JP2016523976A5 - - Google Patents
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- JP2016523976A5 JP2016523976A5 JP2016525490A JP2016525490A JP2016523976A5 JP 2016523976 A5 JP2016523976 A5 JP 2016523976A5 JP 2016525490 A JP2016525490 A JP 2016525490A JP 2016525490 A JP2016525490 A JP 2016525490A JP 2016523976 A5 JP2016523976 A5 JP 2016523976A5
- Authority
- JP
- Japan
- Prior art keywords
- alkylene
- alkyl
- amino
- phenyl
- 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.)
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- 125000002947 alkylene group Chemical group 0.000 claims description 159
- -1 Pi Rimijin 4-yl Chemical group 0.000 claims description 127
- 125000000217 alkyl group Chemical group 0.000 claims description 115
- 230000035772 mutation Effects 0.000 claims description 52
- 150000001875 compounds Chemical class 0.000 claims description 47
- 125000005843 halogen group Chemical group 0.000 claims description 31
- 101000599886 Homo sapiens Isocitrate dehydrogenase [NADP], mitochondrial Proteins 0.000 claims description 29
- 102100037845 Isocitrate dehydrogenase [NADP], mitochondrial Human genes 0.000 claims description 29
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
- 206010028980 Neoplasm Diseases 0.000 claims description 23
- 201000011510 cancer Diseases 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 21
- 125000000623 heterocyclic group Chemical group 0.000 claims description 19
- 125000001424 substituent group Chemical group 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 12
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 102200116484 rs121913502 Human genes 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
- 125000001072 heteroaryl group Chemical group 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 125000001153 fluoro group Chemical group F* 0.000 claims description 9
- 125000001188 haloalkyl group Chemical group 0.000 claims description 9
- HWXBTNAVRSUOJR-UHFFFAOYSA-N 2-hydroxyglutaric acid Chemical compound OC(=O)C(O)CCC(O)=O HWXBTNAVRSUOJR-UHFFFAOYSA-N 0.000 claims description 8
- KPGXRSRHYNQIFN-UHFFFAOYSA-N 2-oxoglutaric acid Chemical compound OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 0.000 claims description 8
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 8
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 claims description 8
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 230000001419 dependent effect Effects 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 7
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- 102000004190 Enzymes Human genes 0.000 claims description 6
- 108090000790 Enzymes Proteins 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 229940124597 therapeutic agent Drugs 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 4
