WO2022135591A1 - Aryl or heteroaryl pyridone or pyrimidone derivative and preparation method therefor and application thereof - Google Patents
Aryl or heteroaryl pyridone or pyrimidone derivative and preparation method therefor and application thereof Download PDFInfo
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- WO2022135591A1 WO2022135591A1 PCT/CN2021/141360 CN2021141360W WO2022135591A1 WO 2022135591 A1 WO2022135591 A1 WO 2022135591A1 CN 2021141360 W CN2021141360 W CN 2021141360W WO 2022135591 A1 WO2022135591 A1 WO 2022135591A1
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- WO
- WIPO (PCT)
- Prior art keywords
- group
- alkyl
- cycloalkyl
- substituted
- deuterium
- Prior art date
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- -1 heteroaryl pyridone Chemical compound 0.000 title claims abstract description 164
- 125000003118 aryl group Chemical group 0.000 title claims abstract description 116
- 238000002360 preparation method Methods 0.000 title abstract description 36
- 150000008318 pyrimidones Chemical class 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 245
- 230000000694 effects Effects 0.000 claims abstract description 12
- 229910052805 deuterium Inorganic materials 0.000 claims description 171
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 157
- 125000000623 heterocyclic group Chemical group 0.000 claims description 151
- 229910052736 halogen Inorganic materials 0.000 claims description 137
- 150000002367 halogens Chemical group 0.000 claims description 137
- 229910052739 hydrogen Inorganic materials 0.000 claims description 129
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 123
- 238000006467 substitution reaction Methods 0.000 claims description 119
- 239000001257 hydrogen Substances 0.000 claims description 108
- 125000000217 alkyl group Chemical group 0.000 claims description 102
- 150000002148 esters Chemical class 0.000 claims description 90
- 125000006708 (C5-C14) heteroaryl group Chemical group 0.000 claims description 84
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 80
- 150000001412 amines Chemical class 0.000 claims description 78
- 150000003839 salts Chemical class 0.000 claims description 77
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 67
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 58
- 239000012453 solvate Substances 0.000 claims description 56
- 150000001408 amides Chemical class 0.000 claims description 54
- 239000000651 prodrug Substances 0.000 claims description 53
- 229940002612 prodrug Drugs 0.000 claims description 53
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 52
- 239000013078 crystal Substances 0.000 claims description 49
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 49
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 45
- 125000003545 alkoxy group Chemical group 0.000 claims description 41
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 claims description 41
- 125000003277 amino group Chemical group 0.000 claims description 37
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 36
- 125000001072 heteroaryl group Chemical group 0.000 claims description 35
- 125000001424 substituent group Chemical group 0.000 claims description 34
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 33
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical group [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 32
- 125000003368 amide group Chemical group 0.000 claims description 26
- 239000008194 pharmaceutical composition Substances 0.000 claims description 22
- XTFIVUDBNACUBN-UHFFFAOYSA-N 1,3,5-trinitro-1,3,5-triazinane Chemical compound [O-][N+](=O)N1CN([N+]([O-])=O)CN([N+]([O-])=O)C1 XTFIVUDBNACUBN-UHFFFAOYSA-N 0.000 claims description 21
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 21
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 21
- 229910052731 fluorine Inorganic materials 0.000 claims description 21
- 239000012442 inert solvent Substances 0.000 claims description 21
- 229910052720 vanadium Inorganic materials 0.000 claims description 20
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 19
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 102200006538 rs121913530 Human genes 0.000 claims description 18
- 125000005843 halogen group Chemical group 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 125000003566 oxetanyl group Chemical group 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 14
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 14
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 13
- 125000003725 azepanyl group Chemical group 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 125000005915 C6-C14 aryl group Chemical group 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 11
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 11
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 10
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 10
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 10
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 10
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 10
- 125000000466 oxiranyl group Chemical group 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- 230000008878 coupling Effects 0.000 claims description 9
- 238000005859 coupling reaction Methods 0.000 claims description 9
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 8
- 239000011737 fluorine Substances 0.000 claims description 8
- 125000001188 haloalkyl group Chemical group 0.000 claims description 8
- 150000004677 hydrates Chemical class 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 229920006395 saturated elastomer Polymers 0.000 claims description 8
- 125000000565 sulfonamide group Chemical group 0.000 claims description 8
- 125000004185 ester group Chemical group 0.000 claims description 7
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 7
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 238000005917 acylation reaction Methods 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 238000012797 qualification Methods 0.000 claims description 6
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 5
- 230000009471 action Effects 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 3
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical group NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 claims description 3
- 230000010933 acylation Effects 0.000 claims description 3
- 238000010168 coupling process Methods 0.000 claims description 3
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 3
- 101100459319 Arabidopsis thaliana VIII-2 gene Proteins 0.000 claims description 2
- 101100347605 Arabidopsis thaliana VIII-A gene Proteins 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 29
- 230000003285 pharmacodynamic effect Effects 0.000 abstract description 6
- 231100000331 toxic Toxicity 0.000 abstract description 3
- 230000002588 toxic effect Effects 0.000 abstract description 3
- 230000005764 inhibitory process Effects 0.000 abstract description 2
- 229940125399 kras g12c inhibitor Drugs 0.000 abstract 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 195
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 144
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 131
- 238000005481 NMR spectroscopy Methods 0.000 description 111
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 98
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 83
- 239000000243 solution Substances 0.000 description 71
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 63
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 59
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 59
- 238000006243 chemical reaction Methods 0.000 description 44
- 238000000926 separation method Methods 0.000 description 44
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 239000000203 mixture Substances 0.000 description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- 239000002585 base Substances 0.000 description 30
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 24
- 239000003814 drug Substances 0.000 description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 19
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
- 229940079593 drug Drugs 0.000 description 19
- 239000000741 silica gel Substances 0.000 description 19
- 229910002027 silica gel Inorganic materials 0.000 description 19
- 206010028980 Neoplasm Diseases 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- 239000003208 petroleum Substances 0.000 description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- 239000007787 solid Substances 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- 239000000460 chlorine Substances 0.000 description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
- 239000003112 inhibitor Substances 0.000 description 10
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 10
- 229910052717 sulfur Inorganic materials 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- MHHOMHMNIRXARC-UHFFFAOYSA-N 1h-pyrido[2,3-d]pyrimidin-2-one Chemical compound C1=CN=C2NC(=O)N=CC2=C1 MHHOMHMNIRXARC-UHFFFAOYSA-N 0.000 description 9
- 125000005842 heteroatom Chemical group 0.000 description 9
- 229910052760 oxygen Inorganic materials 0.000 description 9
- 125000000547 substituted alkyl group Chemical group 0.000 description 9
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 8
- 125000003107 substituted aryl group Chemical group 0.000 description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 8
- MMWRGWQTAMNAFC-UHFFFAOYSA-N 1,2-Dihydropyridine Natural products C1NC=CC=C1 MMWRGWQTAMNAFC-UHFFFAOYSA-N 0.000 description 7
