WO2023036140A1 - 3CLpro蛋白酶抑制剂 - Google Patents
3CLpro蛋白酶抑制剂 Download PDFInfo
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- WO2023036140A1 WO2023036140A1 PCT/CN2022/117336 CN2022117336W WO2023036140A1 WO 2023036140 A1 WO2023036140 A1 WO 2023036140A1 CN 2022117336 W CN2022117336 W CN 2022117336W WO 2023036140 A1 WO2023036140 A1 WO 2023036140A1
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- compound
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- ring
- alkyl
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- 229940124158 Protease/peptidase inhibitor Drugs 0.000 title abstract description 4
- 239000000137 peptide hydrolase inhibitor Substances 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 596
- 241000711573 Coronaviridae Species 0.000 claims abstract description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- -1 methoxy, pyridyl Chemical group 0.000 claims description 165
- 125000000217 alkyl group Chemical group 0.000 claims description 93
- 125000000623 heterocyclic group Chemical group 0.000 claims description 63
- 229910052736 halogen Inorganic materials 0.000 claims description 52
- 150000002367 halogens Chemical class 0.000 claims description 52
- 229910052799 carbon Inorganic materials 0.000 claims description 43
- 150000003839 salts Chemical class 0.000 claims description 38
- 125000003545 alkoxy group Chemical group 0.000 claims description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- 125000003118 aryl group Chemical group 0.000 claims description 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 28
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
- 125000001072 heteroaryl group Chemical group 0.000 claims description 20
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 18
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- 229910052801 chlorine Inorganic materials 0.000 claims description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 241001678559 COVID-19 virus Species 0.000 claims description 11
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 201000010099 disease Diseases 0.000 claims description 11
- 229910052731 fluorine Inorganic materials 0.000 claims description 11
- 125000004076 pyridyl group Chemical group 0.000 claims description 11
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 10
- 229910052794 bromium Inorganic materials 0.000 claims description 10
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 10
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 9
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 9
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 8
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 8
- 229910052805 deuterium Inorganic materials 0.000 claims description 8
- 229910052740 iodine Inorganic materials 0.000 claims description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- 208000035473 Communicable disease Diseases 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 208000015181 infectious disease Diseases 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 230000000241 respiratory effect Effects 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 6
- 125000002883 imidazolyl group Chemical group 0.000 claims description 6
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 6
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 6
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims description 6
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 125000006704 (C5-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 claims 1
- 101800000504 3C-like protease Proteins 0.000 abstract description 6
- 238000000034 method Methods 0.000 abstract description 6
- 238000006243 chemical reaction Methods 0.000 description 643
- 239000000243 solution Substances 0.000 description 593
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 534
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 387
- 239000012074 organic phase Substances 0.000 description 369
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 317
- 238000012544 monitoring process Methods 0.000 description 256
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 250
- 239000002994 raw material Substances 0.000 description 247
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 215
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 214
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 198
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 197
- 238000010791 quenching Methods 0.000 description 182
- 239000000203 mixture Substances 0.000 description 162
- 229910052757 nitrogen Inorganic materials 0.000 description 159
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 150
- 238000010898 silica gel chromatography Methods 0.000 description 137
- 238000005481 NMR spectroscopy Methods 0.000 description 113
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 106
- 238000005406 washing Methods 0.000 description 82
- 239000011780 sodium chloride Substances 0.000 description 75
- 229920006395 saturated elastomer Polymers 0.000 description 65
- 238000002953 preparative HPLC Methods 0.000 description 60
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 57
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 55
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 52
- 239000011259 mixed solution Substances 0.000 description 47
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 41
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 37
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 32
- 238000004821 distillation Methods 0.000 description 32
- 238000003756 stirring Methods 0.000 description 30
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 29
- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 description 24
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 22
- 239000012043 crude product Substances 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 17
- HNVIQLPOGUDBSU-OLQVQODUSA-N (2s,6r)-2,6-dimethylmorpholine Chemical compound C[C@H]1CNC[C@@H](C)O1 HNVIQLPOGUDBSU-OLQVQODUSA-N 0.000 description 16
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 16
- 239000000706 filtrate Substances 0.000 description 16
- 239000012312 sodium hydride Substances 0.000 description 16
- 229910000104 sodium hydride Inorganic materials 0.000 description 16
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 16
- 239000005457 ice water Substances 0.000 description 15
- 239000000460 chlorine Substances 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- AKQXKEBCONUWCL-MRVPVSSYSA-N tert-butyl (3r)-3-aminopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@@H](N)C1 AKQXKEBCONUWCL-MRVPVSSYSA-N 0.000 description 13
- 238000004809 thin layer chromatography Methods 0.000 description 13
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 12
- XZSWHQCDTYJZJA-UHFFFAOYSA-N 5-(methylamino)pyridine-3-carboxylic acid Chemical compound CNC1=CN=CC(C(O)=O)=C1 XZSWHQCDTYJZJA-UHFFFAOYSA-N 0.000 description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 12
- 239000001257 hydrogen Substances 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 239000007858 starting material Substances 0.000 description 12
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- 239000012298 atmosphere Substances 0.000 description 10
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 10
- 239000002585 base Substances 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- VLJNHYLEOZPXFW-UHFFFAOYSA-N pyrrolidine-2-carboxamide Chemical compound NC(=O)C1CCCN1 VLJNHYLEOZPXFW-UHFFFAOYSA-N 0.000 description 8
- 125000005842 heteroatom Chemical group 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 description 5
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 5
- 235000019270 ammonium chloride Nutrition 0.000 description 5
- 239000012295 chemical reaction liquid Substances 0.000 description 5
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
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- 229910002027 silica gel Inorganic materials 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- AKVIZYGPJIWKOS-BDAKNGLRSA-N tert-butyl n-[(1s,2r)-2-aminocyclohexyl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N AKVIZYGPJIWKOS-BDAKNGLRSA-N 0.000 description 5
- YZUPZGFPHUVJKC-UHFFFAOYSA-N 1-bromo-2-methoxyethane Chemical compound COCCBr YZUPZGFPHUVJKC-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
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- 241000700605 Viruses Species 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 4
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
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- 230000000694 effects Effects 0.000 description 4
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- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- STYSIWNZDIJKGC-YUMQZZPRSA-N tert-butyl (3s,4s)-3-amino-4-methoxypyrrolidine-1-carboxylate Chemical compound CO[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1N STYSIWNZDIJKGC-YUMQZZPRSA-N 0.000 description 4
- 239000003643 water by type Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- MTJGVAJYTOXFJH-UHFFFAOYSA-N 3-aminonaphthalene-1,5-disulfonic acid Chemical compound C1=CC=C(S(O)(=O)=O)C2=CC(N)=CC(S(O)(=O)=O)=C21 MTJGVAJYTOXFJH-UHFFFAOYSA-N 0.000 description 3
- MJOUJKDTBGXKIU-UHFFFAOYSA-N 4,4-difluoropiperidine Chemical compound FC1(F)CCNCC1 MJOUJKDTBGXKIU-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- 208000025721 COVID-19 Diseases 0.000 description 3
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 description 3
- 241000127282 Middle East respiratory syndrome-related coronavirus Species 0.000 description 3
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 3
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 3
- 101800001016 Picornain 3C-like protease Proteins 0.000 description 3
- 101800000596 Probable picornain 3C-like protease Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- MCVMLYSLPCECGO-UHFFFAOYSA-N isoquinoline-4-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=CN=CC2=C1 MCVMLYSLPCECGO-UHFFFAOYSA-N 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 3
- 235000011056 potassium acetate Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 2
- GWRAMOWUVSJIRT-UHFFFAOYSA-N 3,3-difluoro-2h-pyridine Chemical compound FC1(F)CN=CC=C1 GWRAMOWUVSJIRT-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- SXOKSXISBYNNQM-UHFFFAOYSA-N 5-bromo-2-fluoro-3-nitrobenzoic acid Chemical compound OC(=O)C1=CC(Br)=CC([N+]([O-])=O)=C1F SXOKSXISBYNNQM-UHFFFAOYSA-N 0.000 description 2
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- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 description 1
- 125000005575 polycyclic aromatic hydrocarbon group Chemical group 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- ALSCEGDXFJIYES-UHFFFAOYSA-N pyrrolidine-2-carbonitrile Chemical compound N#CC1CCCN1 ALSCEGDXFJIYES-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 208000026425 severe pneumonia Diseases 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- SFZCNBIFKDRMGX-UHFFFAOYSA-N sulfur hexafluoride Chemical compound FS(F)(F)(F)(F)F SFZCNBIFKDRMGX-UHFFFAOYSA-N 0.000 description 1
- 229960000909 sulfur hexafluoride Drugs 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 229950009390 symclosene Drugs 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- CMIBWIAICVBURI-SSDOTTSWSA-N tert-butyl (3r)-3-aminopyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC[C@@H](N)C1 CMIBWIAICVBURI-SSDOTTSWSA-N 0.000 description 1
- DODJSPBKCAGGTQ-UHFFFAOYSA-N tert-butyl 4-amino-3,3-difluoropyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(N)C(F)(F)C1 DODJSPBKCAGGTQ-UHFFFAOYSA-N 0.000 description 1
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 1
- WUOQXNWMYLFAHT-MRVPVSSYSA-N tert-butyl n-[(3r)-piperidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H]1CCCNC1 WUOQXNWMYLFAHT-MRVPVSSYSA-N 0.000 description 1
- CGEBPOMWRHSMLI-QMMMGPOBSA-N tert-butyl n-[(7r)-5-azaspiro[2.4]heptan-7-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]1CNCC11CC1 CGEBPOMWRHSMLI-QMMMGPOBSA-N 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Definitions
- the invention belongs to the field of medicinal chemistry, and in particular relates to a coronavirus 3CLpro protease inhibitor, a pharmaceutical composition containing the compound and a method for treating coronavirus infection using the compound of the invention.
- Coronaviruses belong to single positive-strand RNA viruses, and the coronavirus family mainly includes novel coronavirus (SARS-CoV-2), SARS coronavirus (SARS-CoV), human coronavirus 229E, human coronavirus NL63, human coronavirus OC43, human Coronavirus HKU1, Severe Acute Respiratory Syndrome Associated Coronavirus (SARS-CoV), Middle East Respiratory Syndrome Virus (Middle East Respiratory Syndrome Coronavirus, MERS-CoV), among which SARS-CoV and MERS-CoV are Highly pathogenic HCoV, which can cause severe acute respiratory syndrome and has a high fatality rate. Infection with novel coronavirus (2019-nCoV) can cause mild, moderate or severe disease (including severe pneumonia, sepsis and ARDS, etc.).
- SARS-CoV-2 novel coronavirus
- SARS-CoV SARS coronavirus
- human coronavirus 229E human coronavirus NL63
- 3CLPro (3C-like protease, also known as 3C-like protease) is the main protease produced by the new coronavirus (COVID-19, SARS-CoV-2). Most of the functional proteins (non-structural proteins) of the coronavirus are encoded by the ORF1ab gene. It is translated into a polyprotein body (7096aa), and then cut into multiple active proteins such as viral replication protein RdRp by 3CLPro. In addition, this protein may cleave the intracellular protein NEMO to inhibit the activation of interferon signaling pathway. Therefore, inhibiting 3CLPro can effectively inhibit virus infection and replication.
- the present invention provides a compound represented by formula (I), its isomer or pharmaceutically acceptable salt,
- Ring A is selected from C 6-10 aryl, 5-10 membered heteroaryl, C 3-12 cycloalkyl or 3-12 membered heterocyclic group;
- Y is selected from NH or a chemical bond
- Ring B is selected from C 3-12 cycloalkyl, 3-12 membered heterocyclyl or 5-10 membered heteroaryl;
- Ring C is selected from C 6-10 aryl or 5-10 membered heteroaryl
- Ring D is selected from 3-12 membered heterocyclyl or 5-6 membered heteroaryl; or ring D does not exist;
- R 1 is selected from halogen, OH, O, cyano, -NR 1a R 1b , C 1-4 alkane C 1-4 alkoxy, C 3-8 cycloalkyl, C 6-10 aryl, -NR 1a COR 1c , -SR 1d or -CONR 1a R 1b , the C 1-4 alkyl and C 1-4 alkoxy can be further substituted by one or more halogens;
- R 1a , R 1b , R 1c and R 1d are each independently selected from H, C 1-4 alkyl or halogenated C 1-4 alkyl, the C 1-4 alkyl may be substituted by one or more deuterium ;
- R 2c is selected from 5-6 membered heteroaryl, and the 5-6 membered heteroaryl can be further substituted by C 1-4 alkyl;
- R 2a and R 2b are each independently selected from H, C 1-4 alkyl, phenyl, 5-9 membered heteroaryl, 5-6 membered heterocyclic group or C 3-5 cycloalkyl, said C 1-4 alkyl, phenyl, 5-9 membered heteroaryl, 5-6 membered heterocyclyl, C 3-5 cycloalkyl can be further selected from one or more of methyl, ethyl , cyclopropyl, halogen, CF 3 , -CH 2 CF 3 , phenyl, methoxy, pyridyl, pyrimidinyl, tetrahydropyranyl or -CH 2 CH 2 OCH 3 substituents, the The pyridyl, pyrimidyl or tetrahydropyranyl can be further substituted by one or more methyl, CF 3 , halogen, -NHCH 3 or -CHF 2 ;
- the aryl group can be further substituted by one or more substituents selected from C 1-4 alkyl, halogen, hydroxyl or -CH 2 CH 2 OCH 3 ;
- R 2d is selected from C 1-4 alkyl, C 1-4 alkoxy, phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclic group, the phenyl, 5-6 membered heterocyclic group Aryl or 5-6 membered heterocyclic group can be further substituted by one or more substituents selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl ;y is selected from 0, 1 or 2;
- R 3 is selected from nitro, halogen, hydroxyl, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, -NR 3a R 3b or -N(R 3a R 3b R 3c ) + ;
- R 3a , R 3b or R 3c are each independently selected from H or C 1-4 alkyl;
- R 4a , R 4b , R 4c or R 4d are each independently selected from H, C 1-4 alkyl, halogenated C 1-4 alkyl, 5-6 membered heterocyclyl or C 3-6 cycloalkyl;
- R 4c and R 4d form a six-membered heterocyclic ring together with the N atoms connected to them;
- n, p and q are each independently selected from 0, 1, 2, 3, 4 or 5;
- s and t are each independently selected from 0 or 1.
