CA2692085C - Fused thiazole derivatives as kinase inhibitors - Google Patents
Fused thiazole derivatives as kinase inhibitors Download PDFInfo
- Publication number
- CA2692085C CA2692085C CA2692085A CA2692085A CA2692085C CA 2692085 C CA2692085 C CA 2692085C CA 2692085 A CA2692085 A CA 2692085A CA 2692085 A CA2692085 A CA 2692085A CA 2692085 C CA2692085 C CA 2692085C
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- methyl
- compound
- morpholin
- dimethyl
- 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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- 150000007979 thiazole derivatives Chemical class 0.000 title description 4
- 229940043355 kinase inhibitor Drugs 0.000 title description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 title description 2
- 238000011282 treatment Methods 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 7
- 230000001363 autoimmune Effects 0.000 claims abstract description 6
- 230000002757 inflammatory effect Effects 0.000 claims abstract description 6
- 230000002503 metabolic effect Effects 0.000 claims abstract description 6
- 230000003040 nociceptive effect Effects 0.000 claims abstract description 6
- 230000000771 oncological effect Effects 0.000 claims abstract description 6
- 230000002526 effect on cardiovascular system Effects 0.000 claims abstract description 5
- 230000000626 neurodegenerative effect Effects 0.000 claims abstract description 5
- -1 arylsulphinyl Chemical group 0.000 claims description 165
- 150000001875 compounds Chemical class 0.000 claims description 162
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 37
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 30
- 239000001257 hydrogen Substances 0.000 claims description 29
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 27
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 150000002431 hydrogen Chemical class 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 13
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 13
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 13
- 239000012453 solvate Substances 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 125000002757 morpholinyl group Chemical group 0.000 claims description 8
- 230000002265 prevention Effects 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 7
- 239000012828 PI3K inhibitor Substances 0.000 claims description 7
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 6
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 5
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 5
- 125000004104 aryloxy group Chemical group 0.000 claims description 5
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000001425 triazolyl group Chemical group 0.000 claims description 5
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 4
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 4
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 4
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 150000001721 carbon Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 3
- 125000005222 heteroarylaminocarbonyl group Chemical group 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 150000002923 oximes Chemical class 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 2
- 125000005968 oxazolinyl group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 4
- JVSGBNZVDWHFDO-KRWDZBQOSA-N 3-[[(3s)-4-(6,6-dimethyl-4-oxo-5,7-dihydro-[1,3]thiazolo[5,4-c]pyridin-2-yl)morpholin-3-yl]methyl]-n,n,1-trimethylindole-5-carboxamide Chemical compound C1C(C)(C)NC(=O)C(S2)=C1N=C2N1CCOC[C@@H]1CC1=CN(C)C2=CC=C(C(=O)N(C)C)C=C21 JVSGBNZVDWHFDO-KRWDZBQOSA-N 0.000 claims 2