- 125000004122 cyclic group Chemical group 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 238000011156 evaluation Methods 0.000 description 6
- 125000000524 functional group Chemical group 0.000 description 6
- 235000005152 nicotinamide Nutrition 0.000 description 6
- 239000011570 nicotinamide Substances 0.000 description 6
- 229960003966 nicotinamide Drugs 0.000 description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 6
- 235000011056 potassium acetate Nutrition 0.000 description 6
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 201000005202 lung cancer Diseases 0.000 description 5
- 208000020816 lung neoplasm Diseases 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- 230000035772 mutation Effects 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- FPXQHZPCFRQWCP-UHFFFAOYSA-N (2-fluoro-6-hydroxyphenyl)boronic acid Chemical compound OB(O)C1=C(O)C=CC=C1F FPXQHZPCFRQWCP-UHFFFAOYSA-N 0.000 description 4
- ZVYNUGSPFZCYEV-UHFFFAOYSA-N 2,6-dichloro-5-fluoropyridine-3-carboxamide Chemical compound NC(=O)C1=CC(F)=C(Cl)N=C1Cl ZVYNUGSPFZCYEV-UHFFFAOYSA-N 0.000 description 4
- GFMMXOIFOQCCGU-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide Chemical compound C=1C=C(I)C=C(Cl)C=1NC1=C(F)C(F)=CC=C1C(=O)NOCC1CC1 GFMMXOIFOQCCGU-UHFFFAOYSA-N 0.000 description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- LYHAQBZYPULWEX-UHFFFAOYSA-N CS(C1=CC=CC=C1N(C(C(C(N1)=O)=C2)=NC(Cl)=C2F)C1=O)(=O)=O Chemical compound CS(C1=CC=CC=C1N(C(C(C(N1)=O)=C2)=NC(Cl)=C2F)C1=O)(=O)=O LYHAQBZYPULWEX-UHFFFAOYSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 230000001028 anti-proliverative effect Effects 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 125000002393 azetidinyl group Chemical group 0.000 description 4
- 229960000106 biosimilars Drugs 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- KZTYYGOKRVBIMI-UHFFFAOYSA-N diphenyl sulfone Chemical group C=1C=CC=CC=1S(=O)(=O)C1=CC=CC=C1 KZTYYGOKRVBIMI-UHFFFAOYSA-N 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 239000006187 pill Substances 0.000 description 4
- 125000004076 pyridyl group Chemical group 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- NXQKSXLFSAEQCZ-SFHVURJKSA-N sotorasib Chemical compound FC1=CC2=C(N(C(N=C2N2[C@H](CN(CC2)C(C=C)=O)C)=O)C=2C(=NC=CC=2C)C(C)C)N=C1C1=C(C=CC=C1O)F NXQKSXLFSAEQCZ-SFHVURJKSA-N 0.000 description 4
- 239000011593 sulfur Chemical group 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- SADXACCFNXBCFY-IYNHSRRRSA-N (e)-n-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl]-3-[(2r)-1-methylpyrrolidin-2-yl]prop-2-enamide Chemical compound C=12C=C(NC(=O)\C=C\[C@@H]3N(CCC3)C)C(OCC)=CC2=NC=C(C#N)C=1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 SADXACCFNXBCFY-IYNHSRRRSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- MLDQJTXFUGDVEO-FIBGUPNXSA-N 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-n-(trideuteriomethyl)pyridine-2-carboxamide Chemical compound C1=NC(C(=O)NC([2H])([2H])[2H])=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-FIBGUPNXSA-N 0.000 description 3
- AILRADAXUVEEIR-UHFFFAOYSA-N 5-chloro-4-n-(2-dimethylphosphorylphenyl)-2-n-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]pyrimidine-2,4-diamine Chemical compound COC1=CC(N2CCC(CC2)N2CCN(C)CC2)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1P(C)(C)=O AILRADAXUVEEIR-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 3
- 241000282414 Homo sapiens Species 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 3
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 3
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 3
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 3
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 3
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Classifications
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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
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Definitions
- the invention belongs to the field of medicine, in particular to an aryl or heteroaryl pyridone or pyrimidone derivative and a preparation method and application thereof.
- Lung cancer is one of the important causes of human cancer death.
- Lung cancer can be divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) according to cell type, and NSCLC accounts for 85% of all lung cancer patients.
- SCLC small cell lung cancer
- NSCLC non-small cell lung cancer
- the global NSCLC market in 2016 was approximately US$20.9 billion, of which the US market accounted for half, followed by Japan, Germany and China.
- the non-small cell lung cancer market has maintained continuous growth, and the global market is expected to reach US$54 billion in 2023 (Nature, 2018;553(7689):446-454).
- chemotherapy drugs mainly include gemcitabine, paclitaxel and platinum drugs, but these drugs generally have poor selectivity and high toxicity, resulting in relatively strong side effects.
- molecularly targeted drugs have gradually become a research hotspot due to their obvious advantages such as high selectivity, relatively small toxic and side effects, and the ability to achieve precise treatment.
- NSCLC molecularly targeted drugs include EGFR inhibitors (such as afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, pyrotinib, Rociletinib, osimertinib, etc.), ALK inhibitors (such as ceritinib, alectinib, brigatinib, lorlatinib, ocaltinib, etc.), and VEGFR inhibitors ( Sorafenib, Regorafenib, Cabozantinib, Sunitinib, Donafenib, etc.).
- EGFR inhibitors such as afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, pyrotinib, Rociletinib, osimertinib, etc
- KRAS mutations are frequently detected, accounting for about 32% of all oncogene mutations.
- the KRAS G12C mutation accounts for 44% of all oncogene mutations in NSCLC. So far, there are still no drugs on the market that target the KRAS G12C mutation.
- KRAS G12C target proteins are pathologically associated with various diseases, novel KRAS G12C inhibitors are still needed for clinical treatment.
- Highly selective and highly active KRAS G12C inhibitors can be more effective in the treatment of diseases such as cancer caused by KRAS G12C mutations, and have the potential to reduce off-target effects, so there is a more urgent clinical need.
- the purpose of the present invention is to provide a new class of compounds with selective inhibitory effect on KRAS G12C and/or better pharmacodynamic properties and uses thereof.
- the first aspect of the present invention provides a compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug:
- a and B are the same or different, and are each independently selected from the group consisting of CH, CR 5 or N;
- X is selected from the group consisting of 4-14 membered saturated or unsaturated heterocyclic group, C 4 -C 14 cycloalkyl group, C 6 -C 14 aryl group or 5-14 membered heteroaryl group, wherein said heterocyclic group radical, cycloalkyl, aryl or heteroaryl can be optionally substituted with one or more (eg 2, 3 or 4) R8 ;
- U, V, W and Q are the same or different and are each independently selected from the group consisting of CH, CR or N;
- RA is absent, or independently selected from the group consisting of hydrogen, deuterium, fluorine, cyano, or C1 - C3 alkyl; each R B is independently selected from the group consisting of hydrogen, deuterium, cyano, or C1 -C 3 alkyl; wherein the alkyl may be substituted with one or more (eg 2, 3 or 4) substituents selected from the group consisting of deuterium, halogen, cyano, amine, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclyl, NHR 9 or NR 9 R 10 ; R 9 and R 10 are each independently C 1 -C 3 alkyl; or R 9 , R 10 together with the N atom to which it is attached constitutes substituted or unsubstituted 4-8 membered heterocyclyl;
- p is an integer of 1 or 2;
- R 3 is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, halogen, nitro, hydroxyl, cyano, ester, amine group, amide group, sulfonamide group, urea group, 4-20-membered heterocyclic group, C 6 -C 14 aryl group, 5-14-membered heteroaryl group;
- L is selected from the group consisting of a bond, -C(O)-, C 1 -C 3 alkylene;
- R 4 is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, amino, hydroxyl, 4-20-membered heterocyclic group, C 6 -C 14 -aryl, 5-14-membered heteroaryl;
- R 5 is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, halogen, nitro, hydroxyl, cyano, ester, amine group, amide group, sulfonamide group, urea group, 4-20-membered heterocyclic group, C 6 -C 14 aryl group, 5-14-membered heteroaryl group;
- R 6 is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, 4-20 membered heterocyclic group, C 6 -C 14 aryl base, 5-14-membered heteroaryl;
- R 8 is independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, amino, hydroxyl, 4-20-membered heterocyclic group, C 6 -C 14 aryl, 5-14 membered heteroaryl;
- R 1 is selected from the following group: Among them, p is 2;
- R 1 is selected from the group consisting of: Among them, p is 2;
- R is not selected from:
- the compound of the present invention does not include the following compounds:
- the compound does not include the following compounds:
- each R 8 is independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, amino, hydroxyl, 4-8 membered heterocyclyl; the substitution refers to substitution by one or more groups selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, Sulfonamide group or urea group.
- R 8 is each independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 - C 18 alkyl; wherein, the substitution refers to substitution by cyano.
