CN118475558A - Sulfonylurea compound - Google Patents
Sulfonylurea compound Download PDFInfo
- Publication number
- CN118475558A CN118475558A CN202280087510.XA CN202280087510A CN118475558A CN 118475558 A CN118475558 A CN 118475558A CN 202280087510 A CN202280087510 A CN 202280087510A CN 118475558 A CN118475558 A CN 118475558A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- membered
- cycloalkyl
- heterocycloalkyl
- membered heterocycloalkyl
- 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.)
- Pending
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- -1 Sulfonylurea compound Chemical class 0.000 title claims description 241
- 229940100389 Sulfonylurea Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 224
- 150000003839 salts Chemical class 0.000 claims abstract description 104
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 24
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 23
- 201000010099 disease Diseases 0.000 claims abstract description 22
- 230000000694 effects Effects 0.000 claims abstract description 13
- 102000000874 Pyrin Domain-Containing 3 Protein NLR Family Human genes 0.000 claims abstract description 12
- 108010001946 Pyrin Domain-Containing 3 Protein NLR Family Proteins 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 605
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 410
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 378
- 229910052736 halogen Inorganic materials 0.000 claims description 161
- 150000002367 halogens Chemical class 0.000 claims description 161
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 131
- 229910052739 hydrogen Inorganic materials 0.000 claims description 94
- 239000001257 hydrogen Substances 0.000 claims description 94
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 80
- 150000002431 hydrogen Chemical class 0.000 claims description 78
- 125000001424 substituent group Chemical group 0.000 claims description 71
- 125000005843 halogen group Chemical group 0.000 claims description 69
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 47
- 125000001072 heteroaryl group Chemical group 0.000 claims description 42
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 42
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 39
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 39
- 125000004429 atom Chemical group 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 230000000155 isotopic effect Effects 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 229910052805 deuterium Inorganic materials 0.000 claims description 14
- 230000002757 inflammatory effect Effects 0.000 claims description 14
- 238000006467 substitution reaction Methods 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 125000004969 haloethyl group Chemical group 0.000 claims description 8
- 125000004970 halomethyl group Chemical group 0.000 claims description 8
- 208000023275 Autoimmune disease Diseases 0.000 claims description 7
- 208000011594 Autoinflammatory disease Diseases 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 208000026278 immune system disease Diseases 0.000 claims description 7
- 208000027866 inflammatory disease Diseases 0.000 claims description 7
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 150000001975 deuterium Chemical group 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 229940079593 drug Drugs 0.000 abstract description 5
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 147
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 132
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 104
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 92
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 76
- 238000006243 chemical reaction Methods 0.000 description 76
- 238000005160 1H NMR spectroscopy Methods 0.000 description 64
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 53
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 52
- 239000000243 solution Substances 0.000 description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- 239000000203 mixture Substances 0.000 description 38
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 37
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 30
- 239000000706 filtrate Substances 0.000 description 30
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 28
- 229910004298 SiO 2 Inorganic materials 0.000 description 25
- 239000003208 petroleum Substances 0.000 description 25
- 239000012071 phase Substances 0.000 description 24
- 239000012074 organic phase Substances 0.000 description 23
- 238000003756 stirring Methods 0.000 description 23
- 239000012043 crude product Substances 0.000 description 22
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 22
- 239000008346 aqueous phase Substances 0.000 description 20
- 238000010898 silica gel chromatography Methods 0.000 description 20
- 125000003545 alkoxy group Chemical group 0.000 description 19
- 210000004027 cell Anatomy 0.000 description 19
- 239000007858 starting material Substances 0.000 description 19
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- 235000011114 ammonium hydroxide Nutrition 0.000 description 17
- 230000002441 reversible effect Effects 0.000 description 15
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 239000003643 water by type Substances 0.000 description 13
- 238000001914 filtration Methods 0.000 description 12
- 239000012299 nitrogen atmosphere Substances 0.000 description 12
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 11
- 238000010828 elution Methods 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- DHQMUJSACXTPEA-UHFFFAOYSA-N (2-methoxypyridin-4-yl)boronic acid Chemical compound COC1=CC(B(O)O)=CC=N1 DHQMUJSACXTPEA-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- 229910021529 ammonia Inorganic materials 0.000 description 10
- 239000005457 ice water Substances 0.000 description 10
- 238000004262 preparative liquid chromatography Methods 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 229930040373 Paraformaldehyde Natural products 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 229920002866 paraformaldehyde Polymers 0.000 description 9
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 8
- 125000003118 aryl group Chemical group 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- HGDWHTASNMRJMP-UHFFFAOYSA-N [1-(hydroxyamino)-1-oxo-5-(3-phenoxyphenyl)pentan-2-yl]phosphonic acid Chemical compound ONC(=O)C(P(O)(O)=O)CCCC1=CC=CC(OC=2C=CC=CC=2)=C1 HGDWHTASNMRJMP-UHFFFAOYSA-N 0.000 description 7
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 125000004126 inden-3-yl group Chemical group [H]C1=C(*)C2=C([H])C([H])=C([H])C([H])=C2C1([H])[H] 0.000 description 7
- 125000004043 oxo group Chemical group O=* 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 125000006413 ring segment Chemical group 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 238000001990 intravenous administration Methods 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- XJTWGMHOQKGBDO-GOSISDBHSA-N N-[(3-Fluorophenyl)methyl]-1-[(1r)-1-Naphthalen-1-Ylethyl]piperidine-4-Carboxamide Chemical compound C1CN([C@H](C)C=2C3=CC=CC=C3C=CC=2)CCC1C(=O)NCC1=CC=CC(F)=C1 XJTWGMHOQKGBDO-GOSISDBHSA-N 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 125000004414 alkyl thio group Chemical group 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 125000000000 cycloalkoxy group Chemical group 0.000 description 5
- 238000004949 mass spectrometry Methods 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 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 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-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
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical group [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 125000002947 alkylene group Chemical group 0.000 description 4
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 4
- 239000001569 carbon dioxide Substances 0.000 description 4
- 229910002092 carbon dioxide Inorganic materials 0.000 description 4
- 238000005341 cation exchange Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000003456 ion exchange resin Substances 0.000 description 4
- 229920003303 ion-exchange polymer Polymers 0.000 description 4
- 229910001415 sodium ion Inorganic materials 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 3
- 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 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 3
- WUZBOJXXYMKMMF-UHFFFAOYSA-N COC1=CC2=NC=3N(C(N(C(C=3N2C=C1)=O)CCC)=O)CCCCNC(=O)C1=CC=C(C=C1)S(=O)(=O)F Chemical compound COC1=CC2=NC=3N(C(N(C(C=3N2C=C1)=O)CCC)=O)CCCCNC(=O)C1=CC=C(C=C1)S(=O)(=O)F WUZBOJXXYMKMMF-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 3
- 108091008099 NLRP3 inflammasome Proteins 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 206010003246 arthritis Diseases 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 125000005366 cycloalkylthio group Chemical group 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 3
- 125000003367 polycyclic group Chemical group 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- KAFZOLYKKCWUBI-HPMAGDRPSA-N (2s)-2-[[(2s)-2-[[(2s)-1-[(2s)-3-amino-2-[[(2s)-2-[[(2s)-2-(3-cyclohexylpropanoylamino)-4-methylpentanoyl]amino]-5-methylhexanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]butanediamide Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CCC(C)C)C(=O)N[C@@H](CN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(N)=O)C(=O)CCC1CCCCC1 KAFZOLYKKCWUBI-HPMAGDRPSA-N 0.000 description 2
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 2
- COXVPYKZDDKVRF-ULQDDVLXSA-N (4,4-difluorocyclohexyl)methyl N-[(2S)-4-methyl-1-oxo-1-[[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]pentan-2-yl]carbamate Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](C[C@@H]1CCNC1=O)C=O)NC(=O)OCC2CCC(CC2)(F)F COXVPYKZDDKVRF-ULQDDVLXSA-N 0.000 description 2
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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Abstract
The present disclosure provides sulfonylurea compounds. In particular to a compound shown in a formula (I) or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound and application of the compound in preparing medicines for treating diseases related to NLRP3 activity. The groups in the formula I are defined in the specification.
Description
The present disclosure relates to the field of medicine, and in particular to sulfonylurea compounds, uses thereof and a preparation method thereof.
NOD-like receptor protein 3 (NOD-like receptor protein, NLRP 3) is a protein-encoding gene that belongs to the family of nucleotide binding and oligomerization domain-like receptors (NLRs), also known as "pus-containing domain protein 3" (Inoue et al, immunology,2013, 139, 1-18). The gene encodes a protein comprising a pyridine domain, a nucleotide binding site domain (NBD), and a Leucine Rich Repeat (LRR) motif. NLRP3 interacts with adapter proteins, apoptosis-related spotting proteins (ASCs), and zymogen-1 in response to sterile inflammatory risk signals to form NLRP3 inflammasomes. Activation of the NLRP3 inflammasome then leads to the release of the inflammatory cytokines IL-1b and IL-18, which, when the activation of the NLRP3 inflammasome is deregulated, drives the onset of many diseases.
Studies have shown that activation of NLRP3 inflammasome is associated with a variety of diseases, including: inflammatory related diseases, immune diseases such as autoimmune diseases, inflammatory diseases such as autoinflammatory diseases. Thus, there is a need to provide new NLRP3 inflammatory body pathway inhibitors to provide new alternatives to the treatment of the above-mentioned diseases.
Disclosure of Invention
In a first aspect, the present disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof,
Wherein R 1 is
R 2 is
X 1 is selected from S and O;
X 2 is CR 5 or N;
A. B is each independently selected from NR 7、C(R 4a) 2 and O;
E. d is each independently selected from NR 7b、C(R 6a) 2 and O;
R 3 is selected from hydrogen, C 1-6 alkyl, 3-6 membered cycloalkyl; the C 1-6 alkyl, 3-6 membered cycloalkyl is optionally substituted with one or more substituents selected from C 1-6 alkyl, 3-6 membered cycloalkyl, halogen, cyano, hydroxy;
R 7 or R 7b are independently selected from hydrogen, C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 heterocycloalkyl, 5-6 heteroaryl, phenyl, halogen, cyano, amino, nitro, -CONH 2、-CO-C 1-6 alkyl such as-COCH 3、-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3、-C 1-6 alkylene-SO 2 -3-6 heterocycloalkyl, The C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 heterocycloalkyl, 5-6 heteroaryl, phenyl, amino, -CONH 2、-CO-C 1-6 alkyl such as-COCH 3、-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3、-C 1-6 alkylene-SO 2 -3-6 heterocycloalkyl optionally substituted with one or more substituents selected from R 7c;
R 7a is selected from hydrogen, cyano, hydroxy, halogen, and nitro; preferably R 7a is cyano or hydroxy;
R 7c is independently substituted with a substituent selected from the group consisting of C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, halo, amino, cyano, nitro, hydroxy; the C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl optionally substituted with one or more substituents selected from halogen, amino, cyano, nitro, hydroxy;
Each R 4a、R 4b、R 4c、R 4d、R 4e is the same or different and is each independently selected from hydrogen, halogen, cyano, amino, nitro, -CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl; the-CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl is optionally substituted by one or more R 4f;
or R 4a form =s, =o, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl with each other; the 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted with one or more substituents selected from halogen, cyano, amino, nitro, -CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl;
or R 4b and R 4c、R 4d and R 4e together with the atoms to which they are attached form =s, =o, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl; the 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted with one or more substituents selected from halogen, cyano, amino, nitro, -CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl;
R 5 is selected from hydrogen, halogen, cyano, amino, nitro, -CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl; the-CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl is optionally substituted by one or more R 5a;
Each R 6a、R 6b、R 6c、R 6d、R 6e is the same or different and is each independently selected from hydrogen, halogen, cyano, amino, nitro, hydroxy, -CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl; the-CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl is optionally substituted by one or more R 6f;
Or R 6a form =s, =o, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl with each other; the 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted with one or more substituents selected from halogen, cyano, amino, nitro, -CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl;
Or R 6b and R 6c、R 6d and R 6e together with the atoms to which they are attached form =s, =o, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl; the 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted with one or more substituents selected from halogen, cyano, amino, nitro, -CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl;
Z is N or CR 12;
R 12 is selected from hydrogen, C 1-6 alkyl, -O-C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, halogen, cyano, amino, -CONH 2、-SO 2R 12a、-CH 2-SO 2R 12a; the C 1-6 alkyl, -O-C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, amino, -CONH 2 are optionally substituted with one or more R 12b;
R 12b is selected from halogen, cyano, hydroxy, amino, C 1-6 alkyl, -O-C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl; the C 1-6 alkyl, -O-C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl are optionally substituted by one or more R 12c;
R 12a is selected from the group consisting of C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, and amino; the C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, and amino are optionally substituted with one or more substituents selected from halogen, cyano, hydroxy, amino, -O-C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl;
r 8、R 9、R 10、R 11 is independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 heterocycloalkyl, and fused rings formed by 5-6 heteroaryl, 3-6 heterocycloalkyl, 5-6 heteroaryl; the C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, fused rings formed by 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl, 3-6 membered heterocycloalkyl optionally substituted with one or more R 13a;
or R 8 and R 9 together with the atoms to which they are attached form a 4-7 membered cycloalkyl or 5-6 membered heterocycloalkyl, said 4-7 membered cycloalkyl or 5-6 membered heterocycloalkyl being optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3; the C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3 optionally substituted with one or more R 13b;
or R 10 and R 11 together with the atoms to which they are attached form a 4-7 membered cycloalkyl or 5-6 membered heterocycloalkyl, said 4-7 membered cycloalkyl or 5-6 membered heterocycloalkyl being optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3; the C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3 optionally substituted with one or more R 13c;
Each R 13b、R 13c is independently selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3; the C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3 optionally substituted with one or more substituents selected from halogen, hydroxy, cyano;
Each R 13a is independently selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, C 1-6 alkylamino, di-C 1-6 alkylamino, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 heterocycloalkyl, -O-C 1-6 alkylene-3-6 heterocycloalkyl, 5-6 heteroaryl, -CONH 2、-SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3; The amino group, -CONH 2、C 1-6 alkyl group, -O-C 1-6 alkyl group, -O-3-6 membered cycloalkyl group, -O-3-6 membered heterocycloalkyl group, 3-6 membered cycloalkyl group, 3-6 membered heterocycloalkyl group, -O-C 1-6 alkylene-3-6 membered heterocycloalkyl group, 5-6 membered heteroaryl, -CONH 2、-SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3 optionally substituted with one or more groups selected from C 1-6 alkyl, Cyano, hydroxy, halogen, -O-C 1-6 alkyl, halo C 1-6 alkyl, cyano-substituted C 1-6 alkyl-substituted C 1-6 alkyl;
Each R 7c、R 4f、R 5a、R 6f、R 12c is independently selected from the group consisting of C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 heterocycloalkyl, 5-6 heteroaryl, phenyl, halo, amino, cyano, nitro, hydroxy; the C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl optionally substituted with one or more substituents selected from halogen, amino, cyano, nitro, hydroxy;
The conditions are as follows:
When R 2 is optionally substituted When R 1 is not selected from Optionally substitutedAnd optionally substituted
In some embodiments, in a compound of formula I or a pharmaceutically acceptable salt thereof,
R 1 is
R 5 is as defined in formula 1, preferably R 5 is selected from hydrogen, halogen, cyano, amino, nitro, -CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl; the-CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl is optionally substituted by 1-3 halogens, hydroxy, cyano; more preferably R 5 is selected from hydrogen, methyl, ethyl, halogen, cyano, cyclopropyl, methylenecyclopropyl, halomethyl, haloethyl, halocyclopropyl, halomethylcyclopropyl; most preferably R 5 is hydrogen;
R 7b is as defined in formula I, preferably R 7b is selected from hydrogen, C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, halogen, cyano, amino, nitro, -CONH 2、-CO-C 1-6 alkyl such as-COCH 3、-SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3、-C 1-6 alkylene-SO 2 -3-6 membered heterocycloalkyl, The C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 heterocycloalkyl, 5-6 heteroaryl, phenyl, amino, -CONH 2、-CO-C 1-6 alkyl such as-COCH 3、-SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3、-C 1-6 alkylene-SO 2 -3-6 heterocycloalkyl optionally substituted with 1-3 substituents selected from halogen, cyano, hydroxy; more preferably R 7b is selected from the group consisting of hydrogen, C 1-6 alkyl, 3-6 membered heterocycloalkyl, -C 1-6 alkylene-3-6 membered heterocycloalkyl, -C 1-6 alkylene-3-6 membered cycloalkyl, hydroxy substituted C 1-6 alkyl, halo substituted C 1-6 alkyl,
R 7a is as defined in claim 1, preferably R 7a is cyano;
R 6a、R 6b、R 6c、R 6d、R 6e is as defined in formula I.
In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof, R 1 isR 5 is as defined in formula 1, preferably R 5 is selected from hydrogen, halogen, cyano, amino, nitro, -CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl; the-CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl is optionally substituted by 1-3 halogens, hydroxy, cyano; more preferably R 5 is selected from hydrogen, methyl, ethyl, halogen, cyano, cyclopropyl, methylenecyclopropyl, halomethyl, haloethyl, halocyclopropyl, halomethylcyclopropyl; most preferably R 5 is hydrogen;
r 7b is as defined in formula I, preferably R 7b is selected from hydrogen, C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, halogen, cyano, amino, nitro, -CONH 2、-CO-C 1-6 alkyl such as-COCH 3、-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3、-C 1-6 alkylene-SO 2 -3-6 membered heterocycloalkyl, The C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 heterocycloalkyl, 5-6 heteroaryl, phenyl, amino, -CONH 2、-CO-C 1-6 alkyl such as-COCH 3、-SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3、-C 1-6 alkylene-SO 2 -3-6 heterocycloalkyl optionally substituted with 1-3 substituents selected from halogen, cyano, hydroxy; more preferably R 7b is selected from the group consisting of hydrogen, C 1-6 alkyl, 3-6 membered heterocycloalkyl, -C 1-6 alkylene-3-6 membered heterocycloalkyl, -C 1-6 alkylene-3-6 membered cycloalkyl, hydroxy substituted C 1-6 alkyl, halo substituted C 1-6 alkyl,R 7a is as defined in claim 1, preferably R 7a is cyano;
R 6a、R 6b、R 6c、R 6d、R 6e is as defined in formula I.
In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof,
R 1 is
E. D are each independently selected from C (R 6a) 2 and O, and one and only one of E, D is O;
R 5 is as defined in formula 1, preferably R 5 is selected from hydrogen, halogen, cyano, amino, nitro, -CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl; the-CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl is optionally substituted by 1-3 halogens, hydroxy, cyano; more preferably R 5 is selected from hydrogen, methyl, ethyl, halogen, cyano, cyclopropyl, methylenecyclopropyl, halomethyl, haloethyl, halocyclopropyl, halomethylcyclopropyl; most preferably R 5 is hydrogen;
R 6a、R 6b、R 6c、R 6d、R 6e is as defined in formula I.
In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof,
R 1 is
E. D are each independently selected from NR 7b、C(R 6a) 2 and O, and one and only one of E, D is O;
R 5 is as defined in formula 1, preferably R 5 is selected from hydrogen, halogen, cyano, amino, nitro, -CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl; the-CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl is optionally substituted by 1-3 halogens, hydroxy, cyano; more preferably R 5 is selected from hydrogen, methyl, ethyl, halogen, cyano, cyclopropyl, methylenecyclopropyl, halomethyl, haloethyl, halocyclopropyl, halomethylcyclopropyl; most preferably R 5 is hydrogen;
R 7b is as defined in claim 1, preferably R 7b is selected from hydrogen, C 1-6 alkyl, 3-6 membered heterocycloalkyl, -C 1-6 alkylene-3-6 membered heterocycloalkyl, -C 1-6 alkylene-3-6 membered cycloalkyl, hydroxy substituted C 1-6 alkyl, halo substituted C 1-6 alkyl, -CO-C 1-6 alkyl such as-COCH 3;
R 6a、R 6b、R 6c、R 6d、R 6e is as defined in formula I.