- JUXXWKDPXCWDEA-AWEZNQCLSA-N 2-[(3s)-3-(1-benzofuran-3-ylmethyl)morpholin-4-yl]-6,6-dimethyl-5,7-dihydro-[1,3]thiazolo[5,4-c]pyridin-4-one Chemical compound C1=CC=C2C(C[C@H]3COCCN3C3=NC=4CC(NC(=O)C=4S3)(C)C)=COC2=C1 JUXXWKDPXCWDEA-AWEZNQCLSA-N 0.000 claims 1
- UHLCUNGGYHSGQK-KRWDZBQOSA-N 2-[(3s)-3-[[5-(azetidine-1-carbonyl)-1-benzofuran-3-yl]methyl]morpholin-4-yl]-6,6-dimethyl-5,7-dihydro-[1,3]thiazolo[5,4-c]pyridin-4-one Chemical compound C([C@H]1COCCN1C1=NC=2CC(NC(=O)C=2S1)(C)C)C(C1=C2)=COC1=CC=C2C(=O)N1CCC1 UHLCUNGGYHSGQK-KRWDZBQOSA-N 0.000 claims 1
- ZFCOZWRXIYETAF-SFHVURJKSA-N 2-[(3s)-3-[[5-(azetidine-1-carbonyl)-1-methylindol-3-yl]methyl]morpholin-4-yl]-6,6-dimethyl-5,7-dihydro-[1,3]thiazolo[5,4-c]pyridin-4-one Chemical compound C=1C=C2N(C)C=C(C[C@@H]3N(CCOC3)C=3SC=4C(=O)NC(C)(C)CC=4N=3)C2=CC=1C(=O)N1CCC1 ZFCOZWRXIYETAF-SFHVURJKSA-N 0.000 claims 1
- KOGQXIYBCBOANV-HNNXBMFYSA-N 3-[[(3s)-4-(6,6-dimethyl-4-oxo-5,7-dihydro-[1,3]thiazolo[5,4-c]pyridin-2-yl)morpholin-3-yl]methyl]-1-benzofuran-5-carbonitrile Chemical compound C1=C(C#N)C=C2C(C[C@H]3COCCN3C3=NC=4CC(NC(=O)C=4S3)(C)C)=COC2=C1 KOGQXIYBCBOANV-HNNXBMFYSA-N 0.000 claims 1
- UBZDDEORUSXHDB-INIZCTEOSA-N 3-[[(3s)-4-(6,6-dimethyl-4-oxo-5,7-dihydro-[1,3]thiazolo[5,4-c]pyridin-2-yl)morpholin-3-yl]methyl]-1-methylindole-5-carbonitrile Chemical compound C12=CC(C#N)=CC=C2N(C)C=C1C[C@@H]1N(C=2SC=3C(=O)NC(C)(C)CC=3N=2)CCOC1 UBZDDEORUSXHDB-INIZCTEOSA-N 0.000 claims 1
- VMBRTLHHKDIASO-HNNXBMFYSA-N 3-[[(3s)-4-(6,6-dimethyl-4-oxo-5,7-dihydro-[1,3]thiazolo[5,4-c]pyridin-2-yl)morpholin-3-yl]methyl]-1-methylindole-5-carboxylic acid Chemical compound C12=CC(C(O)=O)=CC=C2N(C)C=C1C[C@@H]1N(C=2SC=3C(=O)NC(C)(C)CC=3N=2)CCOC1 VMBRTLHHKDIASO-HNNXBMFYSA-N 0.000 claims 1
- BROYDOKGPFHXGG-INIZCTEOSA-N 3-[[(3s)-4-(6,6-dimethyl-4-oxo-5,7-dihydro-[1,3]thiazolo[5,4-c]pyridin-2-yl)morpholin-3-yl]methyl]-n,n-dimethyl-1-benzofuran-5-carboxamide Chemical compound C1C(C)(C)NC(=O)C(S2)=C1N=C2N1CCOC[C@@H]1CC1=COC2=CC=C(C(=O)N(C)C)C=C21 BROYDOKGPFHXGG-INIZCTEOSA-N 0.000 claims 1
- IFSNARYYAQCALM-IBGZPJMESA-N 3-[[(3s)-4-(6,6-dimethyl-4-oxo-5,7-dihydro-[1,3]thiazolo[5,4-c]pyridin-2-yl)morpholin-3-yl]methyl]-n-(2-methoxyethyl)-n,1-dimethylindole-5-carboxamide Chemical compound C1C(C)(C)NC(=O)C(S2)=C1N=C2N1CCOC[C@@H]1CC1=CN(C)C2=CC=C(C(=O)N(C)CCOC)C=C21 IFSNARYYAQCALM-IBGZPJMESA-N 0.000 claims 1
- KZHJXPFTTKZVJU-HNNXBMFYSA-N 6,6-dimethyl-2-[(3s)-3-[(1-methylindol-3-yl)methyl]morpholin-4-yl]-5,7-dihydro-[1,3]thiazolo[5,4-c]pyridin-4-one Chemical compound C12=CC=CC=C2N(C)C=C1C[C@@H]1N(C=2SC=3C(=O)NC(C)(C)CC=3N=2)CCOC1 KZHJXPFTTKZVJU-HNNXBMFYSA-N 0.000 claims 1
- XEYXAAAKLHDYBZ-HNNXBMFYSA-N methyl 3-[[(3s)-4-(6,6-dimethyl-4-oxo-5,7-dihydro-[1,3]thiazolo[5,4-c]pyridin-2-yl)morpholin-3-yl]methyl]-1-benzofuran-5-carboxylate Chemical compound C1C(C)(C)NC(=O)C(S2)=C1N=C2N1CCOC[C@@H]1CC1=COC2=CC=C(C(=O)OC)C=C21 XEYXAAAKLHDYBZ-HNNXBMFYSA-N 0.000 claims 1
- VQYMPSODBDRLMV-INIZCTEOSA-N methyl 3-[[(3s)-4-(6,6-dimethyl-4-oxo-5,7-dihydro-[1,3]thiazolo[5,4-c]pyridin-2-yl)morpholin-3-yl]methyl]-1-methylindole-5-carboxylate Chemical compound C1C(C)(C)NC(=O)C(S2)=C1N=C2N1CCOC[C@@H]1CC1=CN(C)C2=CC=C(C(=O)OC)C=C21 VQYMPSODBDRLMV-INIZCTEOSA-N 0.000 claims 1
- MIHMPVFWVFAABL-SFHVURJKSA-N n-(cyanomethyl)-3-[[(3s)-4-(6,6-dimethyl-4-oxo-5,7-dihydro-[1,3]thiazolo[5,4-c]pyridin-2-yl)morpholin-3-yl]methyl]-n,1-dimethylindole-5-carboxamide Chemical compound C1C(C)(C)NC(=O)C(S2)=C1N=C2N1CCOC[C@@H]1CC1=CN(C)C2=CC=C(C(=O)N(CC#N)C)C=C21 MIHMPVFWVFAABL-SFHVURJKSA-N 0.000 claims 1
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 abstract description 10
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 abstract description 10