- R A is independently selected from the group consisting of hydrogen, deuterium, fluorine, cyano, or C 1 -C 3 alkyl
- each R B is the same or different, and is independently selected from the group consisting of hydrogen, deuterium, cyano or C 1 -C 3 alkyl
- the alkyl may be substituted with one or more substituents selected from the group consisting of deuterium, halogen, cyano, amino, C 3 -C 7 cycloalkyl, 4- 7-membered heterocyclyl, NHR 9 or NR 9 R 10
- R 9 and R 10 are each independently C 1 -C 3 alkyl; or R 9 , R 10 together with the N atom to which it is attached constitutes a substituted or unsubstituted 4 -8-membered heterocyclyl;
- R 6 is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 3 -C 8 -cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, 4-8 membered heterocyclic group, C 6 -C 14 aryl base, 5-14-membered heteroaryl;
- substituted refers to being substituted by one or more groups selected from the following group unless otherwise specified: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 Alkyl, halogenated C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy oxy, C 6 -C 10 aryl, 5-10 membered heteroaryl, 4-8 membered heterocyclyl, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamido or Urea group;
- RA is independently selected from the following group: hydrogen, fluorine
- each R B is the same or different, and independently selected from the group consisting of hydrogen or C 1 -C 3 alkyl groups, wherein the alkyl group may be substituted with one or more substituents selected from the group consisting of deuterium, halogen, cyano, amino, C 3 -C 7 cycloalkyl, 4-7 membered heterocyclyl, NHR 9 or NR 9 R 10
- R 9 and R 10 are each independently C 1 -C 3 alkyl; or R 9 , to which R 10 is attached The N atoms together constitute a 4-8 membered heterocyclic group.
- R 3 is halogen
- a and B are the same or different, and are each independently CH or N.
- Q is N.
- U is N.
- V and W are each independently CR 3 , and R 3 is H or halogen.
- the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has The structure represented by formula (II-A) or (II-B):
- R 1 , R 2 , R 4 , A, B, L, X, U, V, W, Q are defined as described above.
- the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has The structure shown in formula (III):
- R 1 , R 2 , R 4 , X, L, U, V, W, and Q are as described above.
- the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has The structure shown in formula (IV):
- R 1 , R 2 , R 4 , R 8 , L, U, V, W, Q are defined as above.
- the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has The structure shown in formula (V):
- R 1 , R 2 , R 4 , R 8 , U, V, W, Q are defined as described above.
- the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has The structure shown in formula (VI):
- R 1 , R 2 , R 4 , R 8 , U, V, and Q are as described above.
- the compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs is characterized by In that it has the structure shown in formula (VII):
- R 1 , R 2 , R 4 , R 8 , V and Q are as described above.
- the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has The structure shown by formula (VIII):
- R"' is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 -C 8 -cycloalkyl, C 4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl, wherein the substitution refers to being selected from the group Substituted with one or more groups of: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amido, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 4 - C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl;
- q is selected from: 1, 2, 3 or 4;
- R 1 , R 4 , R 8 , R′, V, and Q are as described above.
- R 8 may be 1, 2, 3 or 4, or two adjacent R 8 may together form a C 3 -C 6 cycloalkyl group with the C atom to which it is attached.
- R 1 is selected from:
- the compound has the structure shown in formula (VIII-A):
- R"' is each independently selected from the group consisting of substituted or unsubstituted groups: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 - C 8 cycloalkyl, C 4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl, wherein the substitution refers to being selected from the following Substituted with one or more groups of the group: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amido, C1 - C6 alkyl, C3 - C8 cycloalkyl, C4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl;
- q is selected from: 1, 2, 3 or 4;
- R 1 , R 4 , R 8 , R′, V, and Q are as described above.
- each R 8 is independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, wherein the substitution refers to substitution by cyano.
- each R 8 is independently a substituted or unsubstituted C 1 -C 3 alkyl group, wherein the substitution refers to being substituted by a cyano group.
- each R 8 is methyl.
- the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has The structure shown by formula (IX):
- R1 is selected from : Wherein, R A is selected from: H, D, halogen or cyano; R B and R B' are the same or different, each independently selected from: H, D, halogen, cyano, substituted or unsubstituted C 1 -C 3 alkyl; wherein, the substitution refers to being substituted by one or more groups selected from the group consisting of D, halogen, cyano, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 4 -6-membered heterocyclyl or NR IV R V ; R IV and R V are the same or different, each independently selected from: H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl or 4-6 membered Heterocyclyl; or R IV , R V and adjacent N are cyclized together to form a 4-6 membered heterocyclyl;
- R4 , R', V, Q, R"' and q are as defined above.
- R"' is selected from the group consisting of substituted or unsubstituted groups: C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 4 -C 10 cycloalkenyl, 4- 8-membered heterocyclyl, C 6 -C 10 aryl, 5-10-membered heteroaryl, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of deuterium, halogen, nitro, Hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 4-8 membered heterocyclic group.
- R"' is selected from the group consisting of substituted or unsubstituted groups: C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 6 cycloalkenyl, 4- 6-membered heterocyclic group, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 3 alkyl.
- R"' is selected from the group consisting of substituted or unsubstituted groups: C 3 -C 8 cycloalkyl, 4-8 membered heterocyclyl, wherein the substitution refers to being selected from the group consisting of Substituted with one or more groups of the group: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C1 - C3 alkyl.
- R"' is selected from the group consisting of substituted or unsubstituted groups: ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl amino, azetidinyl, azepanyl, azetidinyl, oxiranyl, oxetanyl, oxolane, oxanyl, Wherein, the substitution refers to being substituted by one or more (such as 2, 3, 4) groups selected from the group consisting of deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 3 alkyl.
- q is 1.
- R 2 is selected from:
- R 2 is selected from the following group:
- K is independently O, S, CH2 or NH; e and f are each independently 0, 1 or 2, preferably H in the above groups can be optionally deuterium, halogen, nitro, hydroxyl, cyano, Ester group, amine group, amide group, C 1 -C 3 alkyl substitution.
- Parts are selected from the following group:
- K is independently O, S, CH2 or NH; e and f are each independently 0, 1 or 2, preferably H in the above groups can be optionally deuterium, halogen, nitro, hydroxyl, cyano, Ester group, amine group, amide group, C 1 -C 3 alkyl substitution.
- the compound has the structure represented by formula (VIII-1) or (VIII-2):
- Rx is selected from: F or Cl
- Rm is selected from the group consisting of substituted or unsubstituted groups: amine group, C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, 4-6 membered heterocyclic group, wherein the substitution refers to the selected Substituted with one or more groups from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl, C3 - C6 cycloalkyl, 4-6 membered heterocyclyl;
- Rn is selected from the group consisting of substituted or unsubstituted groups: amine, C1 - C6alkyl , C1 - C6alkoxy , C3 - C6cycloalkyl, -OC3 - C6cycloalkane base, C 1 -C 6 alkyl C 3 -C 6 cycloalkyl, -OC 1 -C 6 alkyl C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group, wherein the substitution refers to Substituted with one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl, C1 - C3 haloalkyl , C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group;
- R 1 is defined as above.
- the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has The structure represented by formula (X) or (XI):
- Rm is selected from the group consisting of substituted or unsubstituted groups: amine group, C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, 4-6 membered heterocyclic group, wherein the substitution refers to the selected Substituted with one or more (eg 2, 3, 4) groups from the following group: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C1 - C3 alkyl, C3 -C6 cycloalkyl, 4-6 membered heterocyclyl;
- Rn is selected from the group consisting of substituted or unsubstituted groups: amine, C1 - C6alkyl , C1 - C6alkoxy , C3 - C6cycloalkyl, -OC3 - C6cycloalkane base, C 1 -C 6 alkyl C 3 -C 6 cycloalkyl, -OC 1 -C 6 alkyl C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group, wherein the substitution refers to Substituted with one or more (eg 2, 3, 4) groups selected from the group consisting of deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amido, C1 - C3 alkyl , C 1 -C 3 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group;
- Rx is selected from: F or Cl
- R A is selected from: H, D, halogen, preferably R A is selected from: H or F.
- R"' is as defined above;
- q' is selected from 0, 1, 2, or 3.
- the compound has the structure represented by formula (XII) or (XIII):
- R b , R c can independently represent hydrogen, deuterium, C 1 - C6 alkyl, C3 - C8 cycloalkyl, 4-8 membered heterocyclyl, 5-14 membered heteroaryl or C6 - C14 aromatic ring, or Rb and Rc and N atom Together they can form a 4-8 membered heterocyclic group;
- R e can independently represent hydrogen, C1- C6 alkyl, C3 - C8 cycloalkyl, C
- Rm, Rn, Rx, R A , q', R"' are as described above.
- q' is 0.
- the compound has the structure represented by formula (XIV) or (XV):
- Rm, Rn, Rx, RA are as described above.
