JP2018502930A - TrkAキナーゼの阻害剤 - Google Patents
TrkAキナーゼの阻害剤 Download PDFInfo
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- JP2018502930A JP2018502930A JP2017557507A JP2017557507A JP2018502930A JP 2018502930 A JP2018502930 A JP 2018502930A JP 2017557507 A JP2017557507 A JP 2017557507A JP 2017557507 A JP2017557507 A JP 2017557507A JP 2018502930 A JP2018502930 A JP 2018502930A
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- JP
- Japan
- Prior art keywords
- urea
- methoxyethyl
- phenylpyrrolidin
- alkyl
- methyl
- 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.)
- Granted
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- 229940053128 nerve growth factor Drugs 0.000 claims abstract description 35
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- 206010067601 Dysmyelination Diseases 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 152
- -1 1-((3S, 4R) -1- (2-methoxyethyl) -4-phenylpyrrolidin-3-yl) -3- (quinolin-3-yl) urea 1-((3S, 4R) -1- (2-methoxyethyl) -4-phenylpyrrolidin-3-yl) -3- (2-phenylquinolin-3-yl) urea Chemical compound 0.000 claims description 74
- 239000004202 carbamide Substances 0.000 claims description 61
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 55
- 238000000034 method Methods 0.000 claims description 41
- 125000005842 heteroatom Chemical group 0.000 claims description 34
- 229910052757 nitrogen Inorganic materials 0.000 claims description 27
- 229910052760 oxygen Inorganic materials 0.000 claims description 26
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 25
- 125000003545 alkoxy group Chemical group 0.000 claims description 21
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 19
- 125000003342 alkenyl group Chemical group 0.000 claims description 17
- 125000000304 alkynyl group Chemical group 0.000 claims description 17
- 125000001188 haloalkyl 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 17
- 230000000694 effects Effects 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 15
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
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- 125000003118 aryl group Chemical group 0.000 claims description 11
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- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 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 6
- 125000004548 quinolin-3-yl group Chemical group N1=CC(=CC2=CC=CC=C12)* 0.000 claims description 6
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
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- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 4
- 206010029260 Neuroblastoma Diseases 0.000 claims description 4
- 206010060862 Prostate cancer Diseases 0.000 claims description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 230000001684 chronic effect Effects 0.000 claims description 4
- UZVGSSNIUNSOFA-UHFFFAOYSA-N dibenzofuran-1-carboxylic acid Chemical compound O1C2=CC=CC=C2C2=C1C=CC=C2C(=O)O UZVGSSNIUNSOFA-UHFFFAOYSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
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- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 206010033701 Papillary thyroid cancer Diseases 0.000 claims description 3
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 claims description 3
- 208000005298 acute pain Diseases 0.000 claims description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 208000006990 cholangiocarcinoma Diseases 0.000 claims description 3
- 238000012217 deletion Methods 0.000 claims description 3
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 201000002528 pancreatic cancer Diseases 0.000 claims description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- 208000030045 thyroid gland papillary carcinoma Diseases 0.000 claims description 3
- 150000003672 ureas Chemical class 0.000 claims description 3
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 2
- VXHCMYUEBAFGIK-IOWSJCHKSA-N 1-(1,3-diphenylisoquinolin-4-yl)-3-[(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl]urea Chemical compound C1(=CC=CC=C1)C1=NC(=C(C2=CC=CC=C12)NC(=O)N[C@@H]1CN(C[C@H]1C1=CC=CC=C1)CCOC)C1=CC=CC=C1 VXHCMYUEBAFGIK-IOWSJCHKSA-N 0.000 claims description 2
- MUYMJNAPPGHVGY-WUFINQPMSA-N 1-(1,6-dimethyl-3-phenylisoquinolin-4-yl)-3-[(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl]urea Chemical compound CC1=NC(=C(C2=CC(=CC=C12)C)NC(=O)N[C@@H]1CN(C[C@H]1C1=CC=CC=C1)CCOC)C1=CC=CC=C1 MUYMJNAPPGHVGY-WUFINQPMSA-N 0.000 claims description 2
- QMKZCCUIQHNPOG-WUFINQPMSA-N 1-(1,7-dimethyl-3-phenylisoquinolin-4-yl)-3-[(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl]urea Chemical compound CC1=NC(=C(C2=CC=C(C=C12)C)NC(=O)N[C@@H]1CN(C[C@H]1C1=CC=CC=C1)CCOC)C1=CC=CC=C1 QMKZCCUIQHNPOG-WUFINQPMSA-N 0.000 claims description 2
- GRUVOTSJGDJTEX-LOSJGSFVSA-N 1-(1-chloro-3-phenylisoquinolin-4-yl)-3-[(3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl]urea Chemical compound ClC1=NC(=C(C2=CC=CC=C12)NC(=O)N[C@@H]1CN(C[C@H]1C1=CC(=CC=C1)F)CCOC)C1=CC=CC=C1 GRUVOTSJGDJTEX-LOSJGSFVSA-N 0.000 claims description 2
- YSMOZRPKVYNUKY-AHKZPQOWSA-N 1-(1-cyano-3-phenylisoquinolin-4-yl)-3-[(3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl]urea Chemical compound C(#N)C1=NC(=C(C2=CC=CC=C12)NC(=O)N[C@@H]1CN(C[C@H]1C1=CC(=CC=C1)F)CCOC)C1=CC=CC=C1 YSMOZRPKVYNUKY-AHKZPQOWSA-N 0.000 claims description 2
- WXXPWEBNWCBPIT-LOSJGSFVSA-N 1-(1-fluoro-3-phenylisoquinolin-4-yl)-3-[(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl]urea Chemical compound FC1=NC(=C(C2=CC=CC=C12)NC(=O)N[C@@H]1CN(C[C@H]1C1=CC=CC=C1)CCOC)C1=CC=CC=C1 WXXPWEBNWCBPIT-LOSJGSFVSA-N 0.000 claims description 2
- QUWQZFGUAZWEKQ-XUZZJYLKSA-N 1-(2,5-dimethylquinolin-3-yl)-3-[(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl]urea Chemical compound CC1=NC2=CC=CC(=C2C=C1NC(=O)N[C@@H]1CN(C[C@H]1C1=CC=CC=C1)CCOC)C QUWQZFGUAZWEKQ-XUZZJYLKSA-N 0.000 claims description 2
- MUGZWEZTJSULDB-GHTZIAJQSA-N 1-(2-chloroquinolin-3-yl)-3-[(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl]urea Chemical compound ClC1=NC2=CC=CC=C2C=C1NC(=O)N[C@@H]1CN(C[C@H]1C1=CC=CC=C1)CCOC MUGZWEZTJSULDB-GHTZIAJQSA-N 0.000 claims description 2
- JICCWWGVVJWMBS-RPLLCQBOSA-N 1-(2-cyclohexylquinolin-3-yl)-3-[(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl]urea Chemical compound C1(CCCCC1)C1=NC2=CC=CC=C2C=C1NC(=O)N[C@@H]1CN(C[C@H]1C1=CC=CC=C1)CCOC JICCWWGVVJWMBS-RPLLCQBOSA-N 0.000 claims description 2
- WUKDXTNLONSORQ-XUZZJYLKSA-N 1-(2-cyclopropylquinolin-3-yl)-3-[(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl]urea Chemical compound C1(CC1)C1=NC2=CC=CC=C2C=C1NC(=O)N[C@@H]1CN(C[C@H]1C1=CC=CC=C1)CCOC WUKDXTNLONSORQ-XUZZJYLKSA-N 0.000 claims description 2
- FFJQKXTZSXTVHO-XUZZJYLKSA-N 1-(2-tert-butylquinolin-3-yl)-3-[(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl]urea Chemical compound C(C)(C)(C)C1=NC2=CC=CC=C2C=C1NC(=O)N[C@@H]1CN(C[C@H]1C1=CC=CC=C1)CCOC FFJQKXTZSXTVHO-XUZZJYLKSA-N 0.000 claims description 2
- SAGNGJUATZAZCB-RBBKRZOGSA-N 1-(3-cyanoisoquinolin-4-yl)-3-[(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl]urea Chemical compound C(#N)C=1N=CC2=CC=CC=C2C=1NC(=O)N[C@@H]1CN(C[C@H]1C1=CC=CC=C1)CCOC SAGNGJUATZAZCB-RBBKRZOGSA-N 0.000 claims description 2
- IHGLEMNLBGWIIR-WMZHIEFXSA-N 1-(5-fluoro-2-methylquinolin-3-yl)-3-[(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl]urea Chemical compound FC1=C2C=C(C(=NC2=CC=C1)C)NC(=O)N[C@@H]1CN(C[C@H]1C1=CC=CC=C1)CCOC IHGLEMNLBGWIIR-WMZHIEFXSA-N 0.000 claims description 2
- RUPLSVYZCGXQJZ-RRPNLBNLSA-N 1-(6,7-dimethoxy-1-methyl-3-phenylisoquinolin-4-yl)-3-[(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl]urea Chemical compound COC=1C=C2C(=C(N=C(C2=CC=1OC)C)C1=CC=CC=C1)NC(=O)N[C@@H]1CN(C[C@H]1C1=CC=CC=C1)CCOC RUPLSVYZCGXQJZ-RRPNLBNLSA-N 0.000 claims description 2
- OOEUMESVVKPVGB-NZQKXSOJSA-N 1-(6,7-dimethoxy-2-methylquinolin-3-yl)-3-[(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl]urea Chemical compound COC=1C=C2C=C(C(=NC2=CC=1OC)C)NC(=O)N[C@@H]1CN(C[C@H]1C1=CC=CC=C1)CCOC OOEUMESVVKPVGB-NZQKXSOJSA-N 0.000 claims description 2
- CMNKDILIRMVWMH-JYFHCDHNSA-N 1-(6,7-dimethoxy-2-phenylquinolin-3-yl)-3-[(3S,4R)-1-(2-methoxyacetyl)-4-phenylpyrrolidin-3-yl]urea Chemical compound COC=1C=C2C=C(C(=NC2=CC=1OC)C1=CC=CC=C1)NC(=O)N[C@@H]1CN(C[C@H]1C1=CC=CC=C1)C(COC)=O CMNKDILIRMVWMH-JYFHCDHNSA-N 0.000 claims description 2
- APXIYTVKJQVAHL-WIOPSUGQSA-N 1-(6,7-dimethoxy-2-phenylquinolin-3-yl)-3-[(3S,4R)-1-(2-methoxyethyl)-4-(1-methylpyrazol-4-yl)pyrrolidin-3-yl]urea Chemical compound COC=1C=C2C=C(C(=NC2=CC=1OC)C1=CC=CC=C1)NC(=O)N[C@@H]1CN(C[C@H]1C=1C=NN(C=1)C)CCOC APXIYTVKJQVAHL-WIOPSUGQSA-N 0.000 claims description 2
- NRPTVOYPVHKJMJ-LITSAYRRSA-N 1-(6,7-dimethoxy-2-phenylquinolin-3-yl)-3-[(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl]-1,3-dimethylurea Chemical compound COC=1C=C2C=C(C(=NC2=CC=1OC)C1=CC=CC=C1)N(C(=O)N(C)[C@@H]1CN(C[C@H]1C1=CC=CC=C1)CCOC)C NRPTVOYPVHKJMJ-LITSAYRRSA-N 0.000 claims description 2
- KAIJOKGWQBSKOP-RPLLCQBOSA-N 1-(6,7-dimethoxy-2-phenylquinolin-3-yl)-3-[(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl]urea Chemical compound COC=1C=C2C=C(C(=NC2=CC=1OC)C1=CC=CC=C1)NC(=O)N[C@@H]1CN(C[C@H]1C1=CC=CC=C1)CCOC KAIJOKGWQBSKOP-RPLLCQBOSA-N 0.000 claims description 2
- FPOKQSRWUMDIHZ-JYFHCDHNSA-N 1-(6,7-dimethoxy-2-phenylquinolin-3-yl)-3-[(3S,4R)-1-(2-methoxyethyl)-4-pyridin-3-ylpyrrolidin-3-yl]urea Chemical compound COC=1C=C2C=C(C(=NC2=CC=1OC)C1=CC=CC=C1)NC(=O)N[C@@H]1CN(C[C@H]1C=1C=NC=CC=1)CCOC FPOKQSRWUMDIHZ-JYFHCDHNSA-N 0.000 claims description 2
- IJBUHJJITHBGPS-NZQKXSOJSA-N 1-(6-fluoro-2-methylquinolin-3-yl)-3-[(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl]urea Chemical compound FC=1C=C2C=C(C(=NC2=CC=1)C)NC(=O)N[C@@H]1CN(C[C@H]1C1=CC=CC=C1)CCOC IJBUHJJITHBGPS-NZQKXSOJSA-N 0.000 claims description 2
- NXQIEODPERRBBV-NZQKXSOJSA-N 1-(6-fluoro-2-methylquinolin-3-yl)-3-[(3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl]urea Chemical compound FC=1C=C2C=C(C(=NC2=CC=1)C)NC(=O)N[C@@H]1CN(C[C@H]1C1=CC(=CC=C1)F)CCOC NXQIEODPERRBBV-NZQKXSOJSA-N 0.000 claims description 2
- IEEICZGOKWMKMC-RPLLCQBOSA-N 1-(6-fluoro-2-phenylquinolin-3-yl)-3-[(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl]urea Chemical compound FC=1C=C2C=C(C(=NC2=CC=1)C1=CC=CC=C1)NC(=O)N[C@@H]1CN(C[C@H]1C1=CC=CC=C1)CCOC IEEICZGOKWMKMC-RPLLCQBOSA-N 0.000 claims description 2
- XJRSFQMYNIYTCM-XUZZJYLKSA-N 1-(6-methoxy-2,7-dimethylquinolin-3-yl)-3-[(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl]urea Chemical compound COC=1C=C2C=C(C(=NC2=CC=1C)C)NC(=O)N[C@@H]1CN(C[C@H]1C1=CC=CC=C1)CCOC XJRSFQMYNIYTCM-XUZZJYLKSA-N 0.000 claims description 2
- TZXYFCNVNBUSKQ-UHFFFAOYSA-N 1-(7-fluoro-1-methyl-3-phenylisoquinolin-4-yl)-3-[1-(2-methoxyethyl)-4-phenylmethoxypyrrolidin-3-yl]urea Chemical compound C(C1=CC=CC=C1)OC1C(CN(C1)CCOC)NC(=O)NC1=C(N=C(C2=CC(=CC=C12)F)C)C1=CC=CC=C1 TZXYFCNVNBUSKQ-UHFFFAOYSA-N 0.000 claims description 2
- UTRJOXPVTYXLTR-UHFFFAOYSA-N 1-(7-fluoro-1-methyl-3-phenylisoquinolin-4-yl)-3-[4-hydroxy-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl]urea Chemical compound FC1=CC=C2C(=C(N=C(C2=C1)C)C1=CC=CC=C1)NC(=O)NC1CN(CC1(C1=CC=CC=C1)O)CCOC UTRJOXPVTYXLTR-UHFFFAOYSA-N 0.000 claims description 2
- GFNVRTLVEPZJDV-UHFFFAOYSA-N 1-(7-fluoro-1-methyl-3-phenylisoquinolin-4-yl)-3-[4-hydroxy-1-(2-methoxyethyl)pyrrolidin-3-yl]urea Chemical compound FC1=CC=C2C(=C(N=C(C2=C1)C)C1=CC=CC=C1)NC(=O)NC1CN(CC1O)CCOC GFNVRTLVEPZJDV-UHFFFAOYSA-N 0.000 claims description 2
- AHUUOVNHPUFFOP-GBXCKJPGSA-N 1-(7-fluoro-2,6-dimethylquinolin-3-yl)-3-[(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl]urea Chemical compound FC1=C(C=C2C=C(C(=NC2=C1)C)NC(=O)N[C@@H]1CN(C[C@H]1C1=CC=CC=C1)CCOC)C AHUUOVNHPUFFOP-GBXCKJPGSA-N 0.000 claims description 2
- JNUJJRJLOILDEI-NZQKXSOJSA-N 1-(7-fluoro-2-methylquinolin-3-yl)-3-[(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl]urea Chemical compound FC1=CC=C2C=C(C(=NC2=C1)C)NC(=O)N[C@@H]1CN(C[C@H]1C1=CC=CC=C1)CCOC JNUJJRJLOILDEI-NZQKXSOJSA-N 0.000 claims description 2
- LNGKNCVENHPLAU-NZQKXSOJSA-N 1-(7-fluoro-2-methylquinolin-3-yl)-3-[(3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl]urea Chemical compound FC1=CC=C2C=C(C(=NC2=C1)C)NC(=O)N[C@@H]1CN(C[C@H]1C1=CC(=CC=C1)F)CCOC LNGKNCVENHPLAU-NZQKXSOJSA-N 0.000 claims description 2
- UPXNZCMPTVPGIZ-RPLLCQBOSA-N 1-(7-fluoro-2-phenylquinolin-3-yl)-3-[(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl]urea Chemical compound FC1=CC=C2C=C(C(=NC2=C1)C1=CC=CC=C1)NC(=O)N[C@@H]1CN(C[C@H]1C1=CC=CC=C1)CCOC UPXNZCMPTVPGIZ-RPLLCQBOSA-N 0.000 claims description 2
- MDBNFSOUXSDCKC-IZZNHLLZSA-N 1-(7-fluoro-3-phenylisoquinolin-4-yl)-3-[(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl]urea Chemical compound FC1=CC=C2C(=C(N=CC2=C1)C1=CC=CC=C1)NC(=O)N[C@@H]1CN(C[C@H]1C1=CC=CC=C1)CCOC MDBNFSOUXSDCKC-IZZNHLLZSA-N 0.000 claims description 2
- IMVGLPIJVPNRLW-IZZNHLLZSA-N 1-(7-fluoro-3-phenylisoquinolin-4-yl)-3-[(3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl]urea Chemical compound FC1=CC=C2C(=C(N=CC2=C1)C1=CC=CC=C1)NC(=O)N[C@@H]1CN(C[C@H]1C1=CC(=CC=C1)F)CCOC IMVGLPIJVPNRLW-IZZNHLLZSA-N 0.000 claims description 2
- GAQBQCMVEOMJIT-SIKLNZKXSA-N 1-(8-fluoro-2-methylquinolin-3-yl)-3-[(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl]urea Chemical compound FC=1C=CC=C2C=C(C(=NC=12)C)NC(=O)N[C@@H]1CN(C[C@H]1C1=CC=CC=C1)CCOC GAQBQCMVEOMJIT-SIKLNZKXSA-N 0.000 claims description 2
- QBPAYBKVMGVWSZ-AZGAKELHSA-N 1-(8-fluoro-3-phenylisoquinolin-4-yl)-3-[(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl]urea Chemical compound FC=1C=CC=C2C(=C(N=CC=12)C1=CC=CC=C1)NC(=O)N[C@@H]1CN(C[C@H]1C1=CC=CC=C1)CCOC QBPAYBKVMGVWSZ-AZGAKELHSA-N 0.000 claims description 2
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- YOWAEZWWQFSEJD-UHFFFAOYSA-N quinoxalin-2-amine Chemical compound C1=CC=CC2=NC(N)=CN=C21 YOWAEZWWQFSEJD-UHFFFAOYSA-N 0.000 description 1
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- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 1
- 230000020341 sensory perception of pain Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000003775 serotonin noradrenalin reuptake inhibitor Substances 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
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- 238000001308 synthesis method Methods 0.000 description 1
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Abstract
Description
本明細書で用いるとき、用語「アルキル」は、それ自体で、または別の置換基の一部として、1から10個の炭素原子をもつ直鎖または分枝鎖のアルキル基を指す。
RaおよびRbは、それぞれ独立して、H、アルキル、アルケニル、アルキニル、ハロアルキル、ハロゲン、ヒドロキシ、ヒドロキシアルキル、アルコキシ、ハロアルコキシ、任意に置換されたフェニル、O、N、およびSから選択される1−3個のヘテロ原子を有する任意に置換された5−6員の芳香環から選択され、あるいはRaおよびRbは一緒になって、カルボニル基、任意に置換されたフェニル(これは、さらにハロゲンで任意に置換される)を形成し;
RcおよびRdは、H、アルキル、アルケニル、アルキニル、ハロアルキル、ヒドロキシ、アルコキシ、ハロアルコキシ、任意に置換されたフェニル、O、N、およびSから選択される1−3個のヘテロ原子を有する任意に置換された5−6員の芳香環から選択され、あるいはRcおよびRdは一緒になって、ヘテロ原子の有り無しで環(4−6員)を形成し;
R1は、H、アルキル、アルケニル、アルキニル、ハロアルキル、ヒドロキシ、アルコキシ、ハロアルコキシ、(1−3Cアルコキシ)(1−3C)アルキル、(1−4Cアルコキシカルボニル)(1−6Cアルキル)、モノ、ジ、トリ、ハロ(1−4Cアルキル)、(1−3Cアルキル)アミノカルボニル、シアノ(1−3Cアルキル)、(1−3Cハロアルコキシ)(1−3C)アルキル、任意に置換されたフェニル、O、N、もしくはSから選択される1個以上のヘテロ原子をもち、かつ任意で、独立してH、アルキル、アルケニル、アルキニル、ハロアルキル、ハロゲン、ヒドロキシ、アルコキシ、ハロアルコキシ、ニトロ、またはアミノから選択される1個以上の置換基で置換された3−6員の炭素環式または複素環式環、1−3個の環窒素原子を有する9−10員の二環式ヘテロアリールであり;
R2およびR3は、独立してH、アルキル、アルケニル、アルキニル、イソプロピル、tertブチル、ハロアルキル、ハロゲン、ヒドロキシ、アルコキシ、ハロアルコキシ、任意に置換されたフェニル、またはO、N、もしくはSから選択される1−3個のヘテロ原子を有する任意に置換された5−6員の芳香環から選択されるか、またはR2およびR3は組合されて、1−2個のヘテロ原子をもつ環(5/6員)を形成してもよく;
Lは、−O−、−NH−、−SO2N(R´)−、−C(O)N(R´)−、−N(R´)C(O)−、−C(O)N(R´)C(O)−、−N(R´)SO2−、−N(R´)SO2N(R´)−、−N(R´)C(O)N(R´)−、−NR´C(S)N(R´)−、または−N(R´)C(O)O−から選択されるリガンドであり;
各R´は、独立してHまたはアルキルから選択され;
Het−Ar環は、H1またはH2:
X1−X7は、出現ごとに、結合、−CR5−、−CH2−、またはN、O、もしくはSから選択されるヘテロ原子であり;
X8は、O、S、NH、N−アルキル、SO、SO2、またはC=Oから選択され;
R4、R5、およびR6は、それぞれ独立して、H、アルキル、アルケニル、アルキニル、イソプロピル、tertブチル、ハロアルキル、ハロゲン、モノ、ジ、トリ、ハロ(1−4Cアルキル)ヒドロキシ、アルコキシ、ハロアルコキシ、シアノ、シクロアルキル(3−7炭素)、任意に置換されたフェニル、O、N、もしくはSから選択される1−3個のヘテロ原子を有する任意に置換された5−6員の複素環式環、またはO、N、もしくはSから選択される1個以上のヘテロ原子を有する3−6員の炭素環式環、−NH2、−N(H)(アルキル)、−N(アルキル)2、−N(H)C(O)アルキル、−N(アルキル)C(O)アルキル、−N(H)C(O)Oアルキル、−N(アルキル)C(O)Oアルキル、−N(H)SO2(アルキル)、−N(アルキル)SO2(アルキル)、−C(O)アルキル、−C(O)OH、−C(O)Oアルキル、−C(O)NH2、−C(O)N(H)(アルキル)、−C(O)N(アルキル)2、−S(アルキル)、−S(O)アルキル、−S(O)2アルキル、−S(O)2N(H)2、−S(O)2N(H)(アルキル)、および−S(O)2N(H)(アルキル)2からなる群より選択される]
で表されるか、あるいはその立体異性体、互変異性体、または薬学的に許容される塩、溶媒和物、代謝物、同位体、もしくはプロドラッグである。
本発明の化合物は、以下のスキームおよび特定の実施例、またはその修正法に従い、容易に入手可能な出発物質、試薬、および通常の合成手順を用いて調製し得る。これらの反応においては、それ自体が当業者には公知であるがあまり詳細には言及されていない変形を利用することも可能である。本発明においてクレイムされた化合物を作製するための一般的な方法は、以下のスキームを見ることから、当業者には容易に理解および認識され得る。
方法1
いくつかの中間体は、商業用の供給業者から購入し、式Iの実施例の個々の合成にそのまま使用した。他の中間体は、報告された文献の手順に従うことによるか、もしくは必要に応じで修正するか、または適切な置換基で誘導体化する技術を適用するかのいずれかで調製した。
スキーム1(このスキームは、Chemistry−A European Journal、2012年、第18巻、p.5530−5535;Tetrahedron、2004年、第60巻、p.2937−2942に記載された)。
中間体A1:キノリン−3−アミン
中間体A2:2−クロロキノリン−3−アミン
中間体A3:キノリン−4−アミン
中間体A4:キナゾリン−4−アミン
中間体A5:キノキサリン−2−アミン
中間体A6:2−フェニルキノリン−3−アミン.LCMS(M+H):221.10
中間体A7:2−メチルキノリン−3−アミン.LCMS(M+H):158.95.
中間体A8:2−エチルキノリン−3−アミン.LCMS(M+H):173.12.
中間体A9:2−(シクロプロピル)−キノリン−3−アミン.LCMS(M+H):185.28.
中間体A10:2−(トリフルオロメチル)−キノリン−3−アミン.LCMS(M+H):213.10.
中間体A11:6−フルオロ−2−フェニルキノリン−3−アミン.LCMS(M+H):238.95.
中間体A12:7−フルオロ−2−フェニルキノリン−3−アミン.1H NMR(DMSO−d6、300MHz):δ7.77−7.72(m、3H)、7.60−7.37(m、5H)、7.40−7.30(m、1H)、5.24(s、2H).
中間体A13:6−メトキシ−2−フェニルキノリン−3−アミン.1H NMR(DMSO−d6、300MHz):δ7.72−7.66(m、3H)、7.53−7.44(m、3H)、7.30(s、1H)、7.03−6.97(m、2H)、5.22(s、2H)、3.87(s、3H).
中間体A14:6,7−ジメトキシ−2−フェニルキノリン−3−アミン.LCMS(M+H):281.19.
中間体A15:6,7−ジメトキシ−2−メチルキノリン−3−アミン.LCMS(M+H):219.24.
中間体A16:6−フルオロ−2−メチルキノリン−3−アミン.LCMS(M+H):177.08.
中間体A17:6−メチル−2−メチルキノリン−3−アミン.LCMS(M+H):173.12.
中間体A18:7−メチル−2−メチルキノリン−3−アミン.LCMS(M+H):173.12.
中間体A19:5−メチル−2−メチルキノリン−3−アミン.LCMS(M+H):173.05.
中間体A20:5−フルオロ−2−メチルキノリン−3−アミン.LCMS(M+H):177.04.
中間体A21:8−メチル−2−メチルキノリン−3−アミン.LCMS(M+H):173.30.
