-dihydroxypropan-2-yl)benzamide Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1C=CC(=CC=1)C(=O)NC(CO)CO)C(C)=O)C)C1=CC=C(C#N)C=N1 YRCXOAIUDLTPLT-SSOJOUAXSA-N 0.000 claims description 3
• XDUVPKMBCMRRGT-BXKMTCNYSA-N 4-[(2s,4r)-1-acetyl-4-[(5-cyanopyridin-2-yl)amino]-2-methyl-3,4-dihydro-2h-quinolin-6-yl]-n-(2-hydroxyethyl)benzamide Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1C=CC(=CC=1)C(=O)NCCO)C(C)=O)C)C1=CC=C(C#N)C=N1 XDUVPKMBCMRRGT-BXKMTCNYSA-N 0.000 claims description 3
• OXVNANVRZQBVDL-DQXHVOOISA-N 4-[(2s,4r)-1-acetyl-4-[(5-cyanopyridin-2-yl)amino]-2-methyl-3,4-dihydro-2h-quinolin-6-yl]-n-[(2s)-2,3-dihydroxypropyl]benzamide Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1C=CC(=CC=1)C(=O)NC[C@H](O)CO)C(C)=O)C)C1=CC=C(C#N)C=N1 OXVNANVRZQBVDL-DQXHVOOISA-N 0.000 claims description 3
• XIPNEOJORHOGDM-OYHNWAKOSA-N 5-[(2s,4r)-1-acetyl-4-[(5-cyanopyrazin-2-yl)amino]-2-methyl-3,4-dihydro-2h-quinolin-6-yl]-n-(2-hydroxyethyl)pyridine-2-carboxamide Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1C=NC(=CC=1)C(=O)NCCO)C(C)=O)C)C1=CN=C(C#N)C=N1 XIPNEOJORHOGDM-OYHNWAKOSA-N 0.000 claims description 3
• HJVYIKMOTWPSJB-MHECFPHRSA-N 6-[(2s,4r)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-3,4-dihydro-2h-quinolin-6-yl]-n-[2-(dimethylamino)ethyl]pyridine-3-carboxamide Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1N=CC(=CC=1)C(=O)NCCN(C)C)C(C)=O)C)C1=CC=CC=N1 HJVYIKMOTWPSJB-MHECFPHRSA-N 0.000 claims description 3
• XBNFZIOOHAZWCX-UPCLLVRISA-N 6-[(2s,4r)-1-acetyl-4-[(5-cyanopyridin-2-yl)amino]-2-methyl-3,4-dihydro-2h-quinolin-6-yl]-n-(1,3-dihydroxypropan-2-yl)pyridine-3-carboxamide Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1N=CC(=CC=1)C(=O)NC(CO)CO)C(C)=O)C)C1=CC=C(C#N)C=N1 XBNFZIOOHAZWCX-UPCLLVRISA-N 0.000 claims description 3
• PBBIYKFNBAAKHE-AFMDSPMNSA-N 6-[[(2s,4r)-1-acetyl-2-methyl-6-[4-(morpholine-4-carbonyl)phenyl]-3,4-dihydro-2h-quinolin-4-yl]amino]pyridine-3-carbonitrile Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1C=CC(=CC=1)C(=O)N1CCOCC1)C(C)=O)C)C1=CC=C(C#N)C=N1 PBBIYKFNBAAKHE-AFMDSPMNSA-N 0.000 claims description 3
• 125000003277 amino group Chemical group 0.000 claims description 3
• 230000001684 chronic effect Effects 0.000 claims description 3
• 229910052736 halogen Inorganic materials 0.000 claims description 3
• 150000002367 halogens Chemical class 0.000 claims description 3
• 230000004968 inflammatory condition Effects 0.000 claims description 3
• 230000002757 inflammatory effect Effects 0.000 claims description 3
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• RKODJGZHPKJDQC-KSFYIVLOSA-N propan-2-yl n-[(2s,4r)-1-acetyl-6-[4-(2-hydroxyethylcarbamoyl)phenyl]-2-methyl-3,4-dihydro-2h-quinolin-4-yl]carbamate Chemical compound CC(=O)N([C@@H](C)C[C@H](C1=C2)NC(=O)OC(C)C)C1=CC=C2C1=CC=C(C(=O)NCCO)C=C1 RKODJGZHPKJDQC-KSFYIVLOSA-N 0.000 claims description 3