- Rn is selected from the group consisting of substituted or unsubstituted groups: ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylamino, azetidinyl, azepanyl, azetidine, oxiranyl, oxetanyl, oxolane, oxanyl, wherein, The substitution refers to substitution with one or more (eg 2, 3, 4) groups selected from the group consisting of deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 3 alkyl.
- Rm is selected from the group consisting of substituted or unsubstituted groups: methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo Propylamino, azetidinyl, azepanyl, azetidinyl, oxiranyl, oxetanyl, oxolane, oxanyl , wherein the substitution refers to being substituted by one or more (eg 2, 3, 4) groups selected from the group consisting of deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide , C 1 -C 3 alkyl.
- Rn is selected from the group consisting of substituted or unsubstituted groups: ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylamino, azetidinyl, azepanyl, azetidine, oxiranyl, oxetanyl, oxolane, oxanyl, wherein, The substitution refers to substitution with one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C1 - C3 alkyl;
- Rm is selected from the group consisting of substituted or unsubstituted groups: methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylamino, azetidine alkyl, azepanyl, azepanyl, oxiranyl, oxetanyl, oxolane, oxetanyl, wherein the substitution is means substituted with one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl.
- R 4b , R 4c and R 4d are H.
- Rx is selected from: F or Cl.
- RA is selected from: H, D, halogen, preferably RA is selected from: H or F.
- the compound has the structure shown in formula (XVI):
- R"' is each independently selected from the group consisting of substituted or unsubstituted groups: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 - C 8 cycloalkyl, C 4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl, wherein the substitution refers to being selected from the following Substituted with one or more groups of the group: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amido, C1 - C6 alkyl, C3 - C8 cycloalkyl, C4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl;
- q is selected from: 1, 2, 3 or 4;
- R 1 , R 4 , R 8 , R′, V, and Q are as described above.
- the compound has the structure shown in formula (XVI-A):
- R"' is each independently selected from the group consisting of substituted or unsubstituted groups: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 - C 8 cycloalkyl, C 4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl, wherein the substitution refers to being selected from the following Substituted with one or more groups of the group: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amido, C1 - C6 alkyl, C3 - C8 cycloalkyl, C4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl;
- q is selected from: 1, 2, 3 or 4;
- R 1 , R 4 , R 8 , R′, V, and Q are as described above.
- the compound has the structure represented by formula (XVII):
- R1 is selected from : Wherein, R A is selected from: H, D, halogen or cyano; R B and R B' are the same or different, each independently selected from: H, D, halogen, cyano, substituted or unsubstituted C 1 -C 3 alkyl; wherein, the substitution refers to being substituted by one or more groups selected from the group consisting of D, halogen, cyano, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 4 -6-membered heterocyclyl or NR IV R V ; R IV and R V are the same or different, each independently selected from: H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl or 4-6 membered Heterocyclyl; or R IV , R V and adjacent N are cyclized together to form a 4-6 membered heterocyclyl;
- R4 , R', V, Q, R"' and q are as defined above.
- the compound has a structure represented by formula (XVIII-1) or (XVIII-2):
- Rx is selected from: F or Cl
- Rm is selected from the group consisting of substituted or unsubstituted groups: amine group, C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, 4-6 membered heterocyclic group, wherein the substitution refers to the selected Substituted with one or more groups from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl, C3 - C6 cycloalkyl, 4-6 membered heterocyclyl;
- Rn is selected from the group consisting of substituted or unsubstituted groups: amine, C1 - C6alkyl , C1 - C6alkoxy , C3 - C6cycloalkyl, -OC3 - C6cycloalkane base, C 1 -C 6 alkyl C 3 -C 6 cycloalkyl, -OC 1 -C 6 alkyl C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group, wherein the substitution refers to Substituted with one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl, C1 - C3 haloalkyl , C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group;
- R 1 is defined as above.
- the compound has the structure represented by formula (XIX) or (XX):
- Rm is selected from the group consisting of substituted or unsubstituted groups: amine group, C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, 4-6 membered heterocyclic group, wherein the substitution refers to the selected Substituted with one or more groups from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl, C3 - C6 cycloalkyl, 4-6 membered heterocyclyl;
- Rn is selected from the group consisting of substituted or unsubstituted groups: amine, C1 - C6alkyl , C1 - C6alkoxy , C3 - C6cycloalkyl, -OC3 - C6cycloalkane base, C 1 -C 6 alkyl C 3 -C 6 cycloalkyl, -OC 1 -C 6 alkyl C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group, wherein the substitution refers to Substituted with one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl, C1 - C3 haloalkyl , C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group;
- Rx is selected from: F or Cl
- R A is selected from: H, D, halogen
- q' is selected from 0, 1, 2 or 3;
- R"' is selected from the group consisting of substituted or unsubstituted groups: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 -C 8 ring Alkyl, C 4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl, wherein the substitution refers to one selected from the group or multiple groups substituted: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 4 -C 10 Cycloalkenyl, 4-8 membered heterocyclyl, C6 - C14 aryl, 5-14 membered heteroaryl.
- the compound has a structure represented by formula (XXI) or (XXII):
- R b , R c can independently represent hydrogen, deuterium, C 1 - C6 alkyl, C3 - C8 cycloalkyl, 4-8 membered heterocyclyl, 5-14 membered heteroaryl or C6 - C14 aromatic ring, or Rb and Rc and N atom Together they can form a 4-8 membered heterocyclic group;
- R e can independently represent hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl,
- Rm, Rn, Rx, R A , q', R"' are as described above.
- the compound has the structure represented by formula (XXIII) or (XXIV):
- Rm, Rn, Rx, RA are as described above.
- R 1 , R 2 , R 4 , R 8 , L, U, V, W, Q, p, A, B, X, Rn, Rm, Rx, R A , R"', R 4a , R 4b , R 4c , R 4d , R 4e , q and q' are specific groups corresponding to the specific compounds in the examples.
- the compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs the The compound is selected from the group consisting of:
- the compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs do not contain
- the compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs are selected from the examples compounds shown in.
- the second aspect of the present invention provides a method for preparing a compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, Include steps:
- E is halogen, OH, OCOR 1 , OCO( i Bu), etc.
- E 1 is -BH 2 , -B(OH) 2 , -Sn(Bu) 3 , -ZnBr, etc.;
- PG is an amino protecting group selected from the group consisting of Boc, Bn, Cbz or Fmoc;
- Y and Z are leaving groups selected from the group consisting of halogen or OTf;
- the first base is selected from the group consisting of KHMDS, NaHMDS, LiHMDS, NaH, NaOMe, NaOEt or tBuONa ;
- the second base is selected from the group consisting of TEA, DIPEA, DMAP or N,N-dimethylaniline;
- R 1 , R 2 , R 4 , L, A, B, X, U, V, W and Q are as defined in the first aspect.
- a third aspect of the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising one or more compounds of formula (I), stereoisomers, tautomers and crystal forms thereof according to the first aspect , a pharmaceutically acceptable salt, hydrate, solvate or prodrug; and a pharmaceutically acceptable carrier.
- the pharmaceutical composition further comprises a drug selected from the group consisting of PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, Atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, veltuzumab,
- a preparation method of a pharmaceutical composition comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of formula (I), stereoisomer, tautomer described in the first aspect of the present invention
- the form, pharmaceutically acceptable salt, hydrate, solvate or prodrug are mixed to form a pharmaceutical composition.
- the fourth aspect of the present invention provides the compound of formula (I) described in the first aspect, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs , or the use of the pharmaceutical composition described in the third aspect, for preparing a pharmaceutical composition for preventing and/or treating diseases related to the activity or expression of KRAS G12C .
- the fifth aspect of the present invention provides a method for preventing and/or treating a disease related to the activity or expression level of KRAS G12C , comprising the step of: administering an effective amount of the compound of formula (I) described in the first aspect to a patient in need , a stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, or administer the pharmaceutical composition of the third aspect.
- the disease is a tumor or a disordered disease.
- the disease is selected from the group consisting of lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, stomach cancer, liver cancer, colorectal cancer, melanoma, lymphoma, blood cancer , brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer.