In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof,
R 1 is selected from
E. D is each independently selected from NR 7b、C(R 6a) 2 and O,
R 7b is as defined in formula I, preferably R 7b is selected from hydrogen, C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, halogen, cyano, amino, nitro, -CONH 2、-CO-C 1-6 alkyl such as-COCH 3、-SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3、-C 1-6 alkylene-SO 2 -3-6 membered heterocycloalkyl, The C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 heterocycloalkyl, 5-6 heteroaryl, phenyl, amino, -CONH 2、-CO-C 1-6 alkyl such as-COCH 3、-SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3、-C 1-6 alkylene-SO 2 -3-6 heterocycloalkyl optionally substituted with 1-3 substituents selected from halogen, cyano, hydroxy; more preferably R 7b is selected from the group consisting of hydrogen, C 1-6 alkyl, 3-6 membered heterocycloalkyl, -C 1-6 alkylene-3-6 membered heterocycloalkyl, -C 1-6 alkylene-3-6 membered cycloalkyl, hydroxy substituted C 1-6 alkyl, halo substituted C 1-6 alkyl,
R 6a、R 6b、R 6c、R 6d、R 6e is as defined in formula I.
In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof,
R 1 is selected from
R 6a、R 6b、R 6c、R 6d、R 6e is as defined in formula I.
In some embodiments, each R 6a、R 6b、R 6c、R 6d、R 6e is the same or different and is independently selected from the group consisting of hydrogen, halogen, cyano, amino, nitro, hydroxy, -CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 heterocycloalkyl, 5-6 heteroaryl, phenyl; the-CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl is optionally substituted by one or more R 6f;
R 6f is as defined in formula 1.
In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof, each R 6a、R 6b、R 6c、R 6d、R 6e is the same or different and is each independently selected from hydrogen, halogen, cyano, amino, nitro, hydroxy, -CONH 2; the-CONH 2 is optionally substituted with one or more R 6f;
R 6f is as defined in formula 1.
In some embodiments, each R 6a、R 6b、R 6c、R 6d、R 6e is the same or different and is independently selected from the group consisting of C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl; the C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 heterocycloalkyl, 5-6 heteroaryl, phenyl are optionally substituted with one or more R 6f; r 6f is as defined in formula 1.
In some embodiments, each R 6a、R 6b、R 6c、R 6d、R 6e is the same or different and is each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, -O-C 1-6 alkyl; the C 1-6 alkyl, -O-C 1-6 alkyl is optionally substituted with one or more R 6f; r 6f is as defined in formula 1.
In some embodiments, each R 6f is independently selected from the group consisting of C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl; the C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl is optionally substituted with one or more substituents selected from halogen, amino, cyano, nitro, hydroxy.
In some embodiments, R 6f is independently selected from halogen, amino, cyano, nitro, hydroxy, in a compound of formula I or a pharmaceutically acceptable salt thereof.
In some embodiments, R 6f is independently selected from halo, cyano, hydroxy, C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl; the C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl is optionally substituted with one or more substituents selected from halogen, amino, cyano, nitro, hydroxy.
In some embodiments, R 6a forms =s, =o with each other in a compound of formula I or a pharmaceutically acceptable salt thereof.
In some embodiments, R 6b and R 6c form =s, =o in a compound of formula I or a pharmaceutically acceptable salt thereof.
In some embodiments, R 6d and R 6e form =s, =o in a compound of formula I or a pharmaceutically acceptable salt thereof.
In some embodiments, in a compound of formula I or a pharmaceutically acceptable salt thereof, R 6d and R 6e together with the atoms to which they are attached are 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl; the 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted with one or more substituents selected from halogen, cyano, amino, nitro, -CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl.
In some embodiments, R 6a forms a 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl group with each other in a compound of formula I or a pharmaceutically acceptable salt thereof; the 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted with one or more substituents selected from halogen, cyano, amino, nitro, -CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl.
In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof, R 6b and R 6c form a 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl; the 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted with one or more substituents selected from halogen, cyano, amino, nitro, -CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl.
In some embodiments, R 6d and R 6e form a 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl in a compound of formula I or a pharmaceutically acceptable salt thereof; the 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted with one or more substituents selected from halogen, cyano, amino, nitro, -CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl.
In some embodiments, R 6d and R 6e form a 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl in a compound of formula I or a pharmaceutically acceptable salt thereof; the 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted with one or more substituents selected from halogen, cyano, amino, nitro, -CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl; preferably R 6d and R 6e form a 3-8 membered heterocycloalkyl; the 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted with one or more substituents selected from halogen, cyano, amino, nitro, -CONH 2、C 1-6 alkyl.
In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof,
R 1 is
R 7 is as defined in formula I, preferably R 7 is methyl;
R 3 is as defined in formula I, preferably R 3 is methyl, propyl, isopropyl, hydroxyethyl;
R 4a、R 4b、R 4c、R 4d、R 4e is as defined in formula I, preferably R 4a、R 4b、R 4c、R 4d、R 4e is hydrogen.
On the basis of the provided possible embodiments, the present disclosure also provides the following technical solutions for R 2.
In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof, R 2 isR 8、R 9、R 10、R 11 is as defined in formula I.
In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof, R 2 is
R 8 and R 9 form a 4-7 membered cycloalkyl or 5-6 membered heterocycloalkyl, said 4-7 membered cycloalkyl or 5-6 membered heterocycloalkyl optionally being substituted by one or more groups selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, A halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 heterocycloalkyl, 5-6 heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3; The C 1-6 alkyl, halogenated C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 heterocycloalkyl, 5-6 heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3 optionally substituted with one or more R 13b; Preferably R 8 and R 9 form a 4 membered cycloalkyl group, said 4 membered cycloalkyl group optionally being substituted with 1 to 3 groups selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl;
R 10、R 11 is independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 heterocycloalkyl, and fused rings formed by 5-6 heteroaryl, 3-6 heterocycloalkyl, 5-6 heteroaryl; the C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, fused rings formed by 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl, 3-6 membered heterocycloalkyl optionally substituted with one or more R 13a;
r 12、R 13a、R 13b is as defined in formula I.
In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof, R 2 is
R 8 and R 9 form a 4-7 membered cycloalkyl or 5-6 membered heterocycloalkyl, said 4-7 membered cycloalkyl or 5-6 membered heterocycloalkyl being optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3; the C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3 optionally substituted with one or more R 13b;
r 10 and R 11 form a 4-7 membered cycloalkyl or 5-6 membered heterocycloalkyl, said 4-7 membered cycloalkyl or 5-6 membered heterocycloalkyl being optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3; the C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3 optionally substituted with one or more R 13c;
R 12、R 13b、R 13c is as defined in formula I.
In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof, R 2 is
Z is N or CR 12;
R 8 and R 9 form a 4-7 membered cycloalkyl, said 4-7 membered cycloalkyl being optionally substituted with one or more substituents selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3; the C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3 optionally substituted with one or more R 13b;
R 10、R 11 is independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 heterocycloalkyl, and fused rings formed by 5-6 heteroaryl, 3-6 heterocycloalkyl, 5-6 heteroaryl; the C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, fused rings formed by 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl, 3-6 membered heterocycloalkyl optionally substituted with one or more R 13a; r 12、R 13a、R 13b is as defined in formula I;
r 10、R 11、R 12、R 13a、R 13b is as defined in formula I.
In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof,
R 2 is
Z is N or CR 12;
R 9a、R 9b、R 9c、R 9d、R 9e、R 9f is each independently selected from hydrogen, halogen, hydroxy, cyano, amino, C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3; the C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3 optionally substituted with one or more R 13b;
R 10 is selected from condensed rings formed by 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl, 5-6 membered heteroaryl; the fused ring formed by the 3-6 membered heterocycloalkyl and the 5-6 membered heteroaryl, and the 5-6 membered heteroaryl are optionally substituted by one or more R 13a.
R 11 is selected from hydrogen, halogen, C 1-6 alkyl, -O-C 1-6 alkyl; the C 1-6 alkyl, -O-C 1-6 alkyl is optionally substituted with one or more R 13a;
r 12、R 13a、R 13b is as defined in formula I.
In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof,
R 2 is
Z is N or CR 12;
R 9a、R 9b、R 9c、R 9d、R 9e、R 9f is each independently selected from hydrogen, halogen, hydroxy, cyano, amino, C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3; the C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3 optionally substituted with one or more R 13b;
r 10 is selected from 5-6 membered heteroaryl optionally substituted with one or more R 13a;
R 11 is selected from hydrogen, halogen, C 1-6 alkyl, -O-C 1-6 alkyl; the C 1-6 alkyl, -O-C 1-6 alkyl is optionally substituted with one or more R 13a;
r 12、R 13a、R 13b is as defined in formula I.
In some embodiments, R 2 in the compound of formula I or a pharmaceutically acceptable salt thereof is selected from
Z is N or CR 12;
R 11 is selected from hydrogen, halogen, C 1-6 alkyl, -O-C 1-6 alkyl; the C 1-6 alkyl, -O-C 1-6 alkyl is optionally substituted with one or more R 13a;
R 10a is independently selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl, such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3; The C 1-6 alkyl, halogenated C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 heterocycloalkyl, 5-6 heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3 optionally substituted with one or more R 13c; R 10b is selected from C 1-6 alkyl, said C 1-6 alkyl optionally substituted with C 3-6 cycloalkyl;
n, m are independently selected from integers from 0 to 3; preferably n, m are independently selected from integers from 0 to 2;
r 8、R 9、R 12、R 13a、R 13c is as defined in formula I;
R 9a、R 9b、R 9c、R 9d、R 9e、R 9f is as defined previously.
In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof,
R 2 is
Z is N or CR 12;
R 11 is selected from hydrogen, halogen, C 1-6 alkyl, -O-C 1-6 alkyl; the C 1-6 alkyl, -O-C 1-6 alkyl is optionally substituted with one or more R 13a;
n is an integer from 0 to 3;
R 12、R 13a、R 13c、R 9a、R 9b、R 9c、R 9d、R 9e、R 9f As defined previously.
In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, Z is N.
In other embodiments, a compound of formula I, or a pharmaceutically acceptable salt thereof, Z is CR 12;R 12 as defined in formula I.
In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof, R 12 is selected from hydrogen, C 1-6 alkyl, -O-C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, halo, cyano, amino, -CONH 2、-SO 2R 12a、-CH 2-SO 2R 12a; the C 1-6 alkyl, -O-C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, amino, -CONH 2 are optionally substituted with 1-3R 12b;
R 12a、R 12b is as defined in formula I.
In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof, R 12 is selected from hydrogen, halo C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl, -O-C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, halo, cyano, amino, -CONH 2、-SO 2R 12a、-CH 2-SO 2R 12a,R 12a are as defined in formula I;
Preferably, R 12 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl, -O-C 1-6 alkyl.
In some embodiments, R 12a is selected from the group consisting of C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, and amino in a compound of formula I or a pharmaceutically acceptable salt thereof; the C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl and amino are optionally substituted with one or more substituents selected from halogen, cyano, hydroxy, amino;
Preferably R 12a is selected from the group consisting of C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, 3-6 membered heterocycloalkyl.
In some embodiments, R 12b is selected from the group consisting of halogen, cyano, hydroxy, amino, C 1-6 alkyl, -O-C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl; the C 1-6 alkyl, -O-C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl are optionally substituted with 1-3R 12c, R 12c is as defined in formula 1; preferably 12b is selected from halogen, cyano, hydroxy, amino, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, -O-C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl.
In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof, R 12c is independently selected from halogen, amino, cyano, nitro, hydroxy, C 1-6 alkyl, -O-C 1-6 alkyl; the C 1-6 alkyl, -O-C 1-6 alkyl is optionally substituted with one or more substituents selected from halogen, amino, cyano, nitro, hydroxy.
In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof, R 9a、R 9b、R 9c、R 9d、R 9e、R 9f is independently selected from hydrogen, halogen, hydroxy, cyano, amino, C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl; the C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl is optionally substituted with one or more R 13b, R 13b is as defined in formula I; preferably R 9a、R 9b、R 9c、R 9d、R 9e、R 9f is independently selected from hydrogen, halogen, hydroxy, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, -O-C 1-6 alkyl; more preferably R 9a、R 9b、R 9c、R 9d、R 9e、R 9f is independently selected from hydrogen, halogen, hydroxy, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, -O-C 1-6 alkyl; most preferably R 9a、R 9b、R 9c、R 9d、R 9e、R 9f is hydrogen.
In some embodiments, R 13b is independently selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, -O-C 1-6 alkyl, halo C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, or a pharmaceutically acceptable salt thereof.
In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof, R 11 is selected from hydrogen, halogen, C 1-6 alkyl, -O-C 1-6 alkyl; the C 1-6 alkyl, -O-C 1-6 alkyl is optionally substituted with one or more R 13a groups, R 13a is as defined in formula I.
In some embodiments, in a compound of formula I or a pharmaceutically acceptable salt thereof, R 11 is selected from hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl; preferably R 11 is selected from hydrogen, methyl.
In some embodiments, each R 13a is independently selected from halogen, hydroxy, cyano, amino, C 1-6 alkylamino, di C 1-6 alkylamino, C 1-6 alkyl, -O-C 1-6 alkyl; the amino, C 1-6 alkyl, -O-C 1-6 alkyl is optionally substituted with 1 to 3 substituents selected from C 1-6 alkyl, cyano, hydroxy, halogen, -O-C 1-6 alkyl, halo C 1-6 alkyl, cyano-substituted C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl.
In some embodiments, each R 13a is independently selected from cyano, halo, hydroxy, C 1-6 alkyl, -O-C 1-6 alkyl, methylsulfonyl, -CONH 2、-CH 2-SO 2CH 3, 3-6 membered heterocyclyl, amino, or a pharmaceutically acceptable salt thereof.
In some embodiments, each R 13a is independently selected from the group consisting of C 1-6 alkyl, -O-C 1-6 alkyl, -O-5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-C 1-6 alkylene-3-6 membered heterocycloalkyl; the C 1-6 alkyl, -O-C 1-6 alkyl, -O-5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-C 1-6 alkylene-3-6 membered heterocycloalkyl is optionally substituted with 1-3 substituents selected from halogen, cyano, hydroxy, C 1-6 alkyl.
In some embodiments, each R 13a is independently selected from 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl; the 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally substituted with one or more C 1-6 alkyl groups selected from C 1-6 alkyl, cyano, hydroxy, halogen, -O-C 1-6 alkyl, halo C 1-6 alkyl, cyano.
In some embodiments, R 10a is independently selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, halo 3-6 membered cycloalkyl, halo 3-6 membered heterocycloalkyl, in a compound of formula I or a pharmaceutically acceptable salt thereof.
In some embodiments, R 2 is optionally substituted in a compound of formula I or a pharmaceutically acceptable salt thereofWhen R 1 is not
In some embodiments, R 2 is not a compound represented by formula I or a pharmaceutically acceptable salt thereof
In some embodiments, R 2 is not optionally substituted in a compound represented by formula I or a pharmaceutically acceptable salt thereof
In a second aspect, the present disclosure also provides a compound of the formula:
In a third aspect, the present disclosure also provides an isotopic substitution of the compound of the first or second aspect, preferably wherein the isotopic substitution is deuterium atom substitution
In a fourth aspect, the present disclosure also provides a pharmaceutical composition comprising at least one therapeutically effective amount of a compound according to the first aspect, the second aspect, or a pharmaceutically acceptable salt thereof, or an isotopically substituted compound according to the third aspect, and a pharmaceutically acceptable excipient.
In some embodiments, the pharmaceutical composition is in a unit dose of 0.001mg to 1000mg.
In certain embodiments, the pharmaceutical composition comprises 0.01 to 99.99% of the foregoing compound, or a pharmaceutically acceptable salt or isotopic substitution thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical compositions comprise 0.1-99.9% of the foregoing compounds, or pharmaceutically acceptable salts or isotopic substitutions thereof. In certain embodiments, the pharmaceutical compositions comprise 0.5% to 99.5% of the foregoing compounds, or pharmaceutically acceptable salts or isotopic substituents thereof. In certain embodiments, the pharmaceutical compositions comprise 1% to 99% of the foregoing compounds, or pharmaceutically acceptable salts or isotopic substituents thereof. In certain embodiments, the pharmaceutical compositions comprise 2% to 98% of the foregoing compounds, or pharmaceutically acceptable salts or isotopic substitutions thereof.
In certain embodiments, the pharmaceutical composition contains 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2% to 98% of a pharmaceutically acceptable excipient.
In a fifth aspect, the present disclosure also provides the use of a compound according to the first aspect, the second aspect, or a pharmaceutically acceptable salt thereof, or an isotopic substitution according to the third aspect, or a pharmaceutical composition according to the fourth aspect, in the manufacture of a medicament for treating a disease associated with NLRP3 activity.
The present disclosure also provides a method of preventing and/or treating a disease associated with NLRP3 activity comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to the first aspect, the second aspect, or a pharmaceutically acceptable salt thereof, or an isotopic substitution according to the third aspect, or a pharmaceutical composition according to the fourth aspect.
The present disclosure also provides a compound according to the first aspect, the second aspect, or a pharmaceutically acceptable salt thereof, or an isotopic substitution according to the third aspect, or a pharmaceutical composition according to the fourth aspect, for use in preventing or treating a disease associated with NLRP3 activity.
Diseases associated with NLRP3 activity include inflammatory-related diseases, immune diseases, inflammatory diseases, autoimmune diseases and/or auto-inflammatory diseases.
The present disclosure also provides the use of a compound according to the first aspect, the second aspect or a pharmaceutically acceptable salt thereof, or an isotopic substitution according to the third aspect or a pharmaceutical composition according to the fourth aspect, for the manufacture of a medicament for the treatment of an inflammatory-related disease, an immune disease, an inflammatory disease, an autoimmune disease and/or an autoinflammatory disease.
The present disclosure also provides a compound according to the first aspect, the second aspect or a pharmaceutically acceptable salt thereof, or an isotopic substitution according to the third aspect or a pharmaceutical composition according to the fourth aspect, for use in the treatment of an inflammatory-related disease, an immune disease, an inflammatory disease, an autoimmune disease and/or an autoinflammatory disease.
The present disclosure also provides a method of treating and/or preventing an inflammatory-related disease, an immune disease, an inflammatory disease, an autoimmune disease, and/or an auto-inflammatory disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the first aspect, the second aspect, or a pharmaceutically acceptable salt thereof, or an isotopic substitute of the third aspect, or a pharmaceutical composition of the fourth aspect.
In some embodiments, the inflammatory-related disease, immune disease, inflammatory disease, autoimmune disease, and/or auto-inflammatory disease may be specifically selected from: autoinflammatory fever syndrome (e.g. cold-related periodic syndrome), sickle cell anemia, systemic lupus erythematosus, liver-related diseases (e.g. chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis, alcoholic liver disease), inflammatory arthritis-related diseases (e.g. gout, chondrocalcification, osteoarthritis, rheumatoid arthritis, acute or chronic arthritis), kidney-related diseases (e.g. hyperoxalic acid urine disease, lupus nephritis, hypertensive nephropathy, hemodialysis-related inflammation, type I or type II diabetes and complications thereof (e.g. nephrosis, retinopathy)), neuroinflammation-related diseases (e.g. brain infection, acute injury, multiple sclerosis, alzheimer's disease and neurodegenerative diseases), cardiovascular and metabolic-related disorders or diseases (e.g. reduced risk of cardiovascular disease (CvRR), atherosclerosis, type I and type II diabetes and related complications, peripheral Arterial Disease (PAD), acute heart failure and hypertension), wound healing, scar formation, inflammatory skin diseases (e.g. acne, acne), sarcoidosis, age-related cancer, myelosis, myelodysplasia (MDS), cancer, myelosis (e.g. hyperplasia), cancer, myelosis).
Pharmaceutically acceptable salts of the compounds described in this disclosure may be selected from inorganic or organic salts.
The compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present disclosure. The asymmetric carbon atom containing compounds of the present disclosure may be isolated in optically active pure or racemic forms. Optically pure forms can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.
Optically active (R) -and (S) -isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it may be prepared by asymmetric synthesis or derivatization with chiral auxiliary wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Or when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), forms a diastereomeric salt with an appropriate optically active acid or base, and then undergoes diastereomeric resolution by conventional methods well known in the art, followed by recovery of the pure enantiomer. Furthermore, separation of enantiomers and diastereomers is typically accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amine).
In the chemical structure of the compounds of the present disclosure, the bondIndicating unspecified configuration, i.e. bonds if chiral isomers are present in the chemical structureMay beOr (b)Or at the same time containAndTwo configurations. In the chemical structure of the compounds of the present disclosure, the bondNot specifying configuration, i.e. keysThe configuration of (a) may be E-type or Z-type, or both E and Z configurations may be included.
The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include tautomers via proton transfer, such as keto-enol and imine-enamine, lactam-lactam isomerization. Examples of lactam-lactam balances are between a and B as shown below.