- Ring A is C 6-10 aryl, 5-10 membered heteroaryl, C 3-12 cycloalkyl or 3-12 membered heterocyclic;
- Y is selected from NH or a chemical bond
- Ring B is selected from C 3-12 cycloalkyl, 3-12 membered heterocyclyl or 5-10 membered heteroaryl;
- Ring C is selected from C 6-10 aryl or 5-10 membered heteroaryl
- Ring D is a 3-12 membered heterocyclic group; or ring D does not exist;
- R 1 is selected from halogen, OH, O, cyano, -NR 1a R 1b , C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 6-10 aryl, - NR 1a COR 1c , -SR 1d or -CONR 1a R 1b , the C 1-4 alkyl and C 1-4 alkoxy can be further substituted by one or more halogens;
- R 1a , R 1b , R 1c and R 1d are each independently selected from H, C 1-4 alkyl or halogenated C 1-4 alkyl;
- R 2 is selected from halogen, C 1-4 alkyl, hydroxyl or C 1-4 alkoxy;
- R 3 is selected from nitro, halogen, hydroxyl, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, -NR 3a R 3b or -N(R 3a R 3b R 3c ) + ;
- R 3a , R 3b or R 3c are each independently selected from H or C 1-4 alkyl;
- R 4a , R 4b , R 4c or R 4d are each independently selected from H, C 1-4 alkyl, halogenated C 1-4 alkyl, 5-6 membered heterocyclyl or C 3-6 cycloalkyl;
- R 4c and R 4d form a six-membered heterocyclic ring together with the N atoms connected to them;
- x 0, 1 or 2;
- r is selected from 0, 1, 2 or 3;
- n, p and q are each independently selected from 0, 1, 2, 3, 4 or 5;
- s and t are each independently selected from 0 or 1.
- Ring A is C 6-10 aryl, 5-10 membered heteroaryl, C 3-12 cycloalkyl or 3-12 membered heterocyclic;
- Y is selected from NH or a chemical bond
- Ring B is selected from C 3-12 cycloalkyl, 3-12 membered heterocyclyl or 5-10 membered heteroaryl;
- Ring C is selected from C 6-10 aryl or 5-10 membered heteroaryl
- Ring D is a 3-8 membered heterocyclic group; or ring D does not exist;
- R 1 is selected from halogen, OH, O, cyano, -NR 1a R 1b , C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 6-10 aryl, so The C 1-4 alkyl and C 1-4 alkoxy groups can be further substituted by one or more halogens;
- R 1a and R 1b are each independently selected from H or C 1-4 alkyl
- R 2 is selected from halogen or C 1-4 alkyl
- R 3 is selected from nitro, halogen, hydroxyl, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, -NR 3a R 3b or -N(R 3a R 3b R 3c ) + ;
- R 3a , R 3b or R 3c are each independently selected from H or C 1-4 alkyl;
- R 4a , R 4b , R 4c or R 4d are each independently selected from H, C 1-4 alkyl or halogenated C 1-4 alkyl;
- r is selected from 0, 1, 2 or 3;
- n, p and q are each independently selected from 0, 1, 2 or 3;
- s and t are each independently selected from 0 or 1.
- Ring A is a 9-membered or 10-membered heteroaryl, and Ring D is absent, R 4 is not methylamino.
- ring A is C 6-10 aryl, 5-10 membered heteroaryl or 7-10 membered heterocyclic group
- Y is selected from NH or a chemical bond
- Ring B is selected from C 3-12 cycloalkyl, 3-12 membered heterocyclyl or 5-10 membered heteroaryl;
- Ring C is selected from C 6-10 aryl or 5-10 membered heteroaryl
- Ring D is a 3-8 membered heterocyclic group
- R 1 is selected from halogen, OH, O, cyano, -NR 1a R 1b , C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 6-10 aryl, so The C 1-4 alkyl and C 1-4 alkoxy groups can be further substituted by one or more halogens;
- R 1a and R 1b are each independently selected from H or C 1-4 alkyl
- R 2 is selected from halogen or C 1-4 alkyl
- R 3 is selected from nitro, halogen, hydroxyl, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, -NR 3a R 3b or -N(R 3a R 3b R 3c ) + ;
- R 3a , R 3b or R 3c are each independently selected from H or C 1-4 alkyl;
- R 4 is selected from halogen, hydroxyl or C 1-4 alkyl
- n, p and q are each independently selected from 0, 1 or 2;
- s and t are each independently selected from 0, 1 or 2.
- ring A is selected from phenyl, cyclohexyl, 5-10 membered heteroaryl or 6-10 membered heterocyclic group, and the heteroaryl or heterocyclic group contains 1-3 selected Heteroatoms from N, O or S.
- Ring A is selected from phenyl, cyclohexyl, 5-6 membered monoheteroaryl, 8-10 membered condensed heteroaryl, 6 membered monoheterocyclyl, 8 membered spiroheterocyclyl, 7 -10-membered condensed heterocyclic group, and the heterocyclic group or heteroaryl group contains 1-3 heteroatoms selected from N or O.
- the ring A is selected from pyridyl, pyrimidyl, pyrazinyl, isoquinolyl, cinnolinyl, phthalazinyl, phenyl, imidazolyl, thienyl, isoxazolyl, Benzotriazolyl,
- the ring A is selected from pyridyl, pyrimidyl, pyrazinyl, isoquinolyl, cinnolinyl, phthalazinyl, phenyl, imidazolyl, thienyl, isoxazolyl, Benzotriazolyl,
- the ring A is selected from
- the ring A is selected from pyridyl, pyrimidyl, pyrazinyl, isoquinolyl, cinnolinyl, phthalazinyl, phenyl, imidazolyl, thienyl, isoxazolyl, Benzotriazolyl,
- the ring A is selected from pyridyl, pyrimidyl, pyrazinyl, isoquinolyl, cinnolinyl, phthalazinyl, phenyl, imidazolyl, thienyl, isoxazolyl , benzotriazolyl,
- the ring A is selected from
- the R 1 is selected from F, Cl, Br, I, O, hydroxyl, methyl, methoxy, trifluoromethyl, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , cyano, cyclopropyl, phenyl, -NHCH 2 CH 3 , -SCH 3 , -CONH 2 , -NHCOCF 3 or -NHCOCH 3 ;
- n is selected from 0, 1, 2 or 3.
- the R 1 is selected from F, Cl, Br, I, O, hydroxyl, methyl, methoxy, trifluoromethyl, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , cyano, cyclopropyl, phenyl, -NHCH 2 CH 3 , -SCH 3 , -CONH 2 , -NHCOCF 3 or -NHCOCH 3 ;
- n is selected from 0, 1, 2 or 3.
- the R 1 is selected from F, Cl, Br, I, O, hydroxyl, methyl, methoxy, trifluoromethyl, -NH 2 , -NHCH 3 , -N(CH 3 ) 2- , cyano, cyclopropyl or phenyl;
- the R 1 is selected from F, Cl, Br, I, O, hydroxyl, methyl, methoxy, trifluoromethyl, -NH 2 , -NHCH 3 , cyano, cyclopropyl or phenyl;
- R1 is selected from F, Cl, Br, hydroxyl, methyl, -NH2 , -NHCH3 , cyano or cyclopropyl.
- the ring B is selected from C5-6 cycloalkyl, 4-10 membered heterocyclyl or 5-6 membered heteroaryl.
- the ring B is selected from C5-6 cycloalkyl, 4-6 membered monoheterocyclyl, 6 membered spiroheterocyclyl, 6-9 membered fused heterocyclyl or 6 membered heterocyclyl Aryl, and said heterocyclyl or heteroaryl contains 1-2 heteroatoms selected from N or O.
- the ring B is selected from
- the ring B is selected from
- the ring B is selected from
- Ring B is selected from
- the R 2 is selected from F, methyl, hydroxyl or methoxy, and n is selected from 0, 1 or 2.
- the R 2 is selected from deuterium, cyano, ethynyl, F, methyl, hydroxyl, methoxy, -CONH 2 , -CONHCH 3 ,
- n is selected from 0, 1, 2, 3, 4 or 5.
- the R 2 is selected from F or methyl, and n is selected from 0, 1 or 2.
- the ring C is selected from phenyl or pyridyl; in some embodiments of the present invention, the ring C is phenyl.
- the R 3 is selected from nitro, Br, Cl, I, CN, CF 3 , or -N(CH 3 ) 3 + ; in some embodiments of the present invention, R 3 is selected from From nitro, Br, Cl or CF 3 .
- the ring D is selected from 3-12 membered heterocyclic groups, and the heterocyclic groups contain 1-3 heteroatoms selected from N, O, or S.
- the ring D is selected from a 4-7 membered monoheterocyclic group, a 6-9 membered condensed heterocyclic group, a 7-11 membered spiroheterocyclic group or a 7-9 membered bridged heterocyclic group , and the heterocyclic group contains 1-3 heteroatoms selected from N, O, or S.
- the ring D is selected from 5-6 membered heteroaryl
- the ring D is selected from or ring D does not exist;
- the ring D is selected from Or ring D does not exist.
- the ring D is selected from
- the ring D is selected from
- ring D is selected from
- the R 4 is selected from F or methyl, and q is selected from 0, 1 or 2.
- Ring D when Ring D is absent, Ring A is pyridyl or R4 is q is 1.
- the compound, its isomer or pharmaceutically acceptable salt is selected from:
- ring A, ring B, ring D, X, Y, Z, R 1 , R 2 , R 3 , R 4 , m, n, p and q are as defined in formula (I).
- the compound is selected from:
- ring B, ring D, X, Y, Z, R 1 , R 2 , R 3 , R 4 , m, n, p and q are as defined in formula (I).
- the compound and its isomers are selected from:
- ring B, ring D, R 1 , R 2 , R 3 , R 4 , m, n, p and q are as defined in formula (I).
- the present invention also provides a compound, an isomer or a pharmaceutically acceptable salt thereof, which is selected from:
- the present invention also provides a preparation method of the compound of formula (I): it is prepared by condensation reaction between the compound of formula (I-A) and the compound of formula (I-B);
- ring A, ring B, ring C, ring D, X, Y, Z, R 1 , R 2 , R 3 , R 4 , m, n, p and q are as defined in formula (I).
- the present invention also relates to a pharmaceutical composition, which comprises the compound described in formula (I), its isomer or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent or excipient.
- the present invention also relates to the compounds, their isomers or pharmaceutically acceptable salts, and pharmaceutically acceptable carriers, diluents or excipients or the pharmaceutical compositions used in the preparation and treatment of the disease caused by coronaviruses. Application in the medicine of disease.
- the disease is a respiratory infectious disease.
- the respiratory infectious disease is severe acute respiratory syndrome.
- the coronavirus is SARS-CoV-2.
- the present invention also provides the application of the compound described in formula (I), its isomer or pharmaceutically acceptable salt in the treatment of diseases caused by coronaviruses, preferably, the diseases are respiratory infectious diseases.
- the respiratory infectious disease is severe acute respiratory syndrome.
- the coronavirus is SARS-CoV-2.
- the present invention also provides the application of the compound described in formula (I), its isomer or pharmaceutically acceptable salt in the preparation of 3CLpro protease inhibitor.
- the present invention also provides a method for treating a disease caused by a coronavirus, which is administered with an effective amount of the compound described in formula (I), an isomer or a pharmaceutically acceptable salt thereof; preferably, the disease is a respiratory tract infection sick.
- the respiratory infectious disease is severe acute respiratory syndrome.
- the coronavirus is SARS-CoV-2.
- beneficial effects of the compound of the present invention include but are not limited to: good inhibitory effect on SARS-CoV-2 3CLpro/Mpro protease, better pharmacokinetic properties, and better druggability.