- the sixth aspect of the present invention provides a non-diagnostic and non-therapeutic method for inhibiting KRAS G12C , which comprises the steps of: administering to a patient in need an effective amount of the compound of formula (I) described in the first aspect, its stereoisomeric isomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or administer the pharmaceutical composition of the third aspect.
- a seventh aspect of the present invention provides a method for inhibiting KRAS G12C in vitro, comprising the steps of: adding the compound described in the first aspect, its stereoisomer, tautomer, crystal form and pharmaceutically acceptable salt , hydrate, solvate or prodrug, or the composition of the third aspect, in contact with a somatic cell.
- the somatic cells are derived from primates (eg, humans).
- the present inventors unexpectedly prepared a new class of compounds with selective inhibition of KRAS G12C and/or better pharmacodynamic properties. On this basis, the inventors have completed the present invention.
- substituents are described by conventional chemical formulae written from left to right, such substituents also include chemically equivalent substituents obtained when the structural formula is written from right to left.
- substituents are described by conventional chemical formulae written from left to right, such substituents also include chemically equivalent substituents obtained when the structural formula is written from right to left.
- -CH2O- is equivalent to -OCH2- .
- alkyl refers to a straight or branched chain alkane group, which may include any number of carbon atoms, wherein "C 1 -C 18 alkyl” refers to a group including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms, preferably for example C 1 -C 2 , C 1 -C 3 , C 1 -C 4 , C 1 - C 5 , C 1 -C 6 , C 1 -C 7 , C 1 -C 8 , C 1 -C 9 , C 1 -C 10 , C 2 -C 3 , C 2 -C 4 , C 2 -C 5 , C 2 -C 6 , C 3 -C 4 , C 3 -C 5 , C 3 -C 6 , C 4 -C 5 , C 4 -C 6 or C 5-6 .
- alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, Pentyl, isopentyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and many more.
- the alkyl group also includes a substituted alkyl group. "Substituted alkyl" means that one or more positions in the alkyl group are substituted, especially 1-4 substituents, which may be substituted at any position.
- cycloalkyl refers to a fully saturated cyclic hydrocarbon compound group, wherein "C 3 -C 20 cycloalkyl” refers to a group containing 3, 4, 5, 6, 7, 8, 9, 10, Fully saturated cyclic hydrocarbon groups of 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, including 1-4 rings, each containing 3-8 carbon atom.
- C 3 -C 4 , C 3 -C 5 , C 3 -C 6 , C 3 -C 7 , C 3 -C 8 , C 3 -C 9 , C 3 -C 10 Preferably C 3 -C 4 , C 3 -C 5 , C 3 -C 6 , C 3 -C 7 , C 3 -C 8 , C 3 -C 9 , C 3 -C 10 .
- Substituted cycloalkyl means that one or more positions in the cycloalkyl group are substituted, especially 1-4 substituents, which may be substituted at any position.
- cycloalkyl is intended to include “substituted cycloalkyl”.
- heterocyclyl refers to a fully saturated or partially unsaturated cyclic group
- heterocyclyl refers to a group containing 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ring atoms fully saturated or partially unsaturated cyclic groups (including but not limited to, such as 3-7 membered monocyclic, 6 -11 membered bicyclic ring, or 8-16 membered tricyclic ring system), in which at least one heteroatom is present in the ring having at least one carbon atom.
- Each heteroatom-containing heterocycle may carry 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen or sulfur, wherein nitrogen or sulfur may be oxidized or nitrogen may be quaternized.
- a heterocyclic group can be attached to the residue of any heteroatom or carbon atom of the ring or ring system molecule.
- Typical monocyclic heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazole Alkyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroacridine Heptinyl, 4-piperidinone, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinosulfoxide, thiomorpholinone sulfone, 1,3-dioxanyl And tetrahydro-1,1-dioxythiophene, etc.
- Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups are optionally connected with other groups through a single bond, or through a ring Any two or more atoms above are further cyclolinked to other cycloalkyl, heterocyclyl, aryl, and heteroaryl groups; heterocyclyl groups may be substituted or unsubstituted.
- aryl refers to an aromatic cyclic hydrocarbon compound group, wherein "C6-C14 aryl” refers to a group containing 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring carbon atoms.
- Aromatic cyclic hydrocarbon group having 1 to 5 rings, especially monocyclic and bicyclic groups, such as phenyl, biphenyl or naphthyl. Where there are two or more aromatic rings (bicyclic rings, etc.), the aromatic rings of the aryl group can be linked by a single bond (eg, biphenyl), or fused (eg, naphthalene, anthracene, etc.).
- “Substituted aryl” means that one or more positions in the aryl group are substituted, especially 1-3 substituents, which may be substituted at any position.
- heteroaryl refers to an aromatic cyclic hydrocarbon group containing 1-4 heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen and sulfur.
- heteroatoms are selected from the group consisting of oxygen, nitrogen and sulfur.
- 5-14 membered heteroaryl refers to an aromatic cyclic hydrocarbon compound group containing 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, wherein Contains 1-4 heteroatoms selected from N, O, S.
- Heteroaryl is preferably a 5- to 10-membered ring, more preferably 5- or 6-membered, heteroaryl includes but is not limited to pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadi azolyl, isothiazolyl, furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl and tetrazolyl, etc.
- alkoxy refers to a straight chain or branched chain or cyclic alkoxy group
- C1-C18 alkoxy refers to a straight chain or branched chain or cyclic alkoxy group having 1 to 18 carbon atoms Oxy group, including C1-C18 alkyl-O-, -C1-C6 alkyl-O-C1-C6 alkyl, preferably C1-C8 alkoxy, more preferably C1-C6 alkoxy, alkoxy includes But not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy and the like.
- Cycloalkenyl refers to a cyclic hydrocarbon group with one or more double bonds, wherein, “C 4 -C 10 cycloalkenyl” refers to one or more double bonds, including 4, 5, 6, 7, A cyclic hydrocarbon group of 8, 9 or 10 carbon atoms, preferably C 4 -C 6 cycloalkenyl, cycloalkenyl includes but is not limited to: cyclobutenyl, cyclopentenyl, cyclopentadienyl, cycloalkenyl Hexenyl, cyclohexadienyl, etc.
- esters refers to a group with the structure -COOR, where R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl.
- R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl.
- the alkyl group, the cycloalkyl group, the cycloalkenyl group, the aryl group, the heteroaryl group, and the heterocyclic group have the above-mentioned definitions.
- amino refers to a group bearing the structure -NRR', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or Substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl.
- R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or Substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl.
- the alkyl group, the cycloalkyl group, the cycloalkenyl group, the aryl group, the heteroaryl group, and the heterocyclic group have the above-mentioned definitions.
- R and R' may be the same or different, and when both R and R' are H, the amine group is -NH 2 .
- amine groups include, but are not limited to, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, isopropylamine, butylamine, and the like.
- R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or Substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl.
- the alkyl group, the cycloalkyl group, the cycloalkenyl group, the aryl group, the heteroaryl group, and the heterocyclic group have the above-mentioned definitions.
- R and R' can be the same or different.
- sulfonamido refers to a group with the structure -SO2NRR ', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cyclo Alkenyl or substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl.
- the alkyl group, the cycloalkyl group, the cycloalkenyl group, the aryl group, the heteroaryl group, and the heterocyclic group have the above-mentioned definitions.
- R and R' can be the same or different.
- aminonosulfonyl refers to a group with the structure -NRSO2R ', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, Cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl.
- R and R' can be the same or different.
- ureido refers to a group having the structure -NRCONR'R", where R, R' and R" can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl , cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl.
- the alkyl group, the cycloalkyl group, the cycloalkenyl group, the aryl group, the heteroaryl group, and the heterocyclic group have the above-mentioned definitions.
- R, R' and R" can be the same or different.
- an alkyl group is an alkylene group after one H atom is removed (such as : methylene, ethylene, propylene, isopropylidene (such as ), butylene (such as ), pentylene (such as ), ahexyl (such as ), heptidene (such as ), etc.), cycloalkyl corresponds to cycloalkylene (such as: etc.), the heterocyclic group corresponds to the heterocyclic group (such as: ), cycloalkyl corresponds to heterocyclylene (such as: etc.), alkoxy corresponds to alkyleneoxy (-CH 2 O-, -CH 2 CH 2 -O-CH 2 -, -CH 2 OCH 2 CH 2 CH 2 -) and the like.