中間体A22:8−フルオロ−2−メチルキノリン−3−アミン.LCMS(M+H):177.25.
中間体A23:5−メトキシ−2−メチルキノリン−3−アミン.LCMS(M+H):189.29.
中間体A24:6−メトキシ−2−メチルキノリン−3−アミン.LCMS(M+H):189.29.
中間体A25:7−メトキシ−2−メチルキノリン−3−アミン.LCMS(M+H):189.03.
中間体A26:8−メトキシ−2−メチルキノリン−3−アミン.LCMS(M+H):189.10.
中間体A27:7−フルオロ−2−メチルキノリン−3−アミン.LCMS(M+H):177.08.
中間体A28:6−メトキシ−2−メチル−7−モルホリノキノリン−3−アミン.LCMS(M+H):274.10.
中間体A29:6−フルオロ−7−メチル−2−フェニルキノリン−3−アミン.LCMS(M+H):253.31.
中間体A30:6−ブロモ−8−メトキシ−2−メチルキノリン−3−アミン.
中間体A31:8−メトキシ−2,7−ジメチルキノリン−3−アミン.LCMS(M+H):265.46.
中間体A32:6−フェニル−[1,3]ジオキソロ[4,5−g]キノリン−7−アミン.LCMS(M+H):265.25.
中間体A33:N−(3−アミノ−7−メトキシ−2−フェニルキノリン−6−イル)アセトアミド.LCMS(M+H):308.16.
中間体A34:8−ブロモ−2−メチルキノリン−3−アミン.LCMS(M+H+2H):238.93.
中間体A35:6−メチル−[1,3]ジオキソロ[4,5−g]キノリン−7−アミン.LCMS(M+H):203.07.
中間体A36:7−メチル−2,3−ジヒドロ−[1,4]ジオキシノ[2,3−g]キノリン−8−アミン.LCMS(M+H):217.11.
中間体A37:7−フェニル−2,3−ジヒドロ−[1,4]ジオキシノ[2,3−g]キノリン−8−アミン.LCMS(M+H):279.11.
中間体A38:N−(3−アミノ−6−メトキシ−2−フェニルキノリン−7−イル)アセトアミド.LCMS(M+H):308.16.
中間体A39:N−(3−アミノ−6−メトキシ−2−メチルキノリン−7−イル)アセトアミド.LCMS(M+H):246.13.
中間体A40:6−メトキシ−7−メチル−2−フェニルキノリン−3−アミン.LCMS(M+H):265.16.
中間体A41:3−アミノ−7−フルオロ−2−メチルキノリン−6−カルボニトリル.LCMS(M+H):202.06.
中間体A42:3−アミノ−7−メトキシ−2−メチルキノリン−6−カルボニトリル.
中間体A43:3−アミノ−6−フルオロ−2−メチルキノリン−7−カルボニトリル.LCMS(M+H):202.03.
中間体A44:3−アミノ−6−フルオロ−2−フェニルキノリン−7−カルボニトリル.LCMS(M+H):264.13.
中間体A45:3−アミノ−6−メトキシ−2−フェニルキノリン−7−カルボニトリル.1H NMR(DMSO−d6、300MHz):δ8.17(s、1H)、7.70−7.67(m、2H)、7.55−7.48(m、3H)、7.28(d、J=13.2Hz、2H)、5.81(b s、2H)、3.97(s、3H).
中間体A46:6−(ジフルオロメトキシ)−7−メトキシ−2−メチルキノリン−3−アミン.LCMS(M+H):255.05.
中間体A47:2,2−ジフルオロ−6−メチル−[1,3]ジオキソロ[4,5−g]キノリン−7−アミン.LCMS(M+H):239.20.
中間体A48:2−シクロヘキシルキノリン−3−アミン.LCMS(M+H):227.42.
中間体A49:6−(トリフルオロメチル)−[1,3]ジオキソロ[4,5−g]キノリン−7−アミン.LCMS(M+H):257.19.
中間体A50:7−メチル−2−フェニル−1,8−ナフチリジン−3−アミン.LCMS(M+H):236.22.
中間体A51:6,7−ジメトキシキノリン−3−アミン.LCMS(M+H):205.04.
中間体A52:[1,3]ジオキソロ[4,5−g]キノリン−7−アミン.LCMS(M+H):189.07.
中間体A53:6−メチル−2−フェニルキノリン−3−アミン.LCMS(M+H):235.1.
中間体A54:6−フルオロ−3−アミノ−2−フェニルキノリン.LCMS(M+H):238.95.
中間体A55:7−メチル−3−アミノ−2−フェニルキノリン.LCMS(M+H):234.99.
中間体A56:7−メトキシ−2−フェニルキノリン−3−アミン.LCMS(M+H):251.10.
中間体A57:7−フルオロ−6−メトキシ−2−フェニルキノリン−3−アミン.LCMS(M+H):269.13.
中間体A58:7−フルオロ−6−メチル−2−フェニルキノリン−3−アミン.LCMS(M+H):253.08.
中間体A59:N−(3−アミノ−7−フルオロ−2−フェニルキノリン−6−イル)アセトアミド.
中間体A60:6−メトキシ−7−メチル−2−メチルキノリン−3−アミン.LCMS(M+H):203.20.
中間体A61:6−メトキシ−7−フルオロ−2−メチルキノリン−3−アミン.LCMS(M+H):207.03.
中間体A62:Tert−ブチル(3−アミノ−7−メトキシ−2−メチルキノリン−6−イル)(メチル)カルバメート.LCMS(M+H):380.24.
中間体A63:2−(1−メチル−1H−ピラゾール−4−イル)キノリン−3−アミン.LCMS(M+H).224.94.
中間体A64:2−(ピリジン−3−イル)キノリン−3−アミン.LCMS(M+H).222.23.
中間体A65:2−(ピリジン−4−イル)キノリン−3−アミン.LCMS(M+H).222.23.
中間体A66:2−(ピリミジン−5−イル)キノリン−3−アミン.LCMS(M+H).223.12.
中間体A67:2−(チアゾール−5−イル)キノリン−3−アミン.LCMS(M+H).228.17.
中間体A68:2−(2,4−ジフルオロフェニル)キノリン−3−アミン.LCMS(M+H).257.15.
中間体A69:2−(3,5−ジフルオロフェニル)キノリン−3−アミン.LCMS(M+H).257.15.
中間体A70:2−モルホリノキノリン−3−アミン.LCMS(M+H).230.29.
中間体A71:2−フェニル−5,6,7,8−テトラヒドロキノリン−3−アミン.LCMS(M+H).225.04.
中間体A72:6−(ジフルオロメチル)−[1,3]ジオキソロ[4,5−g]キノリン−7−アミン.LCMS(M+H):239.01.
スキーム6(このスキームは、Synthesis、1983年、p.234−235に記載された)
中間体D1:6−メトキシジベンゾ[b,d]フラン−1−アミン.LCMS(M+H):214.10.
中間体D2:ジベンゾ[b,d]フラン−1−アミン.LCMS(M+H):184.10.
中間体D3:8−メチルジベンゾ[b,d]フラン−1−アミン.LCMS(M+H):198.00.
中間体D4:8−メトキシジベンゾ[b,d]フラン−1−アミン.1H NMR(CDCl3、300MHz):δ8.44(s、1H)、8.28−8.25(m、1H)、8.03−8.00(m、1H)、7.57−7.54(m、1H)、7.45(m、1H)、7.21−7.18(m、1H)、3.94(s、3H).
中間体D5:8−フルオロジベンゾ[b,d]フラン−1−アミン.1H NMR(CDCl3、300MHz):δ7.51−7.45(m、2H)、7.30−7.28(m、1H)、7.15(dt、J=2.4、9.0Hz、1H)、7.01(dt、J=8.4Hz、1H)、6.63(d、J=8.4Hz、1H).
中間体D6:7−フルオロジベンゾ[b,d]フラン−1−アミン.LCMS(M+H):202.20.
中間体D7:7−メトキシジベンゾ[b,d]フラン−1−アミン.LCMS(M+H):214.20.
中間体D8:6−メチルジベンゾ[b,d]フラン−1−アミン.
中間体D9:4−メトキシ−5,5−ジオキソ−ジベンゾ[b,d]チオフェン−1−イルアミン.LCMS(M+H):262.03.
中間体D10:5,5−ジオキソ−ジベンゾ[b,d]チオフェン−1−イルアミン.LCMS(M+H):231.95.
スキーム9(スキームの一部は、国際公開第2007/53346号(A1)、およびChemistry−A Europian Journal、2013年、第19巻、p.11553−11557に記載された)
中間体I1:7−フルオロ−1−メチル−3−フェニルイソキノリン−4−アミン.LCMS:(M+H)=253.10.
中間体I2:1−(1−メチル−1H−ピラゾール−4−イル)−3−フェニルイソキノリン−4−アミン.LCMS(M+H):301.34.
中間体I3:7−メトキシ−1−メチル−3−フェニルイソキノリン−4−アミン.LCMS:(M+H)=265.31.
中間体I4:1−メチル−3−フェニルイソキノリン−4−アミン.LCMS:(M+H):235.09.
中間体I5:1,7−ジメチル−3−フェニルイソキノリン−4−アミン.LCMS:(M+H):249.41.
中間体I6:3−フェニル−1−(ピリジン−3−イル)イソキノリン−4−アミン.LCMS:(M+H):298.41.
中間体I7:8−メトキシ−1−メチル−3−フェニルイソキノリン−4−アミン.LCMS:(M+H):265.08.
中間体I8:1,3−ジフェニルイソキノリン−4−アミン.
中間体I9:6−メトキシ−1−メチル−3−フェニルイソキノリン−4−アミン.LCMS:(M+H):265.25.
中間体I10:1,6−ジメチル−3−フェニルイソキノリン−4−アミン.LCMS:(M+H):249.23.
中間体I11:6,7−ジメトキシ−1−メチル−3−フェニルイソキノリン−4−アミン.LCMS:(M+H):295.39.
中間体I12:6−フルオロ−1−メチル−3−フェニルイソキノリン−4−アミン.LCMS:(M+H):295.39.
中間体I13:1−クロロ−3−フェニルイソキノリン−4−アミン.ESI−MS m/z:255.34(M+H)+.
中間体I14:5−メトキシ−3−フェニルイソキノリン−4−アミン.LCMS:(M+H):251.07.
中間体I15:8−フルオロ−3−フェニルイソキノリン−4−アミン.LCMS:(M+H):239.09.
中間体I16:7−フルオロ−3−フェニルイソキノリン−4−アミン.LCMS:(M+H)=239.07.
中間体I17:1−(1−メチル−1H−ピラゾール−4−イル)イソキノリン−4−アミン.LCMS:(M+H)=225.28.
中間体I18:3−メチル−1−(1−メチル−1H−ピラゾール−4−イル)イソキノリン−4−アミン.ESI−MS m/z:239.36(M+H)+.
中間体I19:3−フェニルイソキノリン−4−アミン.ESI−MS m/z:221.08(M+H)+.
中間体I20:3−メチルイソキノリン−4−アミン.ESI−MS m/z:159.24(M+H)+.
中間体I21:4−アミノイソキノリン−3−カルボニトリル.ESI−MS m/z:170.05(M+H)+.
中間体I22:3−(3−フルオロフェニル)−1−メチルイソキノリン−4−アミン.LC−MS:(M+H)+:253.23.
中間体I23:3−(2−フルオロフェニル)−1−メチルイソキノリン−4−アミン.LC−MS:(M+H):253.32.
中間体I24:1−メトキシ−3−フェニルイソキノリン−4−アミン.LCMS:(M+H):251.03.
中間体I25:tert−ブチル(4−アミノ−3−フェニルイソキノリン−1−イル)カルバメート.LCMS:(M+H):336.24.
中間体I26:1−フルオロ−3−フェニルイソキノリン−4−アミン.ESI−MS m/z:239.29(M+H)+.
中間体I27:4−アミノ−3−フェニルイソキノリン−1−カルボニトリル.ESI−MS m/z:246.21(M+H)+.
中間体I28:1−モルホリノ−3−フェニルイソキノリン−4−アミン.LCMS:(M+H):306.42.
中間体I29:1−(4−アミノ−3−フェニルイソキノリン−1−イル)ピペリジン−4−オール.LCMS:(M+H):320.26.
中間体I30:メチル4−アミノ−7−フルオロ−3−フェニルイソキノリン−1−カルボキシレート.LCMS:(M+H):296.94.
中間体B1:(3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−アミン.LCMS:(M+H):221.10.
中間体B2:(3S,4R)−4−(3,4−ジフルオロフェニル)−1−(2−メトキシエチル)ピロリジン−3−アミン.HCl.LCMS−(M+H):257.20.
中間体B3:(3S,4R)−4−(3−フルオロフェニル)−1−(2−メトキシエチル)ピロリジン−3−アミン.HCl.LCMS(M+H):239.40.
中間体B4:3−((3R,4S)−4−アミノ−1−(2−メトキシエチル)ピロリジン−3−イル)ベンゾニトリル.HCl.LCMS(M+H):245.98.
中間体B5:(3S,4R)−1−(2−メトキシエチル)−4−(ピリジン−3−イル)ピロリジン−3−アミン.HCl.LCMS(M+H):221.98.
中間体B6:(3S,4R)−1−(2−メトキシエチル)−4−(1−メチル−1H−ピラゾール−4−イル)ピロリジン−3−アミン.HCl.LCMS(M+H):225.20.
中間体B7:(3S,4R)−4−(tert−ブチル)−1−(2−メトキシエチル)ピロリジン−3−アミン.HCl.LCMS(M+H):201.41.
中間体B8:メチル2−((3S,4R)−3−アミノ−4−フェニルピロリジン−1−イル)アセテート.LCMS(M+H):235.19.
中間体B9:メチル2−((3R,4S)−3−アミノ−4−フェニルピロリジン−1−イル)アセテート塩酸塩.
中間体B10:(3R,4S)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−アミン塩酸塩.1H NMR(CD3OD、300MHz):δ7.48−7.39(m、5H)、4.29−4.24(m、1H)、4.08−4.05(m、2H)、3.78−3.75(m、2H)、3.65−3.59(m、4H)、3.58(m、1H)、3.43(s、3H).
中間体B11:(3S,4R)−1−(2−フルオロエチル)−4−フェニルピロリジン−3−アミン塩酸塩.LCMS(M+H):209.10.
中間体B12:(3R,4S)−1−(2−フルオロエチル)−4−フェニルピロリジン−3−アミン塩酸塩.LCMS(M+H):209.10.
中間体B13:2−((3S,4R)−3−アミノ−4−フェニルピロリジン−1−イル)アセトニトリル塩酸塩.LCMS(M+H):202.31.
中間体B14:2−((3S,4R)−3−アミノ−4−フェニルピロリジン−1−イル)アセトアミド塩酸塩.LCMS(M+H):220.00.
中間体B15:(3S,4R)−4−フェニル−1−(2,2,2−トリフルオロエチル)ピロリジン−3−アミン塩酸塩.LCMS(M+H):244.92.
中間体B16:(3R,4S)−4−フェニル−1−(2,2,2−トリフルオロエチル)ピロリジン−3−アミン塩酸塩.LCMS(M+H):245.43.
中間体B17:(3S,4R)−1−(2,2−ジフルオロエチル)−4−フェニルピロリジン−3−アミン塩酸塩.LCMS(M+H):227.34.
中間体B18:1−((3S,4R)−3−アミノ−4−フェニルピロリジン−1−イル)−2−メトキシエタン−1−オン塩酸塩.LCMS(M+H):235.33.
中間体B19:(3S,4R)−1−(オキセタン−3−イル)−4−フェニルピロリジン−3−アミン塩酸塩.1H NMR(DMSO−d6、300MHz):δ8.22(br s、2H)、7.42−7.31(m、5H)、4.67−4.64(m、2H)、4.57−4.51(m、2H)、4.02(m、1H)、3.92−3.74(m、2H).3.41−3.34(m、2H)、3.28−2.96(m、2H).
中間体B20:3−アミノ−1−(2−メトキシエチル)−4−フェニルピロリジン−2−オン.
中間体B21:4−アミノ−1−(2−メトキシエチル)−3−フェニルピロリジン−3−オール二塩酸塩.LCMS(M+1):237.17.
実施例1:1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(キノリン−3−イル)尿素
(1HNMR CDCl3, 300 M Hz): δ 8.69 (br s, 1 H), 8.59 (br s, 1 H), 8.01 (d, J = 8.4 Hz, 1 H), 7.75 (d, J = 8.0 Hz, 1 H), 7.56 (t, J = 7.6 Hz, 1 H), 7.48 (t, J = 7.6 Hz, 1 H), 7.35−7.31 (m, 2H), 7.28−7.24 (m, 3H), 4.22−4.13 (m, 1 H), 3.58 (m, 3H), 3.50−3.45 (m, 1 H), 3.33 (s, 3H), 3.28 − 3.26 (m, 1 H), 2.92−2.84 (m, 2H), 2.79−2.75 (m, 1 H), 2.46 (t, J= 9.0 Hz, 1 H); LCMS (M+H): 391.20.
1HNMR (CD3OD, 300 M Hz): δ 8.64 (s, 1 H), 7.98 (d, J= 8.4 Hz, 1 H), 7.87 (d, J = 7.8 Hz, 1 H), 7.68−7.52 (m, 7H), 7.33−7.24 (m, 5H), 4.30−4.26 (m, 1 H), 3.56 (t, J = 5.1 Hz, 2H), 3.35 (s, 3H), 3.19−3.16 (m, 3H), 2.90−2.66 (m, 4H); LCMS (m+H): 467.4.
1 HNMR (CD3OD, 400 MHz): δ 8.51 (s, 1 H), 7.90 (d, J = 8.4 Hz, 1 H), 7.80 (d, J = 7.6 Hz, 1 H), 7.62 (dt, J = 0.8 Hz および 6.8 Hz, 1 H), 7.51 (t, J = 6.8 Hz, 1 H), 7.43−7.33 (m, 4H), 7.26 (t, J = 7.2 Hz, 1 H), 4.45−4.40 (m, 1 H), 3.59 (t, J= 5.6 Hz, 2H), 3.37 (s, 3H), 3.36−3.34 (m, 1 H), 3.33−3.23 (m, 1 H), 3.13−2.97 (m, 1 H), 2.96−2.94 (m, 1 H), 2.88−2.77 (m, 2H), 2.70−2.68 (m, 1 H), 2.65 (s, 3H), LCMS (M+H): 404.87.
1H NMR(CD3OD, 400 MHz): δ 8.45 (s, 1 H), 7.91 (d, J = 8.0 Hz, 1 H), 7.77 (d, J = 8.4 Hz, 1 H), 7.60 (dt, J = 1.2 Hz および 8.4 Hz, 1 H), 7.48 (t, J = 7.2 Hz, 1 H), 7.37−7.32 (m, 4H), 7.30−7.23 (m, 1 H), 4.41−4.39 (m, 1 H), 3.57 (t, J= 5.2 Hz, 2H), 3.35 (s, 3H), 3.26−3.21 (m, 1 H), 3.1 1−3.07 (m, 1 H), 2.99−2.91 (m, 3H), 2.83−2.76 (m, 3H), 2.67 − 2.65 (m, 1 H), 1.30 (t, J = 8.0 Hz, 3H). LCMS (M+H): 419.22.
1H NMR(CD3OD, 300 MHz): δ 8.38 (s, 1 H), 7.83 (d, J = 8.4 Hz, 1 H), 7.72 (d, J = 7.2 Hz, 1 H), 7.56−7.51 (m, 1 H), 7.44−7.29 (m, 5H), 7.25−7.22 (m, 1 H), 4.43−4.38 (m, 1 H), 3.56 (t, J= 5.4 Hz, 2H), 3.35 (s, 3H), 3.23−3.08 (m, 1 H), 3.08−3.05 (m, 1 H), 2.93−2.88 (m, 1 H), 2.83−2.71 (m, 3H), 2.65−2.59 (m, 1 H), 2.23−2.18 (m, 1 H), 1.15−1.09 (m, 2H), 1.07−1.01 (m, 2H). LCMS (M+H): 431.0.
1 H NMR(DMSO−d6, 400 MHz): δ 8.87 (s, 1 H), 8.05−7.99 (m, 3H), 7.76−7.70 (m, 2H), 7.59 (d, J = 7.6 Hz, 1 H), 7.33−7.30 (m,4H), 7.24−7.22 (m, 1 H), 4.20−4.17 (m, 1 H), 3.47 (t, J= 5.6 Hz, 2H), 3.26 (s, 3H), 3.22−3.18 (m, 1 H), 3.13−3.08 (m, 1 H), 2.93−2.89 (m, 1 H), 2.71−2.60 (m, 3H), 2.45−2.43 (m, 1 H). LCMS (M+H): 459.2.
1 H NMR(DMSO−d6, 300 MHz): δ 8.81 (s, 1 H), 7.96−7.91 (m, 1 H), 7.73−7.70 (m, 1 H), 7.69 − 7.65 (m, 1 H), 7.60−7.53 (m, 5H), 7.50−7.44 (m, 1 H), 7.39−7.36 (m, 1 H), 7.34−7.31 (m, 4H), 7.23−7.20 (m, 1 H), 4.18−4.15 (m, 1 H), 3.43 (t, J= 6.0 Hz, 2H), 3.23 (s, 3H), 3.17−3.1 1 (m, 1 H), 3.05−3.00 (m, 1 H), 2.88−2.82 (m, 1 H), 2.62−2.59 (m, 3H), 2.43−2.37 (m, 1 H). LCMS (M+H): 484.86.
1 H NMR(DMSO−d6, 300 MHz): δ 8.62 (s, 1 H), 8.32 (br s, 1 H) 7.88−7.83 (m, 1 H), 7.59−7.55 (m, 2H), 7.43−7.32 (m, 6H), 4.52−4.48 (m, 1 H), 4.04−4.01 (m, 1 H), 3.82−3.67 (m, 4H), 3.58−3.45 (m, 4H), 3.31 (s, 3H), 2.57 (s, 3H). LCMS (M+H): 423.25.
1 H NMR(CD3OD, 400 MHz): δ 8.76 (s, 1 H), 7.70 (d, J = 8.8 Hz, 1 H), 7.56−7.50 (m, 1 H), 7.38−7.31 (m, 4H), 7.25−7.17 (m, 2H), 4.40−4.39 (m, 1 H), 3.56 (t, J= 6.0 Hz, 2H), 3.36 (s, 3H), 3.34−3.33 (m, 1 H), 3.26−3.22 (m, 1 H), 3.12−3.07 (m, 1 H), 2.95−2.91 (m, 1 H), 2.85−2.74 (m, 2H), 2.74−2.62 (m, 4H). LCMS (M+H): 423.33.
1 H NMR(DMSO−d6, 300 MHz): δ 8.74 (s, 1 H), 8.08 (br s, 1 H), 7.59 (d, J= 7.8 Hz, 1 H), 7.43−7.23 (m, 8H), 4.25 −4.18 (m, 1 H), 3.58 − 3.40 (m, 2H), 3.34−3.33 (m, 1 H), 3.26 (s, 3H), 3.18 − 3.04 (m, 2H), 2.90 − 2.86 (m, 2H), 2.74 − 2.70 (m, 2H), 2.61 (s, 3H). LCMS (M+H): 423.36.
1 H NMR(CD3OD, 400 MHz): δ 8.65 (s, 1 H), 7.96−7.92 (m, 1 H), 7.64−7.60 (m, 3H), 7.59−7.54 (m, 3H), 7.43 (dt, J = 2.8 Hz および 8.8 Hz, 1 H), 7.35−7.30 (m, 4H), 7.26−7.22 (m, 1 H), 4.33−4.29 (m, 1 H), 3.54 (t, J= 5.6 Hz, 2H), 3.33 (s, 3H), 3.24−3.21 (m, 1 H), 3.15−3.08 (m, 1 H), 3.04−2.99 (m, 1 H), 2.82-−2.70 (m, 3H), 2.62−2.57 (m, 1 H). LCMS (M+H): 484.80.
1 H NMR(CD3OD, 300 MHz): δ 8.51 (br s, 1 H), 7.85−7.81 (m, 1 H), 7.53−7.35 (m, 7H), 4.59−4.52 (m, 1 H), 4.08 − 3.65 (m, 5H), 3.64 − 3.56 (m, 2H), 3.44 (s, 3H), 3.38 − 3.35 (m, 1 H), 3.30−3.18 (m, 1 H), 2.61 (s, 3H). LCMS (M+H): 423.11.
1 HNMR (CD3OD, 300 MHz): δ 8.53 (s, 1 H), 7.84 (d, J = 9.3 Hz, 1 H), 7.56−7.50 (m, 5H), 7.31−7.19 (m, 7H), 4.30−4.28 (m, 1 H), 3.92 (s, 3H), 3.51 (t, J= 5.7 Hz, 2H), 3.23−3.12 (m, 2H), 3.09−3.02 (m, 2H), 2.98−2.96 (m, 1 H), 2.80−2.65 (m, 4H), 2.59−2.53 (m, 1 H). LCMS (M+H): 496.83.
1 H NMR (DMSO−d6, 400 MHz): δ 8.60 (s, 1 H), 7.79 (d, J = 9.2 Hz, 1 H), 7.64−7.60 (m, 3H), 7.55−7.50 (m, 3H), 7.33−7.28 (m, 5H), 7.23−7.13 (m, 3H), 4.15−4.10 (m, 1 H), 3.87 (s, 3H), 3.43 (t, J = 6.0 Hz, 2H), 3.23 (s, 3H), 3.14−3.10 (m, 1 H), 3.04−2.98 (m, 1 H), 2.85 (t, J = 8.0 Hz, 1 H), 2.67−2.55 (m, 3H), 2.44−2.40 (m, 1 H). LCMS (M+H): 497.10.
1 H NMR (DMSO−d6, 300 MHz): δ 8.72 (s, 1 H), 7.68 (br s, 1 H), 7.56−7.54 (m, 4H), 7.45−7.21 (m, 9H), 7.03 (d, J = 7.8 Hz, 1 H), 4.23 − 4.14 (m, 1 H), 3.91 (s, 3H), 3.49−3.34 (m, 2H), 3.24 (s, 3H), 3.14−3.13 (m, 1 H), 3.03−3.00 (m, 2H), 2.62−2.60 (m, 3H), 2.49−2.48 (m, 1 H). LCMS (M+H): 497.62.
1 H NMR (CD3OD, 300 MHz): δ 8.92 (s, 1 H), 7.60−7.50 (m, 7H), 7.31−7.22 (m, 5H), 6.98 (dd, J= 2.1 HZ および 6.6 Hz, 1 H), 4.31−4.28 (m, 1 H), 4.02 (s, 3H), 3.54−3.50 (m, 2H), 3.31 (s, 3H), 3.23−3.18 (m, 1 H), 3.11−3.00 (m, 2H), 2.84−2.72 (m, 3H), 2.60 − 2.58 (m, 1 H). LCMS (M+H): 497.55.
