CN112979631B - Parg抑制化合物 - Google Patents
Parg抑制化合物 Download PDFInfo
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- CN112979631B CN112979631B CN202110213641.5A CN202110213641A CN112979631B CN 112979631 B CN112979631 B CN 112979631B CN 202110213641 A CN202110213641 A CN 202110213641A CN 112979631 B CN112979631 B CN 112979631B
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- Prior art keywords
- methyl
- methylcyclopropyl
- alkyl
- oxo
- sulfonamide
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 187
- 102100032347 Poly(ADP-ribose) glycohydrolase Human genes 0.000 title description 64
- 230000002401 inhibitory effect Effects 0.000 title description 13
- 101000589450 Homo sapiens Poly(ADP-ribose) glycohydrolase Proteins 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 203
- 238000011282 treatment Methods 0.000 claims abstract description 40
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 39
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 32
- 201000011510 cancer Diseases 0.000 claims abstract description 23
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 21
- 201000010099 disease Diseases 0.000 claims abstract description 18
- 230000002062 proliferating effect Effects 0.000 claims abstract description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 274
- -1 trifluoromethoxy, cyano, hydroxy, amino, carboxy, carbamoyl Chemical group 0.000 claims description 156
- 229910052739 hydrogen Inorganic materials 0.000 claims description 142
- 239000001257 hydrogen Substances 0.000 claims description 142
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 98
- 125000001424 substituent group Chemical group 0.000 claims description 75
- 125000000623 heterocyclic group Chemical group 0.000 claims description 67
- 125000002947 alkylene group Chemical group 0.000 claims description 62
- 229910052736 halogen Inorganic materials 0.000 claims description 60
- 150000002367 halogens Chemical class 0.000 claims description 60
- 150000003839 salts Chemical class 0.000 claims description 53
- 125000001072 heteroaryl group Chemical group 0.000 claims description 50
- 125000003118 aryl group Chemical group 0.000 claims description 47
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 46
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 43
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 37
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 36
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 35
- 229910052717 sulfur Inorganic materials 0.000 claims description 32
- 150000002431 hydrogen Chemical class 0.000 claims description 31
- 125000000304 alkynyl group Chemical group 0.000 claims description 29
- 125000001188 haloalkyl group Chemical group 0.000 claims description 28
- 125000005843 halogen group Chemical group 0.000 claims description 26
- 125000003545 alkoxy group Chemical group 0.000 claims description 17
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 14
- 125000001153 fluoro group Chemical group F* 0.000 claims description 12
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 230000000694 effects Effects 0.000 abstract description 26
- 239000003112 inhibitor Substances 0.000 abstract description 24
- 230000008569 process Effects 0.000 abstract description 3
- 102000004190 Enzymes Human genes 0.000 abstract description 2
- 108090000790 Enzymes Proteins 0.000 abstract description 2
- PWJFNRJRHXWEPT-UHFFFAOYSA-N ADP ribose Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OCC(O)C(O)C(O)C=O)C(O)C1O PWJFNRJRHXWEPT-UHFFFAOYSA-N 0.000 abstract 1
- SRNWOUGRCWSEMX-KEOHHSTQSA-N ADP-beta-D-ribose Chemical compound C([C@H]1O[C@H]([C@@H]([C@@H]1O)O)N1C=2N=CN=C(C=2N=C1)N)OP(O)(=O)OP(O)(=O)OC[C@H]1O[C@@H](O)[C@H](O)[C@@H]1O SRNWOUGRCWSEMX-KEOHHSTQSA-N 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 313
- 239000000543 intermediate Substances 0.000 description 174
- 239000000203 mixture Substances 0.000 description 155
- 239000007787 solid Substances 0.000 description 145
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 129
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 118
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 96
- 239000010410 layer Substances 0.000 description 94
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 93
- 239000000243 solution Substances 0.000 description 85
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 82
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 73
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 71
