CA3147493A1 - 4-substituted indole and indazole sulfonamido derivatives as parg inhibitors - Google Patents
4-substituted indole and indazole sulfonamido derivatives as parg inhibitors Download PDFInfo
- Publication number
- CA3147493A1 CA3147493A1 CA3147493A CA3147493A CA3147493A1 CA 3147493 A1 CA3147493 A1 CA 3147493A1 CA 3147493 A CA3147493 A CA 3147493A CA 3147493 A CA3147493 A CA 3147493A CA 3147493 A1 CA3147493 A1 CA 3147493A1
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- CA
- Canada
- Prior art keywords
- alkyl
- hydrogen
- heterocyclyl
- compound
- pharmaceutically acceptable
- 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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- -1 4-substituted indole Chemical class 0.000 title claims description 116
- 239000003112 inhibitor Substances 0.000 title abstract description 28
- 101150003479 Parg gene Proteins 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 338
- 150000003839 salts Chemical class 0.000 claims abstract description 167
- 125000000217 alkyl group Chemical group 0.000 claims description 128
- 229910052739 hydrogen Inorganic materials 0.000 claims description 107
- 239000001257 hydrogen Substances 0.000 claims description 107
- 150000002431 hydrogen Chemical group 0.000 claims description 84
- 125000000623 heterocyclic group Chemical group 0.000 claims description 83
- 125000001072 heteroaryl group Chemical group 0.000 claims description 58
- 229910052757 nitrogen Inorganic materials 0.000 claims description 52
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 50
- 125000005843 halogen group Chemical group 0.000 claims description 45
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 36
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 33
- 206010028980 Neoplasm Diseases 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 27
- 125000001188 haloalkyl group Chemical group 0.000 claims description 22
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 21
- 201000011510 cancer Diseases 0.000 claims description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims description 21
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 16
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 14
- 125000006413 ring segment Chemical group 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 125000004193 piperazinyl group Chemical group 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000002883 imidazolyl group Chemical group 0.000 claims description 9
- 125000000335 thiazolyl group Chemical group 0.000 claims description 9
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 8
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 7
- 125000004429 atom Chemical group 0.000 claims description 7
- 229910052703 rhodium Inorganic materials 0.000 claims description 7
- 229910052721 tungsten Inorganic materials 0.000 claims description 7
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
- 229910052805 deuterium Inorganic materials 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 6
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 claims description 5
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 5
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 4
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 claims description 4
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 claims description 4
- 125000004521 1,3,4-thiadiazol-2-yl group Chemical group S1C(=NN=C1)* 0.000 claims description 4
- 125000002619 bicyclic group Chemical group 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 claims description 3
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 3
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
- 229910052701 rubidium Inorganic materials 0.000 claims description 3
- 125000005988 1,1-dioxo-thiomorpholinyl group Chemical group 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000002757 morpholinyl group Chemical group 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 14
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
- 108010078356 poly ADP-ribose glycohydrolase Proteins 0.000 abstract description 36
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 194
- 230000015572 biosynthetic process Effects 0.000 description 143
- 238000003786 synthesis reaction Methods 0.000 description 142
- 239000012043 crude product Substances 0.000 description 88
- 239000000203 mixture Substances 0.000 description 81
- 239000000243 solution Substances 0.000 description 81
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 68
- 239000012299 nitrogen atmosphere Substances 0.000 description 66