- 230000008901 benefit Effects 0.000 abstract description 4
- 229940124639 Selective inhibitor Drugs 0.000 abstract description 3
- QGUSXKFSPVAZOB-UHFFFAOYSA-N 6,7-dihydro-5h-[1,3]thiazolo[5,4-c]pyridin-4-one Chemical class O=C1NCCC2=C1SC=N2 QGUSXKFSPVAZOB-UHFFFAOYSA-N 0.000 abstract description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 abstract 1
- 238000000034 method Methods 0.000 description 127
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 93
- 239000000543 intermediate Substances 0.000 description 77
- 239000011541 reaction mixture Substances 0.000 description 61
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 54
- 125000000217 alkyl group Chemical group 0.000 description 53
- 238000000746 purification Methods 0.000 description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 50
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 49
- 239000000243 solution Substances 0.000 description 48
- 239000007787 solid Substances 0.000 description 46
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- 239000012071 phase Substances 0.000 description 35
- 238000004440 column chromatography Methods 0.000 description 34
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 34
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 26
- 239000003921 oil Substances 0.000 description 24
- 235000019198 oils Nutrition 0.000 description 24
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 22
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 20
- 239000000203 mixture Substances 0.000 description 17
- 239000002904 solvent Substances 0.000 description 17
- 125000003545 alkoxy group Chemical group 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 16
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 15
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- 235000019253 formic acid Nutrition 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 239000007832 Na2SO4 Substances 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 description 12
- 229910052938 sodium sulfate Inorganic materials 0.000 description 12
- 235000011152 sodium sulphate Nutrition 0.000 description 12
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 9
- 239000012223 aqueous fraction Substances 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- 108091007960 PI3Ks Proteins 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- 101150041968 CDC13 gene Proteins 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
- 238000002953 preparative HPLC Methods 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 241000400611 Eucalyptus deanei Species 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- 125000001153 fluoro group Chemical group F* 0.000 description 6
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 description 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- 229930194542 Keto Natural products 0.000 description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 description 5
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 150000002085 enols Chemical class 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 125000000468 ketone group Chemical group 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 description 5
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- 125000004414 alkyl thio group Chemical group 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 125000000638 benzylaminocarbonyl group Chemical group C(C1=CC=CC=C1)NC(=O)* 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- 229910052723 transition metal Inorganic materials 0.000 description 4
- 150000003624 transition metals Chemical class 0.000 description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