- 208000005243 Chondrosarcoma Diseases 0.000 claims description 4
- 208000032612 Glial tumor Diseases 0.000 claims description 4
- 206010018338 Glioma Diseases 0.000 claims description 4
- 206010039491 Sarcoma Diseases 0.000 claims description 4
- BVCRERJDOOBZOH-UHFFFAOYSA-N bicyclo[2.2.1]heptanyl Chemical group C1C[C+]2CC[C-]1C2 BVCRERJDOOBZOH-UHFFFAOYSA-N 0.000 claims description 4
- 208000006990 cholangiocarcinoma Diseases 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 208000005017 glioblastoma Diseases 0.000 claims description 4
- 201000001441 melanoma Diseases 0.000 claims description 4
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 4
- 125000003566 oxetanyl group Chemical group 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 4
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 150000001721 carbon Chemical group 0.000 claims description 3
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 3
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 3
- 125000004943 pyrimidin-6-yl group Chemical group N1=CN=CC=C1* 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 125000002393 azetidinyl group Chemical group 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000002757 morpholinyl group Chemical group 0.000 claims description 2
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 2
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims 8
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 3
- XASCYFFKFIHOAR-UHFFFAOYSA-N C1(=CC=CC=C1)C1(NC(=CC(=N1)NCCC1=CC=CC=C1)C1=CC=CC=C1)N Chemical compound C1(=CC=CC=C1)C1(NC(=CC(=N1)NCCC1=CC=CC=C1)C1=CC=CC=C1)N XASCYFFKFIHOAR-UHFFFAOYSA-N 0.000 claims 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 2
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 claims 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 2
- JTZSFNHHVULOGJ-UHFFFAOYSA-N 3-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CC=CN=C1 JTZSFNHHVULOGJ-UHFFFAOYSA-N 0.000 claims 1
- 125000004917 3-methyl-2-butyl group Chemical group CC(C(C)*)C 0.000 claims 1
- HWIYPZYHTJLWEN-UHFFFAOYSA-N 4-(5-cyclopropyl-1H-pyrazol-3-yl)-2-N,6-diphenyl-1H-pyrimidine-2,4-diamine Chemical compound C1(CC1)C1=CC(=NN1)C1(NC(=NC(=C1)C1=CC=CC=C1)NC1=CC=CC=C1)N HWIYPZYHTJLWEN-UHFFFAOYSA-N 0.000 claims 1
- RGFPHLRVXSQLPZ-UHFFFAOYSA-N 4-(5-methyl-1H-pyrazol-3-yl)-2-N,6-diphenyl-1H-pyrimidine-2,4-diamine Chemical compound CC1=CC(=NN1)C1(NC(=NC(=C1)C1=CC=CC=C1)NC1=CC=CC=C1)N RGFPHLRVXSQLPZ-UHFFFAOYSA-N 0.000 claims 1
- QJIHXFLPNCATJJ-UHFFFAOYSA-N 4-[3-(furan-2-yl)-1H-pyrazol-5-yl]-2-N,6-diphenyl-1H-pyrimidine-2,4-diamine Chemical compound O1C(=CC=C1)C1=CC(=NN1)C1(NC(=NC(=C1)C1=CC=CC=C1)NC1=CC=CC=C1)N QJIHXFLPNCATJJ-UHFFFAOYSA-N 0.000 claims 1