- AUQDITHEDVOTCU-UHFFFAOYSA-N cyclopropyl cyanide Chemical compound N#CC1CC1 AUQDITHEDVOTCU-UHFFFAOYSA-N 0.000 description 60
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 57
- 238000005481 NMR spectroscopy Methods 0.000 description 55
- 238000005160 1H NMR spectroscopy Methods 0.000 description 52
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 48
- 238000004809 thin layer chromatography Methods 0.000 description 45
- 238000002953 preparative HPLC Methods 0.000 description 43
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 42
- 210000004027 cell Anatomy 0.000 description 37
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 36
- MXFYYFVVIIWKFE-UHFFFAOYSA-N dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phosphane Chemical compound CC(C)OC1=CC=CC(OC(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 MXFYYFVVIIWKFE-UHFFFAOYSA-N 0.000 description 32
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 31
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 30
- 229920006395 saturated elastomer Polymers 0.000 description 30
- 238000011282 treatment Methods 0.000 description 27
- 102100025524 Cullin-9 Human genes 0.000 description 25
- 101000856395 Homo sapiens Cullin-9 Proteins 0.000 description 25
- FINPLSBBDVRBPA-UHFFFAOYSA-M chloropalladium(1+);dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phosphane;2-methoxy-2-methylpropane;2-phenylethanamine Chemical compound [Pd+]Cl.COC(C)(C)C.NCCC1=CC=CC=[C-]1.CC(C)OC1=CC=CC(OC(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 FINPLSBBDVRBPA-UHFFFAOYSA-M 0.000 description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 23
- 239000010410 layer Substances 0.000 description 23
- XMFYMWXCIWIHAC-UHFFFAOYSA-N n,n-dimethylpiperazine-1-carboxamide Chemical compound CN(C)C(=O)N1CCNCC1 XMFYMWXCIWIHAC-UHFFFAOYSA-N 0.000 description 23
- 229960005419 nitrogen Drugs 0.000 description 23
- 229940124530 sulfonamide Drugs 0.000 description 23
- 101000978371 Homo sapiens C-C motif chemokine 18 Proteins 0.000 description 21
- 229910000024 caesium carbonate Inorganic materials 0.000 description 21
- 230000005764 inhibitory process Effects 0.000 description 20
- 239000007787 solid Substances 0.000 description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 239000012298 atmosphere Substances 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- 208000035475 disorder Diseases 0.000 description 16
- 230000000694 effects Effects 0.000 description 16
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 16
- 239000000284 extract Substances 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 14
- 201000010099 disease Diseases 0.000 description 14
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 description 13
- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 description 13
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 11
- 239000003814 drug Substances 0.000 description 11
- 230000002401 inhibitory effect Effects 0.000 description 11
- 238000013459 approach Methods 0.000 description 10
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- NJGVTIXCHOYDJW-UHFFFAOYSA-N 3-oxa-9-azaspiro[5.5]undecane Chemical compound C1CNCCC21CCOCC2 NJGVTIXCHOYDJW-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- 235000015320 potassium carbonate Nutrition 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 230000002062 proliferating effect Effects 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- 208000024891 symptom Diseases 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- 238000001727 in vivo Methods 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 230000033616 DNA repair Effects 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 229940088598 enzyme Drugs 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 5
- 230000000259 anti-tumor effect Effects 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 5
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- 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 5
- 230000033443 single strand break repair Effects 0.000 description 5
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
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- LRBQNJMCXXYXIU-PPKXGCFTSA-N Chinese gallotannin Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 description 4
- 229910052693 Europium Inorganic materials 0.000 description 4
- 101000610640 Homo sapiens U4/U6 small nuclear ribonucleoprotein Prp3 Proteins 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical class OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- 239000012661 PARP inhibitor Substances 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 description 4