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- A61P3/00—Drugs for disorders of the metabolism
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Landscapes
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
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- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
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| GB0620062A GB0620062D0 (en) | 2006-10-10 | 2006-10-10 | Therapeutic agents |
| GBPCT/GB2007/002390 | 2007-06-26 | ||
| PCT/GB2007/002390 WO2008001076A1 (en) | 2006-06-26 | 2007-06-26 | Fused thiazole derivatives as kinase inhibitors |
| PCT/GB2008/002194 WO2009001089A1 (en) | 2007-06-26 | 2008-06-24 | Fused thiazole derivatives as kinase inhibitors |
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| CA2692085C true CA2692085C (en) | 2015-10-13 |
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| WO2009071895A1 (en) * | 2007-12-04 | 2009-06-11 | Ucb Pharma S.A. | Fused thiazole and thiophene derivatives as kinase inhibitors |
| WO2009071890A1 (en) * | 2007-12-04 | 2009-06-11 | Ucb Pharma S.A. | Tricyclic kinase inhibitors |
| BRPI0821209A2 (pt) | 2007-12-19 | 2019-09-24 | Amgen Inc | composto, composição farmacêutica, métodos de tratar câncer, para reduzir o tamanho de tumor, para tratar distúrbios, e para reduzir metástase em um tumor. |
| WO2009126584A1 (en) | 2008-04-07 | 2009-10-15 | Amgen Inc. | Gem-disubstituted and spirocyclic amino pyridines/pyrimidines as cell cycle inhibitors |
| JPWO2009130900A1 (ja) * | 2008-04-24 | 2011-08-11 | 日本曹達株式会社 | オキシム誘導体、中間体化合物および植物病害防除剤 |
| WO2010011871A2 (en) * | 2008-07-23 | 2010-01-28 | The Regents Of The University Of California | Methods and compositions for providing salicylic acid-independent pathogen resistance in plants |
| EP2341052A4 (en) * | 2008-09-05 | 2011-10-12 | Shionogi & Co | RING-CONDENSED MORPHOLINE DERIVATIVITY WITH PI3K-INHIBITING EFFECT |
| MX2011008645A (es) | 2009-02-17 | 2011-09-30 | Vertex Pharma | Inhibidores de tetrahidrotiazolopiridina de fosfatidilinositol 3 cinasa. |
| EP2408744A1 (en) * | 2009-03-18 | 2012-01-25 | Schering Corporation | Bicyclic compounds as inhibitors of diacylglycerol acyltransferase |
| UY32582A (es) * | 2009-04-28 | 2010-11-30 | Amgen Inc | Inhibidores de fosfoinositida 3 cinasa y/u objetivo mamífero |
| US8410095B2 (en) * | 2009-05-20 | 2013-04-02 | Glaxosmithkline Llc | Thiazolopyrimidinone derivatives as PI3 kinase inhibitors |
| GB0912946D0 (en) | 2009-07-24 | 2009-09-02 | Addex Pharmaceuticals Sa | New compounds 5 |
| CA2771594C (en) | 2009-08-20 | 2018-05-01 | Karus Therapeutics Limited | Tricyclic heterocyclic compounds as phosphoinositide 3-kinase inhibitors |
| AU2010332819B2 (en) | 2009-12-18 | 2014-02-27 | Janssen Pharmaceutica Nv | Bicyclic thiazoles as allosteric modulators of mGluR5 receptors |
| SG181716A1 (en) | 2009-12-18 | 2012-07-30 | Janssen Pharmaceutica Nv | Bicyclic thiazoles as allosteric modulators of mglur5 receptors |
| JP6025717B2 (ja) | 2010-06-15 | 2016-11-16 | バイエル・インテレクチュアル・プロパティ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツングＢａｙｅｒ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ ＧｍｂＨ | 新規なオルト置換されたアリールアミド誘導体 |
| AR084486A1 (es) | 2010-10-01 | 2013-05-22 | Basf Se | Compuestos de imina |
| MX2013004003A (es) * | 2010-10-13 | 2013-10-01 | Millenium Pharmaceuticals Inc | Heteroarilos y usos de los mismos. |
| BR112013012961A2 (pt) * | 2010-11-24 | 2019-09-24 | Exelixis Inc | benzoxazepinas como inhibidores de mtor e métodos de seu uso e fabricação |
| CN102649777B (zh) * | 2011-02-25 | 2014-03-12 | 中国中化股份有限公司 | 一种制备1-芳基-3-羧基-5-吡唑啉酮类化合物的方法 |