- pharmaceutically acceptable means, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction or other problems or complications, and with a reasonable benefit/risk ratio Comparable to those compounds, materials, compositions and/or dosage forms.
- pharmaceutically acceptable salt refers to derivatives prepared from the compounds of the present invention with relatively non-toxic acids or bases. These salts can be prepared during compound synthesis, isolation, purification, or alone by reacting the free form of the purified compound with an appropriate acid or base.
- the compound contains relatively acidic functional groups, it reacts with alkali metal, alkaline earth metal hydroxides or organic amines to obtain base addition salts, including cations based on alkali metals and alkaline earth metals.
- the compound contains a relatively basic functional group, it reacts with an organic acid or an inorganic acid to form an acid addition salt.
- the isomers mentioned in the present invention include geometric isomers and stereoisomers, such as cis-trans isomers, enantiomers, diastereomers, and racemic and other mixtures thereof, all These mixtures are within the scope of the present invention.
- enantiomer refers to stereoisomers that are mirror images of each other.
- diastereomer refers to stereoisomers whose molecules have two or more chiral centers and which are in a non-mirror-image relationship.
- cis-trans isomer refers to the configuration in which the double bond or the single bond of the ring carbon atom in the molecule cannot freely rotate.
- keys with wedge-shaped solid lines and dotted wedge keys Indicates the absolute configuration of a stereocenter.
- Stereoisomers of the compounds of the present invention may be prepared by chiral synthesis or chiral reagents or other conventional techniques.
- one enantiomer of a certain compound of the present invention can be prepared by asymmetric catalytic technology or chiral auxiliary derivatization technology.
- a compound with a single stereo configuration can be obtained from a mixture by chiral resolution technology.
- it can be directly prepared by using chiral starting materials.
- the separation of optically pure compounds in the present invention is usually accomplished by using preparative chromatography, and a chiral chromatographic column is used to achieve the purpose of separating chiral compounds.
- the present invention also includes isotopically labeled compounds, including isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, respectively , 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
- isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, respectively , 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
- Compounds of the present invention that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention.
- the isotope is selected from the group consisting of 2 H, 3 H, 11 C and 18 F. More preferably, the radioisotope is2H .
- deuterated compounds are intended to be encompassed
- chemical bond is a mode of association between particles, where the particles may be atoms or ions. e.g. structural unit When Y is a chemical bond, it means that X is directly connected to ring B, which is
- substituent R 1 When a substituent is bonded across a ring, the substituent may be bonded to any atom on the ring.
- the structural unit Indicates that substituent R 1 can be substituted at any position on ring A.
- R 4 is not methylamino (-NHCH 3 );
- the optional substituent in R1 when the optional substituent in R1 is O, it means that the atom connected to it is oxidized, for example, when ring A contains N atom, nitrogen oxide can be formed, such as
- pharmaceutically acceptable carrier refers to a medium generally acceptable in the art for delivering biologically active agents to animals, especially mammals, including adjuvants, excipients or Excipients such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, Lubricants and dispersants.
- Pharmaceutically acceptable carriers are formulated according to a number of factors that are within the purview of those of ordinary skill in the art.
- compositions containing the agent include, but are not limited to: the type and nature of the active agent being formulated, the subject to whom the composition containing the agent is to be administered, the intended route of administration of the composition, and the intended therapeutic indication.
- Pharmaceutically acceptable carriers include both aqueous and non-aqueous media and various solid and semisolid dosage forms. Such carriers include many different ingredients and additives in addition to the active agent, and the inclusion of additional ingredients in formulations for a variety of reasons (eg, stabilizing the active agent, binders, etc.) is well known to those of ordinary skill in the art.
- excipient generally refers to a carrier, diluent and/or medium required to formulate an effective pharmaceutical composition.
- prophylactically or therapeutically effective amount means that a compound of the present invention or a pharmaceutically acceptable salt thereof means a sufficient amount of the compound to treat the disorder with a reasonable effect/risk ratio applicable to any medical treatment and/or prevention.
- total daily dosage of the compound represented by formula (I) of the present invention or its pharmaceutically acceptable salts and compositions must be determined by the attending physician within the scope of reliable medical judgment.
- the particular therapeutically effective dosage level will depend on a number of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the particular composition employed; The age, weight, general health, sex and diet of the patient; the timing, route of administration, and rate of excretion of the specific compound employed; the duration of treatment; drugs used in combination or concomitantly with the specific compound employed; and Similar factors are well known in the medical arts. For example, it is practice in the art to start doses of the compound at levels lower than that required to obtain the desired therapeutic effect and to gradually increase the dosage until the desired effect is obtained.
- optionally substituted means that it can be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be arbitrary on a chemically realizable basis, for example, the term “optionally "substituted by one or more halogens” means that it may be substituted by one or more halogens, or may not be substituted by halogens.
- cyclic refers to saturated, partially saturated or unsaturated monocyclic as well as polycyclic rings.
- heterocyclyl refers to a substituted or unsubstituted saturated or unsaturated non-aromatic ring containing 1-3 heteroatoms selected from N, O or S. Saturated or partially saturated monocyclic heterocyclyls and polycyclic heterocyclyls are included; the heterocyclyls are independent of the position of attachment (ie, bonding may be through a carbon atom or a heteroatom).
- the polycyclic heterocyclic group includes a fused heterocyclic group, a spiro heterocyclic group, and a bridged heterocyclic group.
- the heterocyclic group can be oxo, for example
- the "fused heterocyclic group” refers to a ring structure formed by two or more rings sharing two adjacent ring atoms, and at least one of the rings is a heterocyclic ring; the fused heterocyclic ring
- the group includes a ring structure formed by condensing a monoheterocyclic group and a monoheterocyclic group or a cycloalkyl group or an aryl group or a heteroaryl group, and also includes a fused ring structure formed by a heteroaryl group and a cycloalkyl group or a monoheterocyclic group ring structure.
- the "spiroheterocyclic group” refers to a ring structure formed by two or more rings sharing one ring atom with each other, and at least one ring is a heterocycle.
- bridged heterocyclic group refers to a ring structure formed by two or more rings sharing non-adjacent ring atoms with each other, and at least one ring is a heterocyclic ring.
- the heterocyclic group can be selected from 4-7 membered monoheterocycle, 6-10 membered condensed heterocycle, 8-11 membered spiro heterocycle or 7-9 membered bridged heterocycle.
- heterocyclyl examples include, but are not limited to
- aryl refers to an unsaturated, usually aromatic, hydrocarbon group which may be a single ring or multiple rings fused together.
- C 6-10 aryl include , but are not limited to, phenyl, naphthyl.
- heteroaryl means a stable monocyclic or polycyclic aromatic hydrocarbon, preferably containing carbon atoms and 1, 2, 3 or 4 ring heterocyclic rings independently selected from N, O and S atom.
- the heteroaryl group can be oxo, for example Preferably 5-12 membered heteroaryl, more preferably 5-10 membered heteroaryl; examples of heteroaryl include but not limited to pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, (isoxazolyl), thiazolyl, furyl, thienyl, pyrimidinyl, pyridyl, isoquinolyl, (cinnolinyl), (phthalazinyl),
- cycloalkyl refers to a saturated monocyclic or polycyclic hydrocarbon group cycloalkyl, preferably C 3-12 cycloalkyl, more preferably C 3-8 cycloalkyl, further preferably C 3-6 cycloalkane
- cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or Cycloalkyl can also be further oxo, for example
- alkyl is used to denote a straight or branched chain saturated hydrocarbon group.
- Preferred C 1-6 alkyl, more preferably C 1-4 alkyl, examples of alkyl include, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, etc.
- alkoxy is used to denote -O-alkyl, preferably alkoxy of C 1-6 , more preferably alkoxy of C 1-4 , examples of alkoxy include But not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy and the like.
- halogen means a fluorine, chlorine, bromine or iodine atom.
- haloalkyl refers to an alkyl group substituted by one or more halogens.
- the haloalkyl group is preferably a halogenated C1-4 alkyl group.
- Examples of a halogenated C1-4 alkyl group include, but are not limited to, CF 3. CH 2 Cl, CH 2 F, etc.
- Severe Acute Respiratory Syndrome is a type of atypical pneumonia.
- Severe acute respiratory syndrome coronavirus 2 (abbreviated as SARS-CoV-2), is a type of severe acute respiratory syndrome-associated coronavirus of the family Coronaviridae Betacoronavirus, and its gene sequence is similar to that of SARS virus and MERS
- the viruses belong to the same lineage but different clades, and are the seventh coronaviruses known to infect humans.
- the hosts of the virus include mammals and birds, which caused the outbreak of coronavirus disease 2019 (COVID-19) in late 2019.
- the virus can invade the human body through the upper respiratory tract of humans, and infects through the ACE2 expressed on the surface of various cells; the main infected organs include the lungs, heart, kidneys and other major organs.
- the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass chromatography (LC-MS), or ultra-high performance liquid chromatography-mass chromatography (UPLC-MS). NMR chemical shifts ( ⁇ ) are given in parts per million (ppm).
- the determination of NMR is to use Bruker Neo 400M or Bruker Ascend 400 nuclear magnetic instrument, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), heavy water (D 2 O), internal standard is tetramethylsilane (TMS).
- Agilent 1260-6125B single quadrupole mass spectrometer was used for liquid chromatography-mass chromatography LC-MS, and the column was Welch Biomate column (C18, 2.7 ⁇ m, 4.6 ⁇ 50mm) or waters H-Class SQD2, and the column was Welch Ultimate column (XB- C18, 1.8 ⁇ m, 2.1 ⁇ 50mm) mass spectrometer (the ion source is electrospray ionization).
- HPLC uses Waters e2695-2998 or Waters ARC and Agilent 1260 or Agilent Poroshell HPH high performance liquid chromatography.
- Thin-layer chromatography silica gel plates use Yantai Jiangyou Silica Gel Development Co., Ltd. GF254 silica gel plates or Rushan Shangbang New Materials Co., Ltd. GF254 silica gel plates.
- the specifications used by TLC are 0.15mm to 0.20mm, preparative 20 ⁇ 20cm, column chromatography Generally used in Chenghua Chemical Industry 200-300 mesh silica gel as carrier.
- the starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or following methods known in the art.
- M in 4M hydrochloric acid-1,4-dioxane solution is the concentration unit, representing mol/L.
- Step A Dissolve compound 1-1 (100 mg, 0.38 mmol) in N,N-dimethylformamide (4 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to 0°C, and then N,N-diisopropylethylamine (147 mg, 1.14 mmol), 2-(7-azobenzotriazole)-N,N,N' , N'-Tetramethyluronium hexafluorophosphate (216 mg, 0.57 mmol) and 3,3-difluorotrimethyleneimine hydrochloride (58.3 mg, 0.46 mmol). The reaction system was stirred at 0°C for 15 minutes.
- Step B Compound 1-2 (108 mg, 0.32 mmol) was dissolved in N,N-dimethylformamide (3 mL) at room temperature under nitrogen protection. Subsequently, tert-butyl ((1S,2R)-2-aminocyclohexyl) carbamate (77 mg, 0.36 mmol) and N,N-diisopropylethylamine (123.3 mg, 0.96 mmol). The reaction system was stirred at 80°C for 2 hours.
- Step C Compound 1-3 (150 mg, 0.28 mmol) was dissolved in dichloromethane (2 mL) at room temperature under nitrogen protection. Subsequently, at 0° C., 4M hydrochloric acid-1,4-dioxane solution (2 mL) was slowly added dropwise to the reaction system. The reaction system was stirred at room temperature for 1 hour.
- Step D Compound 1-4 (140 mg, 0.32 mmol) was dissolved in N,N-dimethylformamide (3 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to 0°C, and isoquinoline-4-carboxylic acid (55mg, 0.32mmol), 2-(7-azobenzotriazole)-N,N,N',N' - Tetramethylurea hexafluorophosphate (182 mg, 0.48 mmol) and N,N-diisopropylethylamine (123 mg, 0.96 mmol). The reaction system was stirred at 0°C for 30 minutes.
- Step A Dissolve compound 1-1 (200 mg, 0.76 mmol) in N,N-dimethylformamide (5 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to -10°C, and N,N-diisopropylethylamine (292 mg, 2.3 mmol), 2-(7-azobenzotriazole)-N,N,N' , N'-Tetramethyluronium hexafluorophosphate (381 mg, 1.06 mmol) and piperidine (77 mg, 0.91 mmol). The reaction was stirred for 3 minutes.
- Step B Dissolve compound 2-2 (100 mg, 0.30 mmol) in N,N-dimethylformamide (5 mL) at room temperature under nitrogen protection. Subsequently, tert-butyl ((1S,2R)-2-aminocyclohexyl)carbamate (77mg, 0.36mmol) and N,N-diisopropylethylamine (96mg, 0.75 mmol). The reaction system was stirred at 80°C for 2 hours.