- 101001110823 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-A Proteins 0.000 description 4
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- 125000002947 alkylene group Chemical group 0.000 description 4
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- 230000007246 mechanism Effects 0.000 description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 4
- GZRKXKUVVPSREJ-UHFFFAOYSA-N pyridinylpiperazine Chemical compound C1CNCCN1C1=CC=CC=N1 GZRKXKUVVPSREJ-UHFFFAOYSA-N 0.000 description 4
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
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- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
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- 230000001594 aberrant effect Effects 0.000 description 3
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- 150000001412 amines Chemical class 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
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- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 3
- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
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Classifications
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61K31/4965—Non-condensed pyrazines
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- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
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- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- 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
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
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- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
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- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
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| PCT/US2020/051486 WO2021055744A1 (en) | 2019-09-20 | 2020-09-18 | 4-substituted indole and indazole sulfonamido derivatives as parg inhibitors |
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| MX (1) | MX2022003276A (enExample) |
| TW (1) | TWI873187B (enExample) |
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| MA41179A (fr) | 2014-12-19 | 2017-10-24 | Cancer Research Tech Ltd | Composés inhibiteurs de parg |
| 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 |
| AU2022359801A1 (en) | 2021-10-04 | 2024-02-01 | Forx Therapeutics Ag | Parg inhibitory compounds |
| WO2023154913A1 (en) * | 2022-02-14 | 2023-08-17 | 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 |
| 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 |
| 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 |
| WO2023183850A1 (en) * | 2022-03-23 | 2023-09-28 | Ideaya Biosciences, Inc. | Piperazine substituted indazole compounds as inhibitors of parg |
| CN117157299B (zh) * | 2022-04-28 | 2024-05-28 | 北京丹擎医药科技有限公司 | 三环杂环衍生物及其组合物和应用 |
| WO2023224998A1 (en) * | 2022-05-17 | 2023-11-23 | 858 Therapeutics, Inc. | Inhibitors of parg |
| 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 |
| WO2024002284A1 (zh) * | 2022-06-29 | 2024-01-04 | 杭州圣域生物医药科技有限公司 | 五元并六元含氮化合物、其中间体、制备方法和应用 |
| EP4559912A1 (en) * | 2022-07-19 | 2025-05-28 | Evopoint Biosciences Co., Ltd. | Sulfur-containing heteroaromatic ring compound, pharmaceutical composition thereof, and use thereof |
| EP4311829A1 (en) | 2022-07-28 | 2024-01-31 | Nodus Oncology Limited | Substituted bicyclic heteroaryl sulfonamide derivatives for the treatment of cancer |
| WO2024074497A1 (en) | 2022-10-03 | 2024-04-11 | Forx Therapeutics Ag | Parg inhibitory compound |
| JP2025533274A (ja) * | 2022-10-13 | 2025-10-03 | ハンミ ファーマシューティカルズ カンパニー リミテッド | Ｙａｐ－ｔｅａｄ相互作用を阻害するための新規なヘテロ二環式化合物及びそれを含む薬学的組成物 |
| WO2024148280A1 (en) | 2023-01-06 | 2024-07-11 | Ideaya Biosciences, Inc. | Treatment of er+ breast cancer comprising homologous recombination deficiency using parc inhibitor |
| WO2024173234A1 (en) * | 2023-02-13 | 2024-08-22 | Arase Therapeutics Inc. | Inhibitors of parg |
| WO2024173530A1 (en) * | 2023-02-14 | 2024-08-22 | Ideaya Biosciences, Inc. | Heteroaryl-substituted pyrazolo/imidazo pyridine compounds |
| WO2024173524A1 (en) * | 2023-02-14 | 2024-08-22 | Ideaya Biosciences, Inc. | Heteroaryl-substituted benzimidazole compounds |
| WO2024173453A1 (en) * | 2023-02-14 | 2024-08-22 | Ideaya Biosciences, Inc. | Heteroaryl-substituted imidazopyridine compounds |
| WO2024173514A1 (en) * | 2023-02-14 | 2024-08-22 | Ideaya Biosciences, Inc. | Amide and ester-substituted imidazopyridine compounds |