1 H NMR (CD3OD, 300 MHz): δ 8.77 (s, 1 H), 7.51−7.44 (m, 2H), 7.38−7.21 (m, 5H), 6.92 (d, J = 6.9 Hz, 1 H), 4.40−4.38 (m, 1 H), 3.98 (s, 3H), 3.57 (t, J= 5.4 Hz, 2H), 3.36 (s, 3H), 3.39−3.24 (m, 2H), 3.16−3.10 (m, 1 H), 2.98−2.97 (m, 1 H), 2.86−2.79 (m, 2H), 2.71−2.68 (m, 1 H), 2.59 (s, 3H). LCMS (M+H): 435.39
1 H NMR (CD3OD, 400 MHz): δ 8.40 (s, 1 H), 7.75 (d, J= 9.2 Hz, 1 H), 7.37−7.31 (m, 4H), 7.25−7.21 (m, 2H), 7.13 (d, J= 2.4 Hz, 1 H), 4.41−4.40 (m, 1 H), 3.89 (s, 3H), 3.57 (t, J= 6.0 Hz, 2H), 3.36 (s, 3H), 3.34−3.31 (m, 1 H), 3.26−3.22 (m, 1 H), 3.13−3.08 (m, 1 H), 2.95−2.91 (m, 1 H), 2.86−2.72 (m, 2H), 2.68−2.62 (m, 1 H), 2.57 (s, 3H). LCMS (M+H): 435.35.
1 H NMR (CD3OD, 400 MHz): δ 8.30 (s, 1 H), 7.69 (d, J= 9.6 Hz, 1 H), 7.38−7.31 (m, 4H), 7.26−7.24 (m, 2H), 7.16 (dd, J= 2.4 Hz および 8.8 Hz, 1 H), 4.41−4.40 (m, 1 H), 3.94 (s, 3H), 3.58 (t, J= 5.6 Hz, 2H), 3.36 (s, 3H), 3.41−3.26 (m, 2H), 3.21−3.17 (m, 1H), 3.01−2.99 (m, 1H), 2.90−2.86 (m, 2H), 2.72−2.70 (m, 1H), 2.58 (s, 3H). LCMS (M+H): 435.39.
1H NMR (CD3OD, 300 MHz): δ 8.45 (s, 1H), 7.41−7.22 (m, 7H), 7.03 (d, J= 7.2 Hz, 1H), 4.40−4.38 (m, 1H), 4.02 (s, 3H), 3.56 (t, J= 5.7 Hz, 2H), 3.35 (s, 3H), 3.31−3.29 (m, 1H), 3.25−3.20 (m, 1H), 3.10−3.04 (m, 1H), 2.92−2.87 (m, 1H), 2.84−2.71 (m, 2H), 2.62 (s, 3H), 2.61 −2.59 (m, 1H). LCMS (M+H): 435.12.
1H NMR (DMSO d6, 300 MHz): δ 8.53 (s, 1H), 7.60−7.58 (m, 3H), 7.53−7.47 (m, 3H), 7.31−7.19 (m, 7H), 7.12 (d, J= 7.8 Hz, 1H), 4.17−4.28 (m, 1H), 3.88 (s, 6H), 3.43 (t, J= 6.0 Hz, 2H), 3.24 (s, 3H), 3.09 (t, J= 8.1 Hz, 1 H), 3.02 (q, J= 6.9 Hz, 1 H), 2.85 (t, J= 7.8 Hz, 1 H), 2.60−2.57 (m, 3H), 2.42 (t, J= 8.4 Hz, 1H). LCMS (M+H): 527.72.
1H NMR (CD3OD, 300 MHz): δ 8.24 (s, 1H), 7.37−7.29 (m, 4H), 7.25−7.20 (m, 2H), 7.13 (s, 1H), 4.42−4.37 (m, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.55 (t, J= 5.4 Hz, 2H), 3.31 (s, 3H), 3.30−3.19 (m, 2H), 3.09−2.92 (m, 1H), 2.90−2.83 (m, 1H), 2.81−2.70 (m, 2H), 2.62 (t, J = 9.0 Hz, 1H), 2.54 (s, 3H). LCMS (M+H): 464.91.
1H NMR (CD3OD, 400 MHz): δ 8.51 (d, J= 2.4 Hz, 1H), 8.22 (d, J = 1.6 Hz, 1H), 7.37−7.30 (m, 4H), 7.25−7.23 ( m, 2H ), 7.15 (s, 1H ), 4.43−4.37 ( m, 1H) , 3.95 (s, 6H ), 3.58 (t, J= 5.6 Hz, 2H), 3.40−3.37 (m, 4H ), 3.31−3.24 (m, 1H), 3.11−3.09 (m, 1H), 2.97−2.95 (m, 1H), 2.87−2.80 (m, 2H), 2.68−2.65 (m, 1H). LCMS (M+H): 450.81.
1HNMR (CD3OD, 300 MHz): δ 8.53 (s, 1H), 7.86 (d, J= 9.0 Hz, 1H), 7.63−7.48 (m, 7H), 7.35−7.22 (m, 5H), 4.31−4.28 (m, 1H), 3.53 (t, J= 5.4 Hz, 2H), 3.32 (s, 3H), 3.23−2.98 (m, 3H), 2.82−2.71 (m, 3H), 2.61−2.58 (m, 1H), 2.53 (s, 3H). LCMS (M+H): 480.90.
1H NMR (CD3OD, 400 MHz): δ 8.38 (s, 1H), 7.77 (d, J= 8.4 Hz, 1H), 7.54 (s, 1H), 7.45−7.43 (m, 1H), 7.37−7.30 (m, 4H), 7.24−7.21 (m, 1H), 4.42−4.37 (m, 1H), 3.56 (t, J= 5.6 Hz, 2H), 3.35 (s, 3H), 3.24− 3.18 (m, 2H), 3.09−3.04 (m, 1H), 2.90−2.88 (m, 1H), 2.84−2.70 (m, 2H), 2.64−2.62 (m, 1H), 2.59 (s, 3H), 2.48 (s, 3H). LCMS (M+H): 419.33.
1H NMR (CD3OD, 300 MHz): δ 8.38 (s, 1H), 7.68−7.65 (m, 2H), 7.38−7.30 (m, 5H), 7.26−7.21 (m, 1H), 4.43−4.36 (m, 1H), 3.57 (t, J= 5.4 Hz, 2H), 3.38−3.31 (m, 1H), 3.36 (s, 3H), 3.25−3.20 (m, 1H), 3.15−3.09 (m, 1H), 2.97−2.92 (m, 1H), 2.90−2.74 (m, 2H), 2.70−2.64 (m, 1H), 2.59 (s, 3H), 2.51 (s, 3H). LCMS (M+H): 419.37.
1H NMR (CD3OD, 400 MHz): δ 8.68 (s, 1H), 7.73 (d, J= 8.8 Hz, 1H), 7.47 (t, J= 8.4 Hz, 1H), 7.38−7.29 (m, 5H),7.25− 7.21 (m, 1H), 4.40−4.38 (m, 1H), 3.56 (t, J= 5.2 Hz, 2H), 3.36 (s, 3H), 3.35−3.33 (m, 1H), 3.26−3.20 (m, 1H), 3.11−3.07 (m, 1H), 2.94−2.90 (m, 1H), 2.85−2.72 (m, 2H), 2.66−2.64 (m, 1H), 2.62 (s, 6H). LCMS (M+H): 419.33.
1H NMR (DMSO−d6, 300 MHz): δ 8.62 (s, 1H), 7.97 (br s, 1H), 7.58 (d, J= 7.8 Hz, 1H), 7.38−7.20 (m, 8H), 4.22−4.18 (m, 1H), 3.47 (t, J= 5.7 Hz, 2H), 3.26 (s, 3H), 3.22−3.19 (m, 1H), 3.14−3.09 (m, 1H), 2.94−2.88 (m, 1H), 2.75−2.67 (m, 3H), 2.64 (s, 3H), 2.60 (s, 3H), 2.44−2.42 (m, 1H). LCMS (M+H): 419.37.
1H NMR (DMSO−d6, 300 MHz): δ 8.66 (s, 1H), 7.76 (d, J= 8.7 Hz, 1H), 7.69−7.59 (m, 2H), 7.54−7.52 (m, 5H), 7.38−7.21 (m, 7H), 4.15−4.10 (m, 1H), 3.43 (t, J= 6.0 Hz, 2H), 3.23 (s, 3H), 3.13− 3.10 (m, 1H), 3.02−3.00 (m, 1H), 2.85−2.84 (m, 1H), 2.60−2.59 (m, 3H), 2.50 (s, 3H), 2.44−2.39 (m, 1H). LCMS (M+H): 480.83.
1HNMR (CD3OD 300 MHz): δ 8.81 ( s, 1H ), 7.84−7.79 ( m, 2H ), 7.65−7.51 (m, 2H ), 7.38−7.29 (m, 4H), 7.25−7.22 (m, 1H), 4.39−4.38 (m, 1H ), 3.56 (t, J= 5.4 Hz, 2H), 3.34 (s, 3H), 3.30−3.20 (m, 1H), 3.13−3.08 ( m, 1H), 2.92−2.74 (m, 4H), 2.69−2.63 (m, 1H). LCMS (M+H): 425.30.
1HNMR (CD3OD, 300 MHz): δ 8.38 (s, 1H), 8.08 (s, 1H), 8.00 (s, 1H), 7.96 (d, J= 8.4 Hz, 1H), 7.83 (d, J= 8.4 Hz, 1H), 7.68−7.62 (m, 1H), 7.53−7.49 (m, 1H), 7.32−7.31 (m, 4H), 7.25−7.22 (m, 1H), 4.42−4.35 (m, 1H), 3.94 (s, 3H), 3.54 (t, J= 5.4 Hz, 2H), 3.34 (s, 3H), 3.31−3.30 (m, 1H), 3.23−3.13 (m, 1H), 3.07−3.01 (m, 1H), 2.89−2.84 (m, 1H), 2.80−2.75 (m, 2H), 2.63−2.57 (m, 1H). LCMS (M+H): 470.82.
1H NMR (CD3OD, 300 MHz): δ 8.83 (s, 1H), 8.64 (d, J= 5.1 Hz, 1H), 8.53 (s, 1H), 8.12−8.09 (m, 1H), 8.03 (d, J= 8.4 Hz, 1H), 7.90 (d, J= 7.8 Hz, 1H), 7.72−7.67 (m, 1H), 7.62−7.53 (m, 2H), 7.34−7.22 (m, 5H), 4.28−4.26 (m, 1H), 3.52 (t, J= 5.4 Hz, 2H), 3.32 (s, 3H), 3.24−3.21 (m, 1H), 3.11−3.08 (m, 1H), 2.96−2.95 (m, 1H), 2.80−2.71 (m, 3H), 2.56−2.55 (m, 1H). LCMS (M+H): 467.87.
1H NMR (CD3OD, 300 MHz): δ 8.67−8.65 (m, 2H), 8.53 (s, 1H), 8.03 (d, J= 8.4 Hz, 1H), 7.91 (d, J= 8.1 Hz, 1H), 7.74−7.69 (m, 3H), 7.64−7.59 (m, 1 H), 7.36−7.23 (m, 5H), 4.30−4.29 (m, 1 H), 3.56 (t, J= 5.4 Hz, 2H), 3.38−3.37 (m, 1H), 3.35 (s, 3H), 3.24−3.16 (m, 2H), 2.91−2.90 (m, 3H), 2.75−2.74 (m, 1H). LCMS (M−H): 465.85.
1H NMR (CD3OD, 400 MHz): δ 9.22(s, 1H), 9.11 (s, 2H), 8.44 (s, 1H), 8.05 (d, J= 8.8 Hz, 1H), 7.92 (d, J= 8.4 Hz, 1 H), 7.74−7.71 (m, 1 H), 7.64−7.60 (m, 1 H), 7.32−7.21 (m, 5H), 4.32−4.29 (m, 1 H), 3.53 (t, J= 5.2, 2H), 3.32 (s, 3H), 3.12−3.10 (m, 1H), 2.93−2.91 (m, 1H), 2.76−2.75 (m, 4H), 2.55−2.54 (m, 1H). LCMS (M+H): 469.60.
1H NMR (CD3OD, 300 MHz): δ 8.48 (s, 1H), 7.80 (d, J= 8.4 Hz, 1H), 7.68 (d, J= 8.4 Hz, 1H), 7.53−7.47 (m, 1H), 7.40−7.29 (m, 5H), 7.25−7.22 (m, 1 H), 4.41−4.40 (m, 1 H), 3.90 (t, J= 4.8 Hz, 4H), 3.56 (t, J= 5.7 Hz, 2H), 3.36 (s, 3H), 3.22−3.16 (m, 5H), 3.12−3.06 (m, 1H), 2.90−2.71 (m, 4H), 2.67−2.61 (m, 1H). LCMS (M+H): 476.21.
1H NMR (DMSO−d6 , 300MHz): δ 8.98 (s, 1H), 8.62 (d, J= 5.1 Hz, 1H), 8.16−8.13 (m, 2H), 7.94 (d, J= 8.1 Hz, 1H), 7.72 (t, J= 7.2 Hz, 1H), 7.61 (t, J= 7.8 Hz, 1H), 7.39−7.23 (m, 6H), 4.25−4.23 (m, 1H), 3.49−3.47 (m, 2H), 3.31−3.28 (m, 1H), 3.26 (s, 3H), 3.15−3.12 (m, 2H), 2.93−2.91 (m, 1H), 2.72−2.69 (m, 3H). LCMS (M+H): 391.10.
1H NMR (CD3OD, 400 MHz): δ 8.80 (s, 1H), 8.36 (d, J= 8.0 Hz, 1H), 7.95−7.87 (m, 2H), 7.69−7.65 (m, 1H), 7.45−7.38 (m, 2H), 7.32−7.29 (m, 2H), 7.23−7.17 (m, 1H), 4.85−4.52 (m, 1H), 3.60−3.58 (m, 2H), 3.46−3.37 (m, 2H), 3.30 (s, 3H), 3.18−3.13 (m, 1H), 3.08−3.04 (m, 1H), 2.92−2.71 (m, 3H). LCMS (M+H): 391.84.
1H NMR (CD3OD, 300 MHz): δ 7.71 (s, 1H), 7.42−7.40(m, 2H),7.34−7.29 (m, 2H), 7.24−7.22 (m, 1H), 7.15 (s, 1H), 4.41−4.39 (m, 1H), 3.99 (s, 3H), 3.97 (s, 3H) 3.58 (t, J =5.7 Hz, 2H), 3.36 (s, 3H), 3.34−3.30 (m, 2H), 3.22−3.16 (m, 1H), 3.02−2.98 (m, 1H), 2.85−2.76 (m, 3H). LCMS (M+H): 485.81.
1H NMR: (DMSO−d6 , 300 MHz): δ 10.05 (s, 1H), 9.07(d, J= 6.9 Hz, 1H), 8.85 (s, 1H), 7.96 (d, J= 8.4 Hz, 1H), 7.88 (d, J= 8.4 Hz, 1 H), 7.80−7.74 (m, 1 H), 7.65−7.59 (m, 1 H), 7.39−7.29 (m, 4H), 7.24−7.21 (m, 1 H), 4.27−4.25 (m, 1H), 3.49 (t, J= 5.4 Hz, 2H), 3.31 (s, 3H), 3.27−3.25 (m, 2H) 2.99−2.98 (m, 1H), 2.80−2.69 (m, 3H), 2.50−2.49 (m, 1H). LCMS (M+H): 392.20.
1H NMR: (CDCl3, 400 MHz): δ8.31 (s, 1H), 8.01 (d, J= 8.4 Hz, 1H), 7.72 (d, J= 8.4 Hz, 1H), 7.62−7.57 (m, 1H), 7.46−7.43 (m, 1H), 7.35−7.23 (m, 5H), 5.25 (br s, 1H), 4.43−4.34 (m, 1H), 3.51−3.48 (m, 2H), 3.47−3.44 (m, 1H), 3.34−3.29 (m, 2H), 3.26 (s, 3H), 3.14−3.12 (m, 1H), 2.91−2.87 (m, 1H), 2.81−2.79 (m, 1H), 2.71−2.70 (m, 1H), 2.49−2.47 (m, 1H), 1.35 (d, J= 2.0 Hz, 3H), 1.33 (d, J= 1.6 Hz, 3H). lCMS (M+H): 433.14.
1H NMR: (CDCl3, 300 MHz): δ8.14 (s, 1H), 8.01 (d, J= 8.7 Hz, 1H), 7.71−7.60 (m, 2H), 7.49−7.44 (m, 1H), 7.35−7.26 (m, 5H), 6.59 (br s, 1H), 4.58−4.50 (m, 1H), 3.58−3.52 (m, 3H), 3.37−3.31 (m, 1H), 3.31 (s, 3H), 3.23−3.19 (m, 1H), 3.04−3.02 (m, 1H), 2.82−2.79 (m, 2H), 2.63−2.59 (m, 1H), 1.50 (s, 9H). LCMS (M+H): 447.13.
1H NMR: (CDCl3, 300 MHz): δ8.37 (s, 1 H), 7.36−7.26 (m, 6H), 6.98 (s, 1 H), 6.79 (br s, 1 H), 4.49−4.42 (m, 1H), 3.95 (s, 3H), 3.92−3.91 (m, 4H), 3.73−3.70 (m, 1H), 3.67 − 3.59 (m, 2H), 3.58−3.49 (m, 1H), 3.35−3.34 (m, 1H), 3.30 (s, 3H), 3.20−3.19 (m, 4H), 3.04−2.91 (m, 3H), 2.74−2.68 (m, 1H), 2.61 (s, 3H). LCMS (M+H): 520.42.
1H NMR (CDCl3, 300 MHz): δ8.76 (s, 1H), 7.86 (d, J= 7.5 Hz, 1H), 7.63−7.60 (m, 2H), 7.56−7.48 (m, 3H), 7.35−7.26 (m, 4H), 7.23−7.22 (m, 2H), 5.16−5.10 (br m, 1H), 4.26−4.23 (m, 1H), 3.44−3.37 (m, 2H), 3.24 (s, 3H), 3.21−3.17 (m, 2H), 3.05−3.02 (m, 1H), 2.73−2.52 (m, 3H), 2.44 (s, 3H), 2.31−2.25 (m, 1H). LCMS (M+H): 499.44.
1 H NMR (CDCI3, 400MHz): δ 8.51 (s, 1 H), 7.45 (d, J= 1.2 Hz, 1 H), 7.33−7.29 (m, 2H), 7.24−7.22 (m, 3H), 6.98 (d, J = 2.0 Hz, 1 H), 6.04 (brs, 1 H) 4.34−4.31 (m, 1 H), 4.01 (s, 3H), 3.53−3.46 (m, 3H), 3.30−3.20 (m, 5H), 2.90−2.84 (m, 2H), 2.74−2.68 (m, 1 H), 2.63 (s, 3H), 2.49 (t, J = 9.2 Hz, 1 H). LCMS (M+H):513.33.
1 H NMR (CDCl3, 400MHz): δ 8.76 (s, 1 H), 7.69−7.61 (m, 3H), 7.55−7.48 (m, 3H), 7.34−7.30 (m, 3H), 7.26−7.24 (m, 2H), 7.13 (d, J = 8.8 Hz, 1 H), 5.22 (br s, 1 H), 4.26−4.20 (m, 1 H), 3.99 (s, 3H), 3.44−3.40 (m, 2H), 3.24 (s, 3H), 3.21−3.17 (m, 2H), 3.08−3.04 (m, 1 H), 2.79−2.52 (m, 3H), 2.32−2.28 (m, 1 H). LCMS (M+H):515.35.
1 H NMR (CD3OD, 300MHz): δ 8.41 (s, 1 H), 7.49 (d, J = 12.0 Hz, 1 H), 7.37−7.23 (m, 6H), 4.42−4.38 (m, 1 H), 3.97 (s, 3H), 3.56 (t, J= 5.4 Hz, 2H), 3.36 (s, 3H), 3.24 − 3.21 (m, 2H), 3.09−2.94 (m, 1 H), 2.94−2.72 (m, 4H), 2.57 (s, 3H). LCMS (M+H):453.26.
1 H NMR (CDCl3, 400MHz): δ 8.73 (s, 1 H), 7.70−7.68 (m, 2H), 7.54−7.43 (m, 4H), 7.33−7.29 (m, 3H), 7.23−7.21 (m, 3H), 5.09−5.07 (d, J= 8.0 Hz, 1 H), 4.26−4.20 (m, 1 H), 4.1 1(s, 3H), 3.41 (t, J= 5.2 Hz, 2H), 3.24 (s, 3H), 3.21−3.17 (m, 2H), 3.03−3.00 (m, 1 H), 2.73−2.62 (m, 2H), 2.57−2.53 (m, 1 H), 2.45 (s, 3H), 2.28 (t, J = 8.8 Hz, 1 H). LCMS (M+H): 511.39.
1 H NMR (CD3OD, 300MHz): δ 8.33 (s, 1 H), 7.61 (s, 1 H), 7.38−7.30 (m, 4H), 7.26−7.23 (m, 1 H), 7.08 (s, 1 H), 4.45−4.36 (m, 1 H), 3.93 (s, 3H), 3.57 (t, J= 5.4 Hz, 2H), 3.36 (s, 3H), 3.25−3.09 (m, 2H), 2.96−2.78 (m, 4H), 2.70−2.64 (m, 1 H), 2.55 (s, 3H), 2.34 (s, 3H). LCMS (M+H): 449.26.
1H NMR (CDCI3, 400MHz): δ 8.73 (s, 1H), 7.64−7.61 (m, 3H), 7.58−7.46 (m, 4H), 7.33−7.30 (m, 2H), 7.24−7.22 (m, 3H), 5.06 (brs, 1H), 4.25−4.21 (m, 1H), 3.41−3.40 (m, 2H), 3.22 (s, 3H), 3.20−3.17 (m, 2H), 3.05−3.02 (m, 1H), 2.73−2.64 (m, 2H), 2.57−2.48 (m, 1H), 2.45 (s, 3H), 2.29−2.26 (m, 1H). LCMS (M+H): 499.33.
1H NMR (DMSO−d6, 300 MHz):δ 8.62 (s, 1H), 7.97 (s, 1H), 7.71 (d, J= 7.8 Hz, 1H), 7.51 (d, J= 10.8 Hz, 1H), 7.34−7.20 (m, 6H), 4.22−4.16 (m, 1H), 3.47 (t, J= 5.7 Hz, 2H), 3.25 (s, 3H), 3.21−3.18 (m, 1H), 3.13−3.09 (m, 1H), 2.93−2.87 (m, 1H), 2.72−2.59 (m, 3H), 2.55 (s, 3H), 2.44−2.41 (m, 1H), 2.37 (s, 3H). LCMS (M+H): 437.28.
1H NMR (CDCl3 , 300MHz): δ 8.61 (s, 1H), 7.63−7.60 (m, 2H), 7.54−7.45 (m, 3H), 7.34−7.29 (m, 3H), 7.27−7.22 (m, 3H), 7.04 (s, 1 H), 6.08 (s, 2H), 5.07 (br s, 1 H), 4.24−4.22 (m, 1 H), 3.41 (t, J= 5.4 HZ, 2H), 3.24 (s, 3H), 3.20−3.16 (m, 2H), 3.04−3.01 (m, 1H), 2.74−2.56 (m, 3H), 2.32−2.26 (m, 1H). LCMS (M+H): 511.39.
1H NMR (CD3OD, 300MHz): δ 8.23 (s, 1H), 7.39−7.32 (m, 4H), 7.29−7.26 (m, 1H), 7.16 (s, 1H), 7.05 (s, 1H), 6.08 (s, 2H), 4.42−4.39 (m, 1H), 3.61 (t, J= 5.4 Hz, 2H), 3.55−3.49 (m, 1H), 3.38 (s, 3H), 3.36−3.32 (m, 1H), 3.14−3.00 (m, 3H), 2.93−2.80 (m, 2H), 2.51 (s, 3H). LCMS (M+H): 449.36.
1H NMR (CD3OD, 400MHz): δ 8.18 (s, 1H), 7.36−7.30 (m, 4H), 7.27−7.23 (m, 2H), 7.14 (s, 1H), 4.42−4.37 (m, 1H), 4.33 (s, 4H), 3.56 (t, J= 5.6 Hz, 2H), 3.35 (s, 3H), 3.34−3.32 (m, 1H), 3.25−3.21 (m, 1H), 3.09−3.06 (m, 1H), 2.93−2.90 (m, 1H), 2.85−2.75 (m, 2H), 2.65 (t, J= 9.6 Hz, 1H), 2.52 (s, 3H). LCMS M+H): 463.25.
1 H NMR (CDCl3, 400MHz): δ 8.57 (s, 1 H), 7.61−7.59 (m, 2H), 7.51−7.45 (m, 4H), 7.33−7.29 (m, 2H), 7.24−7.22 (m, 3H), 7.17 (s, 1 H), 5.22 (brs, 1 H), 4.36 (s, 4H), 4.26−4.22 (m, 1 H), 3.42−3.36 (m, 2H), 3.24 (s, 3H), 3.19−3.16 (m, 2H), 3.04−3.01 (m, 1 H), 2.75−2.65 (m, 2H), 2.59−2.56 (m, 1 H), 2.32−2.28 (m, 1 H). LCMS (M+H):525.32.
1 H NMR (CDCl3, 400 MHz):δ 8.46 (s, 1 H), 7.61−7.59 (m, 2H), 7.52−7.48 (m, 3H), 7.45−7.43 (m, 2H), 7.35−7.23 (m, 4H), 6.88 (s, 1 H), 4.56−4.49 (m, 1 H), 4.19 (br s, 2H), 3.96 (s, 3H), 3.66−3.60 (m, 3H), 3.46−3.44 (m, 2H), 3.32 (s, 3H), 3.16−2.98 (m, 3H), 2.78−2.52 (m, 1 H). LCMS (M+H):512.32.
1 H NMR (CD3OD, 400MHz): δ 8.18 (s, 1 H), 7.55−7.53 (m, 2H), 7.48−7.44 (m, 3H), 7.33−7.27 (m, 4H), 7.24−7.20 (m, 2H), 6.64 (s, 1 H), 4.29−4.21 (m, 1 H), 3.98 (s, 3H), 3.52 (t, J= 5.6 Hz, 2H), 3.33 (s, 3H), 3.12−2.98 (m, 2H), 2.93 (s, 3H), 2.82−2.72 (m, 4H), 2.62−2.52 (m, 1 H). LCMS (M+H): 526.37.
1H NMR (CDCl3, 300MHz): δ 8.78 (s, 1 H), 8.61 (s, 1 H), 7.99 (br s, 1 H), 7.60−7.58 (m, 2H), 7.52−7.43 (m, 3H), 7.39 (s, 1 H), 7.34−7.29 (m, 2H), 7.23−7.19 (m, 2H), 5.22 (brs, 1 H), 4.29−4.21 (m, 1 H), 4.00 (s, 3H), 3.42 (t, J= 5.7 Hz, 2H), 3.24 (s, 3H), 3.21−3.17 (m, 2H), 3.04−3.02 (m, 1 H), 2.75−2.58 (m, 3H), 2.32−2.28 (m, 1 H), 2.26 (s, 3H). LCMS (M+H):554.41.