All tautomeric forms are within the scope of the disclosure. The naming of the compounds does not exclude any tautomers.
The present disclosure also includes some isotopically-labeled compounds of the present disclosure which are identical to those recited herein, but for the replacement of one or more atoms by an atom having an atomic weight or mass number different from the atomic weight or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I and 36 Cl, respectively, and the like.
Unless otherwise indicated, when a position is specifically designated as deuterium (D), that position is understood to be deuterium (i.e., at least 10% deuterium incorporation) having an abundance that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%). The natural abundance of a compound in an example can be at least 1000 times greater than the abundance of deuterium, at least 2000 times greater than the abundance of deuterium, at least 3000 times greater than the abundance of deuterium, at least 4000 times greater than the abundance of deuterium, at least 5000 times greater than the abundance of deuterium, at least 6000 times greater than the abundance of deuterium, or higher than the abundance of deuterium. The present disclosure also includes various deuterated forms of the compounds of formula (I). Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. Those skilled in the art are able to refer to the relevant literature for the synthesis of deuterated forms of the compounds of formula (I). Commercially available deuterated starting materials may be used in preparing the deuterated form of the compound of formula (I) or they may be synthesized using conventional techniques with deuterated reagents including, but not limited to, deuterated boranes, trideuteroborane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.
"Optionally" or "optionally" is intended to mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "optionally halogen-or cyano-substituted C 1-6 alkyl" means that halogen or cyano may be, but need not be, present, and that the description includes both the case where alkyl is substituted with halogen or cyano and the case where alkyl is not substituted with halogen and cyano.
Interpretation of the terms
"Pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
"Pharmaceutically acceptable excipients" include, but are not limited to, any auxiliary, carrier, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent or emulsifying agent that is approved for use in humans or livestock animals.
An "effective amount" or "therapeutically effective amount" as used in this disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount is also meant to be an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on the following factors: such as the condition to be treated, the general health of the patient, the route of administration and the dosage and severity of the side effects. An effective amount may be the maximum dose or regimen that avoids significant side effects or toxic effects.
"Alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1to 20 carbon atoms. Alkyl groups containing 1to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, and various branched isomers thereof, and the like. The alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any useful point of attachment, preferably one or more groups independently selected from halogen, hydroxy, oxo, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl or 3 to 6 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl being optionally substituted with halogen, hydroxy, nitro, cyano or amino.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. Cycloalkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any useful point of attachment, preferably one or more groups independently selected from halogen, hydroxy, oxo, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl or 3 to 6 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl being optionally substituted with halogen, hydroxy, nitro, cyano or amino.
The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group containing 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S (O) m (where m is an integer from 0 to 2), but excluding the ring portion of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferably containing 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 7 ring atoms. Non-limiting examples of "heterocycloalkyl" include:
etc.
The heterocycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a heterocycloalkyl group, non-limiting examples of which include:
Etc.
The heterocycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from halogen, hydroxy, oxo, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl or 3 to 6 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl being optionally substituted with halogen, hydroxy, nitro, cyano or amino.
The term "alkoxy" refers to-O- (alkyl) wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy. The alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, oxo, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 7 membered cycloalkyl or 3 to 7 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl being optionally substituted with halogen, hydroxy, nitro, cyano or amino.
Similarly, "cycloalkoxy" and "heterocycloalkoxy" are defined as "alkoxy" above.
The term "alkylthio" refers to-S- (alkyl), wherein alkyl is as defined above. Non-limiting examples of alkylthio groups include: methylthio, ethylthio, propylthio, butylthio. Alkylthio groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from C 1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, 3 to 6 membered cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 1-6 alkylthio, 3 to 6 membered cycloalkylthio, 3 to 6 membered heterocycloalkylthio, said alkoxy, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocyclyloxy, alkylthio, cycloalkylthio, heterocycloalkylthio being optionally substituted with halogen, hydroxy, cyano or amino.
Similarly, "cycloalkylthio" and "heterocycloalkylthio" are defined as "alkylthio" above.
"Monovalent group" means a compound that "formally" eliminates a monovalent atom or group. "subunit" or "divalent group" refers to a compound that "formally" eliminates two monovalent or one divalent formed atoms or groups of atoms.
The term "alkylene" refers to the portion of an alkane molecule that remains after removal of 2 hydrogen atoms, including straight and branched chain subunits of 1to 20 carbon atoms. Non-limiting examples of alkylene groups containing 1to 6 carbon atoms include methylene (-CH 2 -), ethylene (e.g., -CH 2CH 2 -or-CH (CH 3) -). Unless otherwise specified, an alkylene group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl or C 1-6 alkoxy.
Similarly, "alkyleneoxy", "alkenylene", "alkenyleneoxy", "cycloalkylene", "heterocycloalkylene" are defined as "alkylene".
The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 12 membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, 3 to 6 membered cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 5 to 6 membered aryl or heteroaryl, said C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, 3 to 6 membered cycloalkoxy, 3 to 6 membered heterocycloalkoxy, 3 to 8 membered cycloalkenyloxy, 5 to 6 membered aryl or heteroaryl being optionally substituted with one or more groups selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl or C 1-6 alkoxy.
The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 6 to 12 membered, more preferably 5 or 6 membered. For example. Non-limiting examples of which include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl (oxazolyl), isoxazolyl (isoxazolyl), pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, triazolyl, indazolyl, benzimidazolyl,Etc.
The heteroaryl ring may be fused to an aryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:
Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, or C 1-6 alkoxy.
The term "spiro" refers to a compound in which two rings share one atom. Non-limiting examples of spirocycloalkyl groups include:
the term "fused ring" refers to a compound in which two or more rings are fused by sharing two adjacent atoms. And non-limiting examples of cycloalkyl groups include:
The term "bridged ring" refers to a structure formed by two or more cyclic structures sharing two non-adjacent ring atoms with each other. Cycloalkyl groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:
The term "heterocycle" refers to the atoms that make up the ring, in addition to carbon atoms, and includes heterocycloalkyl and heteroaryl rings.
The term "hydroxy" refers to an-OH group.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "cyano" refers to-CN.
The term "amino" refers to-NH 2.
The term "nitro" refers to-NO 2.
The term "oxo" refers to an =o substituent.
"Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. When the substituent is ketone or oxo (i.e., =o), then two (2) hydrogens on the atom are replaced.
The present disclosure is further described below in connection with the examples, which are not intended to limit the scope of the present disclosure.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). The NMR shift (. Delta.) is given in units of 10 -6 (ppm). NMR was performed using a Bruker AVANCE-400 nuclear magnetic resonance apparatus using deuterated dimethyl sulfoxide (DMSO-d 6), deuterated chloroform (CDCl 3), deuterated methanol (CD 3 OD) as the solvent and Tetramethylsilane (TMS) as the internal standard.
MS was measured using a Shimadzu 2010 Mass Spectrometer or Agilent 6110A MSD mass spectrometer.
HPLC was performed using a Shimadzu LC-20A systems, shimadzu LC-2010HT series or Agilent 1200 LC high pressure liquid chromatograph (Ultimate XB-C18 3.0 x 150mm column or Xtimate C18 2.1 x 30mm column or Gilson-281 Waters Xbridge 150*25mm column or Gilson-281 Waters Xbridge 150*25mm column or Gilson-281 Phenomenex luna C18 250*50mm column).
Chiral HPLC analysis assay uses Chiralpak IC-3 100×4.6mm I.D.,3um、Chiralpak AD-3 150×4.6mm I.D.,3um、Chiralpak AD-3 50×4.6mm I.D.,3um、Chiralpak AS-3 150×4.6mm I.D.,3um、Chiralpak AS-3 100×4.6mm I.D.,3μm、ChiralCel OD-3 150×4.6mm I.D.,3um、Chiralcel OD-3 100×4.6mm I.D.,3μm、ChiralCel OJ-H 150×4.6mm I.D.,5um、Chiralcel OJ-3 150×4.6mm I.D.,3um chromatography columns.
The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
Column chromatography generally uses 100-200 mesh, 200-300 mesh or 300-400 mesh of yellow sea silica gel as a carrier.
Chiral preparative columns used DAICEL CHIRALPAK IC (250 mm. Times.30 mm,10 um) or Phenomnex-Amylose-1 (250 mm. Times.30 mm,5 um).
The CombiFlash rapid preparation instrument used CombiFlash Rf150 (TELEDYNE ISCO).
The average inhibition rate of kinase and IC 50 were measured by NovoStar microplate reader (BMG, germany).
Known starting materials of the present disclosure may be synthesized using or following methods known in the art, or may be purchased from ABCR GmbH & co.kg, acros Organics, ALDRICH CHEMICAL Company, shao remote chemical technology (Accela ChemBio Inc), dary chemicals, and the like.
The examples are not particularly described, and the reaction can be carried out under an argon atmosphere or a nitrogen atmosphere.
An argon or nitrogen atmosphere means that the reactor flask is connected to a balloon of argon or nitrogen of about 1L volume.
The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L volume.
The pressure hydrogenation reaction uses Parr 3916EKX type hydrogenometer and clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenometer.
The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times.
The microwave reaction used was a CEM Discover-S908860 type microwave reactor.
The examples are not specifically described, and the solution refers to an aqueous solution.
The reaction temperature is room temperature and is 20-30 deg.c without specific explanation in the examples.
The reaction progress in the examples was monitored by Thin Layer Chromatography (TLC), a developing agent used in the reaction, a system of column chromatography eluent used for purifying the compound and a developing agent system of thin layer chromatography, and the volume ratio of the solvent was adjusted according to the polarity of the compound, and may be adjusted by adding a small amount of an alkaline or acidic reagent such as triethylamine and acetic acid.
Examples
Example 1
((3-Cyano-6-methyl-4, 5,6, 7-tetrahydrothieno [2,3-c ] pyridin-2-yl) sulfonyl) ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) amine sodium salt
First step
To a 1L reaction flask was added compound 1a (50 g,214 mmol), ethanol (500 mL), malononitrile (9.20 g,139 mmol), diethylamine (16.6 mL,160.8 mmol) and elemental sulfur (5.48 g,161 mmol) at room temperature. Under nitrogen atmosphere, the temperature was raised to 70℃and stirred for 2 hours. Cooled to room temperature, filtered, and the filter cake was collected and dried in vacuo to give compound 1b (33 g, yield: 75.8%). LC-MS M/z (ESI): 314.1 (M+H) +.
Second step
Copper bromide (4.28 g,19.1 mmol), t-butyl nitrite (1.65 g,16.0 mmol), and acetonitrile (50 mL) were sequentially added to a 500mL reaction flask at room temperature. Under nitrogen, the temperature was raised to 65℃and Compound 1b (5.0 g,16.0 mmol) was added thereto and stirred for 2 hours. Cooled to room temperature, water (100 mL) was added, filtered, and the filtrate was extracted with ethyl acetate (20 mL. Times.3). The organic phases were combined, dried, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (SiO 2, 10% ethyl acetate/petroleum ether) to give compound 1c (2.6 g, yield: 36%). LC-MS M/z (ESI): 378.0 (M+H) +,
Third step
To a 1L single vial was added compound 1c (23.0 g,61.0 mmol), tris (dibenzylideneacetone) dipalladium (2.79 g,3.05 mmol), N-diisopropylethylamine (20.2 mL,122 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (3.53 g,6.10 mmol), dioxane (300 mL), and benzyl mercaptan (15.1 g,121.9 mmol) at room temperature. Under nitrogen atmosphere, the temperature was raised to 100℃and stirred for 2 hours. Cooled to room temperature, dichloromethane (500 mL) and water (300 mL) were added, the aqueous phase was extracted with dichloromethane (200 mL. Times.3), the organic phase was collected, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography in an elution system (SiO 2, 10% ethyl acetate/petroleum ether) to give compound 1d (25 g, yield: 97%).
1H NMR(400MHz,DMSO-d 6)δ7.42-7.21(m,10H),5.12(s,2H),4.59(s,2H),4.24(s,2H),3.68(s,2H),2.65(t,2H).
Fourth step
To a 500mL single vial was added compound 1d (25.0 g,59.4 mmol) followed by acetonitrile (250 mL) at room temperature. Cooled to 0℃and 1, 3-dichloro-5, 5-dimethylhydantoin (23.4 g,118.9 mmol), water (6 mL) and acetic acid (6 mL) were added. Stirring for 2 hours, concentrating under reduced pressure, adding ethyl acetate (200 mL) and water (100 mL), drying the organic phase, filtering, concentrating under reduced pressure to give compound 1f (25 g, crude product), which is used directly in the next step.
Fifth step
A500 mL three-necked flask was charged with compound 1f (10.0 g,25.2 mmol) and 7M ammonia in methanol (100 mL,700 mmol) at room temperature. Stirred for 12 hours and concentrated under reduced pressure. Methanol (100 mL) was added to the mixture to slurry, the mixture was filtered, and the cake was washed with methanol (200 mL) to collect the cake, whereby 1g (4.4 g, yield: 46.3%) of the compound was obtained. LC-MS M/z (ESI): 378.2 (M+H) +.
Sixth step
To a 100mL single-necked flask, 1g (4.00 g,10.6 mmol) of the compound, a solution of hydrogen bromide in acetic acid (5 mL, 33%) and acetic acid (15 mL) were successively added at room temperature, and the mixture was stirred for 2 hours. Concentrated under reduced pressure, methanol (100 mL) was added, sodium carbonate solid was slowly added to ph=9, filtered, and the filtrate was concentrated under reduced pressure and purified by reverse column C18 (water/acetonitrile, ammonia system) to give compound 1h (600 mg, yield: 23.3%). LC-MS M/z (ESI) 244.0 (M+H) +.
Seventh step
To a 100mL single-necked flask, the compound (2.00 g,8.22 mmol), methanol (20 mL), acetic acid (2.4 mL,41.1 mmol) were added, and the mixture was stirred for 10 minutes, paraformaldehyde (50 mg) and sodium cyanoborohydride (1.55 g,24.7 mmol) were added, and the mixture was stirred at room temperature for 1 hour. 7M ammonia in methanol (2 mL) was added, concentrated under reduced pressure, and the residue was purified over reverse column C18 (water/acetonitrile, ammonia water system) to give compound 1i (80 mg, yield: 3.8%). LC-MS M/z (ESI): 258.0 (M+H) +.
Eighth step
To a 10mL single vial was added compound 1i (30 mg,0.12 mmol), tetrahydrofuran (2 mL), sodium tert-butoxide (11.76 mg,0.122 mmol) at 0deg.C. Warmed to room temperature, stirred for 30 minutes, 1j (23 mg,0.12 mmol) was added, and stirred for 4 hours. Concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (columns: waters, xbridge250 x 19mm,10 μm; mobile phase: aqueous phase (0.05% ammonia water) and acetonitrile, gradient ratio: 0-10min 50-70% B; flow 25 ml/min) to give crude product, which was exchanged with sodium ion exchange resin to give compound 1 (13.63 mg, yield: 23.7%).
1H NMR(400MHz,DMSO-d 6)δ7.53(s,1H),6.78(s,1H),3.50(s,2H),2.75(t,4H),2.70-2.62(m,8H),2.35(s,3H),1.94-1.87(m,4H).
LC-MS m/z(ESI):479.0(M+Na) +。
Example 2
(1, 2,3,5,6, 7-Hexahydro-s-indacen-4-yl) carbamoyl) ((6-methyl-4, 5,6, 7-tetrahydrothieno [2,3-c ] pyridin-2-yl) sulfonyl) amine sodium salt
First step
In a 1L single-necked flask, compound 2a (31.0 g,251.7 mmol), tetrahydrofuran (80 mL), and borane dimethyl sulfide complex (252 mL,504 mmol) were added at room temperature. The temperature was raised to 80℃under nitrogen atmosphere and stirred overnight. Cooled to room temperature, 6M methanolic hydrochloric acid (150 mL,900 mmol) was added dropwise, concentrated under reduced pressure, the residue was slurried with dichloromethane (300 mL), and the filter cake was concentrated under reduced pressure to give compound 2b (35 g,213.8mmol, yield: 84.9%). LC-MS (ESI) M/z 128.2 (M+H) +.
Second step
In a 1L single vial was added compound 2b (32.0 g,251.6 mmol) and dichloromethane (300 mL), triethylamine (88 mL,633 mmol) and di-tert-butyl dicarbonate (64 mL,279 mmol) at room temperature. Stirring is carried out for 5 hours. Poured into water (400 mL), extracted with methylene chloride (250 mL. Times.3), the organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 2c (41 g, yield: 72%). LC-MS (ESI) M/z 213.2 (M-55+CH 3CN) +).
Third step
In a 500mL single-necked flask, compound 2c (82.0 g,360.8 mmol), paraformaldehyde (20.0 g,190.4 mmol), p-toluenesulfonic acid monohydrate (1.04 g,5.46 mmol) and toluene (200 mL) were sequentially added at room temperature. Then the mixture was connected to a return pipe of a water separator, and stirred at 120℃for 2 hours under nitrogen atmosphere. Concentrated under reduced pressure, ethyl acetate (200 mL) was added, filtered, and the filtrate was poured into water (500 mL) and extracted with ethyl acetate (400 mL. Times.3). The organic phase was washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The residue was chromatographed on silica gel using an elution system (SiO 2, 0-10% ethyl acetate/petroleum ether) to give compound 2d (70 g, yield: 81.1%).
1H NMR(400MHz,DMSO-d 6)δ7.36(d,1H),6.85(d,1H),4.54(s,2H),3.58(t,2H),2.63(t,2H),1.42(m,9H).
Fourth step
To a 500mL single-necked flask, compound 2d (35 g,117 mmol) and a 4M 1, 4-dioxane solution of hydrochloric acid (250 mL) were sequentially added at room temperature, and stirred for 2 hours. Concentrating under reduced pressure. The residue was slurried with ethyl acetate (400 mL) and filtered to give compound 2e (20.5 g, yield: 99.7%).
1H NMR(400MHz,DMSO-d 6)δ9.71(s,2H),7.48(d,1H),6.93(d,1H),4.31(s,2H),3.35-3.32(m,2H),2.88(t,2H).
LC-MS:MS(ESI):m/z 140.2(M+H) +。
Fifth step
To a 50mL single vial was added compound 2e (1.00 g,5.69 mmol) and triethylamine (632 mg,6.26 mmol) in sequence at room temperature, and dissolved in tetrahydrofuran (17 mL). After cooling to 0deg.C, acetyl chloride (491 mg,6.26 mmol) was slowly added and stirred at room temperature for 1 hour. Filtration, addition of ethyl acetate (30 mL) and water (15 mL) to the filtrate, drying of the organic phase, filtration, concentration of the filtrate under reduced pressure, and purification of the residue by silica gel chromatography in an elution system (SiO 2, 0-10% ethyl acetate/petroleum ether) gave compound 2f (1.03 g, yield: 99.8%). LC-MS (ESI): M/z 182.1 (M+H) +.
Sixth step
Compound 2f (2.4 g,13.241 mmol) was dissolved in dichloromethane (60 mL) at room temperature in a 250mL single vial, and acetic anhydride (3.8 mL,40.1 mmol) was added. The temperature was lowered to 0deg.C, concentrated sulfuric acid (0.7 mL,14 mmol) was added and stirred at room temperature for 12 hours. Concentrated under reduced pressure, diethyl ether (100 mL) was added, filtered, and the filter cake was purified using reverse column C18 (water/acetonitrile, hydrochloric acid system) to give 2g of compound (3.42 g, yield: 98.8%).
1H NMR(400MHz,DMSO-d 6)δ6.84-6.83(m,1H),4.62-4.58(m,2H),3.68-3.63(m,2H),2.68-2.52(m,2H),2.09-2.06(m,3H).
Seventh step
2G (8.00 g,30.6 mmol) of the compound was successively added to a 250mL single-necked flask at room temperature, and dissolved in methylene chloride (80 mL). Phosphorus pentachloride (8.67 g,41.6 mmol) was added under nitrogen atmosphere and stirred at room temperature for 20 hours. After pouring into ice and returning to room temperature, dichloromethane (200 mL) was added, the organic phase was dried, filtered, and the filtrate was concentrated under reduced pressure to give the product 2h (8.56 g, crude) which was used directly in the next step.
Eighth step
The compound (2 h) (12 g,42.9 mmol) was dissolved in dichloromethane (10 mL) at room temperature and slowly added dropwise to a 7M methanolic ammonia solution (300 mL,2100 mmol) and stirred for 1h. The filter cake was washed with methanol (10 mL) and collected to give product 2i (10 g, yield: 89.6%). LC-MS (ESI): M/z 261.0 (M+H) +.