- 239000011541 reaction mixture Substances 0.000 description 71
- 108010078356 poly ADP-ribose glycohydrolase Proteins 0.000 description 70
- 239000000047 product Substances 0.000 description 70
- 235000019439 ethyl acetate Nutrition 0.000 description 62
- 229910052757 nitrogen Inorganic materials 0.000 description 62
- 238000005160 1H NMR spectroscopy Methods 0.000 description 55
- 238000005481 NMR spectroscopy Methods 0.000 description 54
- 229960005419 nitrogen Drugs 0.000 description 49
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 48
- 229910000027 potassium carbonate Inorganic materials 0.000 description 47
- 235000011181 potassium carbonates Nutrition 0.000 description 47
- 239000012453 solvate Substances 0.000 description 46
- 210000004027 cell Anatomy 0.000 description 43
- 125000006432 1-methyl cyclopropyl group Chemical group [H]C([H])([H])C1(*)C([H])([H])C1([H])[H] 0.000 description 42
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 41
- 238000004440 column chromatography Methods 0.000 description 40
- 238000006073 displacement reaction Methods 0.000 description 39
- 239000002904 solvent Substances 0.000 description 39
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical class [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 38
- 230000002209 hydrophobic effect Effects 0.000 description 36
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 34
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 33
- 238000006243 chemical reaction Methods 0.000 description 33
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 31
- 229920006395 saturated elastomer Polymers 0.000 description 31
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 29
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 29
- 229910052760 oxygen Inorganic materials 0.000 description 29
- 238000002953 preparative HPLC Methods 0.000 description 29
- 125000005842 heteroatom Chemical group 0.000 description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 27
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 26
- 239000002027 dichloromethane extract Substances 0.000 description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 25
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 24
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 21
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 21
- 238000003756 stirring Methods 0.000 description 21
- JRHPOFJADXHYBR-HTQZYQBOSA-N (1r,2r)-1-n,2-n-dimethylcyclohexane-1,2-diamine Chemical compound CN[C@@H]1CCCC[C@H]1NC JRHPOFJADXHYBR-HTQZYQBOSA-N 0.000 description 20
- SILNNFMWIMZVEQ-UHFFFAOYSA-N 1,3-dihydrobenzimidazol-2-one Chemical class C1=CC=C2NC(O)=NC2=C1 SILNNFMWIMZVEQ-UHFFFAOYSA-N 0.000 description 20
- 125000003342 alkenyl group Chemical group 0.000 description 20
- 208000035475 disorder Diseases 0.000 description 20
- 229940002612 prodrug Drugs 0.000 description 20
- 239000000651 prodrug Substances 0.000 description 20
- 239000000725 suspension Substances 0.000 description 20
- GHILZUOTUJGCDH-UHFFFAOYSA-N (1-methylcyclopropyl)azanium;chloride Chemical compound Cl.CC1(N)CC1 GHILZUOTUJGCDH-UHFFFAOYSA-N 0.000 description 19
- PMRVWCCUZFVRFL-UHFFFAOYSA-N 1-(fluoromethyl)cyclopropan-1-amine hydrochloride Chemical compound Cl.NC1(CF)CC1 PMRVWCCUZFVRFL-UHFFFAOYSA-N 0.000 description 18
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 18
- 229910005965 SO 2 Inorganic materials 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 18
- 125000006239 protecting group Chemical group 0.000 description 18
- 238000001727 in vivo Methods 0.000 description 17
- 239000002244 precipitate Substances 0.000 description 17
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 16
- 229910052799 carbon Inorganic materials 0.000 description 16
- 239000003480 eluent Substances 0.000 description 16
- 239000012065 filter cake Substances 0.000 description 16
- NSMKWTGDPQHTDH-UHFFFAOYSA-N 2-bromo-5-methyl-1,3,4-thiadiazole Chemical compound CC1=NN=C(Br)S1 NSMKWTGDPQHTDH-UHFFFAOYSA-N 0.000 description 15
- 239000012258 stirred mixture Substances 0.000 description 15
- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 description 14
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 description 14
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 14
- 235000019270 ammonium chloride Nutrition 0.000 description 14
- 239000012043 crude product Substances 0.000 description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 14