1 H NMR (CD3OD, 300MHz): δ 8.71 (s, 1 H), 8.34 (s, 1 H), 7.38−7.31 (m, 4H), 7.27−7.20 (m, 1 H), 7.19 (s, 1 H), 4.44−4.39 (m, 1 H), 4.01 (s, 3H), 3.58 (t, J = 5.4 Hz,, 2H), 3.37 (s, 3H), 3.24−3.13 (m, 2H), 3.00−2.84 (m, 3H), 2.72−2.54 (m, 2H), 2.54 (s, 3H), 2.23 (s, 3H). LCMS (M+H): 492.31.
1 H NMR (CD3OD, 400MHz): δ 8.76 (s, 1 H), 8.45 (s, 1 H), 7.57−7.48 (m, 5H), 7.32−7.23 (m, 6H), 4.29−4.24 (m, 1 H), 4.04 (s, 3H), 3.53 (t, J = 4.8 Hz, 2H), 3.33 (s, 3H), 3.14−3.03 (m, 3H), 2.85−2.61 (m, 4H), 2.23 (s, 3H). LCMS (M+H): 554.30.
1 H NMR (CD3OD, 300MHz): δ 8.71 (s, 1 H), 8.33 (s, 1 H), 7.39−7.30 (m, 4H), 7.26−7.19 (m, 2H), 4.45−4.38 (m, 1 H), 4.00 (s, 3H), 3.58 (t, J = 5.4 Hz, 2H), 3.36 (s, 3H), 3.24−3.13 (m, 3H), 3.00−2.82 (m, 3H), 2.72−2.54 (m, 1 H), 2.54 (s, 3H), 2.23 (s, 3H). LCMS (M+H): 492.21.
1 H NMR (CDCl3, 300MHz): δ 8.51 (s, 1 H), 7.84 (s, 1 H), 7.70 (s, 1 H), 7.39−7.38 (m, 2H), 7.33−7.30 (m, 4H), 7.03−7.00 (m, 1 H), 5.51 (brs, 1 H), 4.36− 4.25 (m, 1 H), 4.10 (s, 3H), 3.98 (s, 3H), 3.68 - 3.64 (m, 1 H), 3.52−3.49 (m, 2H), 3.42−3.33 (m, 1 H), 3.26 (s, 3H), 3.18 − 3.10 (m, 2H), 2.89−2.81 (m, 2H), 2.67 (s, 3H), 2.48−2.42 (m, 1 H). LCMS (M+H):515.35.
1 H NMR (CDCl3, 300MHz): δ 8.48 (s, 1 H), 8.42 (s, 1 H), 8.13 (s, 1 H), 7.78 (dd, J = 1.2 Hz および 7.2 Hz, 1 H), 7.61−7.58 (m, 1 H), 7.43 (t, J = 7.2 Hz, 1 H), 7.34−7.28 (m, 6H), 5.66 (brs, 1 H), 4.36−4.32 (m, 1 H), 4.00 (s, 3H), 3.52−3.50 (m, 3H), 3.38−3.26 (m, 1 H),3.26 (s, 3H), 3.22−3.19 (m, 1 H), 2.92−2.82 (m, 2H), 2.76−2.70 (m, 1 H), 2.67 (s, 3H), 2.57−2.50 (m, 1 H). LCMS (m+H): 485.30.
1 H NMR: (CD3OD, 300MHz): δ 8.73 (d, J = 2.4 Hz, 1 H), 8.39 (d, J = 2.1 Hz, 1 H), 7.93 (d, J = 8.4 Hz, 1H), 7.81 (d, J= 7.8 Hz, 1H), 7.63−7.50 (m, 2H), 7.35−7.31 (m, 1H), 7.25−7.16 (m, 2H), 4.39−4.32 ( m, 1H ), 3.58−3.54 (m, 2H), 3.37 (s, 3H), 3.27−3.22 (m, 3H), 3.13−3.07 (m, 1H), 2.85−2.72 (m, 2H), 2.66−2.61 (m, 1H). LCMS: M+H): 426.85.
1H NMR (DMSO−d6, 300MHz): δ 10.21 (br s, 1H), 8.93−8.85 (m, 1H), 7.96 (s, 1H), 7.78−7.69 (m, 3H), 7.41−7.32 (m, 7H), 6.82−6.80 (m, 1H), 4.56−4.54 (m, 1H), 3.93 (s, 1H), 3.75−3.67 (m, 3H), 3.49−3.47 (M, 4H), 3.34−3.31 (m, 4H). LCMS (M+H):390.10.
1H NMR (CD3OD 300 MHz):δ8.63 (s, 1H), 7.97 (d, J= 8.4 Hz, 1H), 7.87 (d, J= 8.1 Hz, 1H), 7.68−7.53 (m, 7H), 7.28−7.06 (m, 3H), 4.26−4.22 (m, 1H), 3.51 (t, J= 5.7 Hz, 2H), 3.31 (s, 3H), 3.29−3.05 (m, 3H), 2.79−2.73 (m, 3H), 2.67−2.54 (m, 1H). LCMS (M+H):502.50.
1H NMR (CD3OD, 300MHz): δ 8.85 (d, J= 1.5 Hz, 1H), 8.65 (dd, J= 1.2 Hz および 5.4Hz, 1H), 8.52 (s, 1H), 8.15−8.11 (m, 1H), 8.02 (d, J= 8.4 Hz, 1H), 7.91 (d, J= 8.1 Hz, 1H), 7.73−7.67 (m, 1H), 7.62−7.55 (m, 2H), 7.26−7.17 (m, 2H), 7.08−7.05 (m, 1H), 4.21−4.19 (m, 1H), 3.51 (t, J= 5.4 Hz, 2H), 3.30 (s, 3H), 3.21−3.15 (m, 1H), 3.10−2.94 (m, 2H), 2.76−2.65 (m, 3H), 2.58−2.52 (m, 1H). LCMS (M+H): 504.76.
1H NMR (CD3OD 300 MHz):δ8.49 (s, 1H), 7.89 (d, J= 8.4 Hz, 1H), 7.78 (d, J= 8.1 Hz, 1H), 7.62−7.57 (m, 1H ), 7.51−7.46 (m, 1H), 7.35−7.29 (m, 1H), 7.22−7.17 (m, 2H), 4.36−4.32 (m, 1H), 3.55 (t, J= 5.4 Hz, 2H), 3.36 (s, 3H), 3.22−3.17 (m, 3H), 3.13−3.07 (m, 1H), 2.84−2.73 (m, 3H), 2.63 (s, 3H). LCMS (M+H):440.90.
1H NMR (CD3OD 400 MHz):δ 8.25 (s, 1H), 7.34−7.29 (m, 1H), 7.22−7.14 ( m, 4H), 4.37−4.32 (m, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.55 (t, J= 5.2 Hz, 2H), 3.35 (s, 3H), 3.25−3.11 (m, 2H), 3.09−3.07 (m, 1H), 2.82−2.70 (m, 3H), 2.65−2.61 (m, 1H ), 2.55 (s, 3H). LCMS (M+H): 501.40.
1H NMR (CD3OD, 400MHz): δ 8.51 (d, J= 2.4 Hz, 1H), 8.23 (d, J= 2.4 Hz, 1H), 7.34−7.29 (m, 1H), 7.25 (s, 1H), 7.21−7.14 (m, 3H), 4.34−4.32 (m, 1H), 3.95 (s, 6H), 3.56 (t, J= 5.2 Hz, 2H), 3.37 (s, 3H), 3.27−3.19 (m, 2H), 3.09−3.06 (m, 1H), 2.85−2.72 (m, 3H), 2.63 (t, J= 8.8 Hz, 1H). LCMS (M+H): 487.40.
1H NMR (DMSO−d6, 300MHz): δ 8.86 (s, 1H), 8.71 (d, J= 2.7 Hz, 1H), 8.41 (d, J= 2.7 Hz, 1H), 7.88 (d, J= 7.8 Hz, 1H), 7.80 (d, J= 8.4 Hz, 1H), 7.57−7.47 (m, 2H), 7.40−7.32 (m, 1H), 7.19 (d, J= 7.8 Hz,2H), 7.07−7.02 (m, 1H), 6.82 (d, J= 8.1 Hz, 1H), 4.21−4.18 (m, 1H), 3.47 (t, J= 5.7 Hz, 2H), 3.26 (s, 3H), 3.22−3.15 (m, 2H), 3.00−2.94 (m, 1H), 2.72−2.64 (m, 3H), 2.50−2.49 (m, 1H). LCMS (M+H): 409.40.
1H NMR (DMSO−d6, 300MHz): δ 8.49 (s, 1H), 7.88 (d, J= 8.4 Hz, 1H), 7.78 (d, J= 8.4 Hz, 1H), 7.60 (t, J= 6.9 Hz, 1H), 7.49 (t, J= 7.5 Hz, 1H), 7.40−7.33 (m, 1H), 7.21−7.15 (m, 2H), 7.03−6.97 (m, 1H), 6.70−6.68 (d, J= 7.8 Hz, 1H), 6.61 (d, J= 7.8 Hz, 1H), 4.47−4.40 (m, 1H), 3.74−3.70 (m, 1H), 3.62 (t, J= 5.4 HZ, 2H), 3.55−3.42 (m, 1H), 3.38 (s, 3H), 3.34−3.30 (m, 1H), 3.26−3.18 (m, 1H), 3.12−2.88 (m, 3H), 2.62 (s, 3H). LCMS (M+H): 423.33.
1H NMR (CD3OD, 300MHz): δ 8.52 (s, 1H), 7.91−7.86 (m, 1H), 7.45−7.29 (m, 3H), 7.19−7.12 (m, 2H), 6.98−6.92 (m, 1H), 4.39−4.37 (m, 1H), 3.56 (t, J= 5.4 Hz, 2H), 3.36 (s, 3H), 3.31−3.22 (m, 2H), 3.12−3.06 (m, 1H), 2.87−2.64 (m, 4H), 2.62 (s, 3H). LCMS (M+H):441.05.
1H NMR (CD3OD, 400 MHz): δ8.49(s, 1H), 7.85−7.81 (m, 1H), 7.51 (dd, J=2.4 Hz および 10.0Hz, 1H), 7.36−7.30 (m, 2H), 7.19−7.12 (m, 2H), 6.99−6.94 (m, 1H), 4.39−4.37 (m, 1H), 3.56 (t, J= 5.2 Hz, 2H), 3.36 (s, 3H), 3.27−3.23 (m, 1H), 3.13−3.08 (m, 1H), 2.89−2.73 (m, 4H), 2.68−2.64 (m, 1H), 2.62 (s, 3H). LCMS (m+H): 441.37.
1H NMR (DMSO−d6 , 400MHz): δ 8.52 (s, 1H), 7.63−7.58 (m, 3H), 7.53−7.45 (m, 3H), 7.38−7.32 (m, 1H), 7.27 (d, J =7.2 Hz, 2H), 7.16−7.11 (m, 3H), 7.06−7.02 (m, 1H), 4.16−4.10 (m, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 3.44 (t, J= 5.6 Hz, 2H), 3.24 (s, 3H), 3.12−3.04 (m, 2H), 2.91−2.87 (m, 1H), 2.62−2.51 (m, 3H), 2.50−2.45 (m, 1H). LCMS (M+H): 545.30.
1H NMR (CD3OD, 400MHz): δ 8.37 (s, 1H), 7.57−7.48 (m, 5H), 7.34−7.29 (m, 1H), 7.24 (s, 1H), 7.14−7.04 (m, 3H), 6.98−6.94 (m, 1H), 6.11 (s, 2H), 4.24−4.22 (m, 1H), 3.51 (t, J= 6.0 Hz, 2H), 3.33 (s, 3H), 3.18−3.16 (m, 1H), 3.13−3.07 (m, 1H), 3.02−2.96 (m, 1H), 2.76−2.68 (m, 3H), 2.59−2.57 (m, 1H). LCMS (M+H): 529.29.
1H NMR (CD3OD, 300MHz): δ 8.23 (s, 1H), 7.37−7.29 (m, 1H), 7.18−7.11 (m, 3H), 7.06 (s, 1H), 6.99−6.93 (m, 1H), 6.08 (s, 2H), 4.40−4.34 (m, 1H), 3.55 (t, J = 5.7 Hz, 2H), 3.35 (s, 3H), 3.26−3.18 (m, 2H), 3.10−3.04 (m, 1H), 2.86−2.70 (m, 3H), 2.66−2.60 (m, 1H), 2.53 (s, 3H). LCMS (M+H): 467.30.
1H NMR (CD3OD, 400MHz): δ 8.72 (s, 1H), 8.38 (s, 1H), 7.91 (d, J= 8.4 Hz, 1H), 7.81−7.74 (m, 2H), 7.71 (d, J= 7.6 Hz, 1H), 7.61−7.58 (m, 2H), 7.55−7.49 (m, 2H), 4.41−4.38 (m, 1H), 3.58− 3.51(m, 2H), 3.49−3.45 (m, 1H), 3.39−3.35 (m, 3H), 3.15−3.11 (m, 1H), 2.84−2.68 (m, 5H). LCMS (M+H):416.00.
1H NMR (CD3OD, 300MHz): δ 8.38 (s, 1H), 7.67−7.59 (m, 5H), 7.54−7.47 (m, 4H), 7.33 (s, 1H), 7.23 (s, 1H), 4.25−4.23 (m, 1H), 3.98 (s, 3H), 3.96 (s, 3H), 3.57−3.50 (m, 2H), 3.37 (s, 3H), 3.25−3.09 (m, 3H), 2.78−2.59 (m, 4H). LCMS (M+H): 551.70.
1H NMR (CD3OD, 400MHz): δ 8.73 (d, J= 2.4 Hz, 1H), 8.54 (d, J= 2.0 Hz, 1H), 8.42 (dd, J = 1.6 Hz および 8.4Hz, 1H), 8.38 (d, J= 2.4 Hz, 1H), 7.94−7.90 (m, 2H), 7.80 (d, J= 7.6 Hz, 1H), 7.62−7.51 (m, 2H), 7.44−7.41 (m, 1H), 4.42−4.41 (m, 1H), 3.58 (t, J= 5.2 Hz, 2H), 3.38 (s, 3H), 3.35−3.31 (m, 2H), 3.21−3.16 (m, 1H), 2.92−2.73 (m, 4H). LCMS (M+H): 392.48.
1H NMR (CD3OD, 300MHz): δ8.46 (d, J= 1.5 Hz, 1H), 8.42 (d, J=4.8 Hz, 1H), 8.38 (s, 1H), 7.86−7.83 (m, 1H), 7.59−7.48 (m, 5H), 7.43−7.39 (m, 1H), 7.33 (s, 1H), 7.22 (s,1H), 4.29−4.27 (m, 1H), 3.97 (s, 3H), 3.96 (s, 3H), 3.54−3.51 (m, 2H), 3.34 (s, 3H), 3.24−3.15 (m, 1H), 3.13−3.03 (m, 2H), 2.82−2.62 (m, 4H). LCMS (M+H): 528.55.
1H NMR (CDCl3, 400MHz):δ8.79 (s, 1H), 8.50 (brs, 1H), 8.01 (d, J=8.0Hz, 1H),7.75 (d, J=8.4 Hz, 1H), 7.55−7.47 (m, 2H), 6.86−6.82 (m, 1H), 3.76−3.72 (m, 2H), 3.58−3.42 (m, 4H), 3.35 (s, 3H), 3.02−2.98 (m, 2H), 2.38−2.24 (m, 2H), 0.97 (s, 9H). LCMS (M+H): 371.34.
1 H NMR (CD3OD, 300MHz): δ 8.43 (s, 1 H), 7.60−7.57 (m, 2H), 7.54−7.48 (m, 4H), 7.38 (s, 1 H), 7.34 (s, 1 H), 7.24 (s, 1 H), 4.18−4.14 (m, 1 H), 3.98 (s, 3H), 3.96 (s, 3H), 3.84 (s, 3H), 3.51 (t, J = 5.4 Hz, 2H), 3.33 (s, 3H), 3.30−3.20 (m, 1 H), 3.07−2.90 (m, 2H), 2.77−2.71 (m, 3H), 2.52−2.49 (m, 1 H). LCMS (M+H): 538.41.
1 H NMR (CD3OD, 300MHz): δ 8.75 (d, J= 2.4 Hz, 1 H), 8.42 (d, J= 2.4 Hz, 1 H), 7.93 (d, J= 8.1 Hz, 1 H), 7.82 (d, J = 7.8 Hz, 1 H), 7.63−7.51 (m, 3H), 7.44 (s, 1 H), 4.28−4.26 (m, 1 H), 3.84 (s, 3H), 3.55 (t, J= 5.4 Hz, 2H), 3.36 (s, 3H), 3.22−3.16 (m, 1 H), 3.01−2.95 (m, 1 H), 2.88−2.73 (m, 4H), 2.52 (t, J= 9.0 Hz, 1 H). LCMS (M+H): 395.14.
1 H NMR (DMSO−d6 , 300MHz): δ 13.5 (s, 1 H), 9.19−9.17 (m, 1 H), 8.62 (dd, J = 8.1 および 1.8Hz, 1 H), 7.74−7.69 (m, 4H), 7.54−7.5 (m, 3H).
1 H NMR (DMSO−d6, 300MHz): δ 8.97−8.89 (m, 1 H), 8.75 (S, 1 H), 8.35 (dd, J = 1.2 Hz および 8.1 Hz, 1 H), 7.68−7.60 (m, 2H), 7.59−7.47 (m, 5H), 7.37−7.32 (m, 4H), 7.26−7.17 (m, 2H), 4.35−4.33 (m, 1 H), 3.55 (t, J= 5.4 Hz, 2H), 3.37−3.31 (m, 4H),3.22−3.14 (m, 2H), 2.95−2.84 (m, 3H), 2.77−2.70 (m, 1 H). LCMS (M+H): 468.1.
1 H NMR (DMSO−d6, 300MHz): δ 8.52 (s, 1 H), 7.62−7.57 (m, 3H), 7.53−7.48 (m, 3H), 7.32−7.22 (m, 7H), 7.12 (d, J = 7.5 Hz, 1 H), 4.22−4.18 (m, 1 H), 3.88 (s, 6H), 3.63 (s, 3H), 3.41−3.38 (m, 2H), 3.18−2.98 (m, 3H), 2.72−2.60 (m, 2H). LCMS (M+H)+: 540.71.
1 H NMR (DMSO−d6, 300MHz): δ 8.86 (s, 1 H), 8.71 (d, J= 2.4 Hz, 1H), 8.40 (d, J= 2.1 Hz, 1H), 7.88 (d, J= 7.8 Hz, 1H), 7.81 (d, J= 7.5 Hz, 1H), 7.55-7.49 (m, 2H), 7.37−7.30 (m, 4H), 7.24−7.22 (m, 1H), 6.81 (d, J= 7.8 Hz, 1H), 4.28−4.23 (m, 1H), 3.64 (s, 3H), 3.51−3.36 (m, 2H), 3.23−3.19 (m, 2H), 3.11−3.06 (m, 1H), 2.80−2.69 (m, 2H). LCMS (M+H): 405.29.
1H NMR (DMSO−d6, 300 MHz): δ 8.53 (s, 1H), 7.60−7.57 (m, 3H), 7.53−7.49 (m, 3H), 7.32−7.25 (m, 7H),7.14 (d, J= 7.5 Hz, 1H), 4.62 (t, J= 5.1 Hz, 1H), 4.46 (t, J= 4.8 Hz, 1H), 4.19− 4.15 (m, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 3.31−3.16 (m, 1H), 3.05−3.03 (m, 1H), 2.90−2.88 (m, 1H), 2.81−2.79 (m, 1H), 2.71−2.61 (m, 3H). LCMS (M+H):515.52.
1H NMR (DMSO−d6, 300MHz): δ 8.53 (s, 1H), 7.61−7.58 (m, 3H), 7.53−7.49 (m, 3H), 7.32−7.22 (m, 7H), 7.14−7.12 (m, 1H),4.62 (t, J=5.1 Hz, 1H), 4.46 (t, J=5.1 Hz, 1 H), 4.17−4.16 (m, 1H), 3.88 (s, 6H), 3.19−3.13 (m, 1H), 3.08−3.03 (m, 1H), 2.93−2.88 (m, 1H), 2.81−2.79 (m, 1H), 2.71−2.61 (m, 3H). LCMS (M+H): 514.76.
1H NMR (CD3OD, 300MHz): δ 8.64 (s, 1H), 7.96 (d, J= 8.4 Hz, 1H), 7.86 (d, J= 8.1 Hz, 1H), 7.67−7.52 (m, 7H), 7.31−7.30 (m, 4H), 7.25−7.22 (m, 1H), 4.63 (t, J= 4.8 Hz, 1H), 4.47 (t, J= 5.1 Hz, 1H), 4.32−4.30 (m, 1H), 3.24−3.21 (m, 1H), 3.15−3.04 (m, 2H), 2.91−2.77 (m, 3H), 2.63 (t, J= 9.0 Hz, 1H).SOR: −33.636°(C = 1, MeOH). LCMS (M+H):454.82.
1H NMR (CD3OD, 300MHz): δ 8.72 (d, J= 2.7 Hz, 1 H), 8.38 (d, J= 2.4 Hz, 1H), 7.92 (d, J= 8.4 Hz, 1H), 7.80 (d, J= 8.4 Hz, 1H), 7.62−7.50 (m, 2H), 7.38−7.29 (m, 4H), 7.24−7.20 (m, 1 H), 4.68 (t, J= 4.8 Hz, 1 H), 4.52 (t, J= 5.1 Hz, 1H), 4.45−4.38 (m, 1H), 3.38−3.35 (m, 1H), 3.26−3.20 (m, 1H), 3.13−3.07 (m, 1H), 2.97−2.81 (m, 3H), 2.67 (t, J= 8.7 Hz, 1H).SOR: −28.000° (C= 1, MeOH). LCMS (m+H): 379.76.
1 H NMR (DMSO−d6 , 300MHz): δ 8.49 (s, 1H), 7.61−7.57 (m, 3H), 7.51−7.47 (m, 3H), 7.33−7.23 (m, 7H), 7.09 (d, J= 7.8 Hz, 1H), 4.24−4.20 (m, 1H), 3.88 (s, 6H), 3.37−3.32 (m, 1H), 3.31−3.22 (m, 2H), 3.14−3.09 (m, 2H), 2.77−2.70 (m, 2H). LCMS (M+H): 550.73.
1 H NMR (DMSO−d6 , 300MHz): δ 8.50 (s, 1H), 7.61−7.57 (m, 3H), 7.51−7.47 (m, 3H), 7.33−7.23 (m, 7H), 7.09 (d, J= 7.5 Hz, 1H), 4.24−4.20 (m, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 3.37−3.34 (m, 1H), 3.28−3.23 (m, 2H), 3.14−3.09 (m, 2H) 2.77−2.70 (m, 2H). LCMS (M+H): 551.53.
1H NMR (DMSO−d6, 300MHz): δ 8.85 (s, 1H), 8.71 (d, J= 2.4 Hz, 1H), 8.40 (d, J= 2.7 Hz, 1H), 7.88 (d, J= 7.8 Hz, 1H), 7.81 (d, J= 7.8 Hz, 1H), 7.56−7.47 (m, 2H), 7.37−7.30 (m, 4H), 7.26 −7.21 (m, 1H), 6.81 (d, J= 7.8 Hz, 1H), 4.31 − 4.22 (m, 1H), 3.46 - 3.33 (m, 2H), 3.28 −3.16 (m, 3H), 2.86 − 2.72 (m, 2H). LCMS (M+H):415.35.
1H NMR (CD3OD, 400MHz): δ 8.40 (s, 1H), 7.56−7.48 (m, 5H), 7.33−7.30 (m, 5H), 7.28−7.21 (m, 2H), 6.08−5.80 (m, 1H), 4.30−4.27 (m, 1H), 3.97 (s, 3H), 3.95 (s, 3H), 3.26−3.21 (m, 1H), 3.11−3.06 (m, 2H), 2.97−2.65 (m, 4H). LCMS (M+H): 533.79.
1H NMR (DMSO−d6 , 400MHz): δ 8.85 (s, 1H), 8.71 (d, J= 2.4 Hz, 1H), 8.40 (d, J= 2.4 Hz, 1H), 7.88 (d, J= 7.6 Hz, 1H), 7.82 (dd, J = 1.2 Hz および 8.0Hz, 1H), 7.56−7.48 (m, 2H), 7.36−7.30 (m, 4H), 7.25 − 7.20 (m, 1H), 6.82 (d, J= 8.0 Hz, 1H), 6.29−6.60 (m, 1H), 4.27−4.20 (m, 1H), 3.26−3.16 (m, 2H), 3.10 −3.03 (m, 1H), 3.01−2.83 (m, 2H), 2.79−2.75 (m, 1H), 2.68 −2.64(m, 1H). LCMS (M+H): 397.45.
1H NMR (DMSO−d6, 400MHz): δ 8.46 (br s, 1H), 7.65−7.62 (m, 1H), 7.56−7.54 (m, 2H), 7.46−7.45 (m, 3H), 7.35 − 7.27 (m, 7H), 7.00−6.95 (m, 1H), 4.37 − 4.28 (m, 1H), 4.03 (s, 2H), 3.90 (s, 6H), 3.85−3.80 (m, 2H), 3.37 −3.35 (m, 1H), 3.31 (s, 3H), 3.20 −3.17 (m, 1H), 3.13−3.10 (m, 1H). LCMS (M+H):540.78.
1H NMR (DMSO−d6 , 400MHz): δ 8.91 (d, J= 9.2 Hz, 1H), 8.71−8.69 (m, 1H), 8.41 (brs, 1H),7.88 (d, J=8.4 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.57−7.49 (m, 2H), 7.40−7.35 (m, 4H), 7.28−7.25 (m, 1H), 6.78−6.72 (m, 1 H), 4.44−4.34 (m, 1 H), 4.05 (s, 2H), 3.99−3.89 (m, 2H), 3.88−3.46 (m, 1 H), 3.36−3.35 (m, 1H), 3.32 (s, 3H), 3.28−3.17 (m, 1H). LCMS (M+H):405.50.
1H NMR (DMSO−d6, 300MHz): δ 8.51 (s, 1H), 7.62−7.58 (m, 3H), 7.53−7.47 (m, 3H), 7.33−7.31 (m, 4H), 7.28−7.22 (m, 3H), 7.14 (d, J= 7.8 Hz, 1H), 4.59 (t, J= 6.3 Hz, 2H), 4.50−4.45 (m, 2H), 4.20−4.18 (m, 1H), 3.88 (s, 6H), 3.66−3.62 (m, 1H), 3.12−3.06 (m, 2H), 2.88−2.82 (m, 1H), 2.55−2.53 (m, 1H), 2.45−2.41 (m, 1H). LCMS (M+H):524.53.
1H NMR (DMSO−d6, 300MHz): δ 8.50 (br s, 1H), 7.61−7.58 (m, 3H), 7.51−7.48 (m, 3H), 7.33−7.31 (m, 4H), 7.28 (d, J= 6.0 Hz, 2H), 7.25−7.21 (m, 2H), 7.10−7.07 (m, 2H), 4.20−4.18 (m, 1H), 3.88 (s, 6H), 3.15−2.97 (m, 5H), 2.60−2.57 (m, 2H). LCMS (M+H):526.54.