| WO2024209035A1 (en) | 2023-04-05 | 2024-10-10 | Forx Therapeutics Ag | Parg inhibitory compounds |
| WO2024211506A1 (en) | 2023-04-05 | 2024-10-10 | Ideaya Biosciences, Inc. | Combination therapy comprising a parg inhibitor and a topoisomerase inhibitor for treating cancer |
| CN121002021A (zh) * | 2023-04-27 | 2025-11-21 | 北京丹擎医药科技有限公司 | 三环杂环衍生物及其组合物和应用 |
| CN119143747A (zh) * | 2023-06-16 | 2024-12-17 | 上海璎黎药业有限公司 | 一种杂芳环结构化合物、其药物组合物及应用 |
| WO2025046148A1 (en) | 2023-09-01 | 2025-03-06 | Forx Therapeutics Ag | Novel parg inhibitors |
| TW202528308A (zh) * | 2023-09-20 | 2025-07-16 | 美商愛德亞生物科學公司 | Parg抑制劑 |
| WO2025064750A1 (en) | 2023-09-20 | 2025-03-27 | Ideaya Biosciences, Inc. | Combination therapy with a parg inhibitor |
| WO2025072544A1 (en) * | 2023-09-27 | 2025-04-03 | Ideaya Biosciences, Inc. | Sulfonamino indazole compounds as inhibitors of parg |
| CN119708015A (zh) * | 2023-09-28 | 2025-03-28 | 杭州圣域生物医药科技有限公司 | 杂芳基化合物、其中间体、制备方法和应用 |
| WO2025073870A1 (en) | 2023-10-03 | 2025-04-10 | Forx Therapeutics Ag | Parg inhibitory compound |
| CN119859145A (zh) * | 2023-10-20 | 2025-04-22 | 上海璎黎药业有限公司 | 一种杂芳环磺酰胺结构化合物、其药物组合物及应用 |
| WO2025087941A1 (en) | 2023-10-23 | 2025-05-01 | Universite De Geneve | Parg inhibitors in combination with parp inhibitors and uses thereof |
| TW202523299A (zh) * | 2023-10-26 | 2025-06-16 | 大陸商上海齊魯製藥研究中心有限公司 | Parg抑制劑 |
| WO2025093755A1 (en) | 2023-11-01 | 2025-05-08 | Forx Therapeutics Ag | Novel parc inhibitors |
| WO2025098445A1 (zh) * | 2023-11-07 | 2025-05-15 | 南京同诺康医药科技有限公司 | Parg抑制剂及其制备方法和用途 |
| WO2025108225A1 (zh) * | 2023-11-20 | 2025-05-30 | 上海复星医药（集团）股份有限公司 | 作为parg抑制剂的含氮三环衍生物 |
| WO2025111339A1 (en) * | 2023-11-21 | 2025-05-30 | 858 Therapeutics, Inc. | Treatment of cancer with a parg inhibitor |
| TW202529739A (zh) * | 2023-11-22 | 2025-08-01 | 美商858療法股份有限公司 | Parg之抑制劑 |
| WO2025133396A1 (en) | 2023-12-22 | 2025-06-26 | Forx Therapeutics Ag | Novel bicyclo heteroaryl parg inhibitors |
| WO2025133191A1 (en) * | 2023-12-22 | 2025-06-26 | Genecode | Novel sulfonamides or sulfones and their use as neuroprotective and/or neurorestorative agents |
| WO2025229549A1 (en) * | 2024-04-30 | 2025-11-06 | Satyarx Pharma Innovations Pvt Ltd | Novel heterocyclic compounds as inhibitors of parg |
| CN118459452B (zh) * | 2024-07-10 | 2024-10-25 | 苏州国匡医药科技有限公司 | 一种多聚adp核糖水解酶抑制剂及其应用 |
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| GB9624482D0 (en) | 1995-12-18 | 1997-01-15 | Zeneca Phaema S A | Chemical compounds |
| CA2242425C (en) | 1996-02-13 | 2006-07-18 | Zeneca Limited | Quinazoline derivatives as vegf inhibitors |
| DE69709319T2 (de) | 1996-03-05 | 2002-08-14 | Astrazeneca Ab, Soedertaelje | 4-anilinochinazolin derivate |
| GB9718972D0 (en) | 1996-09-25 | 1997-11-12 | Zeneca Ltd | Chemical compounds |
| GB9714249D0 (en) | 1997-07-08 | 1997-09-10 | Angiogene Pharm Ltd | Vascular damaging agents |
| GB9900334D0 (en) | 1999-01-07 | 1999-02-24 | Angiogene Pharm Ltd | Tricylic vascular damaging agents |
| GB9900752D0 (en) | 1999-01-15 | 1999-03-03 | Angiogene Pharm Ltd | Benzimidazole vascular damaging agents |
| EE05345B1 (et) | 1999-02-10 | 2010-10-15 | Astrazeneca Ab | Kinasoliini derivaadid angiogeneesi inhibiitoritena |
| CN1431999A (zh) | 2000-05-31 | 2003-07-23 | 阿斯特拉曾尼卡有限公司 | 具有血管损伤活性的吲哚衍生物 |
| UA73993C2 (uk) | 2000-06-06 | 2005-10-17 | Астразенека Аб | Хіназолінові похідні для лікування пухлин та фармацевтична композиція |
| JP2004502766A (ja) | 2000-07-07 | 2004-01-29 | アンギオジェン・ファーマシューティカルズ・リミテッド | 血管損傷剤としてのコルヒノール誘導体 |
| RU2003103603A (ru) | 2000-07-07 | 2004-08-20 | Энджиоджен Фармасьютикалз Лимитед (Gb) | Производные колхинола в качестве ингибиторов ангиогенеза |
| CA2834101A1 (en) * | 2011-01-07 | 2012-07-12 | Taiho Pharmaceutical Co., Ltd. | Novel indole or indazole derivative or salt thereof |
| 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 |
| EP3697777A1 (en) * | 2017-10-19 | 2020-08-26 | eFFECTOR Therapeutics, Inc. | Benzimidazole-indole inhibitors of mnk1 and mnk2 |
| EP3870575B1 (en) * | 2018-10-25 | 2023-03-29 | ViiV Healthcare UK (No.5) Limited | Inhibitors of human immunodeficiency virus replication |
| WO2023183850A1 (en) * | 2022-03-23 | 2023-09-28 | Ideaya Biosciences, Inc. | Piperazine substituted indazole compounds as inhibitors of parg |
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| TWI873187B (zh) | 2025-02-21 |
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| AU2020348489A1 (en) | 2022-05-05 |
| JP2025016684A (ja) | 2025-02-04 |
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| KR20220066922A (ko) | 2022-05-24 |
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