Ninth step
To a 100mL single-necked flask, compound 2i (2.00 g,7.68 mmol) was successively added, followed by stirring at 80℃for 3 hours, with 20% aqueous sodium hydroxide (10 mL) at room temperature. Ph=7 was adjusted with 2M dilute hydrochloric acid solution. The reaction mixture was extracted with a mixed solution of methylene chloride/methanol (10/1, 20 mL), and the organic phase was dried and concentrated under reduced pressure to give product 2j (1.4 g, yield) ：83.6％). 1H NMR(400MHz,DMSO-d 6)δ7.59(s,2H),7.30(s,1H),3.91(s,2H),3.23(s,2H),2.95(t,2H),2.60-2.59(m,1H).
Tenth step
To a 25mL single vial was added compound 2j (375 mg,1.72 mmol), methanol (3 mL), paraformaldehyde (63 mg,0.17 mmol), acetic acid (0.2 mL,3.4 mmol) and sodium cyanoborohydride (324 mg,5.15 mmol) at room temperature, and stirred for 2 hours. 7M methanolic ammonia (2 mL) was added and concentrated under reduced pressure. The residue was purified by reverse phase C18 (water/acetonitrile, ammonia system) to give compound 2k (180 mg, yield: 45.1%). LC-MS (ESI) M/z 233.0 (M+H) +.
Eleventh step
To a 50mL single flask was added compound 2k (150 mg,0.646 mmol) and tetrahydrofuran (5 mL) at room temperature, cooled to 0℃and sodium tert-butoxide (65 mg,0.68 mmol) was added and stirred at room temperature for 40 minutes. 1j (128 mg,0.646 mmol) was added and stirred for 3 hours. Concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (columns: waters, xbridge 250X 19mm,10 μm; mobile phase: aqueous phase (0.05% ammonia water) and acetonitrile, gradient ratio: 0-10min 40-65% B; flow 25 ml/min) to give crude product, which was exchanged with sodium ion exchange resin to give compound 2 (114 mg, yield: 38.9%).
1H NMR(400MHz,DMSO-d 6)δ7.06(s,1H),6.77(s,1H),3.47(s,2H),2.76(m,4H),2.67(m,4H),2.58(m,4H),2.34(s,3H),2.03-1.81(m,4H).
LC-MS:MS(ESI):m/z 432.0(M+H) +。
Example 3
N- (5- (2-cyanopyridin-4-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) -5-methyl-4, 5,6, 7-tetrahydrofurano [3,2-c ] pyridine-2-sulfonamide
First step
To the flask was added compound 3a (10 g,65.12 mmol) and tetrahydrofuran (100 mL) at-78deg.C, 2.5M n-butyllithium (28.6 mL,71.63 mmol) dropwise, and stirred for 1 hour. After the buffer device and the tail gas absorbing device are connected into the reaction system, SO 2 gas is introduced into the reaction solution, the temperature is kept below minus 30 ℃, and the stirring is carried out for 0.5 hour. The reaction solution was slowly warmed to room temperature, filtered, and the filter cake was collected. After dissolving the cake in methylene chloride (100 mL), the temperature was lowered to 0℃and N-chlorosuccinimide (9.56 g,71.63 mmol) was added thereto, followed by stirring at room temperature for 1 hour, water (50 mL) was added to the reaction mixture, and methylene chloride was extracted (30 mL. Times.3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 3b (11 g, yield: 67%). LC-MS M/z (ESI): 251.8 (M+H) +.
Second step
To the reaction flask was added compound 3b (15 g,59.51 mmol) and pyridine (150 mL) at room temperature, cooled to 0deg.C, and bis- (4-methoxybenzyl) -amine (16.84 g,65.46 mmol) was added. The mixture was stirred at room temperature for 12 hours. Concentrated under reduced pressure, and the residue was purified by silica gel chromatography (SiO 2, 10-50% ethyl acetate/petroleum ether) to give compound 3c (5 g, yield: 17.7%).
1H NMR(400MHz,CDCl 3)δ8.40(d,1H),7.39(dd,1H),7.23(d,1H),7.12-7.06(m,4H),6.78-6.72(m,4H),4.41(s,4H),3.76(s,6H).LC-MS m/z(ESI):472.9(M+H) +.
Third step
To the reaction flask was added compound 3c (5 g,10.57 mmol) and N, N-dimethylformamide (50 mL) at room temperature, and after stirring well triethylamine (7.4 mL,52.86 mmol), formic acid (2.43 g,52.86 mmol) and [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride (0.43 g,0.53 mmol) were added sequentially. Stirring was carried out at 70℃for 3 hours under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, then water (100 mL) was added, extraction was performed with ethyl acetate (100 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO 2, 40-50% ethyl acetate/petroleum ether) to give the product 3d (3 g, yield: 64.7%). LC-MS M/z (ESI): 439.1 (M+H) +.
Fourth step
To the reaction flask was added compound 3d (100 mg,0.23 mol), trimethyloxonium tetrafluoroborate (34 mg,0.23 mmol) and methylene chloride (5 mL) at room temperature, and the reaction mixture was stirred at room temperature for 3 hours. Concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (SiO 2, 0-15% ethyl acetate/petroleum ether) to give compound 3e (123 mg, yield: 99.8%). LC-MS M/z (ESI): 453.3 (M) +.
Fifth step
To the reaction flask was added compound 3e (123 mg,0.27 mmol) and methanol (2 mL) at room temperature. Stirring until dissolved, cooling the ice-water bath to 0℃and adding sodium borohydride (51 mg,1.36 mmol). The temperature was raised to 50℃and stirred for 2 hours. The reaction solution was cooled to room temperature, which was then added to a saturated aqueous ammonium chloride solution (10 mL), extraction was performed with ethyl acetate (10 mL. Times.3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using an elution system (SiO 2, 0-15% ethyl acetate/petroleum ether) to give compound 3f (50 mg, yield: 40.4%). LC-MS M/z (ESI): 457.3 (M+H) +.
Sixth step
To the reaction flask was added compound 3f (200 mg,0.44 mmol), dichloromethane (5 mL), trifluoroacetic acid (50 mg,0.44 mmol) at room temperature. Stirring until dissolved. The reaction solution was stirred at room temperature for 48 hours, concentrated under reduced pressure, and the obtained crude product was purified by reverse phase column C18 (acetonitrile/water) to obtain 3g (50 mg, yield: 52.8%) of a compound. LC-MS M/z (ESI): 217.1 (M+H) +.
Seventh step
To the reaction flask was added 3H (2.00 g,9.43 mmol), 3i (2.17 g,9.43 mmol), K 2CO 3 (3.91 mg,28.3 mmol), dioxane (20 mL), H 2 O (4 mL), [1, 1-bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane methane complex (385 mg,0.471 mmol), nitrogen displacement 3 times, stirring at 80℃for 2 hours at room temperature. The reaction solution was concentrated under reduced pressure, water (100 mL) and ethyl acetate (100 mL) were added, and the organic phase was collected and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography using an elution system (SiO 2, 40% -50% ethyl acetate/petroleum ether) to give the product 3j (1.2 g, yield: 54.1%). LC-MS M/z (ESI): 236.2 (M+H) +.
Eighth step
To the reaction flask was added compound 3j (30 mg,0.13 mmol), tetrahydrofuran (1 mL), triethylamine (13 mg,0.13 mmol) at room temperature, and triphosgene (89 mg,0.30 mmol) was added thereto at a temperature lowered to 0℃under nitrogen atmosphere, and the reaction solution was stirred at 25℃for 0.5 hours. The reaction solution was concentrated to give compound 3k (33 mg crude).
Ninth step
To the reaction flask was added 3g (30 mg,0.12 mmol) of the compound and tetrahydrofuran (1 mL) at room temperature, and after the mixture was cooled to 0℃in an ice-water bath, sodium t-butoxide (12 mg,0.13 mmol) was added. The reaction was then stirred at room temperature for 0.5 hours, followed by addition of compound 3k (33 mg,0.13 mmol). The reaction solution was stirred at room temperature for 4 hours. Concentrated under reduced pressure and the residue purified by preparative liquid chromatography (column: waters, xbridge250 x 19mm,10 μm; mobile phase: aqueous phase (0.05% aqueous ammonia) and acetonitrile, gradient: 0-10min 30-50% b; flow 25 ml/min) to give compound 3 (8 mg, 14.5%).
1H NMR(400MHz,DMSO-d 6)δ8.64(d,1H),7.93(s,1H),7.64(d,1H),7.14(s,2H),6.34(s,1H),3.28(s,2H),2.86(m,8H),2.67(s,3H),2.04-1.97(m,2H).
LC-MS:MS(ESI):m/z 478.2(M+H) +。
Example 4
(1, 2,3,5,6, 7-Hexahydro-s-indacen-4-yl) carbamoyl) ((5-methyl-4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) sulfonyl) amine sodium salt
First step
To the reaction flask was added compound 4a (9.00 g,28.2 mmol), tris (dibenzylideneacetone) dipalladium (1.29 g,1.41 mmol), 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene (1.63 g,2.82 mmol), dioxane (100 mL), N-diisopropylethylamine (9 mL,56.4 mmol) under nitrogen atmosphere, benzyl mercaptan (6 mL,56.4 mmol) and stirred at 80℃for 2 hours. The reaction mixture was concentrated under reduced pressure, then water (100 mL) was added, extraction was performed with ethyl acetate (100 mL. Times.3), and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO 2, 20-40% ethyl acetate/petroleum ether) to give the desired product 4b (9 g, yield: 88.1%). LC-MS M/z (ESI) 363.5 (M+H) +.
Second step
To the flask was added compound 4b (8.00 g,22.1 mmol), acetonitrile (100 mL), acetic acid (8 mL), H 2 O (4 mL) at room temperature. After stirring uniformly, the temperature was lowered to 0 ℃, and dichlorohydantoin (15.2 g,77.2 mmol) was slowly added and stirred for 2 hours. Water (200 mL) was added, dichloromethane (300 mL. Times.2) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude compound 4c (6.5 g) which was used in the next reaction without purification. LC-MS M/z (ESI) 380.0 (M+H+CH 3CN) +).
Third step
To the reaction flask was added an methanolic ammonia solution (120 mL) at room temperature, and compound 4c (6.5 g) was added in portions while stirring, and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography using an elution system (SiO 2, 0-40% ethyl acetate/petroleum ether) to give compound 4d (5.5 g, yield: 89.8%). LC-MS m/z (ESI): 320.1 (M+H) +.
Fourth step
To the reaction flask were added compound 4d (1.00 g,3.13 mmol) and dioxane hydrochloride solution (13 mL) at room temperature, and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give compound 4e (600 mg, yield: 87.4%). LC-MS M/z (ESI): 219.9 (M+H) +.
Fifth step
To the reaction flask was added compound 4e (500 mg,1.96 mmol) and methanol (10 mL) at room temperature. After stirring until dissolved, sodium acetate (1.33 g,9.78 mmol) and a small amount of acetic acid were added to adjust the pH of the system to 3-5, and paraformaldehyde (579 mg,1.56 mmol) and 2-methylpyridine borane (209 mg,1.96 mmol) were added and stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give a crude product which was purified by reverse phase column chromatography (system: 0.1% ammonia/acetonitrile/water to give the objective product 4f (100 mg, yield: 30%); LC-MS M/z (ESI): 233.9 (M+H) +).
Sixth step
To the reaction flask was added compound 4f (40 mg,0.17 mmol) and tetrahydrofuran (1 mL) at room temperature, the mixture was cooled to 0℃in an ice-water bath, sodium tert-butoxide (20 mg,0.21 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours, and then a solution of compound 1j (41 mg,0.21 mmol) in tetrahydrofuran (1 mL) was slowly added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was purified by preparative liquid chromatography (columns: waters, xbridge 250 x 19mm,10 μm; mobile phase: aqueous phase (0.05% aqueous ammonia) and acetonitrile, gradient ratio: 0-10min 50-70% b; flow 25 ml/min) to give 4g of compound (1.5 mg, yield: 2%). LC-MS (ESI) M/z 474.2 (M+H+CH 3CN) +).
Seventh step
After filling the IR120 cation exchange resin-sodium column, the column was washed with acetonitrile and water, respectively, after washing, 4g (25.6 mg,0.06 mmol) of the compound was dissolved in acetonitrile (2 mL) and then added dropwise to the column, the column was washed with an elution system (0:1-1:0, acetonitrile/water), the eluted fraction was added to the second column, and the fractions eluted twice were combined and lyophilized to give compound 4 (14.03 mg, yield: 52.1%).
1H NMR(400MHz,DMSO-d6)δ7.63(br s,1H),6.78(s,1H),3.71(s,2H),2.85-2.73(m,8H),2.68-2.64(m,4H),2.44(s,3H),1.94-1.84(m,4H).LC-MS m/z(ESI):433.3(M+H)+.
Example 5
((4-Hydroxy-4-methyl-4, 5,6, 7-tetrahydrobenzo [ b ] thiophen-2-yl) sulfonyl) ((5- (2-methoxypyridin-4-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) amine sodium salt
First step
To a 250mL reaction flask was added 6, 7-dihydro-4 (5H) -benzothiophene ketone (5 a) (9.5 g,62.4 mmol) and dichloromethane (100 mL), and chlorosulfonic acid (10.2 g,87.4 mmol) was slowly added dropwise at-10 ℃. After the completion of the dropwise addition, the temperature was raised to room temperature and stirred for 72 hours. Pouring out the supernatant, dissolving the separated sticky substance in water, and freeze-drying. The residue was purified by reverse phase C18 (0.225% formic acid/acetonitrile/water system) to give compound 5b (2.6 g, yield: 12.6%). LC-MS m/z 230.9[ M-H ] -.
Second step
To a 100mL reaction flask, compound 5b (1.3 g,81.2% purity,5.59 mmol) and dichloromethane (10 mL) were added. Cooled to 0deg.C, phosphorus pentachloride (10.5 g,50.4 mmol) and pyridine (4.05 mL,50.4 mmol) were added. Stirring at room temperature for 16 hours. Phosphorus pentachloride (10.5 g,50.4 mmol) and pyridine (4.1 mL,50.4 mmol) were added and stirred for 2 hours. Phosphorus pentachloride (10.5 g,50.4 mmol) and pyridine (4.1 mL,50.4 mmol) were again added and stirred for 2 hours, and the reaction was complete. Dichloromethane (10 mL) was added to the reaction flask, the reaction solution was added to ammonia in tetrahydrofuran (10 mL,5 mol/L) with ice bath, and ammonia (10 mL, 25%) was added. Stirred at room temperature for 0.5 h, filtered, the filter cake washed with dichloromethane (10 mL) and the filtrate concentrated under reduced pressure. The residue was separated by column chromatography (SiO 2, 30% ethyl acetate/petroleum ether). Obtaining the compound 5c(40mg). 1HNMR(400MHz,DMSO-d 6)δ7.77(s,2H),7.60(s,1H),3.07(t,2H),2.26-2.19(m,2H),2.17-2.10(m,2H).LC-MS m/z:230.0(M-H) -.
Third step
To a 50mL reaction flask, compound 5c (90 mg,0.39 mmol) and tetrahydrofuran (3 mL) were added, the temperature was lowered to 0℃and a 3M solution of methyl magnesium bromide in THF (1.9 mL,5.7 mmol) was added and stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogencarbonate (2 mL) was added, extraction was performed with ethyl acetate (5 mL. Times.3), and the organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography using an open system (petroleum ether: ethyl acetate=1:1) to give compound 5d (55 mg, yield: 57%). LC-MS M/z 246.1 (M-H) -.
Fourth step
To a10 mL reaction flask, compound 5d (65 mg,74.1% purity,0.19 mmol), tetrahydrofuran (1 mL), a solution of compound 6n in tetrahydrofuran (2 mL,0.52mmol,0.26M tetrahydrofuran solution), and 1, 8-diazabicyclo undec-7-ene (148 mg,0.97 mmol) were added. Stirred at room temperature for 1 hour, water (5 mL) was added and extracted with ethyl acetate (1 mL). The aqueous phase was directly purified on reverse phase column C18 (water/acetonitrile), lyophilized, and the residue was purified by high performance liquid chromatography (column: gilson-281,Xbridge 150*25mm,5 μm; mobile phase: aqueous phase (10 mM ammonia water) and acetonitrile, gradient ratio: 0-9min 6-36% B; flow 25 ml/min) to give compound 5e (18 mg, yield: 18.4%).
1HNMR(400MHz,DMSO-d 6)δ9.48(s,1H),8.05(d,1H),7.33-7.29(m,2H),7.11-7.09(m,1H),7.06-7.01(m,1H),6.91(d,1H),6.75(s,1H),4.86(s,1H),3.85(s,3H),2.88(t,2H),2.80-2.70(m,2H),2.64-2.61(m,2H),1.99-1.92(m,3H),1.76-1.73(m,1H),1.69-1.64(m,2H),1.34(s,3H).
LC-MS m/z:512.1(M-H) -。
Fifth step
To an 8mL reaction flask, compound 5e (16 mg,0.03 mmol) and tetrahydrofuran (1 mL) were added. Cooled to 0 ℃, sodium tert-butoxide solid (2.99 mg,0.03 mmol) was added and stirred for 5 minutes. Concentrated and purified to give product 5 (7 mg, yield: 43.6%).
1H NMR(400MHz,DMSO)δ8.06(d,1H),7.26(s,1H),7.22(s,1H),7.06(m,2H),6.95(s,1H),6.78(s,1H),4.82(s,1H),3.86(s,3H),3.31(s,2H),2.89(t,2H),2.78(d,2H),2.65(m,2H),1.98–1.93(m,2H),1.74(d,2H),1.35(s,3H).
LC-MS m/z:512.1(M-H) -。
Example 6
((5- (2-Methoxypyridin-4-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) ((5-methyl-4, 5,6, 7-tetrahydrothieno [3,2-c ] pyridin-2-yl) sulfonyl) amine sodium salt
First step
Compound 6a (45 g,323 mmol) and tetrahydrofuran (500 mL) were added in a 1L three-necked flask at room temperature. Cooled to 0℃N, N-diisopropylethylamine (112 mL,679 mmol) and benzyl chloroformate (50 mL,356 mmol) were added dropwise. Heating to 20 ℃, and stirring for 12 hours. The reaction solution was slowly poured into water (500 mL), then extracted three times with ethyl acetate (200 ml×3), the ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO 2, 20% -25% ethyl acetate/petroleum ether) to give compound 6b (72 g, yield: 80.5%).
1HNMR(400MHz,CDCl 3)δ7.40-7.36(m,5H),7.14(d,1H),6.78(s,1H),5.20(s,2H),4.61(s,2H),3.83(s,2H),2.89(s,2H).
LC-MS：m/z(ESI):274.0(M+H) +。
Second step
To a 500mL three-necked flask, compound 6b (24 g,87.8 mmol) and anhydrous dichloromethane (250 mL) were added, the temperature was lowered to 0℃and chlorosulfonic acid (6 mL,92.2 mmol) was added to react for 5 minutes. Water (150 mL) was added, the dichloromethane was removed by concentration under reduced pressure, the aqueous phase was extracted with ethyl acetate (300 mL. Times.3), the organic phases were combined, dried, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by reverse phase column C18 (0.2% formic acid/acetonitrile/water) to give compound 6C (20 g, yield: 61.9%).
1HNMR(400MHz,DMSO-d 6)δ7.39-7.32(m,5H),6.89(s,1H),5.13(s,2H),4.45-4.41(m,2H),3.68(s,2H),2.76-2.75(m,2H).
LC-MS：m/z(ESI):351.9(M+H) +。
Third step
To a 1L three-necked flask was added compound 6c (20 g,56.6 mmol) and methylene chloride (200 mL), cooled to 0℃and pyridine (13.7 mL,170 mmol) and phosphorus pentachloride (35.4 g,170 mmol) were slowly added. Heating to room temperature, and stirring for 2 hr. Ice water (300 mL) was added to quench, stirred for 5 minutes, left to stand for liquid separation, the aqueous phase was extracted with dichloromethane (100 ml×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 6d (37 g, crude) which was used directly in the next step.
Fourth step
To a 1L three-necked flask, compound 6d (37 g,99.5 mmol) and tetrahydrofuran (250 mL) were added, followed by slow addition of an ammonia/tetrahydrofuran solution (99.5 mL,199mmol, 2M) at 0deg.C, heating to room temperature, and stirring for 12 hours. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (SiO 2, 45% -70% ethyl acetate/petroleum ether) to give the product compound 6e (16 g, yield: 45.6%).