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 13
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 13
- 230000005764 inhibitory process Effects 0.000 description 13
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 12
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- 229910004298 SiO 2 Inorganic materials 0.000 description 12
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 238000010992 reflux Methods 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 11
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 11
- 238000001514 detection method Methods 0.000 description 11
- 150000002148 esters Chemical class 0.000 description 11
- GQUADXWTZXHNAT-UHFFFAOYSA-N 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole Chemical compound FC(F)C1=NN=C(Br)S1 GQUADXWTZXHNAT-UHFFFAOYSA-N 0.000 description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 108010064218 Poly (ADP-Ribose) Polymerase-1 Proteins 0.000 description 10
- 102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 description 10
- 238000003556 assay Methods 0.000 description 10
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 10
- 229910000024 caesium carbonate Inorganic materials 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 10
- 125000004463 2,4-dimethyl-thiazol-5-yl group Chemical group CC=1SC(=C(N1)C)* 0.000 description 9
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
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- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- RWWVDOUACGMOLT-UHFFFAOYSA-N N-(1-methylcyclopropyl)-1H-indole-6-sulfonamide Chemical compound CC1(CC1)NS(=O)(=O)C1=CC=C2C=CNC2=C1 RWWVDOUACGMOLT-UHFFFAOYSA-N 0.000 description 9
- 125000002252 acyl group Chemical group 0.000 description 9
- 150000001350 alkyl halides Chemical class 0.000 description 9
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- 239000007864 aqueous solution Substances 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
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- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 9
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- 101000833118 Homo sapiens ADP-ribosylhydrolase ARH3 Proteins 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 125000003282 alkyl amino group Chemical group 0.000 description 8
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 238000000338 in vitro Methods 0.000 description 8
- 238000002560 therapeutic procedure Methods 0.000 description 8
- GOPQYNXIVUODSP-UHFFFAOYSA-N 3-fluoro-N-(1-methylcyclopropyl)-4-nitrobenzenesulfonamide Chemical compound FC=1C=C(C=CC=1[N+](=O)[O-])S(=O)(=O)NC1(CC1)C GOPQYNXIVUODSP-UHFFFAOYSA-N 0.000 description 7
- 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 7
- UUVUHCAHXNGVLI-UHFFFAOYSA-N 5-fluoro-3-methyl-1h-benzimidazol-2-one Chemical compound FC1=CC=C2NC(=O)N(C)C2=C1 UUVUHCAHXNGVLI-UHFFFAOYSA-N 0.000 description 7
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 7
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- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
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- 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 6
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- PVVVKAMFIFTAMU-UHFFFAOYSA-N 1-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-ethyl-5-fluorobenzimidazol-2-one Chemical compound FC(C1=NN=C(O1)N1C(N(C2=C1C=CC(=C2)F)CC)=O)F PVVVKAMFIFTAMU-UHFFFAOYSA-N 0.000 description 5
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- KKTASLDMXQJLQH-UHFFFAOYSA-N 6-fluoro-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-1H-benzimidazole-5-sulfonamide Chemical compound FC=1C(=CC2=C(NC(N2C=2OC(=NN=2)C)=O)C=1)S(=O)(=O)NC1(CC1)C KKTASLDMXQJLQH-UHFFFAOYSA-N 0.000 description 5
- 239000012623 DNA damaging agent Substances 0.000 description 5
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- 108090000604 Hydrolases Proteins 0.000 description 5
- LPFYIUZRLGKURI-UHFFFAOYSA-N N-(1-methylcyclopropyl)-2,3-dihydro-1H-indole-6-sulfonamide Chemical compound CC1(CC1)NS(=O)(=O)C1=CC=C2CCNC2=C1 LPFYIUZRLGKURI-UHFFFAOYSA-N 0.000 description 5
- 230000002152 alkylating effect Effects 0.000 description 5
- 239000002246 antineoplastic agent Substances 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 5
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- 229910052731 fluorine Inorganic materials 0.000 description 5
- 239000003102 growth factor Substances 0.000 description 5