- Step C Dissolve compound 2-3 (120 mg, 0.23 mmol) in 4M hydrochloric acid-1,4-dioxane solution (5 mL) at room temperature under nitrogen protection. The reaction system was stirred at room temperature for 1 hour.
- Step D Compound 2-4 (100 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (3 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to 0°C, and isoquinoline-4-carboxylic acid (44mg, 0.26mmol), 2-(7-azobenzotriazole)-N,N,N',N' - Tetramethyluronium hexafluorophosphate (133 mg, 0.35 mmol) and N,N-diisopropylethylamine (90 mg, 0.71 mmol). The reaction system was stirred at 0°C for 30 minutes.
- Step A Dissolve compound 1-1 (200 mg, 0.76 mmol) in N,N-dimethylformamide (3.8 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to -10°C, and N,N-diisopropylethylamine (292 mg, 2.3 mmol), 2-(7-azobenzotriazole)-N,N,N' , N'-Tetramethyluronium hexafluorophosphate (404 mg, 1.06 mmol) and pyrrolidine (65 mg, 0.91 mmol). The reaction system was continued to stir for 30 minutes.
- Step B Dissolve compound 3-2 (80 mg, 0.25 mmol) in N,N-dimethylformamide (1.3 mL) at room temperature under nitrogen protection. Subsequently, tert-butyl ((1S,2R)-2-aminocyclohexyl)carbamate (64mg, 0.3mmol) and N,N-diisopropylethylamine (97mg, 0.75mmol) were successively added to the mixture ). The reaction system was stirred at 80°C for 2 hours.
- Step C Dissolve compound 3-3 (127 mg, 0.25 mmol) in dry dichloromethane solution (1.3 mL) at room temperature under nitrogen protection. Subsequently, at 0° C., 4M hydrochloric acid-1,4-dioxane solution (0.63 mL) was slowly added dropwise to the reaction system. The reaction system was raised to room temperature, and stirring was continued for 1 hour.
- Step D Compound 3-4 (60 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (0.75 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to 0°C, and isoquinoline-4-carboxylic acid (26mg, 0.15mmol), 2-(7-azobenzotriazole)-N,N,N',N' - Tetramethyluronium hexafluorophosphate (86 mg, 0.23 mmol) and N,N-diisopropylethylamine (97 mg, 0.75 mmol). The reaction system was stirred at 0°C for 30 minutes.
- Step A Dissolve compound 1-1 (200 mg, 0.76 mmol) in N,N-dimethylformamide (5 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to -10°C, and N,N-diisopropylethylamine (292 mg, 2.3 mmol), 2-(7-azobenzotriazole)-N,N,N' , N'-Tetramethyluronium hexafluorophosphate (381 mg, 1.06 mmol) and piperidine (77 mg, 0.91 mmol). The reaction was stirred for 3 minutes.
- Step B Dissolve compound 1-1 (120 mg, 0.60 mmol) in N,N-dimethylformamide (3 mL) at room temperature under nitrogen protection. Subsequently, (R)-tert-butyl 3-aminopiperidine-1-carboxylate (145 mg, 0.72 mmol) and N,N-diisopropylethylamine (193 mg, 1.5 mmol) were sequentially added to the above reaction solution. The reaction system was stirred at 80°C for 2 hours.
- Step C Dissolve compound 1-2 (160 mg, 0.31 mmol) in 4M hydrochloric acid-1,4-dioxane solution (5 mL) at room temperature under nitrogen protection. The reaction system was stirred at room temperature for 1 hour.
- Step D Compound 1-3 (130 mg, 0.31 mmol) was dissolved in N,N-dimethylformamide (3 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to 0°C, and nicotinic acid (46 mg, 0.37 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexa Fluorophosphate (299 mg, 0.78 mmol) and N,N-diisopropylethylamine (201 mg, 1.56 mmol). The reaction system was stirred at 0°C for 30 minutes.
- Step A Dissolve compound 1-1 (2 g, 7.6 mmol) in N,N-dimethylformamide (38 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to -10°C, and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.05g, 10.6 mmol), N,N-diisopropylethylamine (2.95 g, 23 mmol) and piperidine (777 mg, 9.1 mmol). The reaction was stirred for 3 minutes.
- Step B Dissolve compound 1-2 (1.03 g, 3.1 mmol) in N,N-dimethylformamide (1.5 mL) at room temperature under nitrogen protection. Subsequently, (R)-tert-butyl 3-aminopiperidine-1-carboxylate (744 mg, 3.7 mmol) and N,N-diisopropylethylamine (1.2 g, 9.3 mmol) were added in sequence. The reaction system was stirred at 80°C for 2 hours.
- Step C Compound 1-3 (1.2 g, 2.34 mmol) was dissolved in dry dichloromethane solution (11.8 mL) at room temperature under nitrogen protection. Subsequently, a hydrochloric acid solution (5.9 mL) of 1,4-dioxane was slowly added dropwise to the reaction system. The reaction system was stirred at room temperature for 1 hour.
- Step D The compound 5-bromonicotinic acid (30 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (0.75 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to 0°C, and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (86mg, 0.23mmol) was added in sequence , compound 1-4 (60 mg, 0.15 mmol) and N,N-diisopropylethylamine (97 mg, 0.75 mmol). The reaction system was stirred at 0°C for 30 minutes.
- Step A Dissolve compound 1-1 (2 g, 7.5 mmol) in N,N-dimethylformamide (30 mL) at room temperature under nitrogen protection. Subsequently, N,N-diisopropylethylamine (2.9 g, 22.5 mmol) and (R)-tert-butyl 3-aminopiperidine-1-carboxylate (1.5 g, 7.5 mmol) were added in sequence. The reaction was stirred overnight.
- Step B Compound 6-2 (120 mg, 0.27 mmol) was dissolved in N,N-dimethylformamide (2 mL) at room temperature under nitrogen protection. Subsequently, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (154mg, 0.41mmol), N,N-diisopropyl Ethylamine (105 mg, 0.81 mmol) and 4,4-difluoropiperidine (33 mg, 0.27 mmol). The reaction system was raised to 80°C and stirred for 5 hours.
- Step C Dissolve compound 6-3 (58 mg, 0.1 mmol) in dry dichloromethane solution (0.4 mL) at room temperature under nitrogen protection. Subsequently, trifluoroacetic acid (0.1 mL) was slowly added dropwise to the reaction system. The reaction system was stirred at room temperature for 30 minutes.
- Step D The compound isoquinoline-4-carboxylic acid (17 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide (1 mL) at room temperature under nitrogen protection. Subsequently, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57mg, 0.15mmol), N,N-diisopropyl Ethylamine (39mg, 0.3mmol) and compound 6-4 (50mg, 0.1mmol). The reaction system continued to stir for 1 hour.
- Step A Dissolve compound 6-2 (120 mg, 0.27 mmol) in N,N-dimethylformamide (2 mL) at room temperature under nitrogen protection. Subsequently, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (154mg, 0.41mmol), N,N-diisopropyl Ethylamine (105 mg, 0.81 mmol) and 4,4-difluoropiperidine (33 mg, 0.27 mmol). The reaction system was stirred at 80°C for 5 hours.
- Step B Compound 7-2 (77 mg, 0.14 mmol) was dissolved in dry dichloromethane solution (0.6 mL) under nitrogen protection at room temperature. Subsequently, trifluoroacetic acid (0.15 mL) was slowly added dropwise to the reaction system. The reaction system was stirred at room temperature for 30 minutes.
- Step C Dissolve the compound isoquinoline-4-carboxylic acid (24.3 mg, 0.14 mmol) in N,N-dimethylformamide (1 mL) at room temperature under nitrogen protection. Subsequently, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (80mg, 0.21mmol), N,N-diisopropyl Ethylamine (54mg, 0.42mmol) and compound 7-3 (65mg, 0.14mmol). The reaction system continued to stir for 1 hour.
- Step A Dissolve compound 8-1 (300 mg, 1.84 mmol) in nitrobenzene (6 mL) at room temperature under nitrogen protection. Subsequently, the above solution was heated to 180°C, and liquid bromine (315 mg, 2.02 mmol) was slowly added dropwise. The reaction system was continuously stirred at 180° C. for 16 hours.
- reaction solution is cooled to room temperature, water (20 mL) is added to the reaction solution, the mixture is extracted with ethyl acetate (10 mL ⁇ 3 times), the organic phases are combined, and the organic phase is washed with saturated aqueous sodium chloride solution (20 mL ⁇ 2 times) washing. It was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain compound 8-2 (155 mg, yield 35%).
- Step B Compound 8-2 (155 mg, 0.64 mmol) was dissolved in methanol (6 mL) at room temperature. Subsequently, triethylamine (1.3 g, 12.86 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (95 mg, 0.13 mmol) were sequentially added to the above reaction solution. The reaction system was stirred at 90° C. for 24 hours under a carbon monoxide atmosphere.
- reaction solution was cooled to room temperature, and the reaction solution was filtered through diatomaceous earth to collect the filtrate. Then water (15 mL) was added to the filtrate, the mixture was extracted with ethyl acetate (10 mL ⁇ 3 times), the organic phases were combined, and the organic phase was washed with saturated aqueous sodium chloride solution (20 mL ⁇ 2 times). It was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain compound 8-3 (45 mg, yield 32%).
- Step C Compound 8-3 (45mg, 0.20mmol) was dissolved in THF/methanol/water (1mL/0.5mL0.1mL) at room temperature. Subsequently, the above solution was cooled to 0°C, and lithium hydroxide monohydrate (42 mg, 1.00 mmol) was added. Then the reaction system was warmed to room temperature and stirring was continued for 2 hours.
- Step D Under nitrogen protection at room temperature, compound 8-4 (30mg, 0.15mmol) and (R)-(5-bromo-2-((1-(7-chloroisoquinoline-4-carbonyl) Piperidin-3-yl)amino)-3-nitrophenyl)(piperidin-1-yl)methanone (66mg, 0.16mmol) (4-4) was dissolved in N,N-dimethylformamide ( 1mL).
- Step A Compound 9-1 (400 mg, 1.92 mmol) was dissolved in trifluoroacetic acid (4 mL)/concentrated sulfuric acid (1 mL) at 0°C. Subsequently, N-bromosuccinimide (512.6 mg, 2.88 mmol) was added to the above solution. The reaction was then warmed to room temperature and stirring was continued for 18 hours.
- Step B Dissolve compound 9-2 (390 mg, 1.36 mmol) in N,N-dimethylformamide (6 mL) at 0°C under nitrogen protection. Subsequently, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (770mg, 2.05mmol), N, N-Diisopropylethylamine (526 mg, 4.08 mmol) and piperidine (115 mg, 1.36 mmol). The reaction system continued to stir for 15 minutes.
- Step C Dissolve compound 9-3 (385 mg, 1.1 mmol) and tert-butyl ((1S, 2R)-2-aminocyclohexyl) carbamate (233 mg, 1.1 mmol) at room temperature under nitrogen protection In N,N-dimethylformamide (5 mL). Subsequently, N,N-diisopropylethylamine (425 mg, 3.3 mmol) was added dropwise to the above reaction solution. The reaction system was raised to 135°C and stirring was continued for 16 hours.
- Step D Compound 9-4 (181 mg, 0.33 mmol) was dissolved in dichloromethane (3 mL) at room temperature. Subsequently, the temperature was lowered to 0° C., and 4M hydrochloric acid-1,4-dioxane solution (1.5 mL, 6.6 mmol) was slowly added dropwise to the reaction solution. The reaction was then warmed to room temperature and stirring was continued for 1 hour.
- Step E Compound 9-5 (161 mg, 0.36 mmol) was dissolved in N,N-dimethylformamide (3 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to 0°C, and isoquinoline-4-carboxylic acid (62mg, 0.36mmol), 2-(7-azobenzotriazole)-N,N,N',N' - Tetramethylurea hexafluorophosphate (205.2 mg, 0.54 mmol) and N,N-diisopropylethylamine (139 mg, 1.08 mmol). The reaction was then stirred for an additional 15 minutes.
- Step A Dissolve compound 1-1 (200 mg, 0.76 mmol) in N,N-dimethylformamide (4 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to 0°C, and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (403mg, 1.06mmol) was added in sequence , tert-butyl piperazine-1-carboxylate (169 mg, 0.91 mmol) and N,N-diisopropylethylamine (297 mg, 2.28 mmol). The reaction system continued to stir for 10 minutes.
- Step B Dissolve the compound isoquinoline-4-carboxylic acid (103 mg, 0.6 mmol) in N,N-dimethylformamide (2.5 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to 0°C, and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (266mg, 0.7mmol) was added in sequence , compound 10-3 (100 mg, 0.5 mmol) and N,N-diisopropylethylamine (196 mg, 1.50 mmol). The reaction system continued to stir for 10 minutes.
- Step C Compound 10-4 (175 mg, 0.49 mmol) was dissolved in dichloromethane (2.5 mL) at 0°C. Subsequently, 4M hydrochloric acid-1,4-dioxane solution (2.5 mL) was slowly added dropwise to the reaction system. Then the reaction system was warmed to room temperature and stirred for 1.5 hours.