1H NMR (DMSO−d6, 400MHz): δ 8.52 (br s, 1H), 7.62−7.58 (m, 3H), 7.58−7.45 (m, 3H), 7.35−7.22 (m, 7H), 7.15 (d, J= 7.2 Hz, 1H), 4.23−4.19 (m, 1H), 3.88 (s, 6H), 3.40−3.31 (m, 1H), 3.17−3.08 (m, 3H), 3.05−3.01 (m, 1H) 2.63−2.45(m, 2H). LCMS (M+H):508.57.
1H NMR (DMSO−d6 , 400MHz): δ 8.85 (brs, 1H), 8.71(d, J = 2.4 Hz, 1 H ), 8.40 (d, J= 2.4 Hz, 1 H), 7.88 (d, J= 8.4 Hz, 1 H), 7.82 (dd, 1.2 Hz および 8.0 Hz, 1 H), 7.56−7.48 (m, 2H), 7.34−7.32 (m, 4H), 7.26−7.22 (m, 1 H), 6.88 (d, J= 8.0 Hz, 1 H), 4.23−4.19 (m, 1 H), 3.90 (s, 2H), 3.31−3.17 (m, 2H), 3.13−3.09 (m, 1 H), 2.70 − 2.64 (m, 2H). LCMS (M+H):371.76.
1 H NMR (DMSO−d6 400 MHz):δ 8.85 (br s, 1 H), 8.72 (d, J= 2.8 Hz, 1 H ), 8.40 (d, J= 2.4 Hz, 1 H), 7.88 (d, J= 8.0 Hz, 1 H), 7.81 (d, 8.0 Hz, 1 H), 7.54−7.50 (m, 2H), 7.37−7.22 (m, 6H), 7.16 (br s, 1 H), 6.85 (d, J = 8.0 Hz, 1 H), 4.25−4.24 (m, 1 H), 3.31−3.12 (m, 3H), 3.05−3.00 (m, 2H), 2.73−2.64 (m, 1 H) 2.61−2.55 (m, 1 H). LCMS (M+H): 389.87.
1 H NMR (CD3OD, 400MHz): δ 8.74 (d, J= 3.2 Hz, 1 H), 8.40 (d, J= 2.4 Hz, 1 H), 7.92 (d, J= 8.0 Hz, 1 H), 7.80 (d, J= 8.4 Hz, 1 H), 7.62−7.58 (m, 1 H), 7.55−7.51 (m, 1 H), 7.43−7.41 (m, 2H), 7.37−7.33 (m, 2H), 7.29−7.25 (m, 1 H), 4.71 (d, J = 10.8 Hz, 1 H), 3.84−3.82 (m, 1 H), 3.73−3.46 (m, 6H), 3.38 (s, 3H). LCMS (M+H): 405.2.
1H NMR (CDCI3, 300MHz): δ 8.01 (d, J= 8.1 Hz, 1H), 7.93 (d, J = 7.2 Hz, 1H), 7.61 (d, J= 8.1 Hz, 1H), 7.51 (d, J= 8.1 Hz, 1H), 7.44 (dt, J= 1.2 および 8.4Hz, 1H), 7.36 (d, J= 8.4 Hz, 1H), 7.31−7.25 (m, 5H), 7.22−7.20 (m, 1H), 5.35 (d, J= 7.8 Hz, 1H), 4.36−4.32 (m, 1H), 3.52 (t, J= 6.0 Hz, 2H), 3.49−3.46 (m, 1H), 3.38−3.33 (m, 1H), 3.30 (s, 3H), 3.14−3.11 (m, 1H), 2.92−2.70 (m, 3H), 2.46 (t, J = 9.0 Hz, 1 H). (M+H): 430.35.
1H NMR (DMSO−d6, 300MHz): δ 8.68 (br s, 1H), 8.10 (t, J= 7.5 Hz, 2H), 7.70 (d, J= 6.6 Hz, 1H), 7.66 (dd, J= 1.2 および 7.8 Hz, 1H), 7.53 (dt, J= 1.2 および 7.8 Hz, 1H), 7.42 (d, J= 7.2 Hz, 1H),7.40−7.32 (m, 1H), 7.26 (d, J=7.8 Hz, 1H), 7.21−7.17 (m, 3H), 7.09−7.01 (m, 1H), 4.22−4.16 (m, 1H), 3.47 (t, J= 6.0 Hz, 2H), 3.26 (s, 3H), 3.16−3.11 (m, 2H), 2.98 (t, J= 7.5 Hz, 1H), 2.74−2.60 (m, 4H). LCMS (M+H):448.24.
1H NMR (CD3OD, 300MHz): δ 7.71 (s, 1H), 7.43 (d, J= 8.4 Hz, 1H), 7.39−7.22 (m, 9H), 4.48−4.40 (m, 1H), 3.95−3.90 (m, 1H), 3.54 (t, J= 5.4 Hz, 2H), 3.34 (s, 3H), 3.25−3.20 (m, 1H), 3.10−3.05 (m, 1H), 2.98−2.92 (m, 1H), 2.85−2.75 (m, 2H), 2.61 (t, J=9.0HZ, 1H),2.41 (s, 3H). LCMS (M+H):444.26.
1H NMR (CD3OD, 300MHz): δ 7.46 (d, J= 9.0 Hz, 1H), 7.40−7.35 (m, 3H), 7.31−7.22 (m, 6H), 7.06 (dd, J= 3.0 および 9.0Hz, 1H), 4.46−4.42 (m, 1H), 3.72 (s, 3H), 3.54 (t, J= 5.4 Hz, 2H), 3.38−3.36 (m, 1H), 3.34 (s, 3H), 3.24−3.20 (m, 1H), 3.12−3.07 (m, 1H), 3.02−2.96 (m, 1H), 2.87−2.80 (m, 2H), 2.63 (t, J= 9.0 Hz, 1H). LCMS (M+H): 460.28.
1H NMR (CDCl3, 300MHz): δ 7.58 (dd, J= 2.7 および 8.4 Hz, 1H), 7.46−7.29 (m, 5H), 7.25−7.18 (m, 5H), 7.10 (dt, J =2.1 および 9.0 Hz, 1H), 5.71 (brs, 1H), 4.45−4.35 (m, 1H), 3.40 (t, J= 5.4 Hz, 2H), 3.37−3.33 (m, 1H), 3.21 (s, 3H), 3.20−3.19 (m, 1H), 3.07 (d, J= 10.2 Hz, 1H), 2.83 (t, J= 7.5 Hz, 1 H), 2.73−2.59 (m, 2H), 2.37 (t, J= 9.6 Hz, 1 H). LCMS (M+H):448.25.
1H NMR (CD3OD, 400MHz): δ 7.66 (d, J= 8.8 Hz, 1H), 7.36−7.22 (m, 8H), 7.13 (d, J= 2.0 Hz, 1H), 6.82 (dd, J = 2.4 および 8.8 Hz, 1H), 4.50−4.40 (m, 1H), 3.88 (s, 3H), 3.53 (t, J= 5.2 Hz, 2H), 3.34 (s, 3H), 3.22−3.18 (m, 1H), 3.03 (t, J= 7.6 Hz, 1H), 2.91−2.87 (m, 1H), 2.80−2.72 (m, 3H), 2.58 (t, J= 9.2 Hz, 1H). LCMS (M+H):460.28.
1H NMR (DMSO−d6, 300MHz): δ 8.24 (brs, 1H), 8.14−8.09 (m, 1H), 7.68−7.63 (m, 2H), 7.40−7.28 (m, 7H), 7.25−7.20 (m, 2H), 4.32−4.20 (m, 1H), 3.48 (t, J= 5.7 Hz, 2H), 3.26 (s, 3H), 3.22−3.13 (m, 2H), 3.00−2.90 (m, 1 H), 2.80−2.60 (m, 3H), 2.43−2.40 (m, 1 H). LCMS (M+H): 448.29.
1H NMR (DMSO−d6, 400MHz): δ 8.32 (d, J= 6.8 Hz, 2H), 8.01 (d, J= 7.2 Hz, 1H), 7.78−7.76 (m, 1H), 7.50 (t, J =7.2 Hz, 1H), 7.45−7.41 (m, 3H), 7.36−7.29 (m, 4H), 7.23−7.20 (m, 1H), 7.07 (d, J = 7.6 Hz, 1H), 4.25−4.16 (m, 1H), 3.47 (t, J = 6.0 Hz, 2H), 3.26 (s, 3H), 3.19− 3.15(m, 2H), 2.93 (t, J= 7.6 Hz, 1H), 2.72−2.60 (m, 3H), 2.54−2.50 (m, 1H). LCMS (M+H): 446.20.
1H NMR (CDCI3, 300MHz): δ 8.07−8.04 (m, 1 H), 7.82−7.79 (m, 1 H), 7.66 (t, J= 7.5 Hz, 2H), 7.48−7.42 (m, 3H), 7.34−7.28 (m, 2H), 7.23−7.20 (m, 3H), 7.05−7.01 (m, 1H), 6.40 (brs, 1H), 4.50−4.35 (m, 1H), 3.56 (t, J= 8.1 Hz, 2H), 3.48−3.44 (m, 2H), 3.35−3.32 (m, 1H), 3.22 (s, 3H), 2.95 (t, J= 7.8 Hz, 1H), 2.81−2.77 (m, 2H), 2.56 (t, J= 9.6 Hz, 1H). LCMS (M+H):478.13.
1H NMR (DMSO−d6 300 MHz):δ 8.29 (d, J= 8.1 Hz, 1H), 8.12 (br s, 1H), 8.02 (d, J= 7.8 Hz, 1H), 7.50 (t, J= 7.2 Hz, 1H), 7.39 (t, J= 7.2 Hz, 1H), 7.32−7.19 (m, 6H), 7.06 (d, J = 8.4 Hz, 1H), 6.84 (d, J= 8.1 Hz, 1H), 4.25−4.15 (m, 1H), 3.97 (s, 3H), 3.46 (t, J = 6.0 Hz, 2H), 3.25 (s, 3H), 3.21−3.11 (m, 2H), 2.93−2.89 (m, 2H), 2.67−2.57 (m, 3H). LCMS (M+H): 476.15.
1H NMR (DMSO−d6, 300MHz):δ8.16(brs, 1H), 7.98 ( d, J=8.1 Hz, 1H), 7.91−7.88 (m, 1H), 7.63−7.61 (m, 2H), 7.50 (d, J= 8.7 Hz, 1H), 7.32−7.28 (m, 4H), 7.23 (d,J= 9.0 Hz, 2H), 7.01 (d, J= 7.8 Hz, 1H), 4.20−4.10 (m, 1H), 3.95 (s, 3H), 3.46 (t, J = 5.1 HZ, 2H), 3.25 (s, 3H), 3.18−3.14 (m, 2H), 2.96−2.85 (m, 1H), 2.70−2.62 (m, 3H), 2.58−2.54 (m, 1H). LCMS (M+H): 508.26.
1H NMR (DMSO−d6, 300MHz): δ 8.13 (brs, 1H), 7.73−7.54 (m, 4H), 7.38−7.21 (m, 9H), 4.22−4.18 (m, 1H), 3.47 (t, J= 6.0 Hz, 2H), 3.26 (s, 3H), 3.21−3.15 (m, 2H), 2.95−2.89 (m, 1H), 2.72−2.61 (m, 3H), 2.43−2.41 (m, 1H). LCMS (M+H): 442.21.
1H NMR (CD3OD, 400MHz): δ7.46 (d, J= 8.0 Hz, 1H), 7.42 (d, J= 8.4 Hz, 1H), 7.40−7.30 (m, 6H), 7.26−7.23 (m, 1H), 7.19 (t, J= 8.8 Hz, 1H), 7.08 (d, J= 7.2 Hz, 1H), 4.46−4.43 (m, 1H), 4.02 (s, 3H), 3.54 (t, J= 5.2 Hz, 2H), 3.38−3.36 (m, 1H), 3.35 (s, 3H), 3.26−3.22 (m, 1H), 3.07 (t, J= 8.4 Hz, 1H), 2.95−2.91 (m, 1H), 2.85−2.76 (m, 2H), 2.63 (t, J= 9.2 Hz, 1H). LCMS (M+H): 460.24.
1H NMR (CD3OD, 300MHz): δ 7.71 ( s, 1H), 7.43 (d, J= 8.4 Hz, 1H), 7.39−7.20 (m, 9H), 4.48−4.40 (m, 1H), 3.54 (t, J= 5.4 Hz, 2H), 3.38−3.36 (m, 1H), 3.34 (s, 3H), 3.25−3.20 (m, 1H), 3.08−3.03 (m, 1H), 2.95−2.92 (m, 1H), 2.80−2.74 (m, 2H), 2.59 (t, J= 9.3 Hz, 1H), 2.41 (s, 3H). LCMS (M+H: 444.21.
1H NMR (CD3OD, 300MHz): δ 8.46 (s, 1H), 7.70 (br s, 1H), 7.56−7.49 (m, 5H), 7.31−7.30 (m, 5H), 7.16 (s, 1H), 4.36−4.30 (m, 1H), 3.97 (s, 3H), 3.52 (t, J= 4.8 Hz, 2H), 3.31 (s, 3H), 3.12 − 3.02 (m, 2H), 2.82−2.74 (m, 5H), 2.36 (s, 3H). LCMS (M+H):511.39.
1H NMR (DMSOd6, 400 MHz): δ 8.85 (s, 1H), 8.60 (d, J=7.6Hz, 1H), 8.13 (s, 1H), 7.84 (d, J= 10.8 Hz, 1H), 7.63−7.52 (m, 1H), 7.38−7.30 ( m, 5H), 7.24−7.21 (m, 1H), 4.25−4.22 (m, 1H), 3.47 (t, J= 6.0 Hz, 2H), 3.26 (s, 3H), 3.23−3.22 (m, 2H), 3.12−3.10 (m, 1H), 2.93−2.90 (m, 1H), 2.72−2.66 (m, 2H), 2.64 (s, 3H), 2.44−2.43 (m, 1H). LCMS (M+H):448.21.
1H NMR (DMSOd6, 400 MHz): δ 8.67 (s, 1H), 8.39 (s, 1H), 8.03 (s, 1H), 7.43 (s, 1H), 7.35−7.22 (m, 6H), 4.25−4.22 (m, 1H), 3.98 (s, 3H), 3.47 (t, J= 6.4 HZ, 2H), 3.26 (s, 3H), 3.23− 3.21 (m, 1H), 3.14−3.10 (m, 1H), 2.94−2.88 (m, 1H), 2.75 − 2.65 (m, 3H), 2.59 (s, 3H), 2.50−2.49 (m, 1H). LCMS (M+H): 460.25.
1H NMR (CD3OD, 400MHz): δ 8.73 (s, 1H), 8.26 (d, J= 6.0 Hz, 1H), 7.66 (d, J= 9.6 Hz, 1H), 7.38−7.31 (m, 4H), 7.25−7.23 (m, 1 H), 4.42−4.40 (m, 1H), 3.58 (t, J= 6.4 Hz, 2H), 3.37 (s, 3H), 3.26−3.21 (m, 2H), 3.18−3.13 (m, 1H), 2.98−2.94 (m, 1H), 2.90−2.78 (m, 2H), 2.73 − 2.68 (m, 1 H), 2.65 (s, 3H). LCMS (M+H): 448.29.
1H NMR (CD3OD, 400MHz): δ 8.85 (s, 1H), 8.37 (d, J= 6.0 Hz, 1H), 7.75 (d, J= 10.0 Hz, 1H), 7.62−7.56 (m, 5H), 7.34−7.30 (m, 4H), 7.24−7.20 (m, 1 H), 4.40−4.38 (m, 1 H), 3.53 (t, J= 5.6 Hz, 2H), 3.31 (s, 3H), 3.13−3.05 (m, 2H), 2.84−2.71 (m, 4H), 2.62−2.60 (m, 1H). LCMS (M+H): 510.30.
1H NMR (CD3OD, 400MHz): δ 8.75 (s, 1H), 8.22 (s, 1H), 7.59−7.54 (m, 5H), 7.39 (s, 1H), 7.31−7.30 (m, 4H), 7.24−7.21 (m, 1H), 4.38−4.36 (m, 1H), 4.05 (s, 3H), 3.53 (t, J= 6.0 Hz, 2H), 3.33 (s, 3H), 3.15−3.07 (m, 2H), 2.84−2.74 (m, 4H), 2.62−2.60 (m, 1H). LCMS (M+H): 522.30.
1H NMR (CD3OD, 400MHz) : δ 9.08 (s, 1H), 8.49 (s, 1H), 8.31 (s, 1H), 8.01 (d, J= 8.8 Hz, 1H), 7.86 (d, J= 8.0 Hz, 1 H), 7.73−7.68 (m, 1 H), 7.58−7.54 (m, 1 H), 7.32−7.24 (m, 4H), 7.23−7.21 (m, 1 H), 4.40−4.35 (m, 1H), 3.54 (t, J= 5.6 Hz, 2H), 3.38−3.35 (m, 1H), 3.35 (s, 3H), 3.24−3.13 (m, 1H), 3.12−3.06 (m, 1H), 2.93−2.77 (m, 3H), 2.69−2.64 (m, 1H). LCMS (M+H): 474.37.
1H NMR (CDCI3, 400MHz): δ 7.94 (s, 1H), 7.52 (s, 1H), 7.50 (s, 1H), 7.44 (t, J= 7.2 Hz, 2H), 7.39 (d, J = 6.8 Hz, 1 H), 7.32−7.29 (m, 2H), 7.22−7.21 (m,. 3H), 5.32 (br s, 1 H), 4.28 (brs, 1 H), 3.48 −3.44 (m, 2H), 3.31−3.30 (m, 1 H), 3.28 (s, 3H), 3.20−3.18 (m, 1 H), 3.04−3.02 (m, 1 H), 2.90 (t, J = 6.4 Hz, 2H), 2.82−2.61 (m, 5H), 2.35−2.33 (m, 1 H), 1.89−1.88 (m, 2H), 1.82−1.80 (m, 2H). LCMS (M+H): 471.33.
1 H NMR (CDCl3 , 400MHz): δ 9.20 (br s, 1 H), 8.71 (s, 1 H), 8.06 (d, J = 8.4 Hz, 1 H), 7.80 (d, J = 8.4 Hz, 1 H), 7.74 (d, J = 7.2 Hz, 2H), 7.60 (t, J = 6.8 Hz, 1 H), 7.53−7.42 (m, 4H), 7.34−7.30 (m, 2H), 7.24−7.19 (m, 2H), 4.28−4.25 (m, 1 H), 3.50 (br s, 1 H), 3.34−3.17 (m, 4H), 2.98 (s, 3H), 2.93 (s, 3H), 2.76−2.74 (m, 1 H), 2.57−2.49 (m, 2H), 2.25−2.22 (m, 1 H), 2.13 (t, J = 10.0 Hz, 1 H). LCMS (M+H):481.47.
1 H NMR (CD3OD, 300MHz): δ 8.33 (s, 1 H), 7.49 (s, 1 H), 7.37−7.33 (m, 5H), 7.28−7.25 (m, 1 H), 7.10−6.66 (m, 1 H), 4.40−4.39 (m, 1 H), 3.99 (s, 3H), 3.57 (t, J= 5.4 Hz, 2H), 3.38−3.37 (m, 1 H), 3.36 (s, 3H), 3.26−3.23 (m, 1 H), 3.13−3.10 (m, 1 H), 2.98−2.82 (m, 3H), 2.72−2.69 (m, 1 H), 2.58 (s, 3H). LCMS (M+H):501.25
1H NMR (CDCl3, 400MHz): δ 8.48 (s, 1 H), 7.50 (s, 1 H), 7.35−7.31 (m, 5H), 7.25−7.23 (m, 2H), 5.79−5.78 (m, 1 H), 4.26−4.24 (m, 1 H), 3.53−3.50 (m, 4H), 3.22−3.20 (m, 1 H), 3.19 (s,3H), 2.86−2.80 (m,2H), 2.70−2.64 (m, 1 H), 2.57 (s, 3H), 2.45−2.40 (m, 1 H). LCMS (M+H):485.01.
1 H NMR (CD3OD, 400MHz): δ 8.39 (s, 1 H), 7.36−7.20 (m, 6H), 7.12 (s, 1 H), 6.96−6.69(m, 1 H), 6.13 (s, 2H), 4.37−4.34 (m, 1 H), 3.55 (t, J = 4.4 Hz, 2H), 3.35 (s, 3H), 3.24−3.18 (m, 2H), 3.07−3.03 (m, 1 H), 2.88−2.86 (m, 1 H), 2.85−2.70 (m, 2H), 2.65−2.60 (m, 1 H). LCMS (M+H): 484.94.
1 H NMR (CDCl3, 400MHz): δ 8.46 (s, 1 H), 8.39 (s, 1 H), 7.35−7.32 (m, 2H), 7.29−7.26 (m, 5H), 6.99 (s, 1 H), 6.07 (s, 2H), 5.48−5.46 (m, 1 H), 4.15−4.12 (m, 1 H), 3.59−3.56 (m, 3H), 3.45−3.42 (m, 1 H), 3.32 (s, 3H), 3.26−3.23 (m, 1 H), 2.89−2.84 (m, 2H), 2.79−2.74 (m, 1 H), 2.49− 2.45 (m, 1 H). LCMS (M+H):435.39.
1 H NMR (CD3OD, 400MHz): δ 8.25 (s, 1 H), 7.96 (d, J= 8.4 Hz, 1 H), 7.75 (d, J= 7.2 Hz, 1 H), 7.60 (t, J= 7.2 Hz 1 H),7.46 (t, J= 7.2 Hz, 1 H), 7.37−7.29 (m, 4H), 7.25−7.22 (m, 1 H), 4.40−4.39 (m, 1 H), 3.56 (t, J= 5.6 Hz, 2H), 3.35 (s, 3H), 3.12−3.05 (m, 2H), 3.02−2.96 (m, 1 H), 2.84−2.77 (m, 3H), 2.70−2.69 (m, 1 H), 2.66 (t, J = 8.8 Hz, 1 H), 1.86−1.73 (m, 7H), 1.48−1.35 (m, 3H). LCMS (M+H): 473.45.
1 H NMR (CDCl3, 400MHz): δ 8.57 (s, 1 H), 7.35−7.30 (m, 5H), 7.24−7.22 (m, 1 H), 7.02 (s, 1 H), 6.12 (s, 2H), 5.68−5.66 (m, 1 H), 4.35−4.30 (m, 1 H), 3.53−3.49 (m, 3H), 3.39−3.27 (m, 1 H) 3.26 (s, 3H), 3.18−3.16 (m, 1 H), 2.88−2.69 (m, 3H), 2.46−2.42 (m, 1 H). LCMS (M+H): 503.35.
1 H NMR (DMSO−d6, 300MHz): δ 8.58 (s, 1 H), 8.00 (s, 1 H), 7.45−7.31 (m, 4H), 7.21−7.17 (m, 2H), 7.07−7.02 (m, 2H), 6.21 (s, 2H), 4.19−4.16 (m, 1 H), 3.46 (t, J= 5.7 Hz, 2H), 3.25 (s, 3H), 3.16−3.14 (m, 2H), 2.98−2.92 (m, 1 H), 2.72−2.63 (m, 4H). LCMS (M+H):503.35.
1 H NMR (CDCl3,400 MHz): δ 8.51 (s, 1 H), 8.36 (s, 1 H), 7.29 (s, 1 H), 7.14−7.08 (m, 2H), 7.07 −7.00 (m, 2H), 6.07 (s, 2H), 5.48−5.46 (m, 1 H), 4.15−4.12 (m, 1 H), 3.59−3.56 (m, 2H), 3.45−3.42 (m, 2H), 3.34 (s, 3H), 3.26−3.23 (m, 1 H), 2.91−2.86 (m, 2H), 2.82−2.78 (m, 1 H), 2.49−2.44 (m, 1 H). LCMS (M+H): 471.34.
1 HNMR (CD3OD, 300 MHz):8.65 (s, 1 H), 8.00−7.95 (m, 1 H), 7.61−7.41 (m, 7H), 7.35−7.28 (m, 1 H), 7.13−7.05 (m, 2H), 6.99−6.93 (m, 1 H), 4.32−4.26 (m, 1 H), 3.54 (t, J= 5.7 Hz, 2H),3.32 (s, 3H), 3.23−3.00 (m, 3H), 2.79−2.58 (m, 4H). LCMS (M+H): 503.48.
1 HNMR (CD3OD, 300 MHz):7.77 (s, 1 H), 7.48−7.41 (m, 5H), 7.35−7.28 (m, 1 H), 7.10−7.03 (m, 2H), 6.98−6.92 (m, 1 H), 4.27−4.22 (m, 1 H), 3.53 (t, J= 5.7 Hz, 2H),3.33 (s, 3H), 3.24−3.18 (m, 1 H), 3.12−2.97 (m, 2H), 2.85−2.71 (m, 7H), 2.67−2.57 (m, 1 H), 1.90−1.82 (m, 4H). LCMS (M+H): 489.48.
1 HNMR (CDCl3 , 300 MHz):δ 8.89−8.88 (m, 1 H), 8.05 (d, J = 8.1 Hz, 1 H), 7.74 (d, J = 6.0 Hz, 2H), 7.54−7.47 (m, 3H), 7.35−7.30 (m, 3H), 7.26−7.24 (m, 3H), 4.30−4.28 (m, 1 H), 3.48−3.44 (m, 2H), 3.33 − 3.28 (m, 1 H), 3.24 (s, 3H), 3.22−3.13 (m, 2H), 2.76 (s, 3H), 2.54−2.50 (m, 3H), 2.48−2.30 (m, 1 H). LCMS (M+H): 482.46.
1 HNMR (CDCl3, 400 MHz):δ 8.85 (s, 1 H), 8.05 (d, J = 8.8 Hz, 1 H), 7.81 (d, J = 8.0 Hz, 1 H), 7.64−7.49 (m, 7H), 7.30−7.26 (m, 1 H), 7.04 (d, J = 8.0 Hz, 1 H), 6.97−6.90 (m, 2H), 5.22−5.21 (m, 1 H), 4.26−4.24 (m, 1 H), 3.47−3.37 (m, 2H), 3.26 (s, 3H), 3.20−3.15 (m, 2H) 3.01−2.98 (m, 1 H), 2.73−2.65 (m, 2H), 2.59−2.56 (m, 1 H), 2.31−2.37 (m, 1 H). LCMS (M+H): 485.47.
1 HNMR (CDCl3, 300MHz): δ8.49 (s, 1H), 8.38 (s, 1H), 7.32−7.27 (m, 3H), 7.07 (d, J= 7.5 Hz, 1H), 6.97−6.92 (m, 3H), 6.07 (s, 2H), 5.48−5.46 (m, 1H), 4.18−4.15 (m, 1H), 3.58−3.52 (m, 3H), 3.42−3.40 (m, 1H), 3.33 (s, 3H), 3.21−3.18 (m, 1H), 2.87−2.72 (m, 3H), 2.45−2.39 (m, 1H). LCMS (M+H): 453.38.