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Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/26—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Furan Compounds (AREA)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110213641.5A CN112979631B (zh) | 2014-12-19 | 2015-12-17 | Parg抑制化合物 |
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| Application Number | Priority Date | Filing Date | Title |
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| GB1422771.4 | 2014-12-19 | ||
| GB201422771 | 2014-12-19 | ||
| CN201580075709.0A CN107295799B (zh) | 2014-12-19 | 2015-12-17 | Parg抑制化合物 |
| CN202110213641.5A CN112979631B (zh) | 2014-12-19 | 2015-12-17 | Parg抑制化合物 |
| PCT/GB2015/054064 WO2016097749A1 (en) | 2014-12-19 | 2015-12-17 | Parg inhibitory compounds |
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| CN201580075709.0A Division CN107295799B (zh) | 2014-12-19 | 2015-12-17 | Parg抑制化合物 |
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| CN112979631A CN112979631A (zh) | 2021-06-18 |
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| CN201580075709.0A Active CN107295799B (zh) | 2014-12-19 | 2015-12-17 | Parg抑制化合物 |
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| CN201580075709.0A Active CN107295799B (zh) | 2014-12-19 | 2015-12-17 | Parg抑制化合物 |
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| EP (2) | EP3233845B1 (OSRAM) |
| JP (1) | JP6673920B2 (OSRAM) |
| KR (1) | KR102682782B1 (OSRAM) |
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| SG (1) | SG11201704843QA (OSRAM) |
| WO (1) | WO2016097749A1 (OSRAM) |
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| MA41140A (fr) | 2014-12-12 | 2017-10-17 | Cancer Research Tech Ltd | Dérivés de 2,4-dioxo-quinazoline-6-sulfonamide en tant qu'inhibiteurs de la parg |
| MA41179A (fr) | 2014-12-19 | 2017-10-24 | Cancer Research Tech Ltd | Composés inhibiteurs de parg |
| EP3947351A4 (en) | 2019-03-29 | 2022-12-07 | Board of Regents, The University of Texas System | SMALL MOLECULAR PARG INHIBITORS AND METHODS OF USE |
| MX2022003276A (es) * | 2019-09-20 | 2022-04-11 | Ideaya Biosciences Inc | Derivados de indol e indazol sulfonamido sustituidos en la posicion 4 como inhibidores de parg. |
| AU2022359801A1 (en) | 2021-10-04 | 2024-02-01 | Forx Therapeutics Ag | Parg inhibitory compounds |
| EP4413000A1 (en) | 2021-10-04 | 2024-08-14 | FoRx Therapeutics AG | N,n-dimethyl-4-(7-(n-(1-methylcyclopropyl)sulfamoyl)-imidazo[1,5-a]pyridin-5-yl)piperazine-1-carboxamide derivatives and the corresponding pyrazolo[1,5-a]pyridine derivatives as parg inhibitors for the treatment of cancer |
| WO2023064619A1 (en) | 2021-10-17 | 2023-04-20 | University of South Alabama Foundation for Research and Commercialization | Cancer treatment |
| US12227484B2 (en) | 2022-02-14 | 2025-02-18 | Arase Therapeutics Inc. | Inhibitors of PARG |
| JP2025509180A (ja) * | 2022-03-04 | 2025-04-11 | 上海瓔黎薬業有限公司 | 五員ヘテロアリール環構造含有化合物、その医薬組成物及び使用 |
| WO2023175185A1 (en) | 2022-03-17 | 2023-09-21 | Forx Therapeutics Ag | 2,4-dioxo-1,4-dihydroquinazoline derivatives as parg inhibitors for the treatment of cancer |
| WO2023175184A1 (en) | 2022-03-17 | 2023-09-21 | Forx Therapeutics Ag | 2,4-dioxo-1,4-dihydroquinazoline derivatives as parg inhibitors for the treatment of cancer |
| CN119255994A (zh) * | 2022-03-23 | 2025-01-03 | 艾迪亚生物科学公司 | 哌嗪取代的吲唑化合物作为parg抑制剂 |
| CN114685283B (zh) * | 2022-04-06 | 2024-02-27 | 南京艾康生物科技有限公司 | 一种1-(氟甲基)环丙胺盐酸盐的制备方法 |
| WO2023205914A1 (en) * | 2022-04-28 | 2023-11-02 | Danatlas Pharmaceuticals Co., Ltd. | Tricyclic heterocyclic derivatives, compositions and uses thereof |
| IL316261A (en) * | 2022-04-28 | 2024-12-01 | Danatlas Pharmaceuticals Co Ltd | Tricyclic and heterocyclic derivatives, preparations and uses thereof |
| JP2025522274A (ja) | 2022-05-17 | 2025-07-15 | 858 セラピューティクス,インコーポレーテッド | Pargの阻害剤 |
| KR20250028378A (ko) * | 2022-06-29 | 2025-02-28 | 항저우 신알엑스 테라퓨틱스 바이오메디컬 테크놀로지 컴퍼니 리미티드 | 5원 및 6원 융합 질소 함유 화합물, 이의 중간체, 제조 방법 및 용도 |
| CN119522220A (zh) * | 2022-07-19 | 2025-02-25 | 苏州信诺维医药科技股份有限公司 | 含硫杂芳环化合物、其药物组合物及其用途 |
| EP4311829A1 (en) | 2022-07-28 | 2024-01-31 | Nodus Oncology Limited | Substituted bicyclic heteroaryl sulfonamide derivatives for the treatment of cancer |
| AU2023355735A1 (en) | 2022-10-03 | 2025-04-03 | Forx Therapeutics Ag | Parg inhibitory compound |
| TW202417429A (zh) * | 2022-10-13 | 2024-05-01 | 南韓商韓美藥品股份有限公司 | 用於抑制yap-tead交互作用的新穎雜雙環化合物及包含其之藥學組成物 |
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