- DUAYRVYJJVCRRX-UHFFFAOYSA-N C(C)N(CCCC1(NC(=NC(=C1)C1=CC=CC=C1)NC1=CC=CC=C1)N)CC Chemical compound C(C)N(CCCC1(NC(=NC(=C1)C1=CC=CC=C1)NC1=CC=CC=C1)N)CC DUAYRVYJJVCRRX-UHFFFAOYSA-N 0.000 claims 1
- HCDZSFWAUVRCRB-UHFFFAOYSA-N C1(=CC=CC=C1)C1(NC(=CC(=N1)NCC1=CC=CC=C1)C1=CC=CC=C1)N Chemical compound C1(=CC=CC=C1)C1(NC(=CC(=N1)NCC1=CC=CC=C1)C1=CC=CC=C1)N HCDZSFWAUVRCRB-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- 230000036571 hydration Effects 0.000 claims 1
- 238000006703 hydration reaction Methods 0.000 claims 1
- 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 claims 1
- YJWQLHBXPJQMFN-UHFFFAOYSA-N 3-(2-cyanopropan-2-yl)-n-[3-[[6-(cyclopropylamino)-2-pyridin-3-ylpyrimidin-4-yl]amino]-4-methylphenyl]benzamide Chemical compound C1=C(NC=2N=C(N=C(NC3CC3)C=2)C=2C=NC=CC=2)C(C)=CC=C1NC(=O)C1=CC=CC(C(C)(C)C#N)=C1 YJWQLHBXPJQMFN-UHFFFAOYSA-N 0.000 description 59
- KVXVLMSREIUYQH-UHFFFAOYSA-N methyl 1-[4-[[4-(cyclopentylamino)-6-(3,5-dimethyl-1,2-oxazol-4-yl)pyrimidin-2-yl]amino]phenyl]cyclobutane-1-carboxylate Chemical compound C=1C=C(NC=2N=C(C=C(NC3CCCC3)N=2)C2=C(ON=C2C)C)C=CC=1C1(C(=O)OC)CCC1 KVXVLMSREIUYQH-UHFFFAOYSA-N 0.000 description 34
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 20
- WFIZJFIDQAQBIO-UHFFFAOYSA-N 2,6-diphenyl-1H-pyrimidine-2,4-diamine Chemical compound C1(=CC=CC=C1)C1(NC(=CC(=N1)N)C1=CC=CC=C1)N WFIZJFIDQAQBIO-UHFFFAOYSA-N 0.000 description 12
- ORCFLJAMBJPDEP-UHFFFAOYSA-N 4-(5-methyl-1H-pyrazol-3-yl)-2-phenyl-1H-pyrimidine-4,6-diamine Chemical compound CC1=CC(=NN1)C1(C=C(N=C(N1)C1=CC=CC=C1)N)N ORCFLJAMBJPDEP-UHFFFAOYSA-N 0.000 description 12
- RZVUFMDUHKOGEP-UHFFFAOYSA-N C1(=CC=CC=C1)CC1(C=C(N=CN1)N)N Chemical compound C1(=CC=CC=C1)CC1(C=C(N=CN1)N)N RZVUFMDUHKOGEP-UHFFFAOYSA-N 0.000 description 12
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- ZJARBPALAUYPDP-UHFFFAOYSA-N 4-(oxan-4-yl)-1H-pyrimidine-4,6-diamine Chemical compound O1CCC(CC1)C1(C=C(N=CN1)N)N ZJARBPALAUYPDP-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 7
- XYDBPRIEUQNLCN-UHFFFAOYSA-N 1-[4-[[4-(cyclopentylamino)-6-(3,5-dimethyl-1,2-oxazol-4-yl)pyrimidin-2-yl]amino]phenyl]cyclobutane-1-carboxylic acid Chemical compound CC1=NOC(C)=C1C1=CC(NC2CCCC2)=NC(NC=2C=CC(=CC=2)C2(CCC2)C(O)=O)=N1 XYDBPRIEUQNLCN-UHFFFAOYSA-N 0.000 description 6
- 125000006163 5-membered heteroaryl group Chemical group 0.000 description 6
- UHYLJEHDGUVOEX-UHFFFAOYSA-N C1=CC=C(C=C1)C2=NC(C=C(N2)N)(C3=CC=CC=C3)N Chemical compound C1=CC=C(C=C1)C2=NC(C=C(N2)N)(C3=CC=CC=C3)N UHYLJEHDGUVOEX-UHFFFAOYSA-N 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- RKDHDYFCQFXEAP-UHFFFAOYSA-N 1-[4-[[6-(tert-butylamino)-2-phenylpyrimidin-4-yl]amino]phenyl]cyclobutane-1-carboxylic acid Chemical compound N=1C(C=2C=CC=CC=2)=NC(NC(C)(C)C)=CC=1NC(C=C1)=CC=C1C1(C(O)=O)CCC1 RKDHDYFCQFXEAP-UHFFFAOYSA-N 0.000 description 4