- Step D Compound 10-5 (125 mg, 0.49 mmol) was dissolved in N,N-dimethylformamide (2.5 mL) at room temperature under nitrogen protection. Subsequently, compound 10-2 (210 mg, 0.32 mmol) and N,N-diisopropylethylamine (380 mg, 2.94 mmol) were added sequentially. The reaction system was stirred at 80°C for 2 hours.
- Step E Compound 10-6 (60 mg, 0.09 mmol) was dissolved in dichloromethane (0.46 mL) at 0°C. Subsequently, 4M hydrochloric acid-1,4-dioxane solution (0.23 mL) was slowly added dropwise to the reaction system. The reaction system was warmed to room temperature, and stirring was continued for 1.5 hours.
- Step A Dissolve compound 4-cinnolinecarboxylic acid (26 mg, 0.15 mmol) in N,N-dimethylformamide (1 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to 0°C, and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (86mg, 0.23mmol) was added in sequence , N,N-diisopropylethylamine (97mg, 0.75mmol) and (R)-(5-bromo-3-nitro-2-(piperidin-3-ylamino)phenyl)(piperidine- 1-yl)methanone (60 mg, 0.15 mmol) (4-4). The reaction was stirred for an additional 30 minutes.
- Step A Dissolve compound 1-1 (400 mg, 1.5 mmol) in N,N-dimethylformamide (7.6 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to -10°C, and N,N-diisopropylethylamine (587 mg, 4.5 mmol), 2-(7-azobenzotriazole)-N,N,N' , N'-Tetramethyluronium hexafluorophosphate (806 mg, 2.1 mmol) and piperidine (155 mg, 1.8 mmol). The reaction was stirred for an additional 3 minutes.
- Step B Dissolve compound 2-2 (85 mg, 0.26 mmol) in N,N-dimethylformamide (1.3 mL) at room temperature under nitrogen protection. Subsequently, (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (57 mg, 0.31 mmol) and N,N-diisopropylethylamine (100 mg, 0.77 mmol) were sequentially added to the above reaction solution. The reaction system was stirred at 80°C for 2 hours.
- Step C Dissolve compound 12-3 (75 mg, 0.15 mmol) in 4M hydrochloric acid-1,4-dioxane solution (0.38 mL) at room temperature under nitrogen protection. The reaction system was stirred at room temperature for 2 hours.
- Step D Compound 12-4 (60 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (0.76 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to 0°C, and 4-isoquinoline formic acid (26 mg, 0.15 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetra Methylurea hexafluorophosphate (86mg, 0.23mmol) and N,N-diisopropylethylamine (96mg, 0.76mmol). The reaction system was stirred at 0°C for 15 minutes.
- Step A Dissolve compound 4-4 (50mg, 0.12mmol) and 4-isoquinolinecarboxylic acid (23mg, 0.13mmol) in N,N-dimethylformamide (1mL) under nitrogen protection at room temperature . Subsequently, the above solution was cooled to 0°C, and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (46mg, 0.12mmol) was added in sequence and N,N-Diisopropylethylamine (47mg, 0.36mmol). The reaction system was stirred at 0°C for 30 minutes.
- Step A Dissolve compound 2-2 (60 mg, 0.18 mmol) in N,N-dimethylformamide (1 mL) at room temperature under nitrogen protection. Subsequently, (R)-tert-butyl 3-aminopiperidine-1-carboxylate (47 mg, 0.22 mmol) and N,N-diisopropylethylamine (70 mg, 0.54 mmol) were sequentially added to the above reaction solution. The reaction system was stirred at 80°C for 2 hours.
- Step B Dissolve compound 2-3 (90 mg, 0.17 mmol) in 4M hydrochloric acid-1,4-dioxane solution (0.4 mL) at room temperature under nitrogen protection. The reaction system was stirred at room temperature for 1 hour.
- Step D Compound 2-4 (80 mg, 0.19 mmol) was dissolved in N,N-dimethylformamide (1 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to 0°C, and nicotinic acid (32 mg, 0.16 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexa Fluorophosphate (85 mg, 0.22 mmol) and N,N-diisopropylethylamine (103 mg, 0.80 mmol). The reaction system was stirred at 0°C for 30 minutes.
- Step A Compound 1-1 (100mg, 0.38mmol) was dissolved in N,N-dimethylformamide (4mL) under the condition of ice-salt bath under nitrogen protection. Subsequently, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (216mg, 0.57mmol), triethylamine (115mg, 1.14 mmol) and 3-azabicyclo[3.1.0]hexane hydrochloride (45.3mg, 0.38mmol). The reaction was stirred for an additional 10 minutes.
- Step B Dissolve compound 15-2 (70 mg, 0.21 mmol) in N,N-dimethylformamide (2 mL) at room temperature under nitrogen protection. Subsequently, N,N-diisopropylethylamine (82.5 mg, 0.63 mmol) and (R)-tert-butyl 3-aminopiperidine-1-carboxylate (51 mg, 0.25 mmol) were added in sequence. The reaction was stirred for 2 hours.
- Step C Dissolve compound 15-3 (70 mg, 0.15 mmol) in dry dichloromethane solution (0.6 mL) at room temperature under nitrogen protection. Subsequently, trifluoroacetic acid (0.15 mL) was slowly added dropwise to the reaction system. The reaction was stirred for an additional 30 minutes.
- Step D Dissolve the compound isoquinoline-4-carboxylic acid (25 mg, 0.14 mmol) in N,N-dimethylformamide (1 mL) at room temperature under nitrogen protection. Then add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (80mg, 0.21mmol), N,N-diisopropyl Ethylamine (54 mg, 0.42 mmol) and compound 15-4 (90 mg, 0.1 mmol). The reaction system was stirred for 1 hour.
- Step A Compound 1-1 (200 mg, 0.76 mmol) was dissolved in N,N-dimethylformamide (1 mL) at room temperature. Subsequently, the above solution was cooled to 0°C, and N,N-diisopropylethylamine (294 mg, 2.28 mmol), 2-(7-azobenzotriazole)-N,N,N', N'-Tetramethyluronium hexafluorophosphate (404 mg, 1.06 mmol) and 4,4-difluoropiperidine (144 mg, 0.91 mmol). The reaction was then stirred at 0°C for 5 minutes.
- Step B Dissolve compound 16-2 (217 mg, 0.59 mmol) in N,N-dimethylformamide (1 mL) at room temperature under nitrogen protection. Subsequently, (R)-tert-butyl 3-aminopiperidine-1-carboxylate (152 mg, 0.71 mmol) and N,N-diisopropylethylamine (228 mg, 1.77 mmol) were sequentially added to the above reaction solution. The reaction system was then stirred at 80°C for 2 hours.
- Step C Dissolve compound 16-3 (300 mg, 0.53 mmol) in 4M hydrochloric acid-1,4-dioxane solution (1.3 mL) at room temperature under nitrogen protection. The reaction was then stirred at room temperature for 1 hour.
- Step D Compound 16-4 (60 mg, 0.13 mmol) was dissolved in N,N-dimethylformamide (1 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to 0°C, and 2-oxo-1,2-dihydroquinoline-4-carboxylic acid (20 mg, 0.11 mmol), 2-(7-azobenzotriazole) -N,N,N',N'-Tetramethyluronium hexafluorophosphate (58 mg, 0.15 mmol) and N,N-diisopropylethylamine (71 mg, 0.55 mmol). The reaction system was then stirred at 0°C for 30 minutes.
- Step A Dissolve compound 1-1 (1 g, 3.80 mmol) in N,N-dimethylformamide (19 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to 0°C, and N,N-diisopropylethylamine (1.4g, 11.4mmol) and 2-(7-azobenzotriazole)-N , N,N',N'-Tetramethylurea hexafluorophosphate (2g, 5.32mmol) and (2R,6S)-2,6-dimethylmorpholine (526mg, 4.56mmol). The reaction was stirred for 5 minutes at 0°C.
- Step B Dissolve compound 17-2 (600 mg, 1.67 mmol) in N,N-dimethylformamide (8.4 mL) at room temperature under nitrogen protection. Subsequently, (R)-tert-butyl 3-aminopiperidine-1-carboxylate (400 mg, 2.00 mmol) and N,N-diisopropylethylamine (649 mg, 5.01 mmol) were sequentially added to the above reaction solution. The reaction system was then stirred at 80°C for 2 hours.
- Step C Dissolve compound 17-3 (810 mg, 1.50 mmol) in 4M hydrochloric acid-1,4-dioxane solution (2.8 mL) at room temperature under nitrogen protection. The reaction was then stirred at room temperature for 1 hour.
- compound 17-1 (20 mg, 0.05 mmol) was dissolved in N,N-dimethylformamide (0.5 mL). Subsequently, the above solution was cooled to 0°C, and N,N-diisopropylethylamine (17 mg, 0.14 mmol), 2-(7-azobenzotriazole)-N,N,N', N'-Tetramethyluronium hexafluorophosphate (24 mg, 0.06 mmol) and 1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (9 mg, 0.05 mmol). The reaction system was then continued to stir for 2 hours.
- Step A Dissolve compound 17-1 (30 mg, 0.068 mmol) in N,N-dimethylformamide (1 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to 0°C, and 2-oxylidene piperidine-4-carboxylic acid (10mg, 0.068mmol), 2-(7-azobenzotriazole)-N,N,N ',N'-tetramethyluronium hexafluorophosphate (39mg, 0.78mmol) and N,N-diisopropylethylamine (44mg, 0.34mmol). The reaction system was stirred at 0°C for 30 minutes.
- Step A Compound 1-1 (150 mg, 0.57 mmol) was dissolved in N,N-dimethylformamide (3 mL) at room temperature. Subsequently, the above solution was cooled to 0°C, and N,N-diisopropylethylamine (205 mg, 1.59 mmol), 2-(7-azobenzotriazole)-N,N,N', N'-Tetramethylurea hexafluorophosphate (303mg, 0.80mmol) and 4-(4-piperidinyl)morpholine (97mg, 0.57mmol). The reaction system was then stirred at 0°C for 40 minutes.
- Step B Dissolve compound 19-2 (200 mg, 0.48 mmol) in N,N-dimethylformamide (2 mL) at room temperature under nitrogen protection. Subsequently, (R)-tert-butyl 3-aminopiperidine-1-carboxylate (116 mg, 0.58 mmol) and N,N-diisopropylethylamine (186 mg, 1.44 mmol) were sequentially added to the above reaction solution. The reaction system was then stirred at 100°C for 2 hours.
- Step C Dissolve compound 19-3 (270 mg, 0.45 mmol) in 4M hydrochloric acid-1,4-dioxane solution (1.2 mL) at room temperature under nitrogen protection. The reaction was then stirred at room temperature for 1 hour.
- Step D Compound 19-4 (60 mg, 0.12 mmol) was dissolved in N,N-dimethylformamide (1 mL) at room temperature. Subsequently, the above solution was cooled to 0°C, and 5-methylaminonicotinic acid (15 mg, 0.10 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetra Methylurea hexafluorophosphate (53mg, 0.14mmol) and N,N-diisopropylethylamine (65mg, 0.50mmol). The reaction system was then stirred for 30 minutes at 0°C.
- Step A Dissolve compound 20-1 (60 mg, 0.39 mmol) in N,N-dimethylformamide solution (1.0 mL) at room temperature under nitrogen protection. The above solution was cooled to -10°C, and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (187.4mg, 0.49 mmol), N,N-diisopropylethylamine (212mg, 1.64mmol) and tert-butyl (R)-(5-azaspiro[2.4]heptane-7-yl)carbamate (65.1 mg, 0.30mmol). Then the reaction system was stirred at -10°C for 10 minutes.
- Step B Dissolve compound 20-2 (100 mg, 0.28 mmol) in dry dichloromethane solution (1 mL) under nitrogen protection at room temperature. Subsequently, the above solution was cooled to 0° C., and 4M hydrochloric acid-1,4-dioxane solution (1 mL) was slowly added dropwise. The reaction was then stirred at room temperature for 1 hour.
- Step C Dissolve compound 20-3 (50 mg, 0.17 mmol) in N,N-dimethylformamide (0.73 mL) at room temperature under nitrogen protection. Subsequently, (5-bromo-2-fluoro-3-nitrophenyl)((2R,6S)-2,6-dimethylmorpholine)methanone (53mg, 014mmol) and N,N-Diisopropylethylamine (94.9 mg, 0.73 mmol). The reaction system was then stirred at 80°C for 2 hours.
- Step A Dissolve compound 20-3 (50 mg, 0.18 mmol) in N,N-dimethylformamide (0.9 mL) at room temperature under nitrogen protection. Subsequently, N,N-diisopropylethylamine (114 mg, 0.89 mmol) and (2R,6S)-4-(5-bromo-2-fluoro-3-nitrobenzoyl) were sequentially added to the above solution - tert-butyl 2,6-dimethylpiperazine-1-carboxylate (98 mg, 0.21 mmol). The reaction system was stirred at 80°C for 1 hour.