- halogen refers to chlorine, bromine, fluorine, iodine.
- halo means that the H in the group is replaced by a halogen.
- deuterated refers to the replacement of an H in a group with deuterium.
- hydroxyl refers to a group with the structure OH.
- nitro refers to a group with the structure NO2.
- cyano refers to a group with the structure CN.
- substituted or unsubstituted means that the H atom of the selected group is substituted or unsubstituted, and the selected group does not contain an H atom and will not be substituted.
- the compounds of the present invention may be taken with any number of substituents or functional groups to extend their encompassing scope.
- the general formula for including substituents in the formulations of the present invention refers to the replacement of a hydrogen radical with a specified structural substituent.
- the substituents may be the same or different at each position.
- substituted as used herein includes all permissible substitutions of organic compounds. In a broad sense, permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds.
- heteroatom nitrogen may have hydrogen substituents or any permissible organic compound as described above to supplement its valence.
- the present invention is not intended to limit in any way the permissible substituted organic compounds.
- the present invention contemplates that combinations of substituents and variable groups are well suited for the treatment of diseases, such as infectious or proliferative diseases, in the form of stable compounds.
- stable refers to a compound that is stable enough to be detected for a sufficient period of time to maintain the structural integrity of the compound, preferably for a sufficient period of time, and is used herein for the above-mentioned purposes.
- substituted refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent. Particular substituents are those described correspondingly in the preceding paragraphs, or the substituents appearing in the various examples. Unless otherwise specified, a substituted group may have at any substitutable position of the group a substituent selected from a particular group, which may be the same or different at each position.
- the groups include corresponding substituted groups and subgroups, for example, alkyl groups include substituted alkyl groups, cycloalkyl groups include substituted cycloalkyl groups, and aryl groups include substituted aryl groups , a heteroaryl group includes a substituted heteroaryl group, a heterocyclic group includes a substituted heterocyclic group, and the like. It will be understood by those skilled in the art that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable.
- alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclyl, heteroaryl or aryl and their corresponding substituent groups and subunits may be optionally substituted, wherein , the alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl or aryl groups have the above definitions.
- compound of the present invention or “active ingredient of the present invention” are used interchangeably to refer to a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound (such as deuterated compounds) or prodrugs.
- the term also includes racemates, optical isomers.
- the compound of formula (I) has the following structure:
- R 1 , R 2 , R 4 , L, U, V, W, Q, A, B, and X are as described above.
- the compound of formula (I) has the structure shown in formula (II-A) or (II-B):
- R 1 , R 2 , R 4 , A, B, L, X, U, V, W, Q are defined as described above.
- the compound of formula (I) has the structure shown in formula (III):
- R 1 , R 2 , R 4 , X, L, U, V, W, and Q are as described above.
- the compound of formula (I) has the structure shown in formula (IV):
- R 1 , R 2 , R 4 , R 8 , L, U, V, W, Q are defined as above.
- the compound of formula (I) has the structure shown in formula (V):
- R 1 , R 2 , R 4 , R 8 , U, V, W, Q are defined as described above.
- the compound of formula (I) has the structure shown in formula (VI):
- R 1 , R 2 , R 4 , R 8 , U, V, and Q are as described above.
- the compound of formula (I) has the structure shown in formula (VII):
- R 1 , R 2 , R 4 , R 8 , V and Q are as described above.
- R A is independently selected from the group consisting of hydrogen, deuterium, fluorine, cyano, or C 1 -C 3 alkyl
- each R B is the same or different, and is independently selected from the group consisting of hydrogen, deuterium, cyano or C 1 -C 3 alkyl
- the alkyl may be substituted with one or more (eg 2, 3, 4 or 5) substituents selected from the group consisting of deuterium, halogen, cyano, amine, C 3 -C 7 cycloalkyl, 4-7 membered heterocyclyl, NHR 9 or NR 9 R 10
- R 9 and R 10 are each independently C 1 -C 3 alkyl; or R 9 to which R 10 is attached The N atoms together form a substituted or unsubstituted 4-8 membered heterocyclic group;
- R 6 is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 3 -C 8 -cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, 4-8 membered heterocyclic group, C 6 -C 14 aryl base, 5-14-membered heteroaryl;
- Q is N.
- V and W are each independently CR 3 , and R 3 is H or halogen; preferably, R 3 is halogen.
- R 8 is independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl , C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, amino, hydroxyl, 4-8 membered hetero Cyclic; said substitution means substitution with one or more (eg, 2, 3, 4, or 5) groups selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amido, sulfonamide or ureido; more preferably, R8 is independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C1 - C6 alkyl, deuterated C1- C 6 alky
- each R8 is methyl.
- the compound has the structure shown in formula (VIII):
- R"' is each independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl, wherein the substitution refers to the selected Substituted with one or more groups from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C6 alkyl, C3 - C8 cycloalkyl, C 4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl;
- q is selected from: 1, 2, 3, or 4;
- R 1 , R 4 , R 8 , R′, V, and Q are as described above.
- the compound has the structure shown in formula (IX):
- R 1 , R 4 , R', V, R"', Q and q are as defined above.
- Rx is selected from: hydrogen, deuterium, C 1 -C 3 alkyl, deuterated C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 1 -C C 3 alkoxy, halogen, nitro, hydroxyl, cyano, ester, 4-6 membered heterocyclic group, preferably, part of
- Rx is selected from: hydrogen, deuterium, C 1 -C 3 alkyl, deuterated C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 1 -C C 3 alkoxy, halogen, nitro, hydroxyl, cyano, ester, 4-6 membered heterocyclic group, preferably, part of
- R is selected from the group consisting of :
- K is independently O, S, CH2 or NH; e and f are each independently 0, 1 or 2, preferably H in the above groups can be optionally deuterium, halogen, nitro, hydroxyl, cyano, Ester group, amine group, amide group, C 1 -C 3 alkyl substitution.
- the compound has the structure shown in formula (VIII):
- R"' is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 -C 8 -cycloalkyl, C 4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl, wherein the substitution refers to being selected from the group Substituted with one or more groups of: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amido, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 4 - C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl;
- R 1 , R 4 , R 8 , R', V, Q, and q are as defined above.
- R"' is selected from the group consisting of substituted or unsubstituted groups: C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 4 -C 10 cycloalkenyl, 4-8 membered heterocycle base, C 6 -C 10 aryl, 5-10 membered heteroaryl, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxyl, cyano , ester group, amine group, amide group, C 1 -C 6 alkyl group, C 3 -C 8 cycloalkyl group, 4-8 membered heterocyclic group.
- R"' is selected from the group consisting of substituted or unsubstituted groups: C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 6 cycloalkenyl, 4-6 membered heterocycle group, more preferably, R"' is selected from the group consisting of substituted or unsubstituted groups: radical, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylamino, azetidinyl, azepanyl, azetidine, oxiranyl, oxetanyl, oxolane, oxanyl, wherein, The substitution refers to substitution with one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alky
- Parts are selected from the following group:
- K is independently O, S, CH2 or NH; e and f are each independently 0, 1 or 2, preferably H in the above groups can be optionally deuterium, halogen, nitro, hydroxyl, cyano, Ester group, amine group, amide group, C 1 -C 3 alkyl substitution.
- the compound has a structure represented by formula (X) or (XI):
- Rm is selected from the group consisting of substituted or unsubstituted groups: amine group, C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, 4-6 membered heterocyclic group, wherein the substitution refers to the selected Substituted with one or more groups from the group consisting of deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C1 - C3 alkyl, C3-C6 cycloalkyl, 4- 6-membered heterocyclic group;
- Rn is selected from the group consisting of substituted or unsubstituted groups: amine, C1 - C6alkyl , C1 - C6alkoxy , C3 - C6cycloalkyl, -OC3 - C6cycloalkane base, C 1 -C 6 alkyl C 3 -C 6 cycloalkyl, -OC 1 -C 6 alkyl C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group, wherein the substitution refers to Substituted with one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl, C1 - C3 haloalkyl , C3-C6 cycloalkyl, 4-6 membered heterocyclyl;
- Rx is selected from: F or Cl
- R A is selected from: H, D, halogen, or cyano, preferably R A is selected from: H or F.