- HFPSCDATDAPGFV-UHFFFAOYSA-N 2-[(6-anilino-2-phenylpyrimidin-4-yl)amino]ethanol Chemical compound N=1C(C=2C=CC=CC=2)=NC(NCCO)=CC=1NC1=CC=CC=C1 HFPSCDATDAPGFV-UHFFFAOYSA-N 0.000 description 4
- ZXUWAUANLMIAKV-UHFFFAOYSA-N 2-amino-4-[(6-amino-2-phenylpyrimidin-4-yl)amino]benzenesulfonic acid Chemical compound N=1C(C=2C=CC=CC=2)=NC(N)=CC=1NC1=CC=C(S(O)(=O)=O)C(N)=C1 ZXUWAUANLMIAKV-UHFFFAOYSA-N 0.000 description 4
- HYJCTUIWDHYWJR-UHFFFAOYSA-N 3-[(6-amino-2-phenylpyrimidin-4-yl)amino]benzenesulfonic acid Chemical compound N=1C(C=2C=CC=CC=2)=NC(N)=CC=1NC1=CC=CC(S(O)(=O)=O)=C1 HYJCTUIWDHYWJR-UHFFFAOYSA-N 0.000 description 4
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 4
- HDVQXIOUFYJPRX-UHFFFAOYSA-N 4-(2-morpholin-4-ylethyl)-2-phenyl-1H-pyrimidine-4,6-diamine Chemical compound N1(CCOCC1)CCC1(C=C(N=C(N1)C1=CC=CC=C1)N)N HDVQXIOUFYJPRX-UHFFFAOYSA-N 0.000 description 4
- CBYSWNDJNXAHKF-UHFFFAOYSA-N 4-[(6-amino-2-phenylpyrimidin-4-yl)amino]benzenesulfonamide Chemical compound N=1C(C=2C=CC=CC=2)=NC(N)=CC=1NC1=CC=C(S(N)(=O)=O)C=C1 CBYSWNDJNXAHKF-UHFFFAOYSA-N 0.000 description 4
- LJGHSKBKWYUGHL-UHFFFAOYSA-N 4-[4-(trifluoromethoxy)phenyl]-1H-pyrimidine-4,6-diamine Chemical compound FC(OC1=CC=C(C=C1)C1(C=C(N=CN1)N)N)(F)F LJGHSKBKWYUGHL-UHFFFAOYSA-N 0.000 description 4
- MQDITYTZNOUEER-UHFFFAOYSA-N 4-amino-2-[(6-amino-2-phenylpyrimidin-4-yl)amino]benzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C(NC=2N=C(N=C(N)C=2)C=2C=CC=CC=2)=C1 MQDITYTZNOUEER-UHFFFAOYSA-N 0.000 description 4
- WNWVKZTYMQWFHE-UHFFFAOYSA-N 4-ethylmorpholine Chemical group [CH2]CN1CCOCC1 WNWVKZTYMQWFHE-UHFFFAOYSA-N 0.000 description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 4
- HKYJWNUKGVEENB-UHFFFAOYSA-N 5-[4-amino-6-[(5-cyclopropyl-1h-pyrazol-3-yl)amino]pyrimidin-2-yl]thiophene-2-sulfonamide Chemical compound N=1C(C=2SC(=CC=2)S(N)(=O)=O)=NC(N)=CC=1NC(=NN1)C=C1C1CC1 HKYJWNUKGVEENB-UHFFFAOYSA-N 0.000 description 4
- 108700028369 Alleles Proteins 0.000 description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 4
- CBTGNLZUIZHUHY-UHFFFAOYSA-N methyl cyclobutanecarboxylate Chemical compound COC(=O)C1CCC1 CBTGNLZUIZHUHY-UHFFFAOYSA-N 0.000 description 4
- CVJXKJWEPWPYMN-UHFFFAOYSA-N n-[2-(3-chlorophenyl)-6-(pyridin-4-ylamino)pyrimidin-4-yl]acetamide Chemical compound N=1C(C=2C=C(Cl)C=CC=2)=NC(NC(=O)C)=CC=1NC1=CC=NC=C1 CVJXKJWEPWPYMN-UHFFFAOYSA-N 0.000 description 4
- SRDJUDHSQKYYBL-UHFFFAOYSA-N n-[2-[4-[(5-methyl-1h-pyrazol-3-yl)amino]-6-(oxan-4-ylamino)pyrimidin-2-yl]-1-benzofuran-5-yl]cyclopropanesulfonamide Chemical compound N1C(C)=CC(NC=2N=C(N=C(NC3CCOCC3)C=2)C=2OC3=CC=C(NS(=O)(=O)C4CC4)C=C3C=2)=N1 SRDJUDHSQKYYBL-UHFFFAOYSA-N 0.000 description 4