1HNMR(400MHz,DMSO-d 6)δ7.61(s,2H),7.39-7.32(m,6H),5.13(s,2H),4.52-4.49(m,2H),3.71(s,2H),2.85(t,2H).
Fifth step
To a 250mL three-necked flask at 10℃were added compound 6e (7 g,19.9 mmol) and anhydrous dichloromethane (70 mL), hydrobromic acid/acetic acid (15 mL, 33%) was slowly added dropwise, and the mixture was stirred at room temperature for 2 hours. Filtration, dissolution of the filter cake in methanol (80 mL), slow addition of sodium carbonate solid to ph=10, filtration, concentration of the filtrate under reduced pressure gave compound 6f (5 g, crude) which was used directly in the next step.
Sixth step
To a 100mL single vial was added compound 6f (2.20 g,10.1 mmol), methanol (20 mL), acetic acid (2.88 mL,50.4 mmol), paraformaldehyde (300 mg,10.1 mmol) and sodium cyanoborohydride (1.27 g,20.2 mmol) at room temperature, and stirred for 10 hours. Filtration, concentration of the filtrate under reduced pressure, and purification of the residue by silica gel chromatography using an elution system (SiO 2, 10-30% methanol/methylene chloride) gave 6g of the compound (2.2 g, yield: 81.4%).
1HNMR(400MHz,CD 3OD)δ7.33(s,1H),3.88(s,2H),3.35-3.31(m,2H),3.25-3.21(m,2H),2.72(s,3H).LC-MS m/z(ESI):233.0(M+H) +.
Seventh step
To a 250mL reaction flask was added compound 6h (23.5 g,176.440 mmol), triethylamine (31.9 mL,229.37 mmol) and dichloromethane (150 mL) at room temperature. Acetic anhydride (19.1 mL,202.91 mmol) was added dropwise at 0deg.C with stirring until dissolved, and the reaction mixture was stirred at 0deg.C for 0.1 hr and then at room temperature for 1.4 hr. To the filtrate was added water (25 mL), extracted with methylene chloride (10 mL. Times.3), washed with saturated brine (20 mL. Times.1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (SiO 2, 20-40% ethyl acetate/petroleum ether) to give compound 6i (24.2 g).
1H NMR(400MHz,CDCl 3)δ7.73(d,J＝8.0Hz,1H),7.15(t,J＝7.6Hz,1H),7.03(d,J＝7.6Hz,1H),2.96(t,J＝7.2Hz,2H),2.82(t,J＝7.2Hz,2H),2.19(s,3H)2.08-2.15(m,2H).LC-MS：m/z 176.3(M+H) +.
Eighth step
To a 100mL single flask was added compound 6i (5 g, 28.284 mmol) and toluene (40 mL), p-toluenesulfonic acid (2.99 g,15.694 mmol), palladium acetate (0.30 g, 1.3411 mmol), stirred for 0.5 hours, N-bromosuccinimide (4.32 g,24.254 mmol), and stirred for 2 hours at room temperature. To the reaction solution was added an aqueous sodium thiosulfate solution (50 mL), followed by extraction with ethyl acetate (20 mL. Times.3), washing with saturated brine (20 mL. Times.1), drying over anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure. The residue was purified by column chromatography (SiO 2, 10% -50% ethyl acetate/petroleum ether) to give compound 6j (4 g). LC-MS: m/z 254.1 (M+H) +.
Ninth step
To a 500mL reaction flask was added compound 6j (16 g,62.960 mmol), ethanol (60 mL) and 36% -38% hydrochloric acid (90 mL,2912.781 mmol) at room temperature. The mixture was stirred until dissolved, and the reaction mixture was stirred at 80℃for 36 hours. Concentrating under reduced pressure gave compound 6k (18 g). The crude product was used directly in the next reaction without purification. LC-MS: m/z 212.2 (M+H) +.
Tenth step
To a 250mL single vial was added 6k (6 g,19.803 mol), 2-methoxypyridine-4-boronic acid (6 l) (3.63 g,23.763 mmol), potassium carbonate (8.76 g,63.369 mmol), dioxane (10 mL), and water (10 mL) at room temperature, and stirred under nitrogen for 15 minutes. [1, 1-bis (diphenylphosphino) ferrocene ] palladium dichloride (0.81 g,0.990 mmol) was added and the reaction solution was stirred at 80℃for 36 hours. To the reaction solution was added water (50 mL), followed by extraction with ethyl acetate (40 mL. Times.3), washing with saturated brine (20 mL. Times.1), drying over anhydrous sodium sulfate, filtration, and concentration under reduced pressure. The residue was purified by column chromatography (SiO 2, 15% ethyl acetate/petroleum ether) to give compound 6m (3.08 g).
1H NMR(400MHz,CDCl 3)δ8.22(dd,1H),7.01(dd,1H),6.98(d,1H),6.87–6.86(m,1H),6.77(d,1H),3.99(s,3H),3.50-3.91(m,2H),2.97(t,2H),2.77(t,2H),2.13-2.21(m,2H).
LC-MS:m/z:241.3(M+H) +。
Eleventh step
To a 50mL single vial was added 6m (1 g,4.161 mmol) and tetrahydrofuran (15 mL) at room temperature, stirred until dissolved, cooled to 0deg.C with an ice-water bath, and triethylamine (1.23 g,4.161 mmol) and triphosgene (1.23 g,4.161 mmol) were added. Stirred at room temperature for 0.5 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give compound 6n (800 mg). The crude product was used directly in the next reaction without purification. LC-MS: M/z 267.2 (M+H) +.
Twelfth step
To a 50mL reaction flask was added 6g (300 mg,1.29 mmol) of compound, N-dimethylformamide (5 mL), 6N (378 mg,1.42 mmol) of compound and 1, 8-diazabicyclo [5.4.0] undec-7-ene (2.95 g,19.4 mmol) at 0℃and the mixture was warmed to room temperature and stirred for 1 hour. Water (10 mL) and ethyl acetate (10 mL) were added, the mixture was stirred and allowed to stand to separate, and the aqueous phase was purified using reverse phase column C18 (system: water/acetonitrile, gradient: acetonitrile 20% -30%) to give compound 6o (100 mg, yield: 15.4%).
1H NMR(400MHz,DMSO-d 6)δ9.49(s,1H),8.03(d,1H),7.21(s,1H),7.07(d,1H),7.02(d,1H),6.91(d,1H),6.88(s,1H),6.75(s,1H),3.85(s,3H),3.56-3.54(m,2H),2.76-2.74(m,4H),2.64-2.60(m,4H),2.34(s,3H),1.98-1.94(m,2H).
LC-MS m/z(ESI):499.0(M+H) +。
Thirteenth step
Compound 6o (97.7 mg,0.20 mmol) was dissolved in 2-methyltetrahydrofuran (5 mL), washed with saturated sodium chloride solution (2 mL. Times.3), dried, filtered, the filtrate was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (0.3 mL), cooled to 0℃and 1M sodium t-butoxide in tetrahydrofuran (0.2 mL,0.2 mmol) was added, stirred for 30 minutes, and concentrated under reduced pressure to give compound 6 (55 mg, yield 51.1%).
1H NMR(400MHz,DMSO-d 6)δ8.02(d,1H),7.22(s,1H),7.06(d,1H),7.02(d,1H),6.92(d,1H),6.89(s,1H),6.75(s,1H),3.85(s,3H),2.88(t,2H),2.76-2.74(m,4H),2.67-2.60(m,4H),2.34(s,3H),1.99-1.94(m,2H).
LC-MS m/z(ESI):499.1(M+H) +。
Example 7
N- ((1,2,3,5,6.7-hexahydro-s-indacen-4-yl) carbamoyl) -1-isopropyl-5-methyl-4, 5,6, 7-tetrahydro-1H-pyrazolo [4,3-c ] pyridine-3-sulfonamide
First step
To a 250mL reaction flask was added compound 7a (4.4 g,19.7 mmol), acetonitrile (50 mL) and N-iodosuccinimide (8.87 g,39.41 mmol) at room temperature. The temperature was raised to 60℃and stirred for 16 hours. Quenched by addition of saturated aqueous sodium sulfite (50 mL). The mixture was extracted with ethyl acetate (50 mL. Times.3), and the organic phases were combined, washed with saturated brine (100 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO 2, 0% -100% ethyl acetate/petroleum ether) to give the product compound 7b (2.4 g, yield: 35%).
1HNMR(400MHz,DMSO-d 6)δ12.97(s,1H),4.11(s,2H),3.58(t,2H), 2.68-2.60(m,2H),1.42(s,9H).LC-MS m/z(ESI):350.0(M+H) +.
Second step
To a 100mL reaction flask, compound 7b (2.10 g,6.01 mmol) and N, N-dimethylformamide (20 mL) were added. Cooled to 0 ℃, sodium hydride (0.31 g,7.82mmol, 60%) and isopropyl iodide (1.53 g,9.02 mmol) were added and stirred at room temperature for 1 hour. Water (40 mL) was added and extracted with ethyl acetate (20 mL. Times.3). The organic phase was washed with saturated brine (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a mixture of compounds 7c and 7c-1 (2.05 g, yield: 87.2%). LC-MS m/z (ESI): 392.0 (M+H) +.
Third step
A50 mL reaction flask was charged with a mixture of compounds 7c and 7c-1 (2.05 g,5.24 mmol), p-methoxybenzyl mercaptan (1.21 g,7.86 mmol), tris (dibenzylideneacetone) dipalladium (0.96 g,1.05 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (961 mg,1.05 mmol), dioxane (20 mL), and N, N-diisopropylethylamine (1.30 mL,7.86 mmol). Under nitrogen atmosphere, the temperature was raised to 100℃and stirred for 16 hours. Cooling to room temperature, filtering, and concentrating the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (SiO 2, 25% ethyl acetate/petroleum ether) to give a mixture of compounds 7d and 7d-1 (1.6 g, yield: 73%). LC-MS m/z (ESI): 418.1 (M+H) +.
Fourth step
A50 mL reaction flask was charged with a mixture of compounds 7d and 7d-1 (1.2 g,2.67 mmol), acetic acid (15 mL), and water (5 mL). N-chlorosuccinimide (2.50 g,18.7 mmol) was slowly added thereto while cooling to 0℃and stirred at room temperature for 3 hours. The reaction solution was added to aqueous ammonia (20 mL, 25%) at 0deg.C. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (SiO 2, 50% ethyl acetate/petroleum ether) to give compound 7e (90 mg, yield: 9.8%) and 7e-1 (240 mg, yield: 26.1%).
1H NMR(400MHz,CDCl 3)δ8.04(br s,2H),4.59(s,2H),4.46-4.35(m,1H),3.81-3.67(m,2H),2.72-2.70(m,2H),1.50-1.49(m,15H).
LC-MS m/z(ESI):345.2(M+H) +。
Fifth step
To a 50mL reaction flask were added compound 7e (180 mg,0.52 mmol), dioxane (10 mL) and 6M hydrochloric acid (5 mL,30 mmol), and stirred for 1 hour. Concentration under reduced pressure gave compound 7f (160 mg, crude) which was used directly in the next step.
Sixth step
To a 25mL reaction flask was added compound 7f (160 mg,0.48 mmol), methanol (10 mL), paraformaldehyde (16.0 mg,0.18 mmol), triethylamine (0.1 mL,0.48 mmol) and palladium on carbon (51 mg,0.048mmol, 10%), and the mixture was stirred under hydrogen atmosphere at room temperature for 5 hours. Filtering, and concentrating the filtrate under reduced pressure. The residue was purified by high performance liquid chromatography (column: waters Xbridge 150 x 25mm x 5 μm; mobile phase: aqueous phase (0.05% aqueous ammonia) and acetonitrile, gradient ratio: 0-9min5-33% b; flow 25 ml/min) to give 7g of compound (60 mg, yield: 48.4%).
1HNMR(400MHz,DMSO-d 6)δ7.31(s,1H),4.50-4.46(m,1H),3.40(s,2H), 2.74-2.71(m,2H),2.63-2.62(m,2H),2.36(s,3H),1.37(d,6H).LC-MS m/z(ESI):259.1(M+H) +.
Seventh step
To a 25mL reaction flask was added 7g (60 mg,0.23 mmol) of compound, tetrahydrofuran (5 mL), 1j (69 mg,0.35 mmol) of compound, and 1, 8-diazabicyclo [5.4.0] undec-7-ene (106 mg,0.70 mmol), and the mixture was stirred at room temperature for 1 hour. Concentrated under reduced pressure, and the residue was purified by reverse phase C18 (system: water/acetonitrile, 30% acetonitrile), and the crude product obtained was purified by high performance liquid chromatography (column: waters Xb ridge 150 x 25mM x 5 μm; mobile phase: aqueous phase (10 mM ammonium bicarbonate) and acetonitrile; gradient ratio: 0-10min 21-51% B; flow 25 ml/min) to give compound 7 (12 mg, yield: 10.9%).
1H NMR(400MHz,DMSO-d 6)δ7.85(s,1H),6.89(s,1H),4.55-4.45(m,1H),3.64-3.56(m,2H),2.81-2.74(m,6H),2.63-2.55(m,6H),2.46-2.37(m,3H),1.98-1.81(m,4H),1.35(d,6H).
LC-MS m/z(ESI)：458.2(M+H) +。
Example 8
N- ((5- (2-fluoropyridin-4-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) -5-methyl-4, 5,6, 7-tetrahydrothieno [3,2-c ] pyridine-2-sulfonamide
Using the synthetic route of example 6, compound 8 (18 mg, yield: 12.5%) was obtained by substituting 2-fluoro-4-pyridineboronic acid for the tenth starting material 2-methoxypyridine-4-boronic acid (6 l).
1H NMR(400MHz,DMSO-d 6)δ8.10(d,1H),7.75(br s,1H),7.23(s,1H),7.18-7.05(m,4H),3.83(s,2H),3.12(s,3H),2.96-2.92(m,4H),2.77(s,2H),2.66(s,2H),2.02-1.95(m,2H).
LC-MS m/z(ESI):487.0(M+H) +。
Example 9
5-Methyl-N- ((5- (pyridin-3-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) -4,5,6, 7-tetrahydrothieno [3,2-c ] pyridine-2-sulfonamide
Using the synthetic route of example 6, substituting pyridine-3-boronic acid for the tenth starting material 2-methoxypyridine-4-boronic acid (6 l), compound 9 (15 mg, yield: 8.6%) was prepared.
1H NMR(400MHz,DMSO-d 6)δ8.48-8.47(m,2H),7.66-7.64(m,1H),7.32-7.29(m,1H),7.17-7.13(m,2H),7.07(d,1H),3.67(s,2H),2.93-2.89(m,6H),2.73(t,2H),2.52(s,3H),1.99(m 2H).
LC-MS m/z(ESI):469.1(M+H) +。
Example 10
N- ((5- (5-fluoropyridin-3-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) -5-methyl-4, 5,6, 7-tetrahydrothiophene [3,2-c ] pyridine-2-sulfonamide
Using the synthetic route of example 6, compound 10 (6 mg, yield: 3.2%) was obtained by substituting 5-fluoro-3-pyridineboronic acid for 2-methoxypyridine-4-boronic acid (6 l) which was the tenth step material.
1H NMR(400MHz,DMSO-d 6)δ8.45(d,1H),8.36(s,1H),7.61-7.60(m,1H),7.15-7.09(m,2H),7.01(s,1H),3.43(s,2H),2.92-2.87(m,6H),2.76(t,2H),2.52(s,3H),2.02-1.95(m,2H).
LC-MS m/z(ESI):487.2(M+H) +。
Example 11
N- ((5- (2-cyanopyrimidin-5-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) -5-methyl-4, 5,6, 7-tetrahydrothieno [3,2-c ] pyridine-2-sulfonamide
Using the synthetic route of example 6, substituting 2-methoxypyridine-4-boronic acid (6 l) of the tenth step starting material with 2-cyanopyrimidine-5-boronic acid pinacol ester, compound 11 (9 mg, yield: 6.3%) was obtained.
1H NMR(400MHz,DMSO-d 6)δ8.88(s,2H),7.75(s,1H),7.17(m,2H),6.91(s,1H),3.58(s,2H),2.92(t,2H),2.89-2.83(m,4H),2.81(t,2H),2.52(s,3H),2.04-1.96(m,2H).
LC-MS m/z(ESI):495.3(M+H) +。
Example 12
((5- (3, 6-Dihydro-2H-pyran-4-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) -5-methyl-4, 5,6, 7-tetrahydrothieno [3,2-c ] pyridin-2-yl) sulfonyl) amine sodium salt
Using the synthetic route of example 6, substituting (6 l) the tenth starting material 2-methoxypyridine-4-boronic acid into 3, 6-dihydro-2H-pyran-4-boronic acid pinacol ester gave compound 12 (57 mg, yield: 81.1%).
1H NMR(400MHz,DMSO-d 6)δ7.49(s,1H),7.23(s,1H),7.01-6.98(m,1H),6.89-6.86(m,1H),5.52(s,1H),4.07-4.05(m,2H),3.69-3.65(m,2H),3.52-3.51(m,2H),2.84-2.80(m,6H),2.68-2.63(m,2H),2.51(s,3H),2.14-2.13(m,2H),1.94-1.89(m,2H).
LC-MS m/z(ESI):474.1(M+H) +。
Example 13
N- ((5- (6-cyanopyridin-3-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) -5-methyl-4, 5,6, 7-tetrahydrothieno [3,2-c ] pyridine-2-sulfonamide
Using the synthetic route of example 6, substituting 2-methoxypyridine-4-boronic acid (6 l) of the tenth step starting material with 2-cyano-5-pyridineboronic acid, compound 13 (7 mg, yield: 6.2%) was produced.
1H NMR(400MHz,DMSO-d 6)δ8.66(s,1H),7.91(s,2H),7.55(s,1H),7.12(dd,2H),6.89(s,1H),3.45(s,2H),2.91(t,2H),2.81-2.75(m,6H),2.42(s,3H),2.02-1.95(m,2H).
LC-MS m/z(ESI):494.1(M+H) +。
Example 14
5- (4- (3- ((5-Methyl-4, 5,6, 7-tetrahydrothieno [3,2-c ] pyridin-2-yl) sulfonyl) ureido) -2, 3-dihydro-1H-inden-5-yl) picolinamide
Using the synthetic route of example 6, substituting the tenth starting material 2-methoxypyridine-4-boronic acid (6 l) with (6-carbamoylpyridin-3-yl) boronic acid, compound 14 (10 mg, yield: 12.2%) was produced.
1H NMR(400MHz,DMSO-d 6)δ8.56(d,1H),8.13(s,1H),7.92(d,1H),7.83(dd, 1H),7.59(s,1H),7.42(br s,1H),7.11(dd,2H),6.93(s,1H),3.43(s,2H),2.91(t,2H),2.81-2.74(m,6H),2.41(s,3H),2.02-1.94(m,2H).
LC-MS m/z(ESI):512.3(M+H) +。
Example 15
((5- (2-Fluoropyridin-3-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) ((5-methyl-4, 5,6, 7-tetrahydrothieno [3,2-c ] pyridin-2-yl) sulfonyl) amine sodium salt
Using the synthetic route of example 6, substituting 2-methoxypyridine-4-boronic acid (6 l) of the tenth step starting material with 2-fluoro-3-pyridineboronic acid, compound 15 (11 mg, yield: 56.8%) was produced.
1H NMR(400MHz,DMSO-d 6)δ8.12(d,1H),7.73-7.71(m,1H),7.29(s,1H),7.22-7.17(m,1H),7.06(d,1H),7.00(d,1H),6.84(s,1H),3.32(s,2H),2.90(t,2H),2.82-2.73(m,4H),2.62(t,2H),2.35(s,3H),2.03-1.93(m,2H).
LC-MS m/z(ESI):487.2(M+H) +。
Example 16
((5- (5-Cyanopyridin-3-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) ((5-methyl-4, 5,6, 7-tetrahydrothieno [3,2-c ] pyridin-2-yl) sulfonyl) amine sodium salt
Using the synthetic route of example 6, substituting the tenth starting material 2-methoxypyridine-4-boronic acid (6 l) with 5-cyano-3-pyridineboronic acid, compound 16 (16.93 mg, yield: 57.7%) was produced.
1H NMR(400MHz,DMSO-d 6)δ8.80(d,1H),8.73(d,1H),8.12(t,1H),7.51(br s,1H),7.09(dd,2H),6.77(s,1H),3.31(s,2H),2.90(t,2H),2.81-2.74(m,4H),2.62(t,2H),2.35(s,3H),2.02-1.94(m,2H).