- R"' is as defined above;
- q' is selected from 0, 1, 2, or 3.
- the compound has a structure represented by formula (VIII-1):
- R 1 , Rx, R 4 , Rm and Rn are defined as described above.
- the compound has a structure represented by formula (X)
- R A , Rx, R 4 , Rm, Rn, q"' and q' are defined as described above.
- the compound has the structure represented by formula (XII)
- R 4a , R 4b , R 4c , R 4d , R 4e , Rm, Rn, Rx, R A , q' and R"' are as described above.
- the compound has the structure shown in formula (XIV):
- R 4a , R 4b , R 4c , R 4d , R 4e , Rm, Rn, Rx and RA are as described above.
- Rn is selected from the group consisting of substituted or unsubstituted groups: ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylamino, azetidine alkyl, azepanyl, azepanyl, oxiranyl, oxetanyl, oxolane, oxetanyl, wherein the substitution is means substituted with one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl.
- Rm is selected from the group consisting of substituted or unsubstituted groups: methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylamino, nitrogen cyclobutanyl, azepanyl, azetidinyl, oxiranyl, oxetanyl, oxolane, oxetanyl, wherein the The substitution refers to substitution with one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C1 - C3 alkyl.
- salts that the compounds of the present invention may form are also within the scope of the present invention. Unless otherwise specified, compounds in the present invention are understood to include their salts.
- the term “salt” refers to salts formed with inorganic or organic acids and bases in the acid or basic form.
- a compound of the present invention contains a basic moiety, which includes, but is not limited to, pyridine or imidazole, and when it contains an acidic moiety, including, but is not limited to, a carboxylic acid, the zwitterion (“inner salt”) that may be formed is contained in within the scope of the term "salt”.
- compositions of the present invention may form salts, for example, by reacting Compound I with an amount, eg, an equivalent, of an acid or base, salting out in a medium, or lyophilizing in an aqueous solution.
- the compounds of the present invention contain basic moieties, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids.
- Typical acids that can form salts include acetates (eg with acetic acid or trihaloacetic acids such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates , benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentane propionate, diglycolate, lauryl sulfate, Ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodate, isethionate (eg, 2-hydroxyethanesulfonate), lactate, maleate
- Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases.
- Typical base-formed salts include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts formed from organic bases (such as organic amines) such as benzathine, bicyclohexyl Amine, Hepamine (salt with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucosamide, tert-butyl amines, and salts with amino acids such as arginine, lysine, and the like.
- Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (eg, dimethyl, diethyl, dibutyl, and dipentyl sulfate), long-chain halides (eg, decyl, dodecyl, tetradecyl, and tetradecyl chlorides, bromides) and iodides), aralkyl halides (such as benzyl and phenyl bromides), and the like.
- small halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides
- dialkyl sulfates eg, dimethyl, diethyl, dibutyl, and dipentyl sulfate
- Prodrugs and solvates of the compounds of the present invention are also contemplated.
- the term "prodrug” as used herein refers to a compound that undergoes chemical transformation through a metabolic or chemical process to yield the compound, salt, or solvate of the present invention in the treatment of a related disease.
- the compounds of the present invention include solvates, such as hydrates.
- the compounds, salts or solvates of the present invention may exist in tautomeric forms (eg amides and imine ethers). All of these tautomers are part of the present invention.
- Stereoisomers of all compounds are contemplated by the present invention.
- Individual stereoisomers of the compounds of the present invention may not exist concurrently with other isomers (eg, as a pure or substantially pure optical isomer with specific activity), or may be mixtures such as Racemates, or mixtures with all other stereoisomers or a part thereof.
- the chiral center of the present invention has two configurations, S or R, as defined by the 1974 recommendation of the International Union of Theoretical and Applied Chemistry (IUPAC).
- the racemic form can be resolved by physical methods, such as fractional crystallization, or by derivatization to diastereomer separation crystallization, or by chiral column chromatography.
- the individual optical isomers can be obtained from the racemates by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by crystallization.
- the compound of the present invention the compound obtained by successively preparing, isolating and purifying the compound has a weight content equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compound), described in the text List.
- very pure compounds of the invention are also intended to be part of the invention.
- Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms.
- the present invention covers all compounds including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, Spin mixtures and other mixtures. Additionally asymmetric carbon atoms may represent substituents such as alkyl groups. All isomers, as well as mixtures thereof, are encompassed by the present invention.
- a mixture of isomers may contain isomers in various ratios.
- isomers in various ratios.
- Similar ratios readily understood by those of ordinary skill in the art, as well as ratios that are mixtures of more complex isomers, are also within the scope of the invention.
- the present invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein. In practice, however, it usually occurs that one or more atoms are replaced by atoms with different atomic weights or mass numbers.
- isotopes that may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes 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.
- Isotopically-labeled compounds can be prepared by conventional methods by substituting readily available isotopically-labeled reagents for non-isotopically labeled reagents using the protocols disclosed in the Examples.
- a synthesis of a particular enantiomer of a compound of the present invention can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, separation of the resulting diastereomeric mixture, and removal of the chiral auxiliary to obtain pure enantiomer.
- a suitable optically active acid or base can be used to form a diastereomeric salt with it, and then the diastereomeric salt can be formed by separation crystallization or chromatography, etc. Separation by conventional means then yields the pure enantiomer.
- the preparation method of the compound of formula (I) of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention.
- the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention pertains.
- the preparation process of the compound of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels or synthesized according to the reported literature unless otherwise specified.
- E is halogen, OH, OCOR 1 , OCO( i Bu), etc.
- E 1 is -BH 2 , -B(OH) 2 , -Sn(Bu) 3 , -ZnBr, etc.;
- PG is an amino protecting group selected from the group consisting of Boc, Bn, Cbz or Fmoc;
- Y and Z are leaving groups selected from the group consisting of halogen or OTf;
- the first base is selected from the group consisting of KHMDS, NaHMDS, LiHMDS, NaH, NaOMe, NaOEt or tBuONa ;
- the second base is selected from the group consisting of TEA, DIPEA, DMAP or N,N-dimethylaniline;
- R 1 , R 2 , R 4 , L, A, B, X, U, V, W and Q are as defined above.
- reaction solvent the reaction solvent, reaction catalyst, base used in the reaction, reaction temperature, reaction time, etc.
- reaction solvent the reaction solvent, reaction catalyst, base used in the reaction, reaction temperature, reaction time, etc.
- compositions and methods of administration are provided.
- the pharmaceutical composition of the present invention is used for preventing and/or treating the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease.
- the compounds of formula (I) may be used in combination with other drugs known to treat or ameliorate similar conditions.
- the mode of administration and dosage of the original drug may remain unchanged, while the compound of formula (I) is administered simultaneously or subsequently.
- a pharmaceutical composition containing both one or more known drugs and the compound of formula (I) may preferably be used.
- Drug combinations also include administration of a compound of formula (I) with one or more other known drugs at overlapping time periods.
- the doses of the compound of formula (I) or known drugs may be lower than their doses alone.
- Drugs or active ingredients that can be used in combination with the compound of formula (I) include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR -120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as Duval) Monoclonal antibody, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311, or any of the above Biosimilars, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofat
- the dosage form of the pharmaceutical composition of the present invention includes (but is not limited to): injection, tablet, capsule, aerosol, suppository, film, drop pill, external liniment, controlled-release or sustained-release or nanometer preparation.
- the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount.
- the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
- the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/dose, more preferably, 10-1000 mg of the compound of the present invention/dose.
- the "one dose” is a capsule or tablet.
- “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gelling substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility” as used herein means that the components of the composition can be admixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
- Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
- cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
- gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
- the mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
- Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
- the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea
- Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
- liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.
- inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylform
- compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
- adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
- Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
- suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
- compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
- Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
- Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants.
- the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
- the therapeutic methods of the present invention may be administered alone or in combination with other therapeutic means or therapeutic agents.
- a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is
- the administration dose is usually 1 to 2000 mg, preferably 50 to 1000 mg.
- the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
- the present invention also provides a method for preparing a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of formula (I) or its crystal form, pharmaceutically acceptable salt, hydrate or solvent of the present invention The compounds are mixed to form a pharmaceutical composition.