• KOIZGVJOCMFGDT-MHECFPHRSA-N propan-2-yl n-[(2s,4r)-1-acetyl-6-[4-[2-(dimethylamino)ethylcarbamoyl]phenyl]-2-methyl-3,4-dihydro-2h-quinolin-4-yl]carbamate Chemical compound CC(=O)N([C@@H](C)C[C@H](C1=C2)NC(=O)OC(C)C)C1=CC=C2C1=CC=C(C(=O)NCCN(C)C)C=C1 KOIZGVJOCMFGDT-MHECFPHRSA-N 0.000 claims description 3
• 125000001424 substituent group Chemical group 0.000 claims description 3
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
• JHHSCKQQRHBAGN-MHECFPHRSA-N 1-[(2s,4r)-2-methyl-6-[5-(morpholine-4-carbonyl)pyridin-2-yl]-4-(pyridin-2-ylamino)-3,4-dihydro-2h-quinolin-1-yl]ethanone Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1N=CC(=CC=1)C(=O)N1CCOCC1)C(C)=O)C)C1=CC=CC=N1 JHHSCKQQRHBAGN-MHECFPHRSA-N 0.000 claims description 2
• JHXOGTPVIUYWFH-HFJWLAOPSA-N 1-[(2s,4r)-4-(3-chloroanilino)-2-methyl-6-[6-(morpholine-4-carbonyl)pyridin-3-yl]-3,4-dihydro-2h-quinolin-1-yl]ethanone Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1C=NC(=CC=1)C(=O)N1CCOCC1)C(C)=O)C)C1=CC=CC(Cl)=C1 JHXOGTPVIUYWFH-HFJWLAOPSA-N 0.000 claims description 2
• JJICPYPMPGFEAO-BXKMTCNYSA-N 1-[(2s,4r)-4-[(5-fluoropyridin-2-yl)amino]-2-methyl-6-[6-(morpholine-4-carbonyl)pyridin-3-yl]-3,4-dihydro-2h-quinolin-1-yl]ethanone Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1C=NC(=CC=1)C(=O)N1CCOCC1)C(C)=O)C)C1=CC=C(F)C=N1 JJICPYPMPGFEAO-BXKMTCNYSA-N 0.000 claims description 2
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 2
• JZWQVASLBKUICY-OZWPHOJSSA-N 4-[(2s,4r)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-3,4-dihydro-2h-quinolin-6-yl]-n-[(2s)-2,3-dihydroxypropyl]benzamide Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1C=CC(=CC=1)C(=O)NC[C@H](O)CO)C(C)=O)C)C1=CC=CC=N1 JZWQVASLBKUICY-OZWPHOJSSA-N 0.000 claims description 2
• ZLRQKBQXTQCVFH-AFMDSPMNSA-N 6-[[(2s,4r)-1-acetyl-2-methyl-6-[6-(4-methylpiperazine-1-carbonyl)pyridin-3-yl]-3,4-dihydro-2h-quinolin-4-yl]amino]pyridine-3-carbonitrile Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1C=NC(=CC=1)C(=O)N1CCN(C)CC1)C(C)=O)C)C1=CC=C(C#N)C=N1 ZLRQKBQXTQCVFH-AFMDSPMNSA-N 0.000 claims description 2
• MKVFKVIYFZEWJI-AVRWGWEMSA-N 6-[[(2s,4r)-1-acetyl-2-methyl-6-[6-(piperazine-1-carbonyl)pyridin-3-yl]-3,4-dihydro-2h-quinolin-4-yl]amino]pyridine-3-carbonitrile Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1C=NC(=CC=1)C(=O)N1CCNCC1)C(C)=O)C)C1=CC=C(C#N)C=N1 MKVFKVIYFZEWJI-AVRWGWEMSA-N 0.000 claims description 2
• KLRLZDNXNZMCJR-UPCLLVRISA-N 6-[[(2s,4r)-1-acetyl-6-[6-(3-aminoazetidine-1-carbonyl)pyridin-3-yl]-2-methyl-3,4-dihydro-2h-quinolin-4-yl]amino]pyridine-3-carbonitrile Chemical compound N([C@@H]1C[C@@H](N(C2=CC=C(C=C21)C=1C=NC(=CC=1)C(=O)N1CC(N)C1)C(C)=O)C)C1=CC=C(C#N)C=N1 KLRLZDNXNZMCJR-UPCLLVRISA-N 0.000 claims description 2
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• 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
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