- Step B Dissolve compound 21-2 (100 mg, 0.15 mmol) in dichloromethane solution (1.4 mL) at room temperature under nitrogen protection. Subsequently, 4M hydrochloric acid-1,4-dioxane solution (0.74 mL) was added to the above solution. The reaction system was then stirred for another 30 minutes.
- Step A Compound 22-1 (30 mg, 0.061 mmol) was dissolved in N,N-dimethylformamide (1 mL) at room temperature. Subsequently, the above solution was cooled to 0°C, and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (33mg, 0.085mmol) was sequentially added , N,N-Diisopropylethylamine (26 mg, 0.183 mmol) and 5-(methylamino)nicotinic acid (11 mg, 0.073 mmol). The reaction was stirred at 0°C for 2 hours.
- Step A Dissolve compound 23-1 (500 mg, 2.69 mmol) in dichloromethane (13 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to 0°C, and trifluoroacetic anhydride (846 mg, 4.03 mmol) and triethylamine (815 mg, 8.07 mmol) were added in sequence. The reaction system was then stirred at 0°C for 50 minutes.
- Step B Dissolve compound 23-2 (600 mg, 2.12 mmol) in 4M hydrochloric acid-1,4-dioxane solution (5.0 mL) at room temperature under nitrogen protection. The reaction was then stirred at room temperature for 1 hour.
- Step C The compound 5-bromo-2-fluoro-3-nitrobenzoic acid (200 mg, 0.75 mmol) was dissolved in N,N-dimethylformamide (4 mL) at room temperature. Subsequently, the above solution was cooled to 0°C, and N,N-diisopropylethylamine (484 mg, 3.75 mmol), 2-(7-azobenzotriazole)-N,N,N', N'-Tetramethyluronium hexafluorophosphate (399 mg, 1.05 mmol) and compound 23-3 (166 mg, 0.90 mmol). The reaction system was then stirred at 0°C for 40 minutes.
- Step D Compound 22-4 (160 mg, 0.37 mmol) was dissolved in N,N-dimethylformamide (2 mL) at room temperature under nitrogen protection. Subsequently, (R)-tert-butyl 3-aminopiperidine-1-carboxylate (90 mg, 0.45 mmol) and N,N-diisopropylethylamine (143 mg, 1.11 mmol) were sequentially added to the above reaction solution. The reaction system was then stirred at 100°C for 2 hours.
- Step E Dissolve compound 23-5 (200 mg, 0.33 mmol) in 4M hydrochloric acid-1,4-dioxane solution (0.80 mL) at room temperature under nitrogen protection. The reaction was then stirred at room temperature for 1 hour.
- Step F Compound 23-6 (80 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (1 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to 0°C, and 5-methylaminonicotinic acid (20 mg, 0.13 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetra Methylurea hexafluorophosphate (69 mg, 0.18 mmol) and N,N-diisopropylethylamine (84 mg, 0.65 mmol). The reaction system was then stirred at 0°C for 30 minutes.
- Step A Dissolve the compound 2-oxo-1,2-dihydropyridine-4-carboxylic acid (13mg, 0.09mmol) in N,N-dimethylformamide (0.45mL )middle. Subsequently, the above solution was cooled to 0°C, and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (48mg, 0.11mmol) was sequentially added , N,N-diisopropylethylamine (35mg, 0.27mmol) and compound 6-4 (50mg, 0.11mmol). The reaction system was then stirred at 0°C for 10 minutes.
- Step A Compound 1-1 (100 mg, 0.39 mmol) and 2-piperazinone (38 mg, 0.39 mmol) were dissolved in N,N-dimethylformamide (1 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to 0°C, and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (216mg, 0.57mmol) was added in sequence and N,N-Diisopropylethylamine (245mg, 1.89mmol). The reaction system was then stirred for 30 minutes at 0°C.
- Step B Dissolve compound 25-2 (30 mg, 0.087 mmol) in N,N-dimethylformamide (1 mL) at room temperature under nitrogen protection. Subsequently, tert-butyl ((1S,2R)-2-aminocyclohexyl) carbamate (19 mg, 0.087 mmol) and N,N-diisopropylethylamine (56 mg, 0.433 mmol). Then the reaction system was raised to 80°C and stirred for 4 hours.
- Step C Compound 25-3 (160 mg, 0.27 mmol) was dissolved in dichloromethane (10 mL) at room temperature. Subsequently, the above solution was cooled to 0° C., and added dropwise to 4M hydrochloric acid-1,4-dioxane solution (3 mL). The reaction was then stirred at room temperature for 30 minutes.
- Step D At room temperature, under nitrogen protection, compound 25-4 (23mg, 0.048mmol) and 7-chloroisoquinoline-4-carboxylic acid (10mg, 0.048mmol) were dissolved in N,N-dimethylformaldehyde amide (1 mL). Subsequently, the above solution was cooled to 0°C, and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (27.47mg, 0.072mmol ) and N,N-diisopropylethylamine (32 mg, 0.241 mmol). The reaction system was then stirred at 0°C for 30 minutes.
- Step A Dissolve compound 26-1 (15 mg, 0.10 mmol) in N,N-dimethylformamide (0.50 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to 0°C, and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (53mg, 0.14mmol) was added in sequence , N,N-diisopropylethylamine (39mg, 0.30mmol) and compound (R)-(5-bromo-3-nitro-2-(piperidin-3-ylamino)phenyl)(morpholine base) Methanone (50mg, 0.12mmol). The reaction system was then stirred at 0°C for 10 minutes.
- Step A Dissolve compound 26-1 (20 mg, 0.13 mmol) in N,N-dimethylformamide (0.65 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to 0°C, and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (49mg, 0.18mmol) was added in sequence , N,N-diisopropylethylamine (50mg, 0.39mmol) and (5-bromo-3-nitro-2-((R)-piperidin-3-yl)amino)phenyl ((2R, 6S)-2,6-Dimethylmorpholino)methanone (48 mg, 0.11 mmol). The reaction system was then stirred for 10 minutes at 0°C.
- Step A Dissolve compound 6-4 (34 mg, 0.077 mmol) in N,N-dimethylformamide (1 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to 0°C, and 2-oxylidene piperidine-4-carboxylic acid (12mg, 0.077mmol), 2-(7-azobenzotriazole)-N,N,N ',N'-tetramethyluronium hexafluorophosphate (44 mg, 0.12 mmol) and N,N-diisopropylethylamine (50 mg, 0.39 mmol). The reaction system was stirred at 0°C for 30 minutes.
- Step A Dissolve compound 1-1 (300mg, 1.14mmol) and 1-methylpiperazine (125mg, 1.25mmol) in N,N-dimethylformamide (1mL) under nitrogen protection at room temperature . Subsequently, the above solution was cooled to 0°C, and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (648mg, 1.71mmol) was added in sequence and N,N-Diisopropylethylamine (587mg, 4.55mmol). The reaction system was then stirred for 30 minutes at 0°C.
- Step B Dissolve compound 29-2 (200 mg, 0.58 mmol) in N,N-dimethylformamide (1 mL) at room temperature under nitrogen protection. Subsequently, (R)-tert-butyl 3-aminopiperidine-1-carboxylate (115.7mg, 0.58mmol) and N,N-diisopropylethylamine (224mg, 1.73mmol) were successively added to the above reaction solution . Then the reaction system was raised to 80°C and stirred for 4 hours.
- Step C Compound 29-3 (355 mg, 0.67 mmol) was dissolved in dichloromethane (10 mL) at room temperature. Subsequently, the above solution was cooled to 0° C., and 4M hydrochloric acid-1,4-dioxane solution (5 mL) was slowly added dropwise. The reaction was then stirred at room temperature for 30 minutes.
- Step D At room temperature, under nitrogen protection, compound 29-4 (60mg, 0.13mmol) and 5-(methylamino)nicotinic acid (19.7mg, 0.13mmol) were dissolved in N,N-dimethylformamide ( 1mL). Subsequently, the above solution was cooled to 0°C, and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (74mg, 0.194mmol) was added in sequence and N,N-Diisopropylethylamine (83.8mg, 0.65mmol). The reaction system was then stirred at 0°C for 30 minutes.
- Step A Compound 23-4 (80 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (1 mL) at room temperature. Subsequently, the above solution was cooled to 0°C, and 6-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (20 mg, 0.13 mmol), 2-(7-azobenzo Triazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (69 mg, 0.18 mmol) and N,N-diisopropylethylamine (84 mg, 0.65 mmol). The reaction system was then stirred at 0°C for 30 minutes.
- Step A Compound 31-1 (80 mg, 0.48 mmol) was dissolved in THF (2 mL)/water (0.5 mL) at room temperature. Subsequently, lithium hydroxide monohydrate (40 mg, 0.96 mmol) was added to the above reaction solution. The reaction was stirred at room temperature for 1 hour.
- Step B Dissolve compound 31-2 (50 mg, 0.33 mmol) in N,N-dimethylformamide (1 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to 0°C, and (R)–(5-bromo-3-nitro-2-(piperidin-3-ylamino)phenyl)(piperidin-1-yl)methanone was added sequentially (162mg, 0.26mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (108mg, 0.46mmol) and N,N- Diisopropylethylamine (213 mg, 1.65 mmol). The reaction was stirred at 0°C for 30 minutes.
- Step A Dissolve compound 1-1 (3 g, 11.4 mmol) in N,N-dimethylformamide (57 mL) at room temperature under nitrogen protection. Then, under ice-salt bath conditions, N,N-diisopropylethylamine (4.42g, 34.2mmol), 2-(7-azobenzotriazole)-N,N , N',N'-Tetramethylurea hexafluorophosphate (6.08 g, 16 mmol) and piperidine (1.17 g, 13.7 mmol). Then the reaction system continued to stir for 1 hour under the condition of ice-salt bath.
- Step B Dissolve compound 2-2 (350 mg, 1.06 mmol) in N,N-dimethylformamide (5.3 mL) at room temperature under nitrogen protection. Subsequently, tert-butyl 4-amino-3,3-difluoropyrrolidine-1-carboxylate (282.5mg, 1.27mmol) and N,N-diisopropylethylamine (410.2mg, 3.18mmol) were added to the above solution mmol). The reaction system was then stirred at 100°C for 16 hours.
- Step C Compound 32-3 (320 mg, 0.60 mmol) was dissolved in dry dichloromethane solution (3 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to 0°C, and 4M hydrochloric acid-1,4-dioxane solution (1.5 mL) was slowly added dropwise. The reaction was then stirred at room temperature for 1 hour.
- Step D Dissolve the compound 5-(methylamino)nicotinic acid (5.4 mg, 0.03 mmol) in N,N-dimethylformamide solution (0.2 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to -10°C, and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (20 mg, 0.05mmol), N,N-diisopropylethylamine (22.9mg, 0.17mmol) and compound 32-4 (20mg, 0.04mmol). Then the reaction system was stirred at -10°C for 1 hour.
- Step A Compound 1-1 (37 mg, 0.11 mmol) was dissolved in N,N-dimethylformamide (0.54 mL) at room temperature. Subsequently, (R)-1-tert-butoxycarbonyl-3-aminopiperidine (26 mg, 0.13 mmol) and N,N-diisopropylethylamine (0.05 mL, 0.32 mmol) were added. The reaction was then stirred at 80°C for 1 hour.
- Step B Compound 33-2 (50 mg, 0.10 mmol) was dissolved in dichloromethane (0.5 mL) at room temperature. Subsequently, the temperature was lowered to 0° C., and 4M hydrochloric acid-1,4-dioxane solution (0.7 mL, 2.86 mmol) was slowly added dropwise to the reaction solution. The reaction was then warmed to room temperature and stirring was continued for 1 hour.
- Step C Dissolve (2S,4R)-2-methyl-6-oxopiperidine-4-carboxylic acid (19mg, 0.12mmol) in N,N-dimethylformamide at room temperature under nitrogen protection (0.44 mL). Subsequently, N,N-diisopropylethylamine (0.06mL, 0.35mmol), 2-(7-azobenzotriazole)-N,N,N',N' - Tetramethyluronium hexafluorophosphate (37 mg, 0.10 mmol) and compound 33-3 (45 mg, 0.11 mmol). The reaction was then stirred at room temperature for 20 minutes.
- Step A Dissolve compound 1-1 (1 g, 3.80 mmol) in N,N-dimethylformamide (19 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to 0°C, and N,N-diisopropylethylamine (1.4g, 11.4mmol) and 2-(7-azobenzotriazole)-N , N,N',N'-Tetramethylurea hexafluorophosphate (2g, 5.32mmol) and (2R,6S)-2,6-dimethylmorpholine (526mg, 4.56mmol). The reaction was stirred for 5 minutes at 0°C.
- Step B Dissolve compound 17-2 (600 mg, 1.67 mmol) in N,N-dimethylformamide (8.4 mL) at room temperature under nitrogen protection. Subsequently, (R)-tert-butyl 3-aminopiperidine-1-carboxylate (400 mg, 2.00 mmol) and N,N-diisopropylethylamine (649 mg, 5.01 mmol) were sequentially added to the above reaction solution. The reaction system was then stirred at 80°C for 2 hours.