| ES2543569T3 (es) | 2011-03-23 | 2015-08-20 | Amgen Inc. | Inhibidores duales tricíclicos condensados de CDK 4/6 y FLT3 |
| SG11201402237WA (en) | 2011-12-22 | 2014-09-26 | Novartis Ag | Dihydro-benzo-oxazine and dihydro-pyrido-oxazine derivatives |
| WO2014153090A1 (en) | 2013-03-14 | 2014-09-25 | Epizyme, Inc. | Pyrazole derivatives asprmt1 inhibitors and uses thereof |
| EP2970181B1 (en) | 2013-03-14 | 2017-06-07 | Epizyme, Inc. | Arginine methyltransferase inhibitors and uses thereof |
| WO2014153172A1 (en) | 2013-03-14 | 2014-09-25 | Epizyme, Inc. | Pyrazole derivatives as prmt1 inhibitors and uses thereof |
| WO2014153100A2 (en) | 2013-03-14 | 2014-09-25 | Epizyme, Inc. | Arginine methyltransferase inhibitors and uses thereof |
| SI2970132T1 (sl) | 2013-03-14 | 2021-02-26 | Epizyme, Inc. | Inhibitorji argininmetiltransferaze in njihove uporabe |
| EP2970220A2 (en) | 2013-03-14 | 2016-01-20 | Epizyme, Inc. | Arginine methyltransferase inhibitors and uses thereof |
| US9120757B2 (en) | 2013-03-14 | 2015-09-01 | Epizyme, Inc. | Arginine methyltransferase inhibitors and uses thereof |
| CA2903264A1 (en) | 2013-03-14 | 2014-11-06 | Epizyme, Inc. | Pyrazole derivatives as arginine methyltransferase inhibitors and uses thereof |
| US9133189B2 (en) | 2013-03-14 | 2015-09-15 | Epizyme, Inc. | Arginine methyltransferase inhibitors and uses thereof |
| US9023883B2 (en) | 2013-03-14 | 2015-05-05 | Epizyme, Inc. | PRMT1 inhibitors and uses thereof |
| KR102456277B1 (ko) * | 2013-10-21 | 2022-10-18 | 우미코레 아게 운트 코 카게 | 방향족 아민의 모노아릴화 |
| GB201402431D0 (en) | 2014-02-12 | 2014-03-26 | Karus Therapeutics Ltd | Compounds |
| GB201514758D0 (en) | 2015-08-19 | 2015-09-30 | Karus Therapeutics Ltd | Formulation |
| GB201514754D0 (en) * | 2015-08-19 | 2015-09-30 | Karus Therapeutics Ltd | Compounds |
| GB201514760D0 (en) | 2015-08-19 | 2015-09-30 | Karus Therapeutics Ltd | Compounds and method of use |
| WO2017156350A1 (en) | 2016-03-09 | 2017-09-14 | K-Gen, Inc. | Methods of cancer treatment |
| CN108570043A (zh) * | 2018-06-20 | 2018-09-25 | 王延娇 | 一种化合物及其作为选择性pi3k抑制剂在治疗肿瘤中的应用 |
| US20220202824A1 (en) | 2018-09-13 | 2022-06-30 | Stemline Therapeutics, Inc. | Methods for Treating Centronuclear Myopathy |
| JP7515481B2 (ja) | 2018-12-19 | 2024-07-12 | レオ ファーマ アクティーゼルスカブ | Ｉｌ－１７の小分子調節物質としてのアミノ酸アニリド |
| WO2020145250A1 (ja) * | 2019-01-08 | 2020-07-16 | 杏林製薬株式会社 | １５－ｐｇｄｈ阻害薬 |
| WO2020160151A1 (en) | 2019-01-31 | 2020-08-06 | Kyorin Pharmaceutical Co., Ltd. | 15-pgdh inhibitors |
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| PL2170906T3 (pl) | 2013-08-30 |
| ES2365258T3 (es) | 2011-09-27 |
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| AU2008269577A1 (en) | 2008-12-31 |
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| US20130079330A1 (en) | 2013-03-28 |
| WO2008001076A1 (en) | 2008-01-03 |
| MX2009013740A (es) | 2010-02-01 |
| AU2008269577B2 (en) | 2012-12-20 |
| IL202659A0 (en) | 2010-06-30 |
| CA2692085A1 (en) | 2008-12-31 |
| EP2170906A1 (en) | 2010-04-07 |
| MY148852A (en) | 2013-06-14 |
| EP2035436A1 (en) | 2009-03-18 |
| CO6270229A2 (es) | 2011-04-20 |
| ATE510840T1 (de) | 2011-06-15 |
| EA201000038A1 (ru) | 2010-06-30 |
| RS52824B (enExample) | 2013-10-31 |
| US20100137302A1 (en) | 2010-06-03 |
| DK2170906T3 (da) | 2013-06-24 |
| EP2035436B1 (en) | 2011-05-25 |
| EA017187B1 (ru) | 2012-10-30 |
| ME01592B (me) | 2014-09-20 |
| US20110003785A1 (en) | 2011-01-06 |
| CN101687885B (zh) | 2012-08-22 |
| CN101687885A (zh) | 2010-03-31 |
| US8338592B2 (en) | 2012-12-25 |
| US8710054B2 (en) | 2014-04-29 |
| PT2170906E (pt) | 2013-06-25 |
| HRP20130523T1 (en) | 2013-07-31 |
| US8242116B2 (en) | 2012-08-14 |
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