LC-MS m/z(ESI):494.1(M+H) +。
Example 17
((5- (2-Cyanopyridin-4-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) ((5- (2- (methylsulfonyl) ethyl) -4,5,6, 7-tetrahydrothieno [3,2-c ] pyridin-2-yl) sulfonyl) amine sodium salt
First step
To a10 mL reaction flask was added compound 6f (300 mg,1.0 mmol), absolute ethanol (4 mL), triethylamine (0.6 mL,4.0 mmol) and compound 17a (128 mg,1.2 mmol) at room temperature, and the mixture was heated to 80℃and stirred for 16 hours. Cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (SiO 2, 100% ethyl acetate/petroleum ether) to give compound 17b (200 mg, yield 61.5%).
1H NMR(400MHz,DMSO-d 6)δ7.56(s,2H),7.23(s,1H),3.54(s,2H),3.37(t,2H),3.00(s,3H),3.91(t,2H),2.85-2.82(m,2H),2.80-2.77(m,2H).
LC-MS m/z(ESI):324.9(M+H) +。
Second step
To a 25mL reaction flask was added compound 17b (80 mg,0.25 mmol) and anhydrous tetrahydrofuran (5 mL) at room temperature. Cooled to 0deg.C, 1M sodium t-butoxide/tetrahydrofuran solution (0.4 mL,0.4 mmol) was slowly added dropwise. The reaction was carried out at 0℃for 0.5 hours, and 3k (156 mg, 0.298 mmol) of the compound was added. The reaction was carried out at room temperature for 1 hour. Water (2 mL) and methyl tert-butyl ether (10 mL) were added. The aqueous phase was lyophilized and then purified by preparative liquid chromatography (column: waters Xbridge150 x 25mm x 5um; mobile phase: aqueous phase (0.05% aqueous ammonia) and acetonitrile, gradient ratio: 0-9min 3-33% b; flow 25 ml/min) to give compound 17c (40.48 mg, yield: 27.9%).
1H NMR(400MHz,DMSO-d 6)δ8.56(d,1H),7.90(s,1H),7.76(br s,1H),7.61-7.59(m,1H),7.13(s,2H),6.89(s,1H),3.48(s,2H),3.37(s,2H),3.02(s,3H),2.91(m,4H),2.80(m,6H),2.02-1.99(m,2H).LC-MS m/z(ESI):586.3(M+H) +.
Third step
Compound 17c (38 mg) was dissolved in acetonitrile (1 mL), added dropwise to an IR120 cation exchange resin-Na column, and eluted with an acetonitrile:water=0:1-20:80-40:60-50:50-1:0 system. The fractions were combined and lyophilized to give compound 17 (40 mg, yield: 93.1%).
1H NMR(400MHz,DMSO-d 6)δ8.55(d,1H),7.90(s,1H),7.61-7.59(m,2H),7.10(s,2H),6.80(s,1H),3.47(s,2H),3.38(s,2H),3.01(s,3H),2.91(t,4H),2.83-2.77(m,6H),2.03-1.95(m,2H).
LC-MS m/z(ESI):586.1(M+H) +。
Example 18
N- ((5- (2-methoxypyridin-4-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) -5- (2- (methylsulfonyl) ethyl) -4,5,6, 7-tetrahydrothieno [3,2-c ] pyridine-2-sulfonamide
Using a method of synthesis similar to example 6, compound 17b was reacted with compound 6n to give compound 18 (20 mg, yield: 3.6%).
1H NMR(400MHz,DMSO-d 6)δ8.04(d,1H),7.74(s,1H),7.21(s,1H),7.17(d,1H),7.08(d,1H),6.83(d,1H),6.70(s,1H),3.85(s,3H),3.52(s,2H),3.37-3.30(m,2H),3.00(s,3H),2.93-2.89(m,4H),2.84-2.80(m,4H),2.71-2.67(m,2H),2.02-1.94(m,2H).
LC-MS m/z(ESI):591.4(M+H) +。
Example 19
((5- ((3- (Hydroxymethyl) oxetan-3-yl) methyl) -4,5,6, 7-tetrahydrothieno [3,2-c ] pyridin-2-yl) sulfonyl) ((5- (2-methoxypyridin-4-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) amine sodium salt
First step
To a 50mL single vial was added, in order, compound 19a (1.21 g,6.68 mmol), compound 6f (2.00 g,6.68 mmol), triethylamine (2.80 mL,20.1 mmol) and N, N-dimethylformamide (10 mL) at 100℃for 16 hours at room temperature. Cooled to room temperature and concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography (column: kromasil Eternity XT x 80mM x 10 μm; mobile phase: aqueous phase (10 mM ammonium bicarbonate) and acetonitrile; gradient ratio: 0-20min 5-30% B; flow 140 mL/min) to give compound 19b (600 mg, yield: 24.7%).
1H NMR(400MHz,DMSO-d 6)δ7.46(s,2H),7.23(s,1H),4.82(s,1H),4.36-4.28(m,4H),3.64(s,2H),3.42(s,2H),2.80(t,2H),2.77(s,2H),2.66(t,2H).LC-MS m/z(ESI):319.1(M+H) +.
Second step
Using a method of synthesis similar to example 6, compound 19 was obtained by reacting compound 19b with compound 6n (93 mg, yield: 69.1%).
1H NMR(400MHz,DMSO-d 6)δ8.03(d,1H),7.26(s,1H),7.07(d,1H),7.02(d,1H),6.92-6.89(m,2H),6.76(s,1H),4.82(s,1H),4.35-4.30(m,4H),3.85(s,3H),3.65(s,2H),3.35(s,2H),2.88(t,2H),2.77-2.72(m,6H),2.65-2.62(m,2H),2.00-1.92(m,2H).LC-MS m/z(ESI):585.1(M+H) +.
Example 20
((5- (2- (Oxetan-3-yloxy) pyridin-4-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) ((5-methyl-4, 5,6, 7-tetrahydrothieno [3,2-c ] pyridin-2-yl) sulfonyl) amine sodium salt
First step
To a 25mL reaction flask were added 60% sodium hydrogen (32.9 mg,0.82 mmol) and tetrahydrofuran (5 mL) at room temperature. Cooled to 0deg.C and compound 20a (45.7 mg, 0.611 mmol) was added. Stirring was continued at 0deg.C for 0.5 h and Compound 8 (200 mg,0.411 mmol) was added. The mixture was stirred at room temperature for 8 hours, and the reaction mixture was poured into ice water (5 mL) and extracted with ethyl acetate (3 mL. Times.3). The organic phase was washed with saturated aqueous sodium chloride (5 mL. Times.1) and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, the crude product was purified by preparative liquid chromatography (column: waters Xridge 150X 50mm 10um; mobile phase: aqueous phase (0.05% ammonia water) and acetonitrile, gradient ratio: 0-11min 15-45% B; flow 60 mL/min) to give compound 20b (37 mg, yield: 16.7%).
1H NMR(400MHz,DMSO-d 6)δ8.01(d,1H),7.75(br s,1H),7.17-7.14(m,2H),7.08(d,1H),6.91(d,1H),6.82(s,1H),5.59-5.53(m,1H),4.91(t,2H),4.58(dd,2H), 3.74(s,2H),2.95-2.89(m,6H),2.73(t,2H),2.60(s,3H),2.02-1.95(m,2H).LC-MS m/z(ESI):541.1(M+H) +.
Second step
Compound 20b (37 mg,0.068 mmol) was dissolved in acetonitrile (1 mL) and added dropwise to an IR120 cation exchange resin-Na column eluting with acetonitrile: water=1:0-0:1 system. The fractions were combined and lyophilized to give compound 20 (32 mg, yield: 86.8%).
1H NMR(400MHz,DMSO-d 6)δ7.98(d,1H),7.44(br s,1H),7.10(d,1H),7.06-7.02(m,2H),6.93(d,1H),6.82(s,1H),5.58-5.53(m,1H),4.89(t,2H),4.58(dd,2H),3.49(s,2H),2.89(t,2H),2.83-2.72(m,6H),2.44(s,3H),1.99-1.95(m,2H).
LC-MS m/z(ESI):541.2(M+H) +。
Example 21
((4-Hydroxy-4-methyl-4, 5,6, 7-tetrahydrobenzofuran-2-yl) sulfonyl) ((5- (2-methoxypyridin-4-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) amine sodium salt
Using the synthetic route of example 5, the first starting material 6, 7-dihydro-4 (5H) -benzothiophene (5 a) was replaced with 6, 7-dihydro-4 (5H) -benzofuranone to afford compound 21 (17 mg, yield: 55%).
1H NMR(400MHz,DMSO-d 6)δ8.07(d,1H),7.36(s,1H),7.12-7.01(m,2H),6.98-6.90(m,1H),6.77(s,1H),6.51(s,1H),4.71(s,1H),3.86(s,3H),3.62-3.51(m,2H),2.88(t,2H),2.77(t,2H),2.05-1.89(m,3),1.79-1.64(m,2H),1.62-1.53(m,1H),1.31(s,3H).
LC-MS m/z(ESI):498.2(M+H) +。
Example 22
3-Cyano-N- ((5- (2-cyanopyridin-4-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) -6-methyl-4, 5,6, 7-tetrahydrothieno [2,3-c ] pyridine-2-sulfonamide
To the reaction flask was added compound 1i (50 mg,0.19 mmol) and tetrahydrofuran (1 mL) in order at room temperature. After cooling to 0deg.C in an ice-water bath, sodium t-butoxide (22 mg,0.23 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours, followed by slow addition of a solution of compound 3k (60 mg,0.23 mmol) in tetrahydrofuran (1 mL) and stirring at room temperature for 3 hours. After the reaction is completed, the reaction mixture is purified by preparative liquid chromatography (column: waters, xbridge 250X 19mm,10 μm; mobile phase: aqueous phase (0.05% ammonia) and acetonitrile, gradient ratio: 0-10min 45-60% B; flow 25 ml/min) to give compound 22 (19 mg, 18.5%).
1H NMR(400MHz,DMSO-d 6)δ8.60(d,1H),7.88(s,1H),7.62(s,1H),7.12(s,2H),3.10(s,2H),2.91(t,4H),2.82(d,4H),2.67(s,3H),2.06-1.97(m,2H).
LC-MS m/z(ESI):519.1(M+H) +。
Example 23
N- ((5- (2-cyanopyridin-4-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) -6-methyl-4, 5,6, 7-tetrahydrothieno [2,3-c ] pyridine-2-sulfonamide
Compound 2k was reacted with compound 3k by a similar synthetic method to example 22 to obtain compound 23 (11 mg, 19.5%).
1H NMR(400MHz,DMSO-d 6)δ8.59(d,1H),7.90(s,1H),7.60(d,1H),7.16(d,2H),7.02(s,1H),3.93(s,2H),3.02(s,2H),2.92(t,2H),2.80(t,2H),2.76-2.70(m,2H),2.62(s,3H),2.08-1.93(m,2H).LC-MS m/z(ESI):494.2(M+H) +.
Example 24
N- ((5- (2-methoxypyridin-4-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) -5-methyl-4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridine-2-sulfonamide
Using the synthetic route of example 4, substituting compound 1j from the sixth step with compound 6n, compound 24 (5 mg, 7.7%) was obtained.
1H NMR(400MHz,DMSO-d 6)δ8.09(d,1H),7.11(d,1H),7.05(d,1H),6.95(d,1H),6.76(s,1H),3.87(s,3H),2.97(s,2H),2.89(t,2H),2.84-2.71(m,4H),2.62-2.53(m,5H),2.03-1.92(m,2H).
LC-MS m/z(ESI):500.1(M+H) +。
Example 25
N- ((5- (2-cyanopyridin-4-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) -5-methyl-4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridine-2-sulfonamide
Using the synthetic route of example 4, substituting compound 1j from the sixth step with compound 3k, compound 25 (20 mg, 31.8%) was obtained.
1H NMR(400MHz,DMSO-d 6)δ8.63(d,1H),7.93(s,1H),7.64(s,1H),7.13(s,2H),4.09(s,2H),3.21(s,2H),2.92(m,4H),2.81(dd,2H),2.70(s,3H),2.04-1.95(m,2H).LC-MS m/z(ESI):495.2(M+H) +.
Example 26
((3-Cyano-6- (oxetan-3-ylmethyl) -4,5,6, 7-tetrahydrothieno [2,3-c ] pyridin-2-yl) sulfonyl) ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) amine sodium salt
Using the synthetic route of example 1, the seventh starting material paraformaldehyde was replaced with oxetane-3-carbaldehyde to give compound 26 (14 mg, yield: 37.4%).
1H NMR(400MHz,DMSO-d 6)δ7.50(s,1H),6.77(s,1H),4.63(dd,2H),4.26(t,2H),3.53(s,2H),3.27-3.23(m,2H),2.81-2.66(m,11H),2.05-1.99(m,2H),1.93-1.88(m,4H).LC-MS m/z(ESI):513.1(M+H) +.
Example 27
((3-Cyano-6-ethyl-4, 5,6, 7-tetrahydrothieno [2,3-c ] pyridin-2-yl) sulfonyl) ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) amine sodium salt
Using the synthetic route of example 1, the seventh-step starting material paraformaldehyde was replaced with acetaldehyde to give compound 27 (42 mg, yield: 56.2%).
1H NMR(400MHz,DMSO-d 6)δ7.52(s,1H),6.77(s,1H),3.56(s,2H),2.75-2.53(m,14H),1.98-1.83(m,4H),1.06(t,3H).LC-MS m/z(ESI):471.2(M+H) +.
Example 28
((6-Acetyl-4, 5,6, 7-tetrahydrothieno [2,3-c ] pyridin-2-yl) sulfonyl) ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) amine sodium salt
To a 25mL single-necked flask, compound 2i (100 mg,0.384 mmol), tetrahydrofuran (2 mL) and sodium t-butoxide (37 mg,0.38 mmol) were added at 0℃and stirred at room temperature for 40 minutes. Compound 1j (76 mg,0.38 mmol) was added and stirred for 3 hours. Concentrated under reduced pressure, and the residue purified by preparative liquid chromatography (columns: waters, xbridge250 x 19mm,10 μm; mobile phase: aqueous phase (0.05% aqueous ammonia) and acetonitrile, gradient: 0-10min 30-65% b; flow 25 ml/min) to give crude product, which after sodium ion exchange resin exchange gives compound 28 (48 mg, yield: 26.0%).
1H NMR(400MHz,DMSO-d 6)δ7.43(s,1H),7.09(d,1H),6.77(s,1H),4.62(d,2H),3.75-3.57(m,2H),2.76(t,4H),2.68(t,6H),2.07(m,3H),1.94-1.87(m,4H).
LC-MS m/z(ESI):460.1(M+H) +。
Example 29
((5- (2-Methoxypyridin-4-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) ((6-methyl-4, 5,6, 7-tetrahydrothieno [2,3-c ] pyridin-2-yl) sulfonyl) amine sodium salt
Using the synthetic route of example 2, substituting compound 1j of the eleventh step with compound 6n, compound 29 (16 mg, yield: 14.1%) was obtained.
1H NMR(400MHz,DMSO-d 6)δ8.03(d,1H),7.25(s,1H),7.08(d,1H),7.03(d,1H),6.94(s,1H),6.92(d,1H),6.76(s,1H),3.85(s,3H),3.48(s,2H),2.89(t,2H),2.77(t,2H),2.59(s,4H),2.35(s,3H),2.03-1.88(m,2H).LC-MS m/z(ESI):499.2(M+H).
Example 30
((6-Acetyl-4, 5,6, 7-tetrahydrofurano [2,3-c ] pyridin-2-yl) sulfonyl) ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) amine sodium salt
First step
To a single-port flask, compound 30a (8.00 g,83.3 mmol), ethanol (100 mL), nitromethane (4.4 mL,83 mmol) and 10N aqueous sodium hydroxide solution (8.3 mL,83 mmol) were added in this order, and the mixture was stirred for 1 hour. The reaction solution was poured into 15% aqueous hydrochloric acid (100 mL), the solid was precipitated, filtered, and the cake was decompressed and dried to give a product 30b (6 g, yield: 51.8%). Directly used in the next step.
Second step
To a single-necked flask, 2.5M lithium aluminum hydride in tetrahydrofuran (6.4 mL,16 mmol) and 2mL of tetrahydrofuran were added dropwise sulfuric acid (0.4 mL,8 mmol) at 0℃and stirred for 20 minutes. A solution of compound 30b (500 mg,3.59 mmol) in tetrahydrofuran (2 mL) was added and stirred for 10 min. Heated to reflux and stirred for 5 minutes. Isopropanol (1.7 ml,21.6 mmol) and sodium hydroxide (1.29 g,32.3 mmol) were added to the reaction mixture, the mixture was filtered, the filter cake was washed with ethyl acetate, the filtrate was collected, and concentrated under reduced pressure to give crude product 30c (380 mg, crude product) which was used directly in the next reaction.
LC-MS m/z(ESI):112.1。
Third step
To a 100mL single flask was added compound 30c (380 mg,3.42 mmol), methylene chloride (2 mL), triethylamine (0.8 mL,5.4 mmol) and di-tert-butyl dicarbonate (0.9 mL,3.76 mmol) in this order at room temperature, and the mixture was stirred at room temperature for 1 hour. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (SiO 2, 10% ethyl acetate/petroleum ether) to give compound 30d (480 mg, yield: 55.4%).
1H NMR(400MHz,CDCl 3)δ7.37(t,1H),7.27(s,1H),6.29(s,1H),4.59(s,1H),3.32-3.31(m,2H),2.61(t,2H),1.44(m,9H).
Fourth step
To a 100mL single-necked flask, 30d (380 mg,1.80 mmol), toluene (8 mL), paraformaldehyde (34 mg,0.95 mmol) and p-toluenesulfonic acid (6 mg,0.04 mmol) were successively added at room temperature, followed by stirring under reflux for 2 hours. Water (10 mL) and ethyl acetate (20 mL) were added, the organic phase was washed with brine (10 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography in an elution system (SiO 2, 10% ethyl acetate/petroleum ether) to give compound 30e (200 mg, yield: 49.8%).
1H NMR(400MHz,CDCl 3)δ7.28(d,1H),6.24(d,1H),4.44(s,2H),3.63(s,2H), 2.53-2.51(m,2H),1.48(s,9H).
Fifth step
To a 100mL single flask at room temperature, compound 30e (3.93 g,17.5 mmol), methylene chloride (24 mL), and trifluoroacetic acid (8 mL) were successively added and stirred for 2 hours. Concentration gave compound 30f (3.2 g, crude) which was used directly in the next step.
LC-MS m/z(ESI)：124.4(M+H) +。
Sixth step
To a single vial of 250mL at room temperature, compound 30f (3.20 g,16.3 mmol), tetrahydrofuran (90 mL), triethylamine (4 mL,28.6 mmol) was added, the temperature was lowered to 0℃and acetyl chloride (2 mL,28.6 mmol) was added dropwise, the temperature was raised to room temperature and stirred for 1 hour. Filtration, water (30 mL) was added to the filtrate, extraction with ethyl acetate (30 mL. Times.3), concentration under reduced pressure, and purification of the residue by silica gel column chromatography in an elution system (SiO 2, 15% ethyl acetate/petroleum ether) gave 30g (1.69 g, yield: 62.8%) of the compound.
LC-MS m/z(ESI)：166.0(M+H) +。
Seventh step
30G (1.69 g,10.2 mmol) of the compound and methylene chloride (10 mL) were successively added to a 50mL single-necked flask at room temperature. Cooled to 0 ℃, chlorosulfonic acid (1.79 g,15.3 mmol) was added and stirred at room temperature for 10 minutes. Ice water (20 mL) was added for quenching and the aqueous phase was purified using reverse column C18 (water/acetonitrile, HCl system) to give compound 30h (2.3 g, yield: 92.0%).
LC-MS m/z(ESI)：246.3(M+H) +。
Eighth step
To a 50mL single flask at room temperature, the compound 30h (600 mg,2.45 mmol) and methylene chloride (12 mL) were sequentially added, followed by pyridine (0.2 mL,2.7 mmol), phosphorus pentachloride (764 mg,3.67 mmol) was added under nitrogen atmosphere, stirred for 12 hours, the reaction solution was poured into ice water (15 mL), warmed to room temperature, extracted with methylene chloride (20 mL), the organic phase was dried, filtered, and the filtrate was concentrated under reduced pressure to give the product 30i (500 mg, yield: 77.4%).