- Step C Dissolve compound 17-3 (810 mg, 1.50 mmol) in 4M hydrochloric acid-1,4-dioxane solution (2.8 mL) at room temperature under nitrogen protection. The reaction was then stirred at room temperature for 1 hour.
- Step D The compound 5-(methylamino)nicotinic acid (23 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (1 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to 0°C, and (5-bromo-3-nitro-2-((R)-piperidin-3-yl)amino)phenyl ((2R,6S)-2,6 -Dimethylmorpholino)methanone (80mg, 0.18mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate ( 108mg, 0.46mmol) and N,N-diisopropylethylamine (79mg, 0.21mmol). The reaction was stirred at 0°C for 30 minutes.
- Step A Dissolve compound 31-2 (500 mg, 3.29 mmol) in N,N-dimethylformamide (16 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to 0°C, and N,N-diisopropylethylamine (1.3g, 9.87mmol) and 2-(7-azobenzotriazole)-N , N,N',N'-Tetramethyluronium hexafluorophosphate (1.4 g, 3.62 mmol) and tert-butyl (R)-piperidin-3-ylcarbamate (725 mg, 3.62 mmol). The reaction was then stirred for 10 minutes at 0°C.
- Step B Dissolve compound 35-1 (788 mg, 2.27 mmol) in 4M hydrochloric acid-1,4-dioxane solution (11 mL) at room temperature under nitrogen protection. The reaction was then stirred at room temperature for 1 hour.
- Step C Dissolve compound 35-2 (682 mg, 2.78 mmol) in N,N-dimethylformamide (11.6 mL) at room temperature under nitrogen protection. Subsequently, 5-bromo-2-fluoro-3-nitrobenzoic acid (610 mg, 2.32 mmol) and N,N-diisopropylethylamine (1.2 mL, 6.96 mmol) were sequentially added to the above reaction solution. The reaction was then stirred at 80°C for 1 hour.
- Step D Compound 35-3 (200 mg, 0.41 mmol) was dissolved in N,N-dimethylformamide solution (2.0 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to -10°C, and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (191.2mg , 0.50mmol), N,N-diisopropylethylamine (162.2mg, 1.25mmol) and (R)-2-methylmorpholine (70mg, 0.50mmol). Then the reaction system was stirred at -10°C for 30 minutes.
- Step A Compound 36-1 (15 mg, 0.084 mmol) and (R)-5-bromo-2-((1-(5-(methylamino)nicotinyl)piperidine-3- (yl)amino)-3-nitrobenzoic acid (40 mg, 0.084 mmol, compound 35-3) was dissolved in N,N-dimethylformamide (1.0 mL).
- Step A Compound 37-1 (300 mg, 1.96 mmol) was dissolved in acetonitrile (1 mL) and water (1 mL) at room temperature. Subsequently, benzyl chloroformate (503 mg, 2.94 mmol) and sodium bicarbonate (412 mg, 4.90 mmol) were sequentially added to the above reaction solution. The reaction was then stirred for an additional 2 hours at room temperature.
- Step B Dissolve compound 37-2 (300 mg, 1.20 mmol) in dichloromethane (6 mL) in an ice bath under nitrogen protection. Subsequently, diethylaminosulfur trifluoride (503 mg, 2.94 mmol) was slowly added dropwise to the above reaction solution. The reaction system was then warmed to room temperature and stirring was continued for 16 hours.
- Step C Compound 37-3 (70 mg, 0.28 mmol) was dissolved in methanol (5 mL) at room temperature. Subsequently, 10% palladium/carbon (10 mg) and concentrated hydrochloric acid (5 mg) were successively added to the above reaction solution. The reaction was then hydrogenated at room temperature for 1 hour.
- Step D Compound 37-4 (20 mg, 0.14 mmol) was dissolved in N,N-dimethylformamide (1 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to 0°C, and (R)-5-bromo-2-((1-(5-(methylamino)nicotinyl)piperidin-3-yl)amino)-3-nitro Benzoic acid (40mg, 0.08mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (43mg, 0.11mmol) and N , N-Diisopropylethylamine (52 mg, 0.14 mmol). The reaction was then stirred for 30 minutes at 0°C.
- Step A Compound 37-1 (500 mg, 3.27 mmol) was added into acetonitrile (5.0 mL) and water (5.0 mL) at room temperature. Subsequently, benzyl chloroformate (833 mg, 4.90 mmol) and sodium bicarbonate (1.13 g, 8.2 mmol) were sequentially added to the reaction solution. The reaction was then stirred for an additional 15 hours.
- Step B Under nitrogen protection, oxalyl chloride (760 mg, 5.98 mmol) was added to anhydrous dichloromethane (5.0 mL). Subsequently, the above solution was cooled to -78°C, anhydrous dimethyl sulfoxide (700 mg, 8.96 mmol) was added dropwise, and stirring was continued for 30 minutes. Then a solution of compound 37-2 (600 mg, 2.39 mmol) in dichloromethane (5.0 mL) was slowly added dropwise, and stirring was continued for 1 hour. Finally, at this temperature, triethylamine (1.93 g, 19.1 mmol) was added dropwise, the reaction system was raised to room temperature, and stirring was continued for 1 hour.
- Step C Dissolve compound 55-3 (220 mg, 0.88 mmol) in anhydrous dichloromethane (5.0 mL) under nitrogen protection, then cool the above solution to -78°C and add diethylamino tris Sulfur fluoride (500 mg, 3.09 mmol). The reaction was then warmed to room temperature and stirring was continued for 15 hours.
- Step D Compound 55-4 (50 mg, 0.18 mmol) and 10% palladium/carbon (10 mg) were dissolved in methanol (3 mL) at room temperature, and then the reaction system was hydrogenated at room temperature for 16 hours.
- Step E At room temperature, compound (R)-5-bromo-2-((1-(5-(methylamino)nicotinyl)piperidin-3-yl)amino)-3-nitrobenzene
- Formic acid (30 mg, 0.06 mmol) was dissolved in N,N-dimethylformamide (1.0 mL).
- 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate 28mg, 0.07mmol
- N,N - Diisopropylethylamine (16 mg, 0.12 mmol
- compound 1-5 (10 mg, 0.07 mmol
- Step A At room temperature, under nitrogen protection, compound 1-1 (886mg, 3.37mmol), (3S,4S)-3-amino-4-methoxypyrrolidine-1-carboxylic acid tert-butyl ester (800mg , 3.70mmol) and N,N-diisopropylethylamine (1.3g, 10.11mmol) were dissolved in N,N-dimethylformamide solution (17mL). The reaction was then stirred at 80°C for 1 hour.
- Step B Under nitrogen protection, compound 321-2 (1.7 g, 3.06 mmol) was dissolved in dichloromethane solution (15 mL) at room temperature. Subsequently, the above solution was cooled to 0° C., and 4M hydrochloric acid-1,4-dioxane solution (7.6 mL) was slowly added dropwise. The reaction was then stirred at room temperature for 1 hour.
- Step C Dissolve 5-(methylamino)nicotinic acid (630 mg, 4.15 mmol) in N,N-dimethylformamide solution (17 mL) at room temperature under nitrogen protection. Subsequently, the above solution was cooled to 0°C, and N,N-diisopropylethylamine (2.23g, 17.3mmol), 2-(7-azobenzotriazole)-N,N,N' , N'-tetramethyluronium hexafluorophosphate (1.97 g, 5.19 mmol) and compound 321-3 (1.7 g, 3.46 mmol). Then the reaction system was stirred at 0°C for 30 minutes.
- Step A Compound 325-1 (16mg, 0.06mmol) and ((5-bromo-3-nitro-2-((R)-piperidin-3-yl)amino)phenyl ((2R,6S)-2,6-Dimethylmorpholino)methanone (32mg, 0.72mmol) was dissolved in N,N-dimethylformamide (0.6mL). Subsequently, the above solution was successively Add 2-(7-benzotriazole oxide)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (14.9 mg, 0.04 mmol) and N,N-diisopropylethylamine (11.7 mg, 0.09 mmol). Then the reaction system was stirred at room temperature for 1 hour.
- Step B Compound 325-2 (36 mg, 0.052 mmol) was dissolved in dichloromethane (0.6 mL) at room temperature. Subsequently, 4M hydrochloric acid-1,4-dioxane solution (0.6 mL) was added to the above solution. The reaction was then stirred for an additional 2 hours.
- Step A Compound 1-1 (120 mg, 0.454 mmol) was dissolved in N,N-dimethylformamide (1 mL) at room temperature. Subsequently, the above solution was cooled to 0°C, and 2,2-difluoromorpholine (80.58 mg, 0.505 mmol), 2-(7-azobenzotriazole)-N,N,N',N '-Tetramethylurea hexafluorophosphate (288mg, 0.757mmol) and N,N-diisopropylethylamine (326.37mg, 2.53mmol). The reaction was then stirred at 0°C for 30 minutes.
- Step B Dissolve compound 327-2 (120 mg, 0.325 mmol) in N,N-dimethylformamide (1 mL) at room temperature under nitrogen protection. Subsequently, (R)-tert-butyl 3-aminopiperidine-1-carboxylate (78.14mg, 0.390mmol) and N,N-diisopropylethylamine (98mg, 0.975mmol) were successively added to the above reaction solution . Then the reaction system was raised to 80°C and stirred for 4 hours.
- Step C Compound 327-3 (180 mg, 0.327 mmol) was dissolved in dichloromethane (4 mL) at room temperature under nitrogen protection. Subsequently, 4M hydrochloric acid-1,4-dioxane solution (2 mL) was slowly added dropwise. The reaction was then stirred at room temperature for 4 hours.
- Step D Compound 327-4 (10.99 mg, 0.023 mmol) was dissolved in N,N-dimethylformamide (1 mL) at room temperature. Subsequently, the above solution was cooled to 0°C, and 1-(tert-butoxycarbonyl)-5,5-difluoropiperidine-3-carboxylic acid (5 mg, 0.019 mmol), 2-(7-azobenzo Triazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (10.7 mg, 0.028 mmol) and N,N-diisopropylethylamine (12.18 mg, 0.094 mmol). The reaction was then stirred at 0°C for 30 minutes.
- Step E Compound 327-5 (10 mg, 0.014 mmol) was dissolved in 1,4-dioxane (2 mL) at room temperature under nitrogen protection. Subsequently, 4M hydrochloric acid-1,4-dioxane solution (1 mL) was slowly added dropwise. The reaction was then stirred at room temperature for 1 hour.
- Step A Compound 331-1 (50 mg, 0.19 mmol) was dissolved in N,N-dimethylformamide (0.95 mL) at room temperature. Subsequently, the above solution was cooled to 0°C, and N,N-diisopropylethylamine (70 mg, 0.57 mmol), 2-(7-azobenzotriazole)-N,N,N', N'-Tetramethyluronium hexafluorophosphate (101 mg, 0.27 mmol) and 3,3-difluoropyridine (36 mg, 0.23 mmol). The reaction was then stirred at 0°C for 10 minutes.
- Step B Compound 331-2 (51 mg, 0.14 mmol) was dissolved in N,N-dimethylformamide (0.7 mL) at room temperature. Subsequently, (R)-tert-butyl 3-aminopiperidine-1-carboxylate (33 mg, 0.17 mmol) and N,N-diisopropylethylamine (55 mg, 0.42 mmol) were sequentially added to the above solution. The reaction system was then stirred at 80°C for 2 hours.
- Step C Compound 331-3 (70 mg, 0.13 mmol) was dissolved in dichloromethane (0.33 mL) at room temperature. Subsequently, 4M hydrochloric acid-1,4-dioxane solution (0.33 mL) was slowly added dropwise to the reaction system. The reaction was then stirred for an additional 1 hour.
- Step D Compound 1-(tert-butoxycarbonyl)-5,5-difluoropiperidine-3-carboxylic acid (5.4mg, 0.02mmol) was dissolved in N,N-dimethylformamide at room temperature (0.10 mL). Subsequently, the above solution was cooled to 0°C, and N,N-diisopropylethylamine (7.7 mg, 0.06 mmol), 2-(7-azobenzotriazole)-N,N,N' , N'-tetramethyluronium hexafluorophosphate (10 mg, 0.03 mmol) and compound 1-4 (11 mg, 0.03 mmol). The reaction was then stirred for an additional 10 minutes.
- Step E Compound 331-5 (11.8 mg, 0.02 mmol) was dissolved in dichloromethane (0.1 mL) at room temperature. Subsequently, 4M hydrochloric acid-1,4-dioxane solution (0.1 mL) was slowly added dropwise to the reaction system. The reaction was then stirred for an additional 12 hours.
- Step A At room temperature, compound (R)-5-bromo-2-((1-(5-(methylamino)nicotinyl)piperidin-3-yl)amino)-3-nitrobenzene
- Formic acid 40 mg, 0.08 mmol
- 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate 38mg, 0.1mmol
- N , N-diisopropylethylamine 55 mg, 0.42 mmol
- compound 336-1 (12 mg, 0.1 mmol). Then the reaction system was stirred for 1 hour under ice-water bath condition.