- AZINPNXYQHNGHA-UHFFFAOYSA-N 1-[4-[[4-(butylamino)-6-(3,5-dimethyl-1,2-oxazol-4-yl)pyrimidin-2-yl]amino]phenyl]cyclobutane-1-carboxylic acid Chemical compound N=1C(NCCCC)=CC(C2=C(ON=C2C)C)=NC=1NC(C=C1)=CC=C1C1(C(O)=O)CCC1 AZINPNXYQHNGHA-UHFFFAOYSA-N 0.000 description 3
- GNFPRGCNUUQYFP-UHFFFAOYSA-N 1-[4-[[4-(tert-butylamino)-6-(3,5-dimethyl-1,2-oxazol-4-yl)pyrimidin-2-yl]amino]phenyl]cyclobutane-1-carboxylic acid Chemical compound CC1=NOC(C)=C1C1=CC(NC(C)(C)C)=NC(NC=2C=CC(=CC=2)C2(CCC2)C(O)=O)=N1 GNFPRGCNUUQYFP-UHFFFAOYSA-N 0.000 description 3
- MAAWRYSVTFKZFA-UHFFFAOYSA-N 2-(pyridin-3-ylmethyl)-1H-pyrimidine-2,4-diamine Chemical compound N1=CC(=CC=C1)CC1(NC=CC(=N1)N)N MAAWRYSVTFKZFA-UHFFFAOYSA-N 0.000 description 3
- MNXFYMBOTSRGLY-UHFFFAOYSA-N 2-[(3-phenyl-1,2-oxazol-5-yl)methyl]-1H-pyrimidine-2,4-diamine Chemical compound N1C=CC(N)=NC1(N)CC1=CC(C=2C=CC=CC=2)=NO1 MNXFYMBOTSRGLY-UHFFFAOYSA-N 0.000 description 3
- IIFRHTIWXXTQEA-UHFFFAOYSA-N 2-[(3-phenyl-1,2-oxazol-5-yl)methyl]-6-(4-piperazin-1-ylphenyl)-1H-pyrimidine-2,4-diamine Chemical compound C1(=CC=CC=C1)C1=NOC(=C1)CC1(NC(=CC(=N1)N)C1=CC=C(C=C1)N1CCNCC1)N IIFRHTIWXXTQEA-UHFFFAOYSA-N 0.000 description 3
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 3
- MJMLGWZNIONTEN-UHFFFAOYSA-N 4-[2-(diethylamino)ethyl]-2-phenyl-1H-pyrimidine-4,6-diamine Chemical compound C(C)N(CCC1(C=C(N=C(N1)C1=CC=CC=C1)N)N)CC MJMLGWZNIONTEN-UHFFFAOYSA-N 0.000 description 3
- FJNSITSGRCMSIY-UHFFFAOYSA-N 4-[2-[(5-ethoxycarbonyl-4-methyl-1,3-thiazol-2-yl)amino]-6-[(4-sulfamoylphenyl)methylamino]pyrimidin-4-yl]benzoic acid Chemical compound CC1=C(C(=O)OCC)SC(NC=2N=C(C=C(NCC=3C=CC(=CC=3)S(N)(=O)=O)N=2)C=2C=CC(=CC=2)C(O)=O)=N1 FJNSITSGRCMSIY-UHFFFAOYSA-N 0.000 description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 3
- KBBSJSSYSKJGQU-UHFFFAOYSA-N 6-N-methyl-4-N,2-diphenylpyrimidine-4,6-diamine Chemical compound CNC1=NC(=NC(=C1)NC1=CC=CC=C1)C1=CC=CC=C1 KBBSJSSYSKJGQU-UHFFFAOYSA-N 0.000 description 3
- XQPDIHJKRUKVLM-UHFFFAOYSA-N 6-[[4-(2-chlorophenyl)-6-[(5-cyclopropyl-1h-pyrazol-3-yl)amino]pyrimidin-2-yl]amino]-1,2-dihydroindazol-3-one Chemical compound ClC1=CC=CC=C1C1=CC(NC=2NN=C(C=2)C2CC2)=NC(NC=2C=C3C(C(NN3)=O)=CC=2)=N1 XQPDIHJKRUKVLM-UHFFFAOYSA-N 0.000 description 3
- ZLJCCGMZEINCGL-UHFFFAOYSA-N 6-[[4-[(5-cyclopropyl-1h-pyrazol-3-yl)amino]-6-phenylpyrimidin-2-yl]amino]-1,2-dihydroindazol-3-one Chemical compound C=1C=C2C(=O)NNC2=CC=1NC(N=C(C=1)C=2C=CC=CC=2)=NC=1NC(NN=1)=CC=1C1CC1 ZLJCCGMZEINCGL-UHFFFAOYSA-N 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 3
- KKEPDLSHPKHPGE-UHFFFAOYSA-N ethyl 2-[[4-(4-cyanophenyl)-6-[(4-methylsulfonylphenyl)methylamino]pyrimidin-2-yl]amino]-4-methyl-1,3-thiazole-5-carboxylate Chemical compound CC1=C(C(=O)OCC)SC(NC=2N=C(C=C(NCC=3C=CC(=CC=3)S(C)(=O)=O)N=2)C=2C=CC(=CC=2)C#N)=N1 KKEPDLSHPKHPGE-UHFFFAOYSA-N 0.000 description 3