1HNMR (CDCl3, 400 MHz):δ 8.70 (s, 1H), 8.05 (d, J= 8.8 Hz, 1H), 7.82 (d, J= 7.6 Hz, 1H), 7.65−7.51 (m, 3H), 7.34−7.30 (m, 2H), 7.26−7.22 (m, 4H), 7.08−7.04 (m, 1 H), 6.99−6.94 (m, 1 H), 5.32−5.29 (m, 1 H), 4.28−4.25 (m, 1 H), 3.45 (t, J= 4.8 Hz, 2H), 3.36−3.29 (m, 2H), 3.23 (s, 3H), 3.09−3.06 (m, 1H), 2.76−2.69 (m, 2H), 2.63−2.59 (m,1H), 2.36−2.32 (m, 1H). LCMS (M+H): 503.48.
1HNMR (CDCl3, 300 MHz):δ 8.75 (s, 1H), 8.05 (d, J= 8.4 Hz, 1H), 7.82 (d, J= 8.1 Hz, 1H), 7.65−7.60 (m, 1 H), 7.55−7.50 (m, 1 H), 7.35−7.30 (m, 8H), 6.96−6.90 (m, 1 H), 5.40−5.38 (m, 1 H), 4.19−4.16 (m, 1H), 3.38 (t, J= 5.4 Hz, 2H), 3.24−3.21 (m, 3H), 3.13 (s, 3H), 2.73−2.67 (m, 2H), 2.60−2.55 (m, 1H), 2.30−2.28 (m, 1H). LCMS (M+H): 502.99.
1H NMR (CD3OD, 300MHz): δ 8.29 (s, 1H), 7.38−7.25 (m, 5H), 7.17 (s, 1H), 7.09 (s, 1H), 6.09 (s, 2H), 4.70 (d, J= 10.4 Hz, 1H), 4.59 (d, J= 12.0 Hz, 1H), 4.28−4.25 (m, 1H), 3.98−3.94 (m, 1H), 3.52 (t, J= 5.4 Hz, 2H), 3.33 (s, 3H), 3.16−3.10 (m, 1H), 3.04−2.99 (m, 1H), 2.74−2.60 (m, 4H), 2.56 (s, 3H). LCMS (M+H)+:479.15.
1H NMR (CD3OD, 400MHz): δ 8.31 (d, J= 8.4 Hz, 1H), 7.87−7.85 (m, 1H), 7.80−7.77 (m, 1H), 7.72−7.68 (m, 1 H), 7.33−7.32 (m, 4H), 7.26−7.22 (m, 1 H), 4.45−4.41 (m, 1 H), 3.55−3.47 (m, 2H), 3.33 (s, 3H), 3.20−3.06 (m, 2H), 2.90−2.64 (m, 5H), 2.48 (s, 3H). LCMS 439.08.
1H NMR (CD3OD, 400MHz): δ 8.04(d, J= 8.4 Hz, 2H), 7.78 (t, J= 6.8 Hz, 1H), 7.68−7.67 (m, 4H), 7.62−7.54 (m, 5H), 7.38−7.24 (m, 7H), 4.40−4.36 (m, 1H), 3.50−3.47 (m, 2H), 3.30 (s, 3H), 3.25−3.24 (m, 1H), 2.80−2.68 (m, 5H), 2.50−2.48 (m, 1H). LCMS (M+H): 543.99.
1H NMR (CD3OD, 400MHz): δ 8.29 (d, J= 8.8 Hz, 1H), 8.12 (s, 1H), 7.93 (s, 1H), 7.89 (d, J=7.6Hz, 1 H), 7.75 −7.71 (m, 1H), 7.62−7.58 (m, 1H), 7.36−7.31 (m, 1H), 7.15−7.09 (m, 2H), 6.99−6.95 (m, 1H), 4.45−4.40 (m, 1H), 4.03 (s, 3H) 3.54−3.51(m, 3H), 3.33 (s, 3H), 3.12−3.05 (m, 1H), 2.77−2.64 (m, 5H), 2.55 (s, 3H). LCMS (M+H): 503.44.
1H NMR (DMSOd6, 300 MHz): δ 8.41 (s, 1H), 8.38−8.37 (m, 1H), 8.00 (s, 1H), 7.91 (d, J = 8.1 Hz, 2H), 7.80−7.64 (m, 4H), 7.40−7.39 (m, 3H), 7.34−7.22 (m, 5H), 6.70 (brs, 1H), 4.19−4.11 (m, 1H), 3.96 (s, 3H) 3.46−3.43(m, 2H), 3.25 (s, 3H), 3.19−3.12 (m, 2H), 2.91−2.75 (m, 1H), 2.71−2.54 (m, 4H). LCMS (M+H): 547.12.
1H NMR (DMSOd6, 300 MHz): δ 9.07 (d, J= 9.9 Hz 1H), 8.96 (d, J= 6.9 Hz, 1H), 8.54 (br s1H), 8.25−8.16 (m, 1H), 8.07 (t, J = 9.0 Hz, 2H), 7.84−7.66 (m, 2H), 7.37−7.22 (m, 4H), 7.07 (d, J= 7.5 Hz1 H), 4.25−4.20 (m, 1H), 3.48 (t, J= 5.4 Hz, 2H), 3.26 (s, 3H), 3.18−3.08 (m, 2H), 2.98−2.85 (m, 1H), 2.78−2.60 (m, 3H), 2.48−2.39 (m, 1H). LCMS (M+H):391.47.
1H NMR (DMSOd6, 300 MHz): δ 9.29 (s, 1H), 8.15 (d, J= 8.1 Hz, 1H), 7.95 (br s, 1H), 7.86−7.75 (m, 2H), 7.70.−7.65 (m, 3H), 7.41−7.20 (m, 8H), 6.67 (br s, 1H), 4.20−4.08 (m, 1H), 3.44 (t, J= 5.7 Hz, 2H), 3.25 (s, 3H), 3.13−3.06 (m, 2H), 2.84 (t, J= 8.7 Hz, 1H), 2.65−2.58 (m, 3H), 2.46−2.42 (m, 1H). LCMS (M+H): 467.03.
1H NMR (DMSOd6, 300 MHz): δ 9.09 (s, 1H), 8.08 (s, 1H), 8.05−8.02 (m, 1H), 7.80−7.69 (m, 2H), 7.58 (t, J= 7.8 Hz, 1H), 7.33−7.31 (m, 5H), 7.24−7.23 (m, 1H), 6.70 (d, J= 8.1 Hz, 1H), 4.32−4.11 (m, 1H), 3.48−3.45 (m, 2H), 3.25 (s, 3H), 3.21−3.11 (m, 2H), 2.98−2.91 (m, 1H), 2.68−2.62 (m, 4H), 2.46 (s, 3H). LCMS (M+H): 405.02.
1H NMR (DMSOd6, 300 MHz): δ 8.52−8.39 (m, 1H), 8.27−8.24 (m, 1H), 8.04−8.02 (m, 1H), 7.97−7.91 (m, 2H), 7.65−7.62 (m, 2H), 7.46−7.44 (m, 3H), 7.33−7.19 (m, 5H), 6.88 (d, J= 8.4 Hz, 1H), 4.09−4.07 (m, 1H), 3.45−3.41 (m, 2H), 3.24 (s, 3H), 3.17−3.05 (m, 3H), 2.82−2.76 (m, 1H), 2.63−2.56 (m, 3H). LCMS (M+H): 492.25.
1H NMR (DMSOd6, 400 MHz): δ 8.30 (d, J= 8.4 Hz, 1H), 8.15−8.02 (m, 1H), 7.95−7.88 (m, 2H), 7.85−7.80 (m, 1H), 7.66−7.65 (m, 2H), 7.42−7.41 (m, 3H), 7.37−7.31 (m, 1H), 7.09−7.02 (m, 3H), 6.78−6.65 (m, 1H), 4.19−4.05 (m, 1H), 3.45−3.41 (m, 2H), 3.24 (s, 3H), 3.17−3.05 (m, 3H), 2.92−2.83 (m, 1H), 2.66−2.56 (m, 3H). LCMS (M+H): 519.38.
1H NMR (CD3OD, 300MHz): δ9.22 (s, 1H), 8.17 (d, J= 8.4 Hz, 1H), 7.98 (d, J= 8.1 Hz, 1 H), 7.84−7.79 (m, 1 H), 7.73−7.67 (m, 1 H), 7.62−7.61 (m, 2H), 7.42−7.40 (m, 3H), 7.36−7.29 (m, 1 H), 7.08−6.95 (m, 3H), 4.22−4.32 (m, 1 H), 3.51−3.48 (m, 2H), 3.29 (s, 3H), 3.22−3.19 (m, 1H), 3.08−3.02 (m, 1H), 2.95−2.85 (m, 1H), 2.72−2.67 (m, 3H), 2.55 −2.48 (m, 1 H). LCMS (M+H):485.38.
1H NMR (CD3OD, 400MHz): δ 8.35−8.32 (m, 1H), 8.09 (d, J= 7.2 Hz, 1H), 7.91−7.87 (m, 2H), 7.67−7.64 (m, 2H), 7.44 −7.43 (m, 3H), 7.33−7.30 (m, 1H), 7.09−6.97 (m, 3H), 4.32−4.21 (m, 1H), 3.50−3.47 (m, 2H), 3.30 (s, 3H), 3.22−3.20 (m, 1H), 3.13−3.08 (m, 2H), 2.92−2.90 (m, 1H), 2.74−2.69 (m, 2H), 2.52−2.50 (m, 1H). LCMS (M+H):510.41.
1H NMR (DMSOd6, 300 MHz): δ 11.38 (s, 1H), 8.21 (d, J= 9.0 Hz, 1H), 7.72 (t, J= 7.2 Hz, 1H), 7.53−7.48 (m, 4H), 7.42−7.38 (m, 3H), 7.30−7.21 (m, 6H), 6.50 (br s, 1H), 4.10−4.06 (m, 1H), 3.43−3.39 (m, 2H), 3.23 (s, 3H), 3.08−3.02 (m, 2H), 2.83−2.78 (m, 1H), 2.66−2.52 (m, 3H), 2.47−2.43 (m, 1H). LCMS (M+H): 483.49.
1H NMR (CD3OD, 300MHz): δ 8.13 (d, J= 8.1 Hz, 1H), 7.77−7.73 (m, 1H), 7.71 −7.64 (m, 1H), 7.62−7.48 (m, 3H), 7.42−7.30 (m, 3H), 7.29−7.18 (m, 5H), 4.34−4.28 (m, 1H), 3.50−3.46 (m, 2H), 3.31 (s, 3H), 3.28−3.22 (m, 1H), 2.94−2.90 (m, 2H), 2.64−2.59 (m, 3H), 2.54−2.48 (m, 1H). LCMS (M+H): 482.07.
1H NMR (DMSOd6, 300 MHz): δ 8.19 (d, J= 8.1 Hz, 1H), 7.75−7.59 (m, 6H), 7.39−7.22 (m, 8H), 6.66 (brs, 1H), 4.22−4.10 (m, 1H), 4.09 (s, 3H), 3.45−3.42 (m, 2H), 3.25 (s, 3H), 3.08−3.06 (m, 2H), 2.84−2.80 (m, 1 H), 2.62 − 2.54 (m, 4H). LCMS (M+H): 497.49.
1H NMR (CD3OD, 300MHz): δ 8.25 (d, J= 8.4 Hz, 1H), 7.95 (d, J= 7.8 Hz, 1H), 7.77 (t, J= 8.1 Hz, 1H), 7.68 (t, J= 7.2 Hz, 1H), 7.62−7.56 (m, 2H), 7.42−7.36 (m, 3H), 7.34−7.23 (m, 5H), 4.33−4.28 (m, 1H), 3.49 (t, J= 5.7 Hz, 2H), 3.30 (s, 3H), 3.26−3.23 (m, 1H), 3.10−3.05 (m, 1H), 2.97 (s, 3H), 2.93−2.90 (m, 1H), 2.74−2.64 (m, 2H), 2.54−2.47 (m, 1H). LCMS (M+H): 481.42.
1H NMR (DMSOd6, 400 MHz): δ 7.95 (dd, J= 2.0 および9.6 Hz, 1H), 7.92−7.88 (m, 2H), 7.68 (dd, J = 2.4 および 9.2Hz, 1H ), 7.64−7.62 (m, 2H), 7.39−7.38 (m, 3H), 7.33−7.26 (m, 4H), 7.23 (d, J= 6.8 Hz1H), 6.65 (br s, 1H), 4.14−4.10 (m, 1H), 3.44 (t, J= 5.6 Hz, 2H), 3.25 (s, 3H), 3.11−3.05 (m, 2H), 2.87 (s, 3H), 2.84−2.82 (m, 1H), 2.65−2.55 (m, 3H), 2.46 (t ,J= 7.2 Hz, 1H). LCMS (M+H): 499.38.
1H NMR (CD3OD, 300MHz): δ 8.41 (d, J= 8.4 Hz, 1H), 8.19 (s, 1H), 8.05−7.98 (m, 2H), 7.79 (t, J= 8.1 Hz 1H), 7.70−7.66 (m, 3H), 7.41−7.28 (m, 4H), 7.03−6.94 (m, 3H), 4.33−4.26 (m, 1H), 4.02 (s, 3H), 3.49 (t, J = 5.4 Hz 2H), 3.29 (s, 3H), 3.22−3.18 (m, 2H), 2.94−2.88 (m, 1H), 2.71−2.64 (m, 3H), 2.53−2.48 (m, 1H). LCMS (M+H):565.18.
1H NMR (CD3OD, 300MHz): δ 8.29 (d, J= 8.4 Hz, 1H), 8.12 (s, 1H), 7.93 (s, 1H), 7.87 (d, J= 8.1 Hz, 1H), 7.72 (t, J= 8.1 Hz, 1H), 7.59 (t, J= 6.9 Hz, 1H), 7.41−7.32 (m, 4H), 7.27−7.22 (m, 1H), 4.46−4.43 (m, 1H), 4.03 (s, 3H), 3.54 (t, J= 5.1 Hz, 2H), 3.33 (s, 3H), 3.23−3.19 (m, 2H), 3.09−3.06 (m, 1H), 2.95−2.92 (m, 1H), 2.82−2.78 (m, 2H), 2.54 (s, 3H). LCMS (M+H): 485.20.
1H NMR (CDCl3, 300MHz): δ 8.60 (s, 1H), 8.37 (d, J= 8.4 Hz, 1H), 7.96−7.90 (m, 3H), 7.70−7.57 (m, 2H), 7.34−7.29 (m, 2H), 7.23−7.21 (m, 3H), 5.57 (brs, 1H), 4.48−4.46 (m, 1H), 4.03 (s, 3H), 3.46 (t, J= 5.4 Hz, 2H), 3.41−3.38 (m, 1H), 3.31−3.27 (m, 1H), 3.24 (s, 3H), 3.14−3.10 (m, 1H), 2.94−2.88 (m, 1H), 2.77−2.70 (m, 2H), 2.47 (t, J= 9.3 Hz,1H). LCMS (M+H):471.38.
1H NMR (CDCl3, 400MHz): δ 8.58 (s, 1H), 8.39 (d, J= 8.8 Hz, 1H), 7.98−7.92 (m, 3H), 7.71 (t, J= 7.2 Hz, 1H), 7.63 (t, J= 7.2 Hz, 1H), 7.29−7.27 (m, 2H), 7.03 (d, J= 8.0 Hz, 1H), 6.95−6.91 (m, 2H), 5.25 (br s, 1H), 4.44−4.41 (m, 1H), 4.04 (s, 3H), 3.43 (t, J= 5.2 Hz, 2H), 3.34 (t, J= 8.8 Hz, 1H), 3.25 (s, 3H), 3.17−3.14 (m, 1H), 2.99−2.97 (m, 1H), 2.86 (t, J= 8.0 Hz, 1H), 2.73−2.62 (m, 2H), 2.40 (t, J= 9.2Hz, 1H). LCMS (M+H): 489.48.
1H NMR (CD3OD 300 MHz):8.43−8.40 (m, 1H), 8.33 (d, J= 7.5 Hz, 1H), 8.08−8.01 (m, 1H), 7.91−7.78 (m, 1H), 7.72−7.48 (m, 2H), 7.42−7.24 (m, 1H), 7.22−7.14 (m, 1H), 7.08−6.82 (m, 2H), 4.48−4.40 (m, 1H), 4.01 (s, 3H), 3.57 (t, J= 5.7 Hz, 2H), 3.37 (s, 3H), 3.26−3.21 (m, 1H), 3.11−3.05 (m, 1H), 2.94−2.78 (m, 2H), 2.76−2.68 (m, 1H), 2.63−2.59 (m, 1H),2.48−2.33 (m, 1H), 1.49 (s, 9H). LCMS (M+H):545.53.
1H NMR (CD3OD, 300MHz): δ 8.42−8.01 (m, 3H), 7.79−7.55 (m, 3H), 7.35−7.10 (m, 5H), 4.48−4.44 (m, 1H), 4.01 (s, 3H), 3.57−3.53 (m, 2H), 3.37 (s, 3H), 3.22−3.08 (m, 2H), 2.83−2.70 (m, 4H), 2.37−2.32 (m, 1H), 1.48 (s, 9H). LCMS (M+H):527.52.
1H NMR (DMSOd6, 400 MHz): 8.17 (d, J= 8.4 Hz, 1H), 7.96 (brs, 1H), 7.99−7.89 (m, 2H), 7.78 (t, J= 8.0 Hz, 1H), 7.68−7.64 (m, 2H), 7.44−7.39 (m, 3H), 7.33−7.20 (m, 5H), 6.71 (br s, 1H), 4.15−4.10 (m, 1H), 3.44 (t, J= 4.8 Hz, 2H), 3.38−3.34 (m, 1H), 3.24 (s, 3H), 3.14−3.05 (m, 2H), 2.86−2.80 (m, 1H), 2.69−2.58 (m, 3H). LCMS (M+H): 485.40.
1H NMR (CD3OD, 300MHz): 8.27 (d, J= 8.4 Hz, 1H), 7.96 (d, J= 7.5 Hz, 1H), 7.79 (t, J= 5.1 Hz, 1H), 7.69 (t, J= 7.2 Hz, 1H), 7.62−7.56 (m, 2H), 7.41−7.28 (m, 4H), 7.03−6.94 (m, 3H), 4.29−4.25 (m, 1H), 3.49 (t, J= 5.4 Hz, 2H), 3.34 (s, 3H), 3.28−3.16 (m, 2H), 3.09−3.04 (m, 1H), 2.97 (s, 3H), 2.92−2.86 (m, 1H), 2.68−2.64 (m, 2H), 2.53−2.48 (m, 1H). LCMS (M+H): 499.43.
1H NMR (CD3OD400 MHz): 7.85 (d, J= 8.4 Hz, 1H), 7.58−7.54 (m, 2H), 7.46 (d, J= 2.0 Hz, 1H), 7.41−7.37 (m, 4H), 7.31 (d, J= 6.8 Hz, 2H), 7.25 (J= 6.8Hz, 2H), 7.23−7.19 (m, 1H), 4.31−4.26 (m, 1H), 3.99 (s, 3H), 3.52−3.48 (m, 2H), 3.42−3.38 (m, 1H), 3.30 (s, 3H), 3.28−3.20 (m, 1H), 3.12−3.06 (m, 1H), 2.93 (s, 3H), 2.78−2.74 (m, 3H), 2.58−2.54 (m, 1H). LCMS (M+H): 511.45.
1H NMR (CDCI3, 400MHz): δ 8.07 (d, J= 9.6 Hz, 1H), 7.65 (d, J= 7.2 Hz, 2H), 7.42−7.35 (m, 3H), 7.28−7.25 (m, 1H), 7.22−7.19 (m, 4H), 7.09 (d, J= 6.8 Hz, 2H), 4.86 (br s, 1H), 4.38−4.33 (m, 1H), 3.78 (s, 3H), 3.37−3.35 (m, 2H), 3.23 (s, 3H), 3.18−3.16 (m, 1H), 2.98 (s, 3H), 2.89−2.87 (m, 1H), 2.82−2.76 (m, 2H), 2.63−2.55 (m, 2H), 2.29 (t, J= 9.6 Hz, 1H). LCMS (M+H): 511.45.
1H NMR (CDCl3 400 MHz):8.05 (d, J= 8.4 Hz, 1H), 7.79 (s, 1H), 7.67 (d, J= 7.2 Hz, 2H), 7.46−7.34 (m, 5H), 7.29−7.26 (m, 2H), 7.22 (d, J= 7.2 Hz, 1H), 7.12 (d, J= 7.2 Hz, 2H), 4.85 (br s, 1 H), 4.42−4.28 (m, 1 H), 3.39−3.35 (m, 2H), 3.21 (s, 3H), 2.99 (s, 3H), 2.92−2.85 (m, 1H), 2.83−2.74 (m, 2H), 2.64−2.60 (m, 2H), 2.51 (s, 3H), 2.33−2.29 (m, 2H). LCMS (M+H):495.47.
1H NMR (DMSOd6, 300 MHz): δ 8.91 (d, J= 1.5 Hz, 1H), 8.75 (dd, J= 1.5 および 4.8Hz, 1H), 8.15 (dt, J = 1.8 および 3.6 Hz, 1H), 8.00−7.96 (m, 3H), 7.83 (t, J= 6.9 Hz, 1H), 7.73−7.59 (m, 4H), 7.42−7.21 (m, 8H), 6.73 (br s, 1H), 4.22−4.13 (m, 1H), 3.45 (t, J= 5.7 Hz, 2H), 3.26 (s, 3H), 3.17−3.12 (m, 2H), 2.86−2.83 (m, 1H), 2.70−2.55 (m, 3H), 2.49−2.47 (m, 1H). LCMS (M+H): 544.51.
1H NMR (CD3OD, 400MHz):8.19 (d, J= 7.6 Hz, 1H), 7.88−7.82 (m, 3H), 7.69 (d, J= 6.4 Hz, 1H), 7.57 (t, J= 7.2 Hz, 1H), 7.36−7.28 (m, 4H), 7.30−7.25 (m, 2H), 7.23 (d, J= 7.2 Hz, 2H), 4.33−4.28 (m, 1H), 3.96 (t, J= 4.4 Hz, 4H),3.68−3.52 (m, 2H), 3.55 − 3.44 (m, 4H), 3.30 (s, 3H), 3.27−3.18 (m, 2H), 2.96−2.82 (m, 2H), 2.74−2.63 (m, 2H), 2.53−2.48 (m, 1H). LCMS (M+H):552.52.
1H NMR (CDsOD400 MHz): 8.13 (d, J= 8.0 Hz, 1H), 7.88−7.82 (m, 1H), 7.74−7.63 (m, 3H), 7.56 (t, J= 8.4 Hz, 1H), 7.42−7.28 (m, 5H), 7.25−7.19 (m, 3H), 4.33−4.29 (m, 1H), 3.86−3.79 (m, 3H), 3.52−3.46 (m, 2H), 3.30 (s, 3H), 3.15 (t, J= 9.6 Hz, 4H), 2.96−2.88 (m, 2H), 2.74−2.65 (m, 2H), 2.53−2.47 (m, 1H), 2.07-2.05 (m, 2H), 1.86−1.79 (m, 2H). LCMS (M+H): 566.56.
1H NMR (CD3OD, 400MHz):δ8.27 (d, J=8.4Hz, 1H), 7.97−7.95 (m, 1H), 7.79 (t, J=7.2 Hz, 1H), 7.70 (t, J= 8.0 Hz, 1H), 7.44−7.38 (m, 3H), 7.32−7.20 (m, 5H), 7.12 (t, J= 6.8 Hz, 1H), 4.31−4.26 (m, 1H), 3.52−3.47 (m, 2H), 3.30 (s, 3H), 3.25−3.14 (m, 2H), 2.98 (s, 3H), 2.88−2.82 (m, 1H), 2.78−2.62 (m, 3H), 2.52−2.47 (m, 1H). LCMS (M+H): 499.47.
1H NMR (CDCl3 , 400MHz): δ 8.18 (d, J= 8.4 Hz, 1H), 8.03 (d, J= 8.4 Hz, 1H), 7.73−7.64 (m, 2H), 7.57−7.51 (m, 1H), 7.39−7.35 (m, 1H), 7.29−7.28 (m, 2H), 7.23−7.20 (m, 2H), 7.16−7.08 (m, 3H), 4.82 (br s, 1H), 4.25−4.22 (m, 1H), 3.41−3.43 (m, 2H), 3.28−3.26 (m, 1H), 3.21 (s, 3H), 3.03 (s, 3H), 2.94−2.90 (m, 2H), 2.71−2.54 (m, 3H), 2.33−2.30 (m, 1H). LCMS (M+H): 499.47.
1H NMR (CDCl3, 300MHz): δ 7.63 (d, J= 6.9 Hz, 2H), 7.42−7.32 (m, 5H), 7.23−7.19 (m, 3H), 7.09 (d, J = 6.6 Hz, 2H), 4.85 (br s, 1 H), 4.45−4.37 (m, 1 H), 4.08 (s, 3H), 3.83 (s, 3H), 3.40−3.36 (m, 2H), 3.24 (s, 3H), 3.23−3.22 (m, 1 H), 2.96 (s, 3H), 2.87−2.77 (m, 3H), 2.61−2.56 (m, 2H), 2.30 (t, J = 8.4 Hz, 1 H). LCMS (M+H):541.50.
1 H NMR (CD3OD, 400MHz): δ 8.36−8.32 (m, 1 H), 7.57−7.45 (m, 4H), 7.39−7.38 (m, 3H), 7.33−7.22 (m, 5H), 4.30−4.28 (m, 1 H), 3.52−3.51 (m, 2H), 3.31 (s, 3H), 3.31−3.30 (m, 2H), 3.1 1−3.09 (m, 1 H), 2.96 (s, 3H), 2.79−2.73 (m, 3H), 2.57−2.55 (m, 1 H). LCMS (M+H): 499.51.
1 H NMR (CD3OD, 400MHz): δ 8.03 (s, 1 H), 7.84 (d, J= 8.0 Hz, 1 H), 7.62 (d, J= 8.8 Hz 1 H), 7.58−7.56 (m, 2H), 7.39−7.36 (m, 3H), 7.33−7.29 (m, 2H), 7.25−7.21 (m, 3H), 4.32−4.27 (m, 1 H), 3.52−3.48 (m, 2H), 3.30 (s, 3H), 3.24−3.22 (m, 1 H), 3.12−2.99 (m, 1 H), 2.95 − 2.93 (m, 1 H), 2.92 (s, 3H), 2.80−2.70 (m, 3H), 2.59 (s, 3H), 2.53−2.48 (m, 1 H). LCMS (M+H):495.55.
1 H NMR CD3OD, 300MHz): δ 8.95 (dd, J= 2.7 Hzおよび 10.8 Hz, 1 H), 8.08−8.03 (m, 1 H), 7.71−7.69 (m, 3H), 7.63−7.56 (m, 2H), 7.41−7.33 (m, 5H), 7.31−7.25 (m, 2H), 4.32−4.27 (m, 1 H), 3.52 (t, J= 4.5 Hz, 2H), 3.31 (s, 3H), 3.17−3.11 (m, 2H), 2.97 (t, J = 8.1 Hz, 1 H), 2.82−2.74 (m, 3H), 2.59 (t, J = 9.3 Hz, 1 H). LCMS (M+H):510.54.