- Step A Triethylamine trihydrofluoride (486 mg, 3.02 mmol) was added to N,N-dimethylacetamide (5.0 mL) at room temperature. Subsequently, to the above solution, triethylamine (153 mg, 1.51 mmol), (diethylamino) sulfur difluoride tetrafluoroborate (1.03 g, 4.52 mmol) and N-tert-butoxycarbonyl-4- Piperidone (300 mg, 1.51 mmol). The reaction was then stirred for an additional 2 hours.
- reaction solution was quenched by adding saturated aqueous sodium bicarbonate solution (20mL), the mixture was extracted with ethyl acetate (10mL ⁇ 3 times), the organic phases were combined, and the organic phase was washed with saturated brine (10mL ⁇ 3 times). 2 times) wash. It was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain compound 337-2 (180 mg).
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Abstract
Description
实施例 | IC 50(nM) | 实施例 | IC 50(nM) | 实施例 | IC 50(nM) |
1 | B | 2 | A | 3 | A |
4 | C | 5 | A | 6 | A |
7 | B | 8 | A | 9 | A |
10 | B | 11 | C | 12 | B |
13 | A | 14 | B | 15 | B |
16 | B | 17 | B | 18 | D |
19 | B | 20 | B | 21 | B |
22 | B | 23 | B | 24 | D |
25 | B | 26 | B | 27 | B |
28 | B | 29 | B | 30 | B |
31 | B | 32 | B | 33 | B |
34 | B | 35 | B | 36 | B |
37 | B | 38 | A | 39 | A |
40 | B | 41 | B | 42 | B |
43 | B | 44 | A | 45 | B |
46 | B | 47 | B | 48 | B |
49 | B | 50 | C | 51 | B |
52 | B | 53 | C | 54 | B |
55 | B | 56 | B | 57 | B |
59 | B | 60 | C | 61 | C |
62 | B | 63 | B | 64 | B |
65 | B | 66 | B | 67 | B |
68 | C | 69 | C | 70 | B |
71 | B | 72 | A | 73 | B |
74 | C | 75 | A | 76 | A |
77 | B | 78 | B | 79 | C |
80 | B | 81 | B | 82 | B |
83 | B | 84 | B | 85 | B |
86 | B | 87 | B | 88 | B |
89 | B | 90 | B | 91 | B |
92 | B | 93 | B | 94 | B |
95 | B | 96 | C | 97 | B |
98 | B | 99 | D | 100 | B |
101 | C | 102 | B | 103 | B |
104 | B | 105 | C | 106 | B |
107 | B | 108 | B | 109 | B |
110 | B | 111 | A | 112 | B |
113 | A | 114 | B | 115 | B |
116 | A | 117 | B | 118 | B |
119 | B | 120 | A | 121 | A |
122 | B | 123 | A | 124 | B |
125 | A | 126 | B | 127 | B |
128 | B | 129 | B | 130 | B |
131 | B | 132 | B | 133 | B |
134 | B | 135 | B | 136 | A |
137 | B | 138 | B | 139 | B |
140 | B | 141 | B | 142 | B |
143 | B | 144 | B | 145 | B |
146 | B | 147 | B | 148 | C |
149 | B | 150 | C | 151 | B |
152 | B | 153 | B | 154 | C |
155 | C | 156 | B | 157 | C |
158 | B | 159 | A | 160 | B |
161 | B | 162 | B | 163 | B |
164 | B | 165 | B | 166 | B |
167 | B | 168 | B | 169 | B |
170 | B | 171 | B | 172 | B |
173 | B | 174 | B | 175 | B |
176 | B | 177 | B | 178 | C |
179 | C | 180 | C | 181 | B |
182 | B | 183 | B | 184 | A |
185 | B | 186 | B | 187 | B |
188 | B | 189 | B | 190 | B |
191 | B | 192 | B | 193 | B |
194 | B | 195 | B | 196 | B |
197 | B | 198 | B | 199 | C |
200 | B | 201 | B | 202 | B |
203 | B | 204 | B | 205 | A |
206 | C | 207 | B | 208 | B |
209 | B | 210 | B | 211 | B |
212 | B | 213 | B | 214 | B |
215 | B | 216 | B | 217 | C |
218 | B | 219 | B | 220 | C |
221 | B | 222 | B | 223 | B |
224 | B | 225 | A | 226 | B |
227 | B | 228 | B | 229 | B |
230 | A | 231 | B | 232 | B |
233 | C | 234 | B | 235 | B |
236 | B | 237 | B | 238 | B |
239 | B | 240 | B | 241 | B |
242 | B | 243 | B | 244 | B |
245 | C | 246 | B | 247 | B |
248 | B | 249 | B | 250 | B |
251 | C | 252 | B | 253 | C |
254 | B | 255 | B | 256 | B |
257 | B | 258 | B | 259 | B |
260 | B | 261 | B | 262 | B |
263 | B | 264 | B | 265 | B |
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403 | C | 404 | D | 405 | B |
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451 | B | 452 | C | 453-P1 | C |
454 | B | 455 | B | 456 | B |
457 | D | 458 | B | 459 | B |
460 | B | 461 | B | 462 | B |
Claims (23)
- 式(I)所示的化合物、其异构体或药学上可接受的盐,其中,环A选自C 6-10芳基、5-10元杂芳基、C 3-12环烷基或3-12元杂环基;X选自-(CH 2) s-C(=O)-或-NH-C(=O)-;Y选自NH或化学键;环B选自C 3-12环烷基、3-12元杂环基或5-10元杂芳基;Z选自-O-、-S-、-CH 2-、-C(=O)-NH-或-(CH 2) tNH-;环C选自C 6-10芳基或5-10元杂芳基;环D选自3-12元杂环基或5-6元杂芳基;或者环D不存在;R 1选自卤素、OH、O、氰基、-NR 1aR 1b、C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 6-10芳基、-NR 1aCOR 1c、-SR 1d或-CONR 1aR 1b,所述的C 1-4烷基和C 1-4烷氧基可进一步被一个或多个卤素取代;R 1a、R 1b、R 1c和R 1d各自独立地选自H、C 1-4烷基或卤代C 1-4烷基,所述C 1-4烷基可以被一个或多个氘取代;或者,位于环A同一个C原子上的两个R 1可以一起形成=CH 2、=S或者C 3-5环烷基;R 2选自氘、氰基、C 2-4炔基、卤素、C 1-4烷基、羟基、C 1-4烷氧基、氘代C 1-4烷氧基、-C(=O)-NR 2aR 2b、-C 2-4炔基-R 2c、5-6元的杂芳基或-O-(CH 2) y-R 2d;R 2c选自5-6元的杂芳基,所述的5-6元的杂芳基可进一步被C 1-4烷基所取代;R 2a和R 2b各自独立地选自H、C 1-4烷基、苯基、5-9元的杂芳基、5-6元的杂环基或C 3-5环烷基,所述的C 1-4烷基、苯基、5-9元的杂芳基、5-6元的杂环基、C 3-5环烷基可进一步被一个或多个选自甲基、乙基、环丙基、卤素、CF 3、-CH 2CF 3、苯基、甲氧基、吡啶基、嘧啶基、四氢吡喃基或-CH 2CH 2OCH 3的取代基所取代,所述的吡啶基、嘧啶基或四氢吡喃基可进一步被一个或多个甲基、CF 3、卤素、-NHCH 3或-CHF 2所取代;或者,R 2a、R 2b与其相连的N原子一起形成4-9元的杂环基或5-9元的杂芳基,所述的4-9元的杂环基或5-9元的杂芳基可进一步被一个或多个选自C 1-4烷基、卤素、羟基或-CH 2CH 2OCH 3的取代基所取代。R 2d选自C 1-4烷基、C 1-4烷氧基、苯基、5-6元杂芳基或5-6元的杂环基,所述的苯基、5-6元杂芳基或5-6元的杂环基可进一步被一个或多个选自卤素、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基的取代基所取代;y选自0、1或2。R 3选自硝基、卤素、羟基、氰基、C 1-4烷基、卤代C 1-4烷基、-NR 3aR 3b或-N(R 3aR 3bR 3c) +;R 3a、R 3b或R 3c各自独立地选自H或C 1-4烷基;R 4选自卤素、羟基、C 1-4烷基、卤代C 1-4烷基、3-8元杂环基、-C(=O)R 4a、-NHC(=O)R 4a、-(CH 2) rOR 4b、-NR 4cR 4d、C 1-4烷氧基、-(CH 2) x-C 3-6环烷基、-NR 4a-(CH 2) x-C 6-10芳基,所述的芳基可进一步被卤素取代;R 4a、R 4b、R 4c或R 4d各自独立地选自H、C 1-4烷基、卤代C 1-4烷基、5-6元杂环基或C 3-6环烷基;或者R 4c、R 4d与其相连的N原子一起形成六元杂环;x为0、1或2;r选自0、1、2或3;m、n、p和q各自独立选自0、1、2、3、4或5;s和t各自独立选自0或1。
- 根据权利要求1所述的化合物、其异构体或药学上可接受的盐,其中,环D为3-12元杂环基;或者环D不存在;R 1选自卤素、OH、O、氰基、-NR 1aR 1b、C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 6-10芳基、-NR 1aCOR 1c、-SR 1d或-CONR 1aR 1b,所述的C 1-4烷基和C 1-4烷氧基可进一步被一个或多个卤素取代;R 1a、R 1b、R 1c和R 1d各自独立地选自H、C 1-4烷基或卤代C 1-4烷基;或者,位于环A同一个C原子上的两个R 1可以一起形成=CH 2、=S或者C 3-5环烷基;R 2选自卤素、C 1-4烷基、羟基或C 1-4烷氧基;环A、环B、环C、X、Y、Z、R 3、R 4、m、n、p和q各自定义同式(I)化合物。
- 根据权利要求1所述的化合物、其异构体或药学上可接受的盐,其中:环D为3-8元杂环基;或者环D不存在;R 1选自卤素、OH、O、氰基、-NR 1aR 1b、C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 6-10芳基,所述的C 1-4烷基和C 1-4烷氧基可进一步被一个或多个卤素取代;R 1a和R 1b各自独立地选自H或C 1-4烷基;R 2选自卤素或C 1-4烷基;R 4选自卤素、羟基、C 1-4烷基、卤代C 1-4烷基、3-8元杂环基、-C(=O)R 4a、-NHC(=O)R 4a、-(CH 2) rOR 4b或-NR 4cR 4d;R 4a、R 4b、R 4c或R 4d各自独立地选自H、C 1-4烷基或卤代C 1-4烷基;r选自0、1、2或3;m、n、p和q各自独立选自0、1、2或3;环A、环B、环C、X、Y、Z、R 3各自定义同式(I)化合物。
- 根据权利要求1或2所述的化合物其异构体或药学上可接受的盐,其中,环A为C 6-10芳基、5-10元杂芳基或7-10元杂环基;环D为3-8元杂环基;R 1选自卤素、OH、O、氰基、-NR 1aR 1b、C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 6-10芳基,所述的C 1-4烷基和C 1-4烷氧基可进一步被一个或多个卤素取代;R 1a和R 1b各自独立地选自H或C 1-4烷基;R 2选自卤素或C 1-4烷基;R 4选自卤素、羟基或C 1-4烷基;m、n、p和q各自独立选自0、1或2;环B、环C、X、Y、Z、R 3各自定义同式(I)化合物。
- 根据权利要求1-7中任一项所述的化合物、其异构体或药学上可接受的盐,其中X选自-CH 2-C(=O)-、-C(=O)-或-NH-C(=O)-。
- 根据权利要求1-11中任一项所述的化合物、其异构体或药学上可接受的盐,其中Z选自-NH-、-O-、-S-、-CH 2-、-CH 2NH-或-C(=O)-NH-。
- 根据权利要求1-12中任一项所述的化合物、其异构体或药学上可接受的盐,其中环C选自苯基或吡啶基。
- 根据权利要求1-13中任一项所述的化合物、其异构体或药学上可接受的盐,其中R 3选自硝基、Br、Cl、I、CN、CF 3、或-N(CH 3) 3 +。
- 一种药物组合物,其包含权利要求1-20任一项所述的化合物、其异构体或药学上可接受的盐,以及药学上可接受的载体、稀释剂或赋形剂。
- 权利要求1-20任一项所述的化合物、其异构体或药学上可接受的盐,以及药学上可接受的载体、稀释剂或赋形剂或权利要求22所述的药物组合物在制备用于治疗由冠状病毒引起的疾病的药物中的应用;优选地,所述疾病为呼吸道传染病;优选地,所述呼吸道传染病为严重急性呼吸综合征;优选地,所述冠状病毒为SARS-CoV-2。
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CN113072497A (zh) | 2021-01-12 | 2021-07-06 | 西湖大学 | 蛋白酶抑制剂、其制备和用途 |
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WO2000034238A1 (en) * | 1998-12-09 | 2000-06-15 | American Home Products Corporation | Thiourea inhibitors of herpes viruses |
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