- ANZVAFVJCMQMBD-UHFFFAOYSA-N ethyl 2-[[4-[(3,4-dimethoxyphenyl)methylamino]-6-(1,3-oxazol-5-yl)pyrimidin-2-yl]amino]-4-methyl-1,3-thiazole-5-carboxylate Chemical compound CC1=C(C(=O)OCC)SC(NC=2N=C(C=C(NCC=3C=C(OC)C(OC)=CC=3)N=2)C=2OC=NC=2)=N1 ANZVAFVJCMQMBD-UHFFFAOYSA-N 0.000 description 3
- WDVRXKMQWKAXDR-UHFFFAOYSA-N ethyl 2-[[4-[(4-chlorophenyl)methylamino]-6-(1,3-oxazol-5-yl)pyrimidin-2-yl]amino]-4-methyl-1,3-thiazole-5-carboxylate Chemical compound CC1=C(C(=O)OCC)SC(NC=2N=C(C=C(NCC=3C=CC(Cl)=CC=3)N=2)C=2OC=NC=2)=N1 WDVRXKMQWKAXDR-UHFFFAOYSA-N 0.000 description 3
- WOORGOPZFITJLP-UHFFFAOYSA-N ethyl 4-methyl-2-[[4-[(4-methylsulfonylphenyl)methylamino]-6-(3,4,5-trimethoxyphenyl)pyrimidin-2-yl]amino]-1,3-thiazole-5-carboxylate Chemical compound CC1=C(C(=O)OCC)SC(NC=2N=C(C=C(NCC=3C=CC(=CC=3)S(C)(=O)=O)N=2)C=2C=C(OC)C(OC)=C(OC)C=2)=N1 WOORGOPZFITJLP-UHFFFAOYSA-N 0.000 description 3
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 3
- FYPNBOSYCLWDRA-UHFFFAOYSA-N methyl 1-[4-[[4-(tert-butylamino)-6-(3,5-dimethyl-1,2-oxazol-4-yl)pyrimidin-2-yl]amino]phenyl]cyclobutane-1-carboxylate Chemical compound C=1C=C(NC=2N=C(C=C(NC(C)(C)C)N=2)C2=C(ON=C2C)C)C=CC=1C1(C(=O)OC)CCC1 FYPNBOSYCLWDRA-UHFFFAOYSA-N 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- 125000004284 isoxazol-3-yl group Chemical group [H]C1=C([H])C(*)=NO1 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 description 1
- WUVSSXGDGLCPOI-UHFFFAOYSA-N C1=CC(=CC(=C1)N2C=CN=C2C3(C=C(NC=N3)N)N)C(F)(F)F Chemical compound C1=CC(=CC(=C1)N2C=CN=C2C3(C=C(NC=N3)N)N)C(F)(F)F WUVSSXGDGLCPOI-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 125000004498 isoxazol-4-yl group Chemical group O1N=CC(=C1)* 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Natural products CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
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| CN107556366B (zh) * | 2016-06-30 | 2025-02-07 | 上海海和药物研究开发股份有限公司 | 具有突变型异柠檬酸脱氢酶抑制活性的化合物、其制备方法及用途 |
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| CN109467538A (zh) | 2017-09-07 | 2019-03-15 | 和记黄埔医药（上海）有限公司 | 环烯烃取代的杂芳环类化合物及其用途 |
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-
2014
- 2014-07-10 US US14/903,947 patent/US10376510B2/en not_active Expired - Fee Related
- 2014-07-10 AU AU2014287121A patent/AU2014287121B2/en not_active Ceased
- 2014-07-10 JP JP2016525490A patent/JP6529492B2/ja not_active Expired - Fee Related
- 2014-07-10 CA CA2917671A patent/CA2917671A1/en not_active Abandoned
- 2014-07-10 CN CN201480048552.8A patent/CN105593215B/zh not_active Expired - Fee Related
- 2014-07-10 WO PCT/US2014/046202 patent/WO2015006591A1/en not_active Ceased
- 2014-07-10 EP EP14745308.8A patent/EP3019480B1/en active Active
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