LC-MS m/z(ESI):264.2(M+H) +。
Ninth step
Compound 30i (500 mg,1.90 mmol) was dissolved in dichloromethane (2 mL) at room temperature, and a solution of compound 30i (500 mg,1.90 mmol) in dichloromethane (2 mL) was added dropwise to a 7M methanolic ammonia solution (20 mL) and stirred for 1 hour. Concentrated under reduced pressure, and purified by reverse column C18 (water/acetonitrile, ammonia system) to give compound 30j (150 mg, yield: 32.3%).
LC-MS m/z(ESI)：245.3(M+H)。
Tenth step
To a 50mL single vial was added compound 30j (100 mg,0.384 mmol) and tetrahydrofuran (2 mL) at 0deg.C, and sodium t-butoxide (19.7 mg,0.205 mmol). Stirred at room temperature for 40 minutes. Tetrahydrofuran (2 mL) was added as compound 1j (40.8 mg,0.205 mmol). Stirring for 3 hours. The reaction solution was purified by preparative liquid chromatography (columns: waters, xbridge 250 x 19mm,10 μm; mobile phase: aqueous phase (0.05% aqueous ammonia) and acetonitrile, gradient ratio: 0-10min 45-60% b; flow 25 ml/min) to give crude product, which was exchanged with sodium ion exchange resin to give compound 30 (42 mg, yield: 23.5%).
1H NMR(400MHz,DMSO-d 6)δ7.45(s,1H),6.77(s,1H),6.45(s,1H),4.51-4.46(m,2H),3.67-3.60(m,2H),2.75(m,4H),2.69-2.63(m,4H),2.39-2.33(m,2H),2.09-2.06(m,3H),1.98-1.81(m,4H).
LC-MS m/z(ESI):444.2(M+H) +。
Example 31
((5-Methyl-4, 5,6, 7-tetrahydrofurano [3,2-c ] pyridin-2-yl) sulfonyl) ((2, 4,5, 6-tetrahydro-1H-cyclobutano [ f ] inden-3-yl) carbamoyl) amine sodium salt
First step
3G (104 mg,0.481 mmol) of the compound was dissolved in anhydrous tetrahydrofuran (5 mL), cooled to 0℃and a sodium tert-butoxide solution (0.5 mL,0.5mmol,1M tetrahydrofuran solution) was added thereto after stirring at 0℃for half an hour, and then, compound 31a (81 mg,0.437mmol, prepared by the method disclosed in example 141 on page 339 of the specification of WO 2020018975) was added thereto, followed by continuing the reaction at 0℃for half an hour. After the reaction solution was concentrated, the crude product was purified by a reverse phase column (0-23.5%, acetonitrile/0.2% aqueous ammonia) to give compound 31b (70 mg, yield: 39.87%).
1H NMR(400MHz,DMSO-d 6)δ7.69(s,1H),6.72(s,1H),6.58(s,1H),3.76(s,2H),3.06-3.00(m,2H),2.84-2.83(m,4H),2.78(t,2H),2.69-2.66(m,4H),2.49(s,3H),1.96-1.88(m,2H).
LC-MS m/z:402.2(M+H) +。
Second step
After two IR120 cation exchange resin-sodium type columns (about 15 cm in height) were packed, the columns were rinsed with deionized water (20 mL), acetonitrile (20 mL), and deionized water (20 mL), after rinsing, compound 31b (70 mg,0.174 mmol) was dissolved in acetonitrile (2 mL), and then added dropwise to the columns, the columns were rinsed with an elution system (0:1-1:0, acetonitrile/water), the eluted fractions were added to the second column, and the eluted fractions were combined and lyophilized to give compound 31 (49 mg, yield ：66.15％) 1H NMR(400MHz,DMSO-d 6)δ7.54(s,1H),6.52(s,1H),6.43(s,1H),3.22(s,2H),3.05-3.03(m,2H),2.82-2.75(m,4H), 2.69-2.62(m,6H),2.33(s,3H),1.97-1.87(m,2H).
LC-MS m/z(ESI):402.1(M+H) +。
Example 32
((5-Methyl-4, 5,6, 7-tetrahydrothieno [3,2-c ] pyridin-2-yl) sulfonyl) ((2, 4,5, 6-tetrahydro-1H-cyclobutano [ f ] inden-3-yl) carbamoyl) amine sodium salt
Using the synthetic route of example 31, the first-step compound 3g was replaced with compound 6g, to give compound 32 (9 mg, yield: 6.3%).
1H NMR(400MHz,DMSO-d 6)δ7.42(s,1H)7.02(s,1H)6.51(s,1H)3.29(s,2H)3.03-3.09(m,2H)2.81(t,2H)2.77(t,2H)2.74(t,2H)2.67(t,2H)2.56(t,2H)2.32(s,3H)1.90(m,2H).
LC-MS m/z:418.0(M+H) +。
Example 33
((5-Ethyl-4, 5,6, 7-tetrahydrothieno [3,2-c ] pyridin-2-yl) sulfonyl) ((2, 4,5, 6-tetrahydro-1H-cyclobutano [ f ] inden-3-yl) carbamoyl) amine sodium salt
First step
To dimethyl sulfoxide (15 mL) was added compound 6f (1 g,3.34 mmol), the ice-water bath was cooled to 0 ℃, cesium fluoride (0.76 g,5.01 mmol) was slowly added, and further ethyl iodide (0.63 g,4.01 mmol) was added, and the mixture was naturally warmed to room temperature and stirred at 20℃for 1 hour. The reaction solution was directly purified by reverse phase column chromatography (C18, 30%, acetonitrile/0.2% ammonia water) without treatment to give compound 1b (220 mg, yield 26.7%).
1H NMR(400MHz,DMSO-d 6)δ7.55(s,2H),7.24(s,1H),3.43(s,2H),2.82(t,J＝5.6Hz,2H),2.70(t,J＝5.6Hz,2H),2.52(q,J＝7.2Hz,2H),1.07(t,J＝7.2Hz,3H).
LC-MS m/z(ESI)：247.1(M+H) +。
Second step
Using the synthetic route of example 31, substituting 3g of the first step compound with compound 33a, compound 33 (55.91 mg, 14.4% yield) was obtained.
1H NMR(400MHz,DMSO-d 6)δ10.19(s,1H),7.71(s,1H),7.30(s,1H),6.60(s,1H),3.93(s,2H),3.21-3.13(m,2H),3.08-3.03(m,2H),2.99-2.93(m,4H),2.85-2.80(m,2H),2.76(t,J＝7.6Hz,2H),2.65(t,J＝7.6Hz,2H),1.95-1.88(m,2H),1.18(t,J＝7.2Hz,3H).
LC-MS m/z(ESI):432.2(M+H) +。
Example 34
((5-Isopropyl-4, 5,6, 7-tetrahydrothieno [3,2-c ] pyridin-2-yl) sulfonyl) ((2, 4,5, 6-tetrahydro-1H-cyclobutano [ f ] inden-3-yl) carbamoyl) amine sodium salt
Using the synthetic route of example 33, the starting material, iodoethane, was replaced with iodoisopropyl to afford compound 34 (86.82 mg, yield) 12％) 1H NMR(400MHz,DMSO-d 6)δ7.58(s,1H),7.17(s,1H),6.56(s,1H),3.77(s,2H),3.17-3.14(m,1H),3.06-3.00(m,4H),2.87-2.83(m,4H),2.77(t,J＝7.2Hz,2H),2.67(t,J＝7.2Hz,2H),1.94-1.87(m,2H),1.13(d,J＝6.4Hz,6H).
LC-MS m/z(ESI)：446.2(M+H) +。
Example 35
((5-Cyanomethyl-4, 5,6, 7-tetrahydrothieno [3,2-c ] pyridin-2-yl) sulfonyl) ((2, 4,5, 6-tetrahydro-1H-cyclobutano [ f ] inden-3-yl) carbamoyl) amine sodium salt
Using the synthetic route of example 33, substituting bromoacetonitrile for the starting material iodoethane produced compound 35 (18.61 mg, yield 39.85%).
1H NMR(400MHz,DMSO-d 6)δ7.45(s,1H),7.08(s,1H),6.52(s,1H),3.90(s,2H),3.51(s,2H),3.08-3.03(m,2H),2.82-2.75(m,8H),2.67(t,J＝7.2Hz,2H),1.93-1.86(m,2H).
LC-MS m/z(ESI):465.2(M+Na) +。
Example 36
((5-Ethyl-4, 5,6, 7-Tetrahydrofurano [3,2-c ] pyridin-2-yl) sulfonyl) ((2, 4,5, 6-tetrahydro-1H-cyclobutano [ f ] inden-3-yl) carbamoyl) amine sodium salt
Using the synthetic route of example 3, substituting triethyloxonium tetrafluoroborate for the starting trimethyloxonium tetrafluoroborate in the fourth step and substituting compound 31a for the starting 3k in the ninth step, compound 36 (18.61 mg, 39.85% yield) was prepared.
1H NMR(400MHz,DMSO-d 6):δ7.60(br s,1H),6.54(s,2H),3.53-3.44(m,2H),3.07-3.02(m,2H),2.96-2.86(m,2H),2.82-2.76(m,4H),2.69-2.65(m,6H),1.91(quint,J＝7.2Hz,2H),1.10(t,J＝7.2Hz,3H).
LC-MS m/z(ESI)：416.0(M+H) +。
Example 37
((6-Methyl-4, 5,6, 7-tetrahydrofurano [2,3-c ] pyridin-2-yl) sulfonyl) ((2, 4,5, 6-tetrahydro-1H-cyclobutano [ f ] inden-3-yl) carbamoyl) amine sodium salt
Using the synthetic route of example 3, substituting starting material 3a with furo [2,3-C ] pyridine and substituting starting material 3k with 31a in the ninth step, compound 37 (38.36 mg, yield: 99.23%) was prepared.
1H NMR(400MHz,DMSO-d 6)δ7.54(s,1H),6.52(s,1H),6.46-6.45(m,1H),3.37(s,2H),3.04-3.03(m,2H),2.81-2.80(m,2H),2.77(t,2H),2.67(t,2H),2.57-2.54(m,2H),2.43-2.41(m,2H),2.35(s,3H),1.94-1.86(m,2H).
LC-MS m/z(ESI):402.3(M+H) +。
Example 38
(1, 2,3,5,6, 7-Hexahydro-s-indacen-4-yl) carbamoyl) ((6-methyl-4, 5,6, 7-tetrahydrofurano [2,3-c ] pyridin-2-yl) sulfonyl) amine sodium salt
Using the synthetic route of example 37, starting material 31a was replaced with compound 1j to afford compound 38 (110 mg, yield: 95.4%).
1H NMR(400MHz,DMSO-d 6)δ7.53(s,1H),6.77(s,1H),6.44(s,1H),3.36(s,2H),2.75(t,4H),2.65(t,4H),2.57-2.54(m,2H),2.43-2.40(m,2H),2.35(s,3H),1.94-1.87(m,4H).
LC-MS m/z(ESI)：416.2(M+H) +。
Biological evaluation
Test example 1: inhibition of NLRP3 inflammatory somal Activity in THP-1 cells
1) Experimental materials
2) Experimental procedure
THP-1 cells were resuspended in cell culture medium of RPMI1640, 10% FBS, 1% P/S to adjust the cell density to 1X 10 6/mL. 10mL of THP-1 cells were plated on a cell culture dish having a diameter of 10cm, and PMA was added thereto for differentiation treatment, and the final concentration of PMA was 10ng/mL. After incubation of the cells in a cell incubator at 37 ℃ with 5% carbon dioxide for 24 hours, the dishes were removed, the supernatant and the unadhered cells were removed, the cells were resuspended after digestion and seeded in 96-well plates at 10 5 cells/well. The cell plates were incubated overnight in an incubator for 12 hours, removed from the medium, and 50uL of fresh medium containing 200ng/mL LPS was added and incubated in a cell incubator at 37℃for 3.5 hours with 5% carbon dioxide. Meanwhile, a compound stock solution with a concentration of 30mM was prepared in a test tube with DMSO, then the sample was diluted in a gradient with DMSO as a solvent as needed, and finally diluted 333 times in the medium. 50uL of the sample to be tested was transferred per well in a 96-well plate and incubated for 0.5 hours at 37℃in a 5% carbon dioxide cell incubator. The 96-well plate was removed and 50uL of medium containing 15uM Negericin per well was added and incubated for 1 hour in a 5% carbon dioxide cell incubator at 37 ℃. The cell plates were removed, centrifuged, and the supernatants were assayed for IL-1β following ELISA kit instructions. The cells in the cell plate were added with reagents and the cell activity was measured according to the instructions of CellTiter-Glo Luminescent Cell Viability Assay Kit.
Table 1 shows the IC 50 values of the compounds of the invention for inhibition of NLRP3 inflammatory small body activity in THP-1 cells.
TABLE 1 IC 50 values of the Compounds of the invention for inhibition of NLRP3 inflammatory somal Activity in THP-1 cells
| Examples numbering | IC 50 | Numbering device | IC 50 |
| Example 1 | B | Example 16 | A |
| Example 2 | B | Example 17 | B |
| Example 3 | A | Example 18 | B |
| Example 4 | C | Example 19 | A |
| Example 5 | B | Example 20 | A |
| Example 6 | A | Example 21 | B |
| Example 7 | B | Example 22 | A |
| Example 8 | A | Example 23 | A |
| Example 9 | A | Example 24 | B |
| Example 10 | B | Example 25 | B |
| Example 11 | C | Example 26 | B |
| Example 12 | A | Example 27 | B |
| Example 13 | B | Example 28 | B |
| Example 14 | B | Example 29 | A |
| Example 15 | A | Example 30 | B |
| Example 31 | A | Example 32 | A |
| Example 33 | A | Example 34 | A |
| Example 35 | B | Example 36 | B |
| Example 37 | B | Example 38 | B |
Note that: a <0.1uM;0.1uM < B <1uM;1uM < C <10uM
Conclusion:
Test example 2: pharmacokinetic evaluation of the Compounds of the invention
1) Evaluation of mouse pharmacokinetics
Male CD-1 mice (n=3, 6 compounds, available from St Bei Fu (Beijing) Biotechnology Co., ltd.) were given clear solutions after dissolution of the test compounds, and administered by tail vein injection and stomach infusion, respectively. Plasma samples were collected at 5 minutes, 15 minutes, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours post-administration at 1mg/kg for intravenous administration, 3mg/kg for intragastric group administration, 5% dmso, 5% solutol and 90% water in intravenous vehicles, 0.5% hpmc, 0.1% tw80 in water in oral vehicles. Plasma was obtained after blood collection from saphenous vein and centrifugation, plasma concentration was determined using LC-MS/MS, and non-atrioventricular analysis was performed using Phoenix WinNonlin to estimate pharmacokinetic parameters such as: clearance (Cl), peak concentration (C max), half-life (T 1/2), area under the drug curve (AUC 0-t), bioavailability (F), etc.
Table 2 shows the pharmacokinetic parameters of the compounds of the invention in mice.
TABLE 2 pharmacokinetic parameters of the Compounds of the invention in mice
Note that: i.g. intragastric administration; i.v. intravenous administration.
Conclusion: the compound disclosed by the disclosure has good drug absorption activity in mice and has pharmacokinetic advantage.
2) SD rat pharmacokinetic evaluation
Male SD rats (n=3, 6 compounds, purchased from St Bei Fu (Beijing) biotechnology Co., ltd.) were given clear solutions after dissolution of the test compounds, and administered by tail vein injection and stomach infusion, respectively. Plasma samples were collected at 5 minutes, 15 minutes, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours post-administration at 1mg/kg for intravenous administration, 3mg/kg for intragastric group administration, 5% dmso, 5% solutol and 90% water in intravenous vehicles, 0.5% hpmc, 0.1% tw80 in water in oral vehicles. Plasma was obtained after blood collection from saphenous vein and centrifugation, plasma concentration was determined using LC-MS/MS, and non-atrioventricular analysis was performed using Phoenix WinNonlin to estimate pharmacokinetic parameters such as: clearance (Cl), peak concentration (C max), half-life (T 1/2), area under the drug curve (AUC 0-t), bioavailability (F), etc.
Table 3 shows the pharmacokinetic parameters of the compounds of the invention in rats.
TABLE 3 pharmacokinetic parameters of the compounds of the invention in rats
Note that: i.g. intragastric administration; i.v. intravenous administration.
Conclusion: the compound disclosed by the disclosure has good drug absorption activity in rats and has pharmacokinetic advantage.
Claims (47)
- A compound of formula I or a pharmaceutically acceptable salt thereof,Wherein:R 1 isR 2 isX 1 is selected from S and O;X 2 is CR 5 or N;A. B is each independently selected from NR 7、C(R 4a) 2 and O;E. d is each independently selected from NR 7b、C(R 6a) 2 and O;R 3 is selected from hydrogen, C 1-6 alkyl, 3-6 membered cycloalkyl; the C 1-6 alkyl, 3-6 membered cycloalkyl is optionally substituted with one or more substituents selected from C 1-6 alkyl, 3-6 membered cycloalkyl, halogen, cyano, hydroxy;R 7 or R 7b are independently selected from hydrogen, C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 heterocycloalkyl, 5-6 heteroaryl, phenyl, halogen, cyano, amino, nitro, -CONH 2、-CO-C 1-6 alkyl such as-COCH 3、-SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3、-C 1-6 alkylene-SO 2 -3-6 heterocycloalkyl, The C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 heterocycloalkyl, 5-6 heteroaryl, phenyl, amino, -CONH 2、-CO-C 1-6 alkyl such as-COCH 3、-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO 2CH 3、-C 1-6 alkylene-SO 2 -3-6 heterocycloalkyl optionally substituted with one or more substituents selected from R 7c;R 7a is selected from hydrogen, cyano, hydroxy, halogen, and nitro; preferably R 7a is cyano or hydroxy;R 7c is independently substituted with a substituent selected from the group consisting of C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, halo, amino, cyano, nitro, hydroxy; the C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl optionally substituted with one or more substituents selected from halogen, amino, cyano, nitro, hydroxy;Each R 4a、R 4b、R 4c、R 4d、R 4e is the same or different and is each independently selected from hydrogen, halogen, cyano, amino, nitro, -CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl; the-CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl is optionally substituted by one or more R 4f;or R 4a form =s, =o, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl with each other; the 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted with one or more substituents selected from halogen, cyano, amino, nitro, -CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl;or R 4b and R 4c、R 4d and R 4e together with the atoms to which they are attached form =s, =o, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl; the 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted with one or more substituents selected from halogen, cyano, amino, nitro, -CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl;R 5 is selected from hydrogen, halogen, cyano, amino, nitro, -CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl; the-CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl is optionally substituted by one or more R 5a;Each R 6a、R 6b、R 6c、R 6d、R 6e is the same or different and is each independently selected from hydrogen, halogen, cyano, amino, nitro, hydroxy, -CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl; the-CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl is optionally substituted by one or more R 6f;Or R 6a form =s, =o, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl with each other; the 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted with one or more substituents selected from halogen, cyano, amino, nitro, -CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl;Or R 6b and R 6c、R 6d and R 6e together with the atoms to which they are attached form =s, =o, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl; the 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted with one or more substituents selected from halogen, cyano, amino, nitro, -CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl;Z is N or CR 12;r 12 is selected from hydrogen, C 1-6 alkyl, -O-C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, halogen, cyano, amino, -CONH 2、-SO 2R 12a、-CH 2-SO 2R 12a; the C 1-6 alkyl, -O-C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, amino, -CONH 2 are optionally substituted with one or more R 12b;R 12b is selected from halogen, cyano, hydroxy, amino, C 1-6 alkyl, -O-C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl; the C 1-6 alkyl, -O-C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl are optionally substituted by one or more R 12c;R 12a is selected from the group consisting of C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, and amino; the C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, and amino are optionally substituted with one or more substituents selected from halogen, cyano, hydroxy, amino, -O-C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl;R 8、R 9、R 10、R 11 is independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, fused rings of 3-6 heterocycloalkyl and 5-6 heteroaryl, 3-6 cycloalkyl, 3-6 heterocycloalkyl, 5-6 heteroaryl; the C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, fused rings formed by 3-6 heterocycloalkyl and 5-6 heteroaryl, 3-6 cycloalkyl, 5-6 heteroaryl, 3-6 heterocycloalkyl optionally substituted with one or more R 13a;Or R 8 and R 9 together with the atoms to which they are attached form a 4-7 membered cycloalkyl or 5-6 membered heterocycloalkyl, said 4-7 membered cycloalkyl or 5-6 membered heterocycloalkyl being optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3; the C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3 optionally substituted with one or more R 13b;or R 10 and R 11 together with the atoms to which they are attached form a 4-7 membered cycloalkyl or 5-6 membered heterocycloalkyl, said 4-7 membered cycloalkyl or 5-6 membered heterocycloalkyl being optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3; the C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3 optionally substituted with one or more R 13c;Each R 13b、R 13c is independently selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3; the C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3 optionally substituted with one or more substituents selected from halogen, hydroxy, cyano;Each R 13a is independently selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, C 1-6 alkylamino, di-C 1-6 alkylamino, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 heterocycloalkyl, -O-C 1-6 alkylene-3-6 heterocycloalkyl, 5-6 heteroaryl, -CONH 2、-SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3; The amino group, -CONH 2、C 1-6 alkyl group, -O-C 1-6 alkyl group, -O-3-6 membered cycloalkyl group, -O-3-6 membered heterocycloalkyl group, 3-6 membered cycloalkyl group, 3-6 membered heterocycloalkyl group, -O-C 1-6 alkylene-3-6 membered heterocycloalkyl group, 5-6 membered heteroaryl, -CONH 2、-SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3 optionally substituted with one or more groups selected from C 1-6 alkyl, Cyano, hydroxy, halogen, -O-C 1-6 alkyl, halo C 1-6 alkyl, cyano-substituted C 1-6 alkyl-substituted C 1-6 alkyl;Each R 7c、R 4f、R 5a、R 6f、R 12c is independently selected from the group consisting of C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 heterocycloalkyl, 5-6 heteroaryl, phenyl, halo, amino, cyano, nitro, hydroxy; the C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl optionally substituted with one or more substituents selected from halogen, amino, cyano, nitro, hydroxy;The conditions are as follows:When R 2 is optionally substituted In the time-course of which the first and second contact surfaces,R 1 is not selected fromOptionally substitutedAnd optionally substituted
- A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:R 1 isR 5 is as defined in claim 1, preferably R 5 is selected from hydrogen, methyl, ethyl, halogen, cyano, cyclopropyl, methylenecyclopropyl, halomethyl, haloethyl, halocyclopropyl, halomethylcyclopropyl; more preferably R 5 is hydrogen;R 7b is as defined in claim 1, preferably R 7b is selected from hydrogen, C 1-6 alkyl, 3-6 membered heterocycloalkyl, -C 1-6 alkylene-3-6 membered heterocycloalkyl, -C 1-6 alkylene-3-6 membered cycloalkyl, hydroxy substituted C 1-6 alkyl, halo substituted C 1-6 alkyl, -C 1-6 alkylene-SO 2CH 3, R 7a、R 6a、R 6b、R 6c、R 6d、R 6e is as defined in claim 1.