1 H NMR (CD3OD, 400MHz): δ 8.00 (d, J= 8.4 Hz, 2H), 7.91 (s, 1 H), 7.60 (d, J= 8.4 Hz, 1 H), 7.49−7.42 (m, 3H), 7.29−7.26 (m, 3H), 7.23 (d, J = 8.0 HZ, 1 H), 7.20 (d, J = 6.8 Hz 1 H), 7.03 (d, J = 8.4 Hz 1 H), 4.44−4.39 (m, 1 H), 4.02 (s, 3H), 3.54 (t, J = 5.6 Hz, 2H), 3.48−3.46 (m, 1 H), 3.33 (s, 3H), 3.14 (s, 3H), 3.08−3.02 (m, 1 H), 2.91−2.87 (m, 3H), 2.80−2.71 (m, 2H). LCMS (M+H):510.94.
1H NMR (CD3OD, 400MHz): δ 9.22 (s, 1H), 8.15 (d, J= 8.0 Hz, 1H), 7.98−7.86 (m, 1H), 7.82−7.78 (m, 1H), 7.70−7.68 (m, 1H), 7.62−7.58 (m, 1H), 7.45−7.39 (m, 3H), 7.34−7.29 (m, 1H), 7.26−7.15 (m, 3H) 7.02−6.94(m, 1H), 4.35−4.22 (m, 1H), 3.50 (t, J= 4.4 Hz, 2H), 3.37−3.35 (m, 1H), 3.30 (s, 3H), 3.26−3.22 (m, 1H), 3.12−3.08 (m, 1H), 2.95−2.92 (m, 1H), 2.78−2.66 (m, 2H), 2.56 (t, J= 7.6 Hz, 1H). LCMS (M+H):485.35.
1H NMR (CD3OD, 300MHz): δ 9.20 (s, 1 H), 8.01−7.96 (m, 1 H), 7.84 (dd, J= 2.4 および 9.0 Hz, 1 H), 7.64−7.57 (m, 3H), 7.41−7.39 (m, 3H), 7.35−7.23 (m, 5H), 4.32−4.28 (m, 1H), 3.53−3.50 (m, 2H), 3.33 (s, 3H), 3.24−3.22 (m, 1H), 3.12−3.07 (m, 1H), 2.98−2.94 (m, 1H), 2.80−2.74 (m, 3H), 2.56−2.54 (m, 1H). LCMS (M+H):484.88.
1H NMR (CD3OD, 300MHz): δ 9.21 (s, 1H), 8.04−7.99 (m, 1H),7.84 (dd, J=2.4 および 9.0 Hz, 1H), 7.65−7.58 (m, 3H), 7.42−7.29 (m, 4H), 7.09−6.95 (m, 3H), 4.32−4.28 (m, 1H), 3.50 (t, J= 5.7 Hz, 2H), 3.31 (s, 3H), 3.24−3.19 (m, 1H), 3.10−3.07 (m, 1H), 2.95−2.90 (m, 1H), 2.79−2.65 (m, 3H), 2.56−2.54 (m, 1H).). LCMS (M+H):502.82.
1H NMR (CD3OD, 400MHz): δ 8.99 (s, 1H), 7.58 (d, J= 8.0 Hz, 1H), 7.53−7.52 (m, 2H), 7.48 (d, J= 8.0 Hz, 1H), 7.28−7.26 (m, 3H), 7.19 (d, J= 7.2 Hz, 2H), 7.15−7.10 (m, 4H), 4.07−4.09 (m, 1H), 3.69 (s, 3H), 3.42−3.41 (m, 2H), 3.31−3.29 (m, 1H), 3.21 (s, 3H), 3.04−3.02 (m, 1H), 2.86−2.82 (m, 1H), 2.72−2.64 (m, 3H), 2.50−2.48 (m, 1H). LCMS (M+H):497.39.
1H NMR (CD3OD, 300MHz): δ 8.03−7.98 (m, 1H), 7.91 (dd, J= 2.4 および 9.9 Hz, 1H), 7.61−7.57 (m, 3H), 7.40−7.28 (m, 4H), 7.07−6.94 (m, 3H), 4.27−4.24 (m, 1H), 3.49 (m, J= 5.1 Hz, 2H), 3.31 (s, 3H), 3.29−3.21 (m, 2H), 3.20−3.05 (m, 1 H), 2.93 (s, 3H), 2.75−2.65 (m, 3H), 2.54−2.50 (m, 1 H). LCMS (M+H):517.10.
1 H NMR (CD3OD, 300MHz): δ 8.83 (s, 1 H), 8.68−8.65 (m, 1 H), 8.06−8.03 (m, 1 H), 7.84−7.80 (m, 2H), 7.37−7.19 (m, 4H), 6.46−6.41 (m, 1 H), 3.90−3.84 (m, 1 H), 3.82−3.76 (m, 1 H), 3.64 (t, J = 5.1 Hz, 2H), 3.56 (d, J= 8.7 Hz 1 H), 3.42 (s, 3H), 3.35−3.31 (m, 1 H), 3.07−2.94 (m, 2H), 2.87−2.79 (m, 1 H), 2.58 (t, J = 9.6 Hz, 1 H). LCMS (M+H):415.91.
1 H NMR (CD3OD, 400MHz): δ 8.16 (d, J = 8.0 Hz, 1 H), 7.89−7.85 (m, 1 H), 7.70−7.66 (m, 3H), 7.58 (t, J = 8.0 Hz, 1 H), 7.33−7.22 (m, 8H), 4.33−4.29 (m, 1 H), 3.52−3.49 (m, 6H), 3.35−3.50 (m, 4H), 3.25−3.12 (m, 5H), 2.91−2.68 (m, 5H). LCMS (M+H):551.39.
1 H NMR (DMSOd6, 400 MHz): δ 8.40 (brs, 1 H), 8.12−8.09 (m, 1 H), 7.93−7.85 (m, 2H), 7.63−7.61 (m, 2H), 7.52−7.45 (m, 3H), 7.33−7.20 (m, 5H), 6.90 (d, J = 8.0 Hz, 1 H), 4.09−4.04 (m, 1 H), 3.43 (t, J = 5.6 Hz, 2H), 3.24 (s, 3H), 3.13−3.04 (m, 2H), 2.80 (t, J = 8.0 Hz, 1 H), 2.65−2.55 (m, 3H), 2.44 (t, J= 8.4 Hz, 1 H). LCMS (M+H):510.36.
1 H NMR (DMSOd6 300 MHz): 8.41(d, J = 8.4 Hz, 1 H), 8.17 (br s, 1 H), 8.00 (d, J= 7.5 Hz, 1 H), 7.90−7.77 (m, 2H), 7.69−7.65 (m, 2H), 7.58−7.38 (m, 4H), 7.35−7.31 (m, 1 H), 7.1 1−7.01 (m, 3H), 6.79 (d, J =7.8 Hz, 1 H), 4.15−4.03 (m, 1 H), 3.44 (t, J = 5.7 Hz, 2H), 3.24 (s, 3H), 3.09−3.05 (m, 2H), 2.86 (t, J = 7.5 Hz, 1 H), 2.74−2.71 (m, 1 H), 2.66−2.57 (M, 2H), 2.28−2.24 (m, 1 H). ESI−MS m/z: 535.49 (M+H)+.
1 H NMR (CD3OD, 400MHz): δ 8.22−8.14 (m, 1 H), 8.02−7.94 (m, 1 H), 7.65−7.53 (m, 3H), 7.36−7.29 (m, 8H), 4.42−4.36 (m, 1 H), 3.89−3.85 (m, 1 H), 3.66−3.63 (m, 2H), 3.59−3.47 (m, 2H), 3.38 (s, 3H), 3.35−3.31 (m, 3H), 3.28−3.21 (m, 1 H). LC−MS (M+H):529.69.
1 H NMR (CD3OD, 300MHz): δ 8.95 (dd, J= 2.7 Hzおよび 10.8 Hz, 1 H), 8.08−8.03 (m, 1 H), 7.71−7.69 (m, 2H), 7.63−7.56 (m, 2H), 7.41−7.33 (m, 5H), 7.31−7.25 (m, 2H), 4.32−4.27 (m, 1 H), 3.52 (t, J= 4.5 HZ, 2H), 3.31 (s, 3H), 3.17−3.11 (m, 2H), 2.97 (t, J= 8.1 Hz, 1 H), 2.82−2.74 (m, 3H), 2.59 (t, J= 9.3 Hz, 1 H). LC−MS (M+H): 528.38.
1 H NMR (CD3OD, 400MHz): δ 8.98 (s,1 H), 8.65 (d, J = 8.0 Hz 1 H), 7.80 (d, J = 8.4 Hz, 1 H), 7.72−7.64 (m, 2H), 7.40−7.33 (m, 4H), 7.25 (t, J= 6.8 HZ, 1 H), 4.44−4.38 (m, 1 H), 3.58 (t, J = 5.4 Hz 2H), 3.37 (s, 3H), 3.35−3.34 (m, 2H), 3.18 (t, J = 9.2 Hz, 1 H), 2.99−2.95 (m, 1 H), 2.91−2.80 (m, 3H). LC−MS (M+H): 434.24.
1 H NMR (DMSO−d6 , 300MHz): δ 7.84 (dd, J = 2.4, 10.2 Hz, 1 H), 7.80−7.78 (m, 1 H), 7.73−7.68 (m, 1 H), 7.65−7.58 (m, 3H), 7.36−7.21 (m, 8H), 6.63 (br s, 1 H), 4.21−4.16 (m, 1 H), 4.13 (s, 2H), 3.64 (s, 3H), 3.44 (t, J = 5.4Hz, 2H), 3.31 (s, 3H), 3.25 (s, 3H), 3.11−3.04 (m, 2H), 2.88−2.85 (m, 1 H), 2.67−2.58 (m, 3H), 2.49 (t, J = 1.8 Hz, 1 H).LC−MS(M+H):586.08.
1 H NMR (DMSO−d6 , 300MHz): δ 7.85−7.82 (m, 1 H), 7.78 (d, J = 8.0 Hz, 1 H), 7.62−7.55 (m, 3H), 7.34−7.32 (m, 9H), 6.62 (br s, 1 H), 4.16−4.10 (m, 1 H), 4.04 (s, 2H), 3.44 (t, J = 5.7 Hz, 2H), 3.32 (s, 3H), 3.24 (s, 3H), 3.13−3.02 (m, 2H), 2.88−2.85 (m, 1 H), 2.66−2.55 (m, 3H).LC−MS(M+H): 572.35.
1 H NMR (CD3OD, 400MHz): δ 8.06 (d, J = 9.6 Hz, 1 H), 7.93−7.88 (m, 1 H), 7.86−7.79 (m, 1 H), 7.66−7.60 (m, 2H), 7.48−7.42 (m, 1 H), 7.36−7.28 (m, 7H), 4.68−4.59 (m, 1 H), 3.92−3.89 (m, 4H), 3.78−3.72 (m, 1 H), 3.70−3.61 (m, 3H), 3.59 (s, 3H), 3.52−3.45 (m, 2H), 3.38−3.34 (m, 3H), 3.12 (s, 3H).LC−MS(M+H): 558.45.
1 H NMR (CD3OD, 400MHz): δ 9.10 (s, 1 H), 7.87 (d, J= 9.2 Hz, 1 H), 7.57−7.56 (m, 2H), 7.48 (d, J= 9.6 Hz, 2H), 7.39−7.21 (m, 8H), 4.91 (s, 2H), 4.35−4.32 (m, 1 H) 4.28 (q, J = 7.2 Hz, 2H), 3.50 (t, J = 10.8 Hz, 2H), 3.30 (s, 3H), 3.24−3.19 (m, 1 H), 3.12−3.04 (m, 1 H), 2.92−2.90 (m, 1 H), 2.76−2.70 (m, 3H), 2.53 (t, J = 10.8 Hz, 1 H), 1.30 (t, J = 6.8 Hz, 3H).LC−MS: (M+H):569.31.
1 H NMR (CD3OD, 300MHz): δ 9.09 (s, 1 H), 7.82−7.76 (m, 1 H), 7.60−7.54 (m, 1 H), 7.50−7.45 (m, 3H), 7.42−7.36 (m, 5H), 7.32−7.28 (m, 3H), 4.58 (s, 2H), 4.42−4.34 (m, 1 H), 3.75−3.71 (m, 1 H), 3.62 (t, J= 4.8 Hz, 2H), 3.52−3.44 (m, 2H), 3.38 (s, 3H), 3.23−3.18 (m, 1 H), 3.12−3.05 (m, 3H).LC−MS(M+H):541.35.
1 H NMR (CD3OD, 300MHz): 9.10 (s, 1 H), 7.84 (d, J= 9.3 Hz, 1 H), 7.57−7.51 (m, 3H), 7.47 (dd, J = 2.4 および9.3Hz, 1 H), 7.39−7.24 (m, 8H), 4.32−4.28 (m, 1 H), 4.24 (t, J= 4.2 Hz, 2H), 3.96 (t, J= 4.8 Hz, 2H), 3.50 (t, J= 5.4 Hz, 2H), 3.31 (s, 3H), 3.26−3.22 (m, 1 H), 3.12−3.05 (m, 1 H), 2.93 (t, J = 6.9 Hz, 1 H), 2.76−2.71 (m, 3H), 2.54 (t, J = 9.3 Hz, 1 H).LC−MS (M+H):527.46.
1 H NMR (CD3OD, 400MHz): δ 8.13−8.09 (m, 1 H), 7.94 (dd, J= 2.4 および 9.6 Hz, 1 H), 7.64−7.59 (m, 3H), 7.42−7.33 (m, 3H), 7.28−7.25 (m, 5H), 4.57−4.54 (m, 1 H), 4.44−4.40 (m, 1 H), 4.34−4.10 (m, 1 H), 3.78−3.60 (m, 2H), 3.44 (s, 3H), 3.30−3.25 (m, 1 H), 3.10−2.98 (m, 1 H), 2.94 (s, 3H), 2.87−2.78 (m, 1 H), 2.68−2.57 (m, 2H), 2.49−2.42 (m, 2H). LCMS (M+H): 529.08.
1 H NMR (DMSO−d6, 400MHz): δ 8.50−7.79 (m, 2H), 7.76−7.67 (m, 3H), 7.45 (t,= 7.2 Hz, 2H), 7.39 (t, J= 7.6 Hz, 1 H), 6.54−6.48 (m, 2H), 4.00−3.89 (m, 1 H), 3.87−3.79 (m, 2H), 3.51−3.42 (m, 3H), 3.25 (s, 3H), 3.23−3.20 (m, 1 H), 3.10−3.00 (m, 2H), 2.89 (s, 3H), 2.64−2.58 (m, 1 H). LCMS (M+H):439.25.
1 H NMR (DMSO−d6, 300MHz): δ 7.91 (dd, J = 2.1 および 9.9 Hz, 1 H), 7.69 (brs, 1 H), 7.53−7.50 (m, 5H), 7.41−7.35 (m, 7H), 6.28 (brs, 1 H ), 5.44 (brs, 1 H), 4.30−4.23 (m, 1 H), 3.51−3.47 (m, 2H), 3.28 (s, 3H), 3.24−3.15 (m, 3H), 2.84 (s, 3H), 2.80−2.75 (m, 3H), 2.61−2.58 (m, 1 H). LCMS (M+H): 515.35.
1 H NMR (CDCl3, 300MHz): δ 7.67 (d, J = 7.5 Hz, 2H), 7.50−7.42 (m, 4H), 7.40−7.33 (m, 5H), 7.22−7.17 (m, 3H), 5.91 (brs, 1 H), 4.63−4.53 (m, 1 H), 3.46 (t, J = 5.4 Hz, 2H), 3.32 (s, 3H), 3.16−3.06 (m, 2H), 3.01−2.97 (m, 1 H), 2.93 (s, 3H), 2.75−2.73 (m, 2H), 2.63−2.61 (m, 1 H). LCMS (M+H): 517.33.
実施例A:TrkA細胞ベースのリン酸化アッセイ
ヒトTrkAを過剰発現する組換えAD293細胞を用いて、NGF刺激時のTrkA Y490リン酸化を測定した。無血清DMEM培地中で96ウェルプレートにプレーティングした25k細胞を、5% CO2インキュベーター内で37℃において2時間飢餓させた。試験化合物を、2.5% DMSOの最終濃度においてプレートに添加し、37℃で20分間インキュベートした。6nM NGFを添加し、37℃で5分間インキュベートした。プレートを直ちに2000rpmで1分間遠心分離し、培地を除去した。1% NP−40代替品、20mM トリス(pH8.0)、137mM NaClの最終濃度を含有する溶解緩衝液を添加し、1分間混合し、5分ごとに振盪しながら15分間にわたり氷上に保持した。細胞溶解物100μlを、プレコートしたウェルを備えたPathScan(登録商標)Phospho−TrkA(Tyr490)Sandwich ELISAプレートに添加し、発色のため、製造業者の指示に従ってELISAを実施した。IC50は、Graph Pad Prismソフトウェアにて非線形回帰フォーマットで生じさせた。
Claims (18)
- 式I:
[式中:
RaおよびRbは、それぞれ独立して、H、アルキル、アルケニル、アルキニル、ハロアルキル、ハロゲン、ヒドロキシ、ヒドロキシアルキル、アルコキシ、ハロアルコキシ、任意に置換されたフェニル、O、N、およびSから選択される1−3個のヘテロ原子を有する任意に置換された5−6員の芳香環から選択され、あるいはRaおよびRbは一緒になって、カルボニル基、任意に置換されたフェニル(これは、さらにハロゲンで任意に置換される)を形成し;
RcおよびRdは、H、アルキル、アルケニル、アルキニル、ハロアルキル、ヒドロキシ、アルコキシ、ハロアルコキシ、任意に置換されたフェニル、O、N、またはSから選択される1−3個のヘテロ原子を有する任意に置換された5−6員の芳香環から選択され、あるいはRcおよびRdは一緒になって、ヘテロ原子の有り無しで環(4−6員)を形成し;
R1は、アルケニル、アルキニル、ハロアルキル、ヒドロキシ、アルコキシ、ハロアルコキシ、(1−3Cアルコキシ)(1−3C)アルキル、(1−4Cアルコキシカルボニル)(1−6Cアルキル)、モノ、ジ、トリ、ハロ(1−4C)アルキル、(1−3Cアルキル)アミノカルボニル、シアノ(1−3Cアルキル)、(1−3Cハロアルコキシ)(1−3C)アルキル、O、N、もしくはSから選択される1個以上のヘテロ原子をもち、かつ任意で、独立してH、アルキル、アルケニル、アルキニル、ハロアルキル、ハロゲン、ヒドロキシ、アルコキシ、ハロアルコキシ、ニトロ、またはアミノから選択される1個以上の置換基で置換された複素環式環、1−3個の環窒素原子を有する9−10員の二環式ヘテロアリールであり;
R2およびR3は、独立してH、アルキル、アルケニル、アルキニル、イソプロピル、tertブチル、ハロアルキル、ハロゲン、ヒドロキシ、アルコキシ、ハロアルコキシ、任意に置換されたフェニル、またはO、N、もしくはSから選択される1−3個のヘテロ原子を有する任意に置換された5−6員の芳香環から選択され、但し、R2とR3とが同時に水素原子ではあり得ないという条件付きであり、あるいはR2およびR3は組合されて、1−2個のヘテロ原子をもつ環(5/6員)を形成してもよく;
Lは、−O−、−NH−、−SO2N(R´)−、−C(O)N(R´)−、−N(R´)C(O)−、−C(O)N(R´)C(O)−、−N(R´)SO2−、−N(R´)SO2N(R´)−、−N(R´)C(O)N(R´)−、−NR´C(S)N(R´)−、または−N(R´)C(O)O−から選択されるリガンドであり;
各R´は、独立してHまたはアルキルから選択され;
Het−Ar環は、H1またはH2:
から選択され;
X1−X7は、出現ごとに、結合、−CR5−、−CH2−、またはN、O、もしくはSから選択されるヘテロ原子であり;
X8は、O、S、NH、N−アルキル、SO、SO2、またはC=Oから選択され;
R4、R5、およびR6は、それぞれ独立して、H、アルキル、アルケニル、アルキニル、イソプロピル、tertブチル、ハロアルキル、ハロゲン、モノ、ジ、トリ、ハロ(1−4Cアルキル) ヒドロキシ、アルコキシ、ハロアルコキシ、シアノ、シクロアルキル(3−7炭素)、任意に置換されたフェニル、O、N、もしくはSから選択される1−3個のヘテロ原子を有する任意に置換された5−6員の複素環式環、またはO、N、もしくはSから選択される1個以上のヘテロ原子を有する3−6員の炭素環式環、−NH2、−N(H)(アルキル)、−N(アルキル)2、−N(H)C(O)アルキル、−N(アルキル)C(O)アルキル、−N(H)C(O)Oアルキル、−N(アルキル)C(O)Oアルキル、−N(H)SO2(アルキル)、−N(アルキル)SO2(アルキル)、−C(O)アルキル、−C(O)OH、−C(O)Oアルキル、−C(O)NH2、−C(O)N(H)(アルキル)、−C(O)N(アルキル)2、−S(アルキル)、−S(O)アルキル、−S(O)2アルキル、−S(O)2N(H)2、−S(O)2N(H)(アルキル)、および−S(O)2N(H)(アルキル)2からなる群より選択される]
の化合物、あるいはその立体異性体、互変異性体、または薬学的に許容される塩、同位体、溶媒和物、プロドラッグ、もしくは代謝物。 - Lが、尿素または任意に置換された尿素から選択される、請求項1に記載の化合物。
- H1が:
からなる群より選択され、かつR4およびR5が、それぞれ独立して、H、アルキル、アルケニル、アルキニル、イソプロピル、tertブチル、ハロアルキル、ハロゲン、モノ、ジ、トリ、ハロ(1−4Cアルキル)ヒドロキシ、アルコキシ、ハロアルコキシ、シアノ、シクロアルキル(3−7炭素)、任意に置換されたフェニル、O、N、もしくはSから選択される1−3個のヘテロ原子を有する任意に置換された5−6員の複素環式環、またはO、N、もしくはSから選択される1個以上のヘテロ原子を有する3−6員の炭素環式環、−NH2、−N(H)(アルキル)、−N(アルキル)2、−N(H)C(O)アルキル、−N(アルキル)C(O)アルキル、−N(H)C(O)Oアルキル、−N(アルキル)C(O)Oアルキル、−N(H)SO2(アルキル)、−N(アルキル)SO2(アルキル)、−C(O)アルキル、−C(O)OH、−C(O)Oアルキル、−C(O)NH2、−C(O)N(H)(アルキル)、−C(O)N(アルキル)2、−S(アルキル)、−S(O)アルキル、−S(O)2アルキル、−S(O)2N(H)2、−S(O)2N(H)(アルキル)、および−S(O)2N(H)(アルキル)2から選択される、請求項1に記載の化合物。 - H2が:
からなる群より選択され、かつ各R6が、独立して、H、アルキル、アルケニル、アルキニル、イソプロピル、tertブチル、ハロアルキル、ハロゲン、モノ、ジ、トリ、ハロ(1−4Cアルキル)ヒドロキシ、アルコキシ、ハロアルコキシ、シアノ、シクロアルキル(3−7炭素)、任意に置換されたフェニル、O、N、もしくはSから選択される1−3個のヘテロ原子を有する任意に置換された5−6員の複素環式環、またはO、N、もしくはSから選択される1個以上のヘテロ原子を有する3−6員の炭素環式環、−NH2、−N(H)(アルキル)、−N(アルキル)2、−N(H)C(O)アルキル、−N(アルキル)C(O)アルキル、−N(H)C(O)Oアルキル、−N(アルキル)C(O)Oアルキル、−N(H)SO2(アルキル)、−N(アルキル)SO2(アルキル)、−C(O)アルキル、−C(O)OH、−C(O)Oアルキル、−C(O)NH2、−C(O)N(H)(アルキル)、−C(O)N(アルキル)2、−S(アルキル)、−S(O)アルキル、−S(O)2アルキル、−S(O)2N(H)2、−S(O)2N(H)(アルキル)、および−S(O)2N(H)(アルキル)2からなる群より選択される、請求項1に記載の化合物。 - 治療有効量の請求項1に記載の式Iの化合物、またはその薬学的に許容される塩を含む医薬組成物。
- 前記組成物が、異常なまたは調節解除されたTrkA活性によって引き起こされる障害または疾患の、治療または予防のために使用される、請求項5に記載の医薬組成物。
- 前記疾患または障害が、疼痛、炎症もしくは炎症性疾患、癌、アテローム性動脈硬化症、再狭窄、血栓症、神経変性疾患、勃起不全(ED)、皮膚疾患、自己免疫疾患、シェーグレン症候群、子宮内膜症、糖尿病性抹消神経障害、前立腺炎、感染症、骨再形成の調節不均衡に関連する疾患、子宮内膜症、骨盤痛症候群、並びに異常な組織再形成および線維性障害の結果として生じる疾患;または、髄鞘形成不全もしくは脱髄に関連する疾患、障害、損傷、もしくは機能不全、または神経成長因子(NGF)受容体TrkAの異常な活性に関連づけられる疾患もしくは障害からなる群より選択される、請求項6に記載の医薬組成物。
- Trk受容体により媒介されるか、または異常なもしくは調節解除されたTrkAキナーゼ活性に関連づけられる疾患もしくは障害を、その必要がある患者において治療するための方法であって、これにおいて前記疾患もしくは障害が、疼痛、炎症または炎症性疾患、癌、アテローム性動脈硬化症、再狭窄、血栓症、神経変性疾患、勃起不全(ED)、皮膚疾患、自己免疫疾患、シェーグレン症候群、子宮内膜症、糖尿病性抹消神経障害、前立腺炎、感染症、骨再形成の調節不均衡に関連する疾患、子宮内膜症、骨盤痛症候群、並びに異常な組織再形成および線維性障害の結果として生じる疾患;または髄鞘形成不全もしくは脱髄に関連する疾患、障害、損傷、もしくは機能不全、または神経成長因子(NGF)受容体TrkAの異常な活性に関連づけられる疾患もしくは障害からなる群より選択され、治療有効量の請求項1に記載の化合物またはその薬学的に許容される塩と、薬学的に許容される担体とを投与することを含む、該方法。
- 前記炎症性疾患が、肺疾患、腸疾患、間質性膀胱炎、または疼痛性膀胱症候群からなる群より選択される、請求項8に記載の方法。
- 前記疼痛が、慢性および急性疼痛を含む、請求項8に記載の方法。
- 前記疼痛が、癌性疼痛、骨折痛、炎症性疼痛、神経障害性疼痛、外科手術、骨折、腫瘍転移により生じる骨格痛、変形性関節症、乾癬性関節炎、リウマチ様関節炎、間質性膀胱炎、慢性膵炎、内臓痛、炎症性疼痛、片頭痛、慢性腰痛、膀胱痛症候群に関連づけられる、請求項10に記載の方法。
- 前記異常な組織再形成および線維性障害の結果として生じる疾患が、突発性肺線維腫、レイノー症候群、子宮内膜線維症、心房線維症、骨髄線維症、進行性塊状線維症、腎性全身性線維症、強皮症、全身性硬化症、アテローム線維症、眼線維症、瘢痕化、および硬変からなる群より選択される、請求項8に記載の方法。
- 前記癌が、TrkAの異常調節に関連づけられる、請求項8に記載の方法。
- 前記TrkAの異常調節が、結果としてTrkA遺伝子融合を生じる、1つ以上の染色体転座または逆位を含む、請求項13に記載の方法。
- 前記TrkA遺伝子融合が、LMNA−TrkA、TFG−TrkA、TPM3−TrkA、CD74−TrkA、NFASC−TrkA、MPRIP−TrkA、BCAN−TrkA、TP53−TrkA、RNF213−TrkA、RABGAP1L−TrkA、IRF2BP2−TrkA、SQSTMI−TrkA、SSBP2−TrkA、またはTPR−TrkAである、請求項14に記載の方法。
- 前記TrkAの異常調節が、TrkAタンパク質における1つ以上の欠失、挿入、または突然変異を含む、請求項8および13に記載の方法。
- 前記癌が、肺腺癌、乳癌、甲状腺癌、膵臓癌、甲状腺乳頭癌、卵巣癌、胃癌(gastric carcinoma)、悪性中皮腫、前立腺癌、神経芽細胞腫、結腸直腸癌、スピッツ様黒色腫、唾液腺腺様嚢胞癌、多形性膠芽腫、胃癌(stomach cancer)、腎臓癌、尿道癌、口腔扁平上皮癌、肥満細胞症、乳腺外ページェット病、急性骨髄性白血病、胆管癌または肉腫を包含する群から選択される、請求項8に記載の方法。
- 化合物が:
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(キノリン−3−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(2−フェニルキノリン−3−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(2−メチルキノリン−3−イル)尿素
・1−(2−エチルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(2−シクロプロピルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(2−(トリフルオロメチル)キノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(6−フルオロ−2−フェニルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(6−フルオロ−2−メチルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(5−フルオロ−2−メチルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(8−フルオロ−2−メチルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(7−フルオロ−2−フェニルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(7−フルオロ−2−メチルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(6−メトキシ−2−フェニルキノリン−3−イル)尿素
・1−(7−メトキシ−2−フェニルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(8−メトキシ−2−フェニルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(5−メトキシ−2−フェニルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(5−メトキシ−2−メチルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(6−メトキシ−2−メチルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(7−メトキシ−2−メチルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(8−メトキシ−2−メチルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(6,7−ジメトキシ−2−フェニルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(6,7−ジメトキシ−2−メチルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(6,7−ジメトキシキノリン−3−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(6−メチル−2−フェニルキノリン−3−イル)尿素
・1−(2,6−ジメチルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(2,7−ジメチルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(2,5−ジメチルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素.