- A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:R 1 isR 5 is as defined in claim 1, preferably R 5 is selected from hydrogen, methyl, ethyl, halogen, cyano, cyclopropyl, methylenecyclopropyl, halomethyl, haloethyl, halocyclopropyl, halomethylcyclopropyl; more preferably R 5 is hydrogen;R 7b is as defined in claim 1, preferably R 7b is selected from hydrogen, C 1-6 alkyl, 3-6 membered heterocycloalkyl, -C 1-6 alkylene-3-6 membered heterocycloalkyl, -C 1-6 alkylene-3-6 membered cycloalkyl, hydroxy substituted C 1-6 alkyl, halo substituted C 1-6 alkyl, -C 1-6 alkylene-SO 2CH 3, More preferably R 7b is selected from C 1-6 alkyl;R 7a is as defined in claim 1, preferably R 7a is cyano;R 6a、R 6b、R 6c、R 6d、R 6e is as defined in claim 1.
- A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:R 1 isE. D are each independently selected from C (R 6a) 2 and O, and one and only one of E, D is O;R 5 is as defined in claim 1, preferably R 5 is selected from hydrogen, methyl, ethyl, halogen, cyano, cyclopropyl, methylenecyclopropyl, halomethyl, haloethyl, halocyclopropyl, halomethylcyclopropyl; more preferably R 5 is hydrogen;R 6a、R 6b、R 6c、R 6d、R 6e is as defined in claim 1.
- A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:R 1 isE. D are each independently selected from NR 7b、C(R 6a) 2 and O, and one and only one of E, D is O;R 5 is as defined in claim 1, preferably R 5 is selected from hydrogen, methyl, ethyl, halogen, cyano, cyclopropyl, methylenecyclopropyl, halomethyl, haloethyl, halocyclopropyl, halomethylcyclopropyl; more preferably R 5 is hydrogen;R 7b is as defined in claim 1, preferably R 7b is selected from hydrogen, C 1-6 alkyl, 3-6 membered heterocycloalkyl, -C 1-6 alkylene-3-6 membered heterocycloalkyl, -C 1-6 alkylene-3-6 membered cycloalkyl, hydroxy substituted C 1-6 alkyl, halo substituted C 1-6 alkyl, -CO-C 1-6 alkyl such as-COCH 3;R 6a、R 6b、R 6c、R 6d、R 6e is as defined in claim 1.
- A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:r 1 is selected fromE. D is each independently selected from NR 7b、C(R 6a) 2 and O,R 7b is as defined in claim 1, preferably R 7b is selected from hydrogen, C 1-6 alkyl, 3-6 membered heterocycloalkyl, -C 1-6 alkylene-3-6 membered heterocycloalkyl, -C 1-6 alkylene-3-6 membered cycloalkyl, hydroxy substituted C 1-6 alkyl, halo substituted C 1-6 alkyl, -CO-C 1-6 alkyl such as-COCH 3;R 6a、R 6b、R 6c、R 6d、R 6e as defined in claim 1.
- A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:r 1 is selected fromR 6a、R 6b、R 6c、R 6d、R 6e is as defined in claim 1.
- A compound of formula I according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein:Each R 6a、R 6b、R 6c、R 6d、R 6e is the same or different and is each independently selected from hydrogen, halogen, cyano, amino, nitro, hydroxy, -CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl; the-CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl is optionally substituted by one or more R 6f;R 6f is as defined in claim 1.
- A compound of formula I according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein:Each R 6a、R 6b、R 6c、R 6d、R 6e is the same or different and is each independently selected from hydrogen, halogen, cyano, amino, nitro, hydroxy, -CONH 2; the-CONH 2 is optionally substituted with one or more R 6f;R 6f is as defined in claim 1.
- A compound of formula I according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein:Each R 6a、R 6b、R 6c、R 6d、R 6e is the same or different and is each independently selected from the group consisting of C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl; the C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 heterocycloalkyl, 5-6 heteroaryl, phenyl are optionally substituted with one or more R 6f;R 6f is as defined in claim 1.
- A compound of formula I according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein: each R 6a、R 6b、R 6c、R 6d、R 6e is the same or different and is each independently selected from hydrogen, halogen, hydroxy, C 1-6 alkyl, -O-C 1-6 alkyl; the C 1-6 alkyl, -O-C 1-6 alkyl is optionally substituted with one or more R 6f;R 6f is as defined in claim 1.
- A compound of formula I according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein: each R 6f is independently selected from C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl; the C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl is optionally substituted with one or more substituents selected from halogen, amino, cyano, nitro, hydroxy.
- A compound of formula I according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein: r 6f is independently selected from halogen, amino, cyano, nitro, hydroxy.
- A compound of formula I according to any one of claims 1to 11, or a pharmaceutically acceptable salt thereof, wherein: r 6f is independently selected from halogen, cyano, hydroxy, C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl; the C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl is optionally substituted with one or more substituents selected from halogen, amino, cyano, nitro, hydroxy.
- A compound of formula I according to any one of claims 1to 7, wherein R 6d and R 6e together with the atoms to which they are attached are 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl; the 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted with one or more substituents selected from halogen, cyano, amino, nitro, -CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl.
- A compound of formula I according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein: r 6a forms a 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl with each other, or R 6b and R 6c、R 6d and R 6e form a 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl; the 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted with one or more substituents selected from halogen, cyano, amino, nitro, -CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl.
- A compound of formula I according to any one of claims 1to 7, or a pharmaceutically acceptable salt thereof, wherein: r 6d and R 6e form a 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl; the 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted with one or more substituents selected from halogen, cyano, amino, nitro, -CONH 2、C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl;Preferably R 6d and R 6e form a 3-8 membered heterocycloalkyl; the 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted with one or more substituents selected from halogen, cyano, amino, nitro, -CONH 2、C 1-6 alkyl.
- A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:R 1 isR 7 is as defined in claim 1, preferably R 7 is methyl;r 3 is as defined in claim 1, preferably R 3 is methyl, propyl, isopropyl, hydroxyethyl;R 4a、R 4b、R 4c、R 4d、R 4e is as defined in claim 1, preferably R 4a、R 4b、R 4c、R 4d、R 4e is hydrogen.
- A compound of formula I according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein:R 2 isR 8、R 9、R 10、R 11 is as defined in claim 1.
- A compound of formula I according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein:R 2 isR 8 and R 9 form a 4-7 membered cycloalkyl or 5-6 membered heterocycloalkyl, said 4-7 membered cycloalkyl or 5-6 membered heterocycloalkyl being optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3; the C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3 optionally substituted with one or more R 13b;R 10、R 11 is independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 heterocycloalkyl, and fused rings formed by 5-6 heteroaryl, 3-6 heterocycloalkyl, 5-6 heteroaryl; the C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, fused rings formed by 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl, 3-6 membered heterocycloalkyl optionally substituted with one or more R 13a;R 12、R 13a、R 13b is as defined in claim 1.
- A compound of formula I according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein:R 2 isR 8 and R 9 form a 4-7 membered cycloalkyl or 5-6 membered heterocycloalkyl, said 4-7 membered cycloalkyl or 5-6 membered heterocycloalkyl being optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3; the C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3 optionally substituted with one or more R 13b;R 10 and R 11 form a 4-7 membered cycloalkyl or 5-6 membered heterocycloalkyl, said 4-7 membered cycloalkyl or 5-6 membered heterocycloalkyl being optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3; the C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3 optionally substituted with one or more R 13c;R 12、R 13b、R 13c is as defined in claim 1.
- A compound of formula I according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein:R 2 isZ is N or CR 12;R 8 and R 9 form a 4-7 membered cycloalkyl, said 4-7 membered cycloalkyl being optionally substituted with one or more substituents selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3; the C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3 optionally substituted with one or more R 13b;R 10、R 11 is independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 cycloalkyl, -O-3-6 heterocycloalkyl, 3-6 cycloalkyl, 3-6 heterocycloalkyl, and fused rings formed by 5-6 heteroaryl, 3-6 heterocycloalkyl, 5-6 heteroaryl; the C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, fused rings formed by 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl, 3-6 membered heterocycloalkyl optionally substituted with one or more R 13a;r 10、R 11、R 12、R 13a、R 13b is as defined in claim 1.
- A compound of formula I according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein:R 2 isZ is N or CR 12;r 9a、R 9b、R 9c、R 9d、R 9e、R 9f is each independently selected from hydrogen, halogen, hydroxy, cyano, amino, C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3; the C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3 optionally substituted with one or more R 13b;R 10 is selected from condensed rings formed by 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl, 5-6 membered heteroaryl; the condensed ring formed by the 3-6 membered heterocycloalkyl and the 5-6 membered heteroaryl, the 5-6 membered heteroaryl being optionally substituted by one or more R 13a;R 11 is selected from hydrogen, halogen, C 1-6 alkyl, -O-C 1-6 alkyl; the C 1-6 alkyl, -O-C 1-6 alkyl is optionally substituted with one or more R 13a;R 12、R 13a、R 13b is as defined in claim 1.
- A compound of formula I according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein:R 2 isZ is N or CR 12;R 9a、R 9b、R 9c、R 9d、R 9e、R 9f is each independently selected from hydrogen, halogen, hydroxy, cyano, amino, C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3; the C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3 optionally substituted with one or more R 13b;r 10 is selected from 5-6 membered heteroaryl optionally substituted with one or more R 13a;R 11 is selected from hydrogen, halogen, C 1-6 alkyl, -O-C 1-6 alkyl; the C 1-6 alkyl, -O-C 1-6 alkyl is optionally substituted with one or more R 13a;R 12、R 13a、R 13b is as defined in claim 1.
- A compound of formula I according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein:r 2 is selected from:Z is N or CR 12;R 11 is selected from hydrogen, halogen, C 1-6 alkyl, -O-C 1-6 alkyl; the C 1-6 alkyl, -O-C 1-6 alkyl is optionally substituted with one or more R 13a;R 10a is independently substituted with a substituent selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3; the C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -SO 2-C 1-6 alkyl such as-SO 2CH 3、-C 1-6 alkylene-SO 2CH 3 optionally substituted with one or more R 13c;R 10b is selected from C 1-6 alkyl, said C 1-6 alkyl optionally substituted with C 3-6 cycloalkyl;n, m are independently selected from integers from 0 to 3; preferably n, m are independently selected from integers from 0 to 2;r 8、R 9、R 12、R 13a、R 13c is as defined in claim 1;R 9a、R 9b、R 9c、R 9d、R 9e、R 9f is as defined in claim 23.
- A compound of formula I according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein:R 2 isZ is N or CR 12;R 11 is selected from hydrogen, halogen, C 1-6 alkyl, -O-C 1-6 alkyl; the C 1-6 alkyl, -O-C 1-6 alkyl is optionally substituted with one or more R 13a;n is an integer from 0 to 3;R 12、R 13a、R 13c is as defined in claim 1;R 9a、R 9b、R 9c、R 9d、R 9e、R 9f is as defined in claim 23.
- A compound of formula I according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein Z is N.
- A compound of formula I according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein Z is CR 12;R 12 is as defined in claim 1.
- A compound of formula I according to any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R 12 is selected from hydrogen, C 1-6 alkyl, -O-C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, halogen, cyano, amino, -CONH 2、-SO 2R 12a、-CH 2-SO 2R 12a; the C 1-6 alkyl, -O-C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, amino, -CONH 2 are optionally substituted with 1-3R 12b;R 12a、R 12b is as defined in claim 1.
- A compound of formula I according to any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R 12 is selected from hydrogen, halo C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl, -O-C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, halogen, cyano, amino, -CONH 2、-SO 2R 12a、-CH 2-SO 2R 12a,R 12a are as defined in claim 1;Preferably, R 12 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl, -O-C 1-6 alkyl.
- The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 23-30,Wherein R 9a、R 9b、R 9c、R 9d、R 9e、R 9f is independently selected from hydrogen, halogen, hydroxy, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, -O-C 1-6 alkyl; said C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl optionally substituted with one or more R 13b, R 13b being as defined in claim 1;Preferably R 9a、R 9b、R 9c、R 9d、R 9e、R 9f is hydrogen.
- A compound of formula I according to any one of claims 1-31, or a pharmaceutically acceptable salt thereof, R 13b is independently selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, -O-C 1-6 alkyl, halo C 1-6 alkyl, hydroxy substituted C 1-6 alkyl.
- A compound of formula I according to any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R 11 is selected from hydrogen, halogen, C 1-6 alkyl, -O-C 1-6 alkyl; the C 1-6 alkyl, -O-C 1-6 alkyl is optionally substituted with one or more R 13a, R 13a is as defined in claim 1.
- A compound of formula I according to any one of claims 1-20, 23-33, or a pharmaceutically acceptable salt thereof, wherein R 11 is selected from hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy substituted C 1-6 alkyl; preferably R 11 is selected from hydrogen, methyl.
- A compound of formula I according to any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein: each R 13a is independently selected from halogen, hydroxy, cyano, amino, C 1-6 alkylamino, di C 1-6 alkylamino, C 1-6 alkyl, -O-C 1-6 alkyl; the amino, C 1-6 alkyl, -O-C 1-6 alkyl is optionally substituted with 1 to 3 substituents selected from C 1-6 alkyl, cyano, hydroxy, halogen, -O-C 1-6 alkyl, halo C 1-6 alkyl, cyano-substituted C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl.
- A compound of formula I according to any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein: each R 13a is independently selected from cyano, halogen, hydroxy, C 1-6 alkyl, -O-C 1-6 alkyl, methanesulfonyl, -CONH 2、-CH 2-SO 2CH 3, 3-6 membered heterocyclyl, amino.
- A compound of formula I according to any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein: each R 13a is independently selected from the group consisting of C 1-6 alkyl, -O-C 1-6 alkyl, -O-5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-C 1-6 alkylene-3-6 membered heterocycloalkyl; the C 1-6 alkyl, -O-C 1-6 alkyl, -O-5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-C 1-6 alkylene-3-6 membered heterocycloalkyl is optionally substituted with 1-3 substituents selected from halogen, cyano, hydroxy, C 1-6 alkyl.
- A compound of formula I according to any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein: each R 13a is independently selected from 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl; the 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally substituted with one or more C 1-6 alkyl groups selected from C 1-6 alkyl, cyano, hydroxy, halogen, -O-C 1-6 alkyl, halo C 1-6 alkyl, cyano.
- A compound of formula I according to any one of claims 25-38, or a pharmaceutically acceptable salt thereof, wherein: r 10a is independently selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl, -O-3-6 membered cycloalkyl, -O-3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, halo 3-6 membered cycloalkyl, halo 3-6 membered heterocycloalkyl.
- A compound of formula I according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein R 2 is optionally substitutedWhen R 1 is not
- A compound of formula I according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein R 2 is not
- A compound of formula I according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein R 2 is not optionally substituted
- A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, selected from:
- an isotopic substitution of a compound of formula I or a pharmaceutically acceptable salt thereof as recited in any one of claims 1-43, preferably wherein said isotopic substitution is deuterium atom substitution.
- A pharmaceutical composition comprising at least one therapeutically effective amount of a compound of formula I as defined in any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, or an isotopically substituted compound as defined in claim 44, and a pharmaceutically acceptable excipient.
- Use of a compound of formula I as set forth in any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, or an isotopically substituted compound as set forth in claim 44, or a pharmaceutical composition as set forth in claim 45, in the manufacture of a medicament for treating a disease associated with NLRP3 activity.
- Use of a compound of formula I according to any one of claims 1 to 43 or a pharmaceutically acceptable salt thereof, or an isotopically substituted compound according to claim 44, or a pharmaceutical composition according to claim 45, for the manufacture of a medicament for the treatment of an inflammatory-related disease, an immune disease such as autoimmune disease, an inflammatory disease such as autoinflammatory disease.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111577493 | 2021-12-22 | ||
| CN2021115774931 | 2021-12-22 | ||
| PCT/CN2022/140921 WO2023116812A1 (en) | 2021-12-22 | 2022-12-22 | Sulfonylurea compound |
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| CN118475558A true CN118475558A (en) | 2024-08-09 |
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| CN (1) | CN118475558A (en) |
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| WO (1) | WO2023116812A1 (en) |
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| KR20250005070A (en) * | 2022-02-21 | 2025-01-09 | 비바 스타 바이오사이언시즈 (쑤저우) 컴퍼니 리미티드 | Novel bicyclic substituted sulfonylurea compounds as inhibitors of interleukin-1 activity |
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| BR112019014549A2 (en) * | 2017-01-23 | 2020-02-18 | Genentech, Inc. | COMPOUNDS OF FORMULAS I, IG, IH, IE, COMPOUNDS, PHARMACEUTICAL COMPOSITION, TREATMENT METHODS, MODULATION OF THE ACTIVITY OF A BIOLOGICAL TARGET, INHIBITION OF THE INFLAMASSOMA ACTIVATION AND USE OF A COMPOUND |
| PL3661925T3 (en) * | 2017-07-07 | 2022-02-28 | Inflazome Limited | Novel sulfonamide carboxamide compounds |
| EP3649112A1 (en) * | 2017-07-07 | 2020-05-13 | Inflazome Limited | Sulfonylureas and sulfonylthioureas as nlrp3 inhibitors |
| BR112020003014A2 (en) * | 2017-08-15 | 2020-07-28 | Inflazome Limited | sulfonylureas and sulfonylthioureas as inhibitors of vnlrp3 |
| US20230011652A1 (en) * | 2018-10-24 | 2023-01-12 | Novartis Ag | Compounds and compositions for treating conditions associated with nlrp activity |
| IL289885B2 (en) * | 2019-07-17 | 2025-04-01 | Zomagen Biosciences Ltd | N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,6,7-tetrahydrobenzofuran -2-sulfonamide derivatives and related compounds as nlpr3 modulators for the treatment of multiple sclerosis (ms) |
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- 2022-12-22 CN CN202280087510.XA patent/CN118475558A/en active Pending
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