・1−(2,8−ジメチルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(7−メチル−2−フェニルキノリン−3−イル)尿素
・1−(2−クロロキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(2−(1−メチル−1H−ピラゾール−4−イル)キノリン−3−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(2−(ピリジン−3−イル)キノリン−3−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(2−(ピリジン−4−イル)キノリン−3−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(2−(ピリミジン−5−イル)キノリン−3−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(2−モルホリノキノリン−3−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(キノリン−4−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(キナゾリン−4−イル)尿素
・1−(2−クロロ−6,7−ジメトキシキナゾリン−4−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(キノキサリン−2−イル)尿素
・1−(2−イソプロピルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(2−tert−ブチルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(6−メトキシ−2−メチル−7−モルホリノキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(6−フルオロ−7−メチル−2−フェニルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(6−ブロモ−8−メトキシ−2−フェニルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(7−フルオロ−6−メトキシ−2−フェニルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(7−フルオロ−6−メトキシ−2−メチルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(8−メトキシ−7−メチル−2−フェニルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(6−メトキシ−2,7−ジメチルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(7−フルオロ−6−メチル−2−フェニルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(7−フルオロ−2,6−ジメチルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(6−フェニル−[1,3]ジオキソロ[4,5−g]キノリン−7−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(6−メチル−[1,3]ジオキソロ[4,5−g]キノリン−7−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(7−メチル−2,3−ジヒドロ−[1,4]ジオキシノ[2,3−g]キノリン−8−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(7−フェニル−2,3−ジヒドロ−[1,4]ジオキシノ[2,3−g]キノリン−8−イル)尿素
・1−(6−アミノ−7−メトキシ−2−フェニルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(7−メトキシ−6(メチルアミノ)−2−フェニルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・N−(7−メトキシ−3−(3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)ウレイド)−2−フェニルキノリン−6−イル)アセトアミド
・N−(7−メトキシ−3−(3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)ウレイド)−2−メチルキノリン−6−イル)アセトアミド
・N−(6−メトキシ−3−(3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)ウレイド)−2−フェニルキノリン−7−イル)アセトアミド
・N−(6−メトキシ−3−(3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)ウレイド)−2−メチルキノリン−7−イル)アセトアミド
・1−(8−メトキシ−6−(1−メチル−1H−ピラゾール−4−イル)−2−フェニルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(2−メチル−8−(1−メチル−1H−ピラゾール−4−イル)キノリン−3−イル)尿素
・1−((3S,4R)−4−(3,4−ジフルオロフェニル)−1−(2−メトキシエチル)ピロリジン−3−イル)−3−(キノリン−3−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(ナフタレン−2−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(ナフタレン−2−イル)尿素
・1−((3S,4R)−4−(3,4−ジフルオロフェニル)−1−(2−メトキシエチル)ピロリジン−3−イル)−3−(2−(ピリジン−3−イル)キノリン−3−イル)尿素
・1−((3S,4R)−4−(3,4−ジフルオロフェニル)−1−(2−メトキシエチル)ピロリジン−3−イル)−3−(2−メチルキノリン−3−イル)尿素
・1−((3S,4R)−4−(3,4−ジフルオロフェニル)−1−(2−メトキシエチル)ピロリジン−3−イル)−3−(6,7−ジメトキシ−2−メチルキノリン−3−イル)尿素
・1−((3S,4R)−4−(3,4−ジフルオロフェニル)−1−(2−メトキシエチル)ピロリジン−3−イル)−3−(6,7−ジメトキシキノリン−3−イル)尿素
・1−((3S,4R)−4−(3−フルオロフェニル)−1−(2−メトキシエチル)ピロリジン−3−イル)−3−(キノリン−3−イル)尿素
・1−((3S,4R)−4−(3−フルオロフェニル)−1−(2−メトキシエチル)ピロリジン−3−イル)−3−(2−メチルキノリン−3−イル)尿素
・1−(6−フルオロ−2−メチルキノリン−3−イル)−3−((3S,4R)−4−(3−フルオロフェニル)−1−(2−メトキシエチル)ピロリジン−3−イル)尿素
・1−(7−フルオロ−2−メチルキノリン−3−イル)−3−((3S,4R)−4−(3−フルオロフェニル)−1−(2−メトキシエチル)ピロリジン−3−イル)尿素
・1−(6,7−ジメトキシ−2−フェニルキノリン−3−イル)−3−((3S,4R)−4−(3−フルオロフェニル)−1−(2−メトキシエチル)ピロリジン−3−イル)尿素
・1−((3S,4R)−4−(3−フルオロフェニル)−1−(2−メトキシエチル)ピロリジン−3−イル)−3−(6−フェニル−[1,3]ジオキソロ[4,5−g]キノリン−7−イル)尿素
・1−((3S,4R)−4−(3−フルオロフェニル)−1−(2−メトキシエチル)ピロリジン−3−イル)−3−(6−メチル−[1,3]ジオキソロ[4,5−g]キノリン−7−イル)尿素
・1−((3S,4R)−4−(3−シアノフェニル)−1−(2−メトキシエチル)ピロリジン−3−イル)−3−(キノリン−3−イル)尿素
・1−((3S,4R)−4−(3−シアノフェニル)−1−(2−メトキシエチル)ピロリジン−3−イル)−3−(6,7−ジメトキシ−2−フェニルキノリン−3−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−(ピリジン−3−イル)ピロリジン−3−イル)−3−(キノリン−3−イル)尿素
・1−(6,7−ジメトキシ−2−フェニルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−(ピリジン−3−イル)ピロリジン−3−イル)尿素
・1−((3S,4R)−4−tert−ブチル−1−(2−メトキシエチル)ピロリジン−3−イル)−3−(キノリン−3−イル)尿素
・1−(6,7−ジメトキシ−2−フェニルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−(1−メチル−1H−ピラゾール−4−イル)ピロリジン−3−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−(1−メチル−1H−ピラゾール−4−イル)ピロリジン−3−イル)−3−(キノリン−3−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−(フェニルピロリジン−3−イル)−3−(2−フェニル−1,8−ナフチリジン−3−イル)尿素
・メチル2−((3S,4R)−3−(3−(6,7−ジメトキシ−2−フェニルキノリン−3−イル)ウレイド)−4−フェニルピロリジン−1−イル)アセテート
・メチル2−((3R,4S)−3−フェニル−4−(3−(キノリン−3−イル)ウレイド)ピロリジン−1−イル)アセテート
・1−((3S,4R)−1−(2−フルオロエチル)−4−フェニルピロリジン−3−イル)−3−(6,7−ジメトキシ−2−フェニルキノリン−3−イル)尿素
・1−((3R,4S)−1−(2−フルオロエチル)−4−フェニルピロリジン−3−イル)−3−(6,7−ジメトキシ−2−フェニルキノリン−3−イル)尿素
・1−((3S,4R)−1−(2−フルオロフエチル)−4−フェニルピロリジン−3−イル)−3−(2−フェニルキノリン−3−イル)尿素
・1−((3S,4R)−1−(2−フルオロエチル)−4−フェニルピロリジン−3−イル)−3−(キノリン−3−イル)尿素
・1−((3S,4R)−1−(2,2,2−トリフルオロエチル)−4−フェニルピロリジン−3−イル)−3−(6,7−ジメトキシ−2−フェニルキノリン−3−イル)尿素
・1−((3R,4S)−1−(2,2,2−トリフルオロエチル)−4−フェニルピロリジン−3−イル)−3−(6,7−ジメトキシ−2−フェニルキノリン−3−イル)尿素
・1−((3S,4R)−1−(2,2,2−トリフルオロエチル)−4−フェニルピロリジン−3−イル)−3−(キノリン−3−イル)尿素
・1−((3S,4R)−1−(2,2−ジフルオロエチル)−4−フェニルピロリジン−3−イル)−3−(6,7−ジメトキシ−2−フェニルキノリン−3−イル)尿素
・1−((3S,4R)−1−(2,2−ジフルオロエチル)−4−フェニルピロリジン−3−イル)−3−(キノリン−3−イル)尿素
・1−(6,7−ジメトキシ−2−フェニルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシアセチル)−4−フェニルピロリジン−3−イル)尿素
・1−((3S,4R)−1−(2−メトキシアセチル)−4−フェニルピロリジン−3−イル)−3−(キノリン−3−イル)尿素
・1−(6,7−ジメトキシ−2−フェニルキノリン−3−イル)−3−((3S,4R)−1−(オキセタン−3−イル)−4−フェニルピロリジン−3−イル)尿素
・2−((3S,4R)−3−(3−(6,7−ジメトキシ−2−フェニルキノリン−3−イル)ウレイド)−4−フェニルピロリジン−1−イル)アセトアミド
・1−((3S,4R)−1−(シアノメチル)−4−フェニルピロリジン−3−イル)−3−(6,7−ジメトキシ−2−フェニルキノリン−3−イル)尿素
・1−((3S,4R)−1−(シアノメチル)−4−フェニルピロリジン−3−イル)−3−(キノリン−3−イル)尿素
・2−((3R,4S)−3−フェニル−4−(3−(キノリン−3−イル)ウレイド)ピロリジン−1−イル)アセトアミド
・1−(1−(2−メトキシエチル)−2−オキソ−4−フェニルピロリジン−3−イル)−3−(キノリン−3−イル)尿素
・1−(ジベンゾ[b,d]フラン−1−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(ジベンゾ[b,d]フラン−1−イル)−3−((3S,4R)−4−(3−フルオロフェニル)−1−(2−メトキシエチル)ピロリジン−3−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(8−メチルジベンゾ[b,d]フラン−1−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(8−メトキシジベンゾ[b,d]フラン−1−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(8−フルオロジベンゾ[b,d]フラン−1−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(7−メトキシジベンゾ[b,d]フラン−1−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(7−フルオロジベンゾ[b,d]フラン−1−イル)尿素
・1−(ジベンゾ[b,d]チオフェン−1−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(5,5−ジオキソジベンゾ[b,d]チオフェン−1−イル)−3−[1−(2−メトキシ−エチル)−4−フェニル−ピロリジン−3−イル)尿素
・1−(4−メトキシジベンゾ[b,d]チオフェン−1−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(4−メトキシ−5,5−ジオキソジベンゾ[b,d]チオフェン−1−イル)−3−[1−(2−メトキシ−エチル)−4−フェニル−ピロリジン−3−イル)−尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(9−オキソ−9H−7−フルオレン−4−イル)尿素
・1−(6−メトキシジベンゾ[b,d]フラン−1−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(6−メチルジベンゾ[b,d]フラン−1−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(6−メトキシ−7−メチル−2−フェニルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(6−シアノ−7−フルオロ−2−メチルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(6−シアノ−7−メトキシ−2−メチルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(7−シアノ−6−フルオロ−2−メチルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(7−シアノ−6−フルオロ−2−フェニルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(7−シアノ−6−メトキシ−2−フェニルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(2−(チアゾール−5−イル)キノリン−3−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(2−フェニル−5,6,7,8−テトラヒドロキノリン−3−イル)尿素
・1−(6,7−ジメトキシ−2−フェニルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−1,3−ジメチル尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−1−メチル−3−(2−フェニルキノリン−3−イル)尿素
・1−(6−(ジフルオロメトキシ)−7−メトキシ−2−メチルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(2,2−ジフルオロ−6−メチル−[1,3]ジオキソロ[4,5−g]キノリン−7−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(6−(ジフルオロメチル)−[1,3]ジオキソロ[4,5−g]キノリン−7−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−([1,3]ジオキソロ[4,5−g]キノリン−7−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(2−シクロヘキシルキノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(6−(トリフルオロメチル)−[1,3]ジオキソロ[4,5−g]キノリン−7−イル)尿素
・1−(6−(ジフルオロメチル)−[1,3]ジオキソロ[4,5−g]キノリン−7−イル)−3−((3S,4R)−4−(3−フルオロフェニル)−1−(2−メトキシエチル)ピロリジン−3−イル)尿素
・1−([1,3]ジオキソロ[4,5−g]キノリン−7−イル)−3−((3S,4R)−4−(3,4−ジフルオロフェニル)−1−(2−メトキシエチル)ピロリジン−3−イル)尿素
・1−(6−フルオロ−2−フェニルキノリン−3−イル)−3−((3S,4R)−4−(3−フルオロフェニル)−1−(2−メトキシエチル)ピロリジン−3−イル)尿素
・1−((3S,4R)−4−(3−フルオロフェニル)−1−(2−メトキシエチル)ピロリジン−3−イル)−3−(2−フェニル−5,6,7,8−テトラヒドロキノリン−3−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(7−メチル−2−フェニル−1,8−ナフチリジン−3−イル)尿素
・1−((3S,4R)−4−(3−フルオロフェニル)−1−(2−メトキシエチル)ピロリジン−3−イル)−3−(2−フェニルキノリン−3−イル)尿素
・1−([1,3]ジオキソロ[4,5−g]キノリン−7−イル)−3−((3S,4R)−4−(3−フルオロフェニル)−1−(2−メトキシエチル)ピロリジン−3−イル)尿素
・1−(2−(2,4−ジフルオロフェニル)キノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(2−(3,5−ジフルオロフェニル)キノリン−3−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(4−(ベンジルオキシ)−1−(2−メトキシエチル)ピロリジン−3−イル)−3−(6−メチル−[1,3]ジオキソロ[4,5−g]キノリン−7−イル))尿素
・1−(1−クロロ−3−メチルイソキノリン−4−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(1,3−ジフェニルイソキノリン−4−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−((3S,4R)−4−(3−フルオロフェニル)−1−(2−メトキシエチル)ピロリジン−3−イル)−3−(3−メチル−1−(1−メチル−1H−ピラゾール−4−イル)イソキノリン−4−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(1−(1−メチル−1H−ピラゾール−4−イル)−3−フェニルイソキノリン−4−イル)尿素
・1−(イソキノリン−4−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(3−フェニルイソキノリン−4−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(3−メチルイソキノリン−4−イル)尿素
・1−(1−シアノ−3−フェニルイソキノリン−4−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(1−クロロ−3−フェニルイソキノリン−4−イル)−3−((3S,4R)−4−(3−フルオロフェニル)−1−(2−メトキシエチル)ピロリジン−3−イル)尿素
・1−((3S,4R)−4−(3−フルオロフェニル)−1−(2−メトキシエチル)ピロリジン−3−イル)−3−(3−フェニルイソキノリン−4−イル)尿素
・1−(1−シアノ−3−フェニルイソキノリン−4−イル)−3−((3S,4R)−4−(3−フルオロフェニル)−1−(2−メトキシエチル)ピロリジン−3−イル)尿素
・1−(1−ヒドロキシ−3−フェニルイソキノリン−4−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(1−アミノ−3−フェニルイソキノリン−4−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(1−メトキシ−3−フェニルイソキノリン−4−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(1−メチル−3−フェニルイソキノリン−4−イル)尿素
・1−(7−フルオロ−1−メチル−3−フェニルイソキノリン−4−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−((3S,4R)−4−(3−フルオロフェニル)−1−(2−メトキシエチル)ピロリジン−3−イル)−3−(1−(1−メチル−1H−ピラゾール−4−イル)−3−フェニルイソキノリン−4−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(3−メチル−1−(1−メチル−1H−ピラゾール−4−イル)イソキノリン−4−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(1−(1−メチル−1H−ピラゾール−4−イル)イソキノリン−4−イル)尿素
・1−((3S,4R)−4−(3−フルオロフェニル)−1−(2−メトキシエチル)ピロリジン−3−イル)−3−(1−(1−メチル−1H−ピラゾール−4−イル)イソキノリン−4−イル)尿素
・1−(3−(tert−ブチル)−1−(1−メチル−1H−ピラゾール−4−イル)イソキノリン−4−イル)−3−((3S,4R)−4−(3−フルオロフェニル)−1−(2−メトキシエチル)ピロリジン−3−イル)尿素
・1−(3−(tert−ブチル)−1−(1−メチル−1H−ピラゾール−4−イル)イソキノリン−4−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(1−フルオロ−3−フェニルイソキノリン−4−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−((3S,4R)−4−(3−フルオロフェニル)−1−(2−メトキシエチル)ピロリジン−3−イル)−3−(1−メチル−3−フェニルイソキノリン−4−イル)尿素
・1−(7−メトキシ−1−メチル−3−フェニルイソキノリン−4−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(6−メトキシ−1−メチル−3−フェニルイソキノリン−4−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(1,6−ジメチル−3−フェニルイソキノリン−4−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(3−フェニル−1−(ピリジン−3−イル)イソキノリン−4−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(1−モルホリノ−3−フェニルイソキノリン−4−イル)尿素
・1−(1−(4−ヒドロキシピペリジン−1−イル)−3−フェニルイソキノリン−4−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(3−(3−フルオロフェニル)−1−メチルイソキノリン−4−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(3−(2−フルオロフェニル)−1−メチルイソキノリン−4−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(6,7−ジメトキシ−1−メチル−3−フェニルイソキノリン−4−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(6−フルオロ−1−メチル−3−フェニルイソキノリン−4−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(1,7−ジメチル−3−フェニルイソキノリン−4−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・4−(3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)ウレイド)−3−フェニルイソキノリン−1−カルボキサミド
・1−(8−メトキシ−1−メチル−3−フェニルイソキノリン−4−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(8−フルオロ−3−フェニルイソキノリン−4−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(7−フルオロ−3−フェニルイソキノリン−4−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(7−フルオロ−3−フェニルイソキノリン−4−イル)−3−((3S,4R)−4−(3−フルオロフェニル)−1−(2−メトキシエチル)ピロリジン−3−イル)尿素
・1−(5−メトキシ−3−フェニルイソキノリン−4−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(7−フルオロ−1−メチル−3−フェニルイソキノリン−4−イル)−3−((3S,4R)−4−(3−フルオロフェニル)−1−(2−メトキシエチル)ピロリジン−3−イル)尿素
・1−(3−シアノイソキノリン−4−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(3−フェニル−1−(ピペラジン−1−イル)イソキノリン−4−イル)尿素
・1−(1−シアノ−7−フルオロ−3−フェニルイソキノリン−4−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(1−(ジフルオロメチル)−3−フェニルイソキノリン−4−イル)−3−((3S,4R)−4−(3−フルオロフェニル)−1−(2−メトキシエチル)ピロリジン−3−イル)尿素
・7−フルオロ−4−(3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)ウレイド)−3−フェニルイソキノリン−1−カルボン酸
・7−フルオロ−4−(3−((3S,4R)1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)ウレイド)−3−フェニルイソキノリン−1−カルボキサミド
・4−(3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)ウレイド)イソキノリン−3−カルボキサミド
・メチル2−((7−フルオロ−4−(3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)ウレイド)−3−フェニルイソキノリン−1−イル)(メチル)アミノ)アセテート
・2−((7−フルオロ−4−(3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)ウレイド)−3−フェニルイソキノリン−1−イル)(メチル)アミノ)酢酸
・1−(7−フルオロ−1−((2−ヒドロキシエチル)(メチル)アミノ)−3−フェニルイソキノリン−4−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・エチル2−((4−(3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)ウレイド)−3−フェニルイソキノリン−7−イル)オキシ)アミノ)アセテート
・2−((4−(3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)ウレイド)−3−フェニルイソキノリン−7−イル)オキシ)酢酸
・1−(7−(2−ヒドロキシエトキシ)−3−フェニルイソキノリン−4−イル)−3−((3S,4R)−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(4−(ベンジルオキシ)−1−(2−メトキシエチル)ピロリジン−3−イル)−3−(7−フルオロ−1−メチル−3−フェニルイソキノリン−4−イル)尿素
・1−(7−フルオロ−1−メチル−3−フェニルイソキノリン−4−イル)−3−(4−ヒドロキシ−1−(2−メトキシエチル)ピロリジン−3−イル)尿素
・1−(7−フルオロ−1−メチル−3−フェニルイソキノリン−4−イル)−3−(4−ヒドロキシ−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)尿素
・1−(4−フルオロ−1−(2−メトキシエチル)−4−フェニルピロリジン−3−イル)−3−(7−フルオロ−1−メチル−3−フェニルイソキノリン−4−イル)尿素
である該化合物、あるいはその立体異性体、互変異性体、または薬学的に許容される塩、同位体、溶媒和物、プロドラッグ、もしくは代謝物。
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IN362CH2015 | 2015-01-23 | ||
PCT/IB2016/050328 WO2016116900A1 (en) | 2015-01-23 | 2016-01-22 | Inhibitors of trka kinase |
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EP3330256B1 (en) | 2015-07-07 | 2021-06-16 | Shionogi & Co., Ltd. | HETEROCYCLIC DERIVATIVE HAVING TrkA-INHIBITING ACTIVITY |
EP3412663B1 (en) | 2016-02-04 | 2022-09-07 | Shionogi & Co., Ltd. | Nitrogen-containing heterocycle and carbocycle derivatives having trka inhibitory activity |
WO2018079759A1 (ja) * | 2016-10-31 | 2018-05-03 | 塩野義製薬株式会社 | TrkA阻害活性を有する縮合複素環および縮合炭素環誘導体 |
CN106749098B (zh) * | 2016-12-07 | 2018-10-26 | 大连万福制药有限公司 | 一种以氧气为氧化剂制备盐酸二氧丙嗪的制备方法 |
UY37764A (es) | 2017-06-13 | 2019-01-02 | Glaxosmithkline Ip Dev Ltd | Nuevos compuestos inhibidores de la prostaglandina d sintasa hematopoyética (h-pgds) |
US10180422B1 (en) * | 2017-08-22 | 2019-01-15 | Scripps Health | Methods of treating a neuroendocrine tumor |
US11325895B2 (en) * | 2017-09-15 | 2022-05-10 | Mochida Pharmaceutical Co., Ltd. | Crystals of tetrahydronaphthyl urea derivative |
IL277044B2 (en) | 2018-03-05 | 2023-10-01 | Bristol Myers Squibb Co | Phenylpyrrolidinone formyl peptide 2 receptor agonists |
CN108314648A (zh) * | 2018-04-12 | 2018-07-24 | 苏州康润医药有限公司 | 4-溴-7-氟异喹啉的合成方法 |
WO2020011227A1 (zh) | 2018-07-12 | 2020-01-16 | 南京明德新药研发有限公司 | 吡咯烷基脲衍生物及其在TrkA相关疾病的应用 |
CN108947900B (zh) * | 2018-08-06 | 2021-07-30 | 河南大学 | 光诱导无金属催化的碳芳基化串联反应合成杂环化合物的方法 |
EP3942045A1 (en) | 2019-03-21 | 2022-01-26 | Onxeo | A dbait molecule in combination with kinase inhibitor for the treatment of cancer |
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CN112979615A (zh) * | 2019-12-17 | 2021-06-18 | 上海医药集团股份有限公司 | 一种喹唑啉脲类化合物、其制备方法、制备中间体、药物组合物及应用 |
WO2021139794A1 (zh) | 2020-01-10 | 2021-07-15 | 漳州片仔癀药业股份有限公司 | 一种吡咯烷基脲衍生物的晶型及其应用 |
JP7337279B2 (ja) | 2020-01-10 | 2023-09-01 | ▲ザン▼州片仔▲ファン▼薬業股▲フン▼有限公司 | ピロリジニル尿素誘導体の調製方法 |
WO2021148581A1 (en) | 2020-01-22 | 2021-07-29 | Onxeo | Novel dbait molecule and its use |
WO2021257857A1 (en) | 2020-06-19 | 2021-12-23 | Incyte Corporation | Naphthyridinone compounds as jak2 v617f inhibitors |
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WO2022006456A1 (en) | 2020-07-02 | 2022-01-06 | Incyte Corporation | Tricyclic pyridone compounds as jak2 v617f inhibitors |
AU2021300429A1 (en) | 2020-07-02 | 2023-02-16 | Incyte Corporation | Tricyclic urea compounds as JAK2 V617F inhibitors |
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AU2020223776A1 (en) | 2020-10-01 |
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CA2974784A1 (en) | 2016-07-28 |
US10336723B2 (en) | 2019-07-02 |
WO2016116900A1 (en) | 2016-07-28 |
JP6706630B2 (ja) | 2020-06-10 |
RU2017129757A3 (ja) | 2019-06-06 |
US20180009781A1 (en) | 2018-01-11 |
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