- the present invention also provides a method of treatment, which comprises the steps of: administering the compound of formula (I) described in the present invention, or a crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof to a subject in need of treatment, Or administer the pharmaceutical composition of the present invention for selectively inhibiting KRAS G12C .
- the present invention has the following main advantages:
- the compound has a good selective inhibitory effect on KRAS G12C ;
- the compound has better pharmacodynamics, pharmacokinetic properties and lower toxic and side effects; wherein, the experimental results show that the compound containing phenylsulfone structure has better pharmacokinetic properties than other structures, For example, compounds with pyridine sulfone structure, compounds containing dimethylpiperazine structure have better efficacy than monomethylpiperazine;
- R 4 is a phenyl group
- the biological activity is better than that of a heteroaryl group.
- the structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).
- LC-MS Liquid chromatography-mass spectrometry
- TLC silica gel plate used Qingdao GF254 silica gel plate, TLC used 0.15-0.20mm, preparative thin layer chromatography used 0.4mm-0.5mm.
- Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.
- the starting materials in the examples of the present invention are all known and commercially available, or can be synthesized by adopting or according to the literature data reported in the field.
- 2,6-Dichloro-5-fluoronicotinamide (873 mg, 4.2 mmol) was dissolved in 15 mL of dry tetrahydrofuran, and oxalyl chloride (3.6 mL, 42.0 mmol) in dichloromethane (4.5 mL) was slowly added dropwise to this solution. mL) solution. After the dropwise addition, the mixture was stirred at 75°C under reflux for 2 hours, and then concentrated to dryness under reduced pressure. The residue was diluted with 15 mL of dry tetrahydrofuran and cooled to zero.
- Step 7 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4 Preparation of -methyl-2-(methylsulfo)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one
- Example 5-1 Two isomers Example 5A and Example 5B were obtained by chiral separation:
- Example 5A LC-MS: m/z 610 (M+H) + .
- Example 5B LC-MS: m/z 610 (M+H) + .
- Example 6-1 obtained two isomers Example 5A and Example 5B by chiral separation:
- Example 6A LC-MS: m/z 622 (M+H) + .
- Example 6B LC-MS: m/z 622 (M+H) + .
- Example 10-1 Two isomers Example 10A and Example 10B were obtained by chiral separation:
- Example 10A LC-MS: m/z 624 (M+H) + .
- Example 10B LC-MS: m/z 624 (M+H) + .
- Example 12 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-1-(2-ethyl-6-(methylsulfonyl)phenyl )-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
- Example 16-1 Two isomers Example 16A and Example 16B were obtained by chiral separation:
- Example 16A LC-MS: m/z 625 (M+H) + .
- Example 16B LC-MS: m/z 625 (M+H) + .
- Example 18-1 Two isomers Example 18A and Example 18B were obtained by chiral separation:
- Example 18A LC-MS: m/z 625 (M+H) + .
- Example 18B LC-MS: m/z 625 (M+H) + .
- Example 20-1 Two isomers Example 20A and Example 20B were obtained by chiral separation:
- Example 20A LC-MS: m/z 625 (M+H) + .
- 1 H NMR 400MHz, DMSO
- Example 20B LC-MS: m/z 625 (M+H) + .
- Example 25-1 Two isomers Example 25A and Example 25B were obtained by chiral separation:
- Example 25A LC-MS: m/z 636 (M+H) + .
- Example 25B LC-MS: m/z 636 (M+H) + .
- Example 29-1 Two isomers Example 29A and Example 29B were obtained by chiral separation:
- Example 29A LC-MS: m/z 625 (M+H) + .
- Example 29B LC-MS: m/z 625 (M+H) + .
- Example 30-1 Two isomers Example 30A and Example 30B were obtained by chiral separation:
- Example 30A LC-MS: m/z 624 (M+H) + .
- Example 30B LC-MS: m/z 624 (M+H) + .
- 1 H NMR 400MHz, DMSO
- Example 31-1 Two isomers Example 31A and Example 31B were obtained by chiral separation:
- Example 31A LC-MS: m/z 666 (M+H) + .
- 1 H NMR 400MHz, DMSO
- 7.66(t,J 7.8Hz,1H)
- 7.56(td,J 8.4,6.6Hz,1H)
- Example 32-1 Two isomers Example 32A and Example 32B were obtained by chiral separation:
- Example 32A LC-MS: m/z 642 (M+H) + .
- Example 32B LC-MS: m/z 642 (M+H) + .
- Example 33-1 Two isomers Example 33A and Example 33B were obtained by chiral separation:
- Example 33A LC-MS: m/z 625 (M+H) + .
- Example 33B LC-MS: m/z 625 (M+H) + .
- Example 34-1 Two isomers Example 34A and Example 34B were obtained by chiral separation:
- Example 34A LC-MS: m/z 643 (M+H) + .
- Example 34B LC-MS: m/z 643 (M+H) + .
- Example 35-1 Two isomers Example 35A and Example 35B were obtained by chiral separation:
- Example 35A LC-MS: m/z 636 (M+H) + .
- Example 35B LC-MS: m/z 636 (M+H) + .
- Example 36-1 Two isomers Example 36A and Example 36B were obtained by chiral separation:
- Example 36A LC-MS: m/z 654 (M+H) + .
- Example 36B LC-MS: m/z 654 (M+H) + .
- Example 37-1 Two isomers Example 37A and Example 37B were obtained by chiral separation:
- Example 37A LC-MS: m/z 625 (M+H) + .
- Example 37B LC-MS: m/z 625 (M+H) + .
- Example 38-1 Two isomers Example 38A and Example 38B were obtained by chiral separation:
- Example 38A LC-MS: m/z 625 (M+H) + .
- Example 38B LC-MS: m/z 625 (M+H) + .
- Example 39-1 Two isomers Example 39A and Example 39B were obtained by chiral separation:
- Example 39A LC-MS: m/z 625 (M+H) + .
- Example 39B LC-MS: m/z 625 (M+H) + .
- Example 40-1 Two isomers Example 39A and Example 39B were obtained by chiral separation:
- Example 40A LC-MS: m/z 625 (M+H) + .
- Example 40B LC-MS: m/z 625 (M+H) + .
- Example 41-1 Two isomers Example 41A and Example 41B were obtained by chiral separation:
- Example 41A LC-MS: m/z 606 (M+H) + .
- Example 41B LC-MS: m/z 606 (M+H) + .
- Example 42-1 Two isomers Example 42A and Example 42B were obtained by chiral separation:
- Example 42A LC-MS: m/z 606 (M+H) + .
- Example 42B LC-MS: m/z 606 (M+H) + .
- Example 43-1 Two isomers Example 43A and Example 43B were obtained by chiral separation:
- Example 43A LC-MS: m/z 606 (M+H) + .
- Example 43B LC-MS: m/z 606 (M+H) + .
- Example 44-1 Two isomers Example 44A and Example 44B were obtained by chiral separation:
- Example 44A LC-MS: m/z 606 (M+H) + .
- Example 44B LC-MS: m/z 606 (M+H) + .
- Example 45-1 Two isomers Example 45A and Example 45B were obtained by chiral separation:
- Example 45A LC-MS: m/z 680 (M+H) + .
- Example 45B LC-MS: m/z 680 (M+H) + .
- Example 46-1 Two isomers Example 46A and Example 46B were obtained by chiral separation:
- Example 46A LC-MS: m/z 694 (M+H) + .
- Example 46B LC-MS: m/z 694 (M+H) + .
- Example 47-1 Two isomers Example 47A and Example 47B were obtained by chiral separation:
- Example 47A LC-MS: m/z 681 (M+H) + .
- Example 47B LC-MS: m/z 681 (M+H) + .
- Example 48 (2-(4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-1-(2-isopropyl-6-(methylsulfonyl) )phenyl)-2-oxo-1,2-dihydropyridine[2,3-d]pyrimidin-7-yl)-3-fluorophenyl)carbamate
- Example 48-1 Two isomers Example 48A and Example 48B were obtained by chiral separation:
- Example 48A LC-MS: m/z 681 (M+H) + .
- Example 48B LC-MS: m/z 681 (M+H) + .
- Example 49-1 Two isomers Example 49A and Example 49B were obtained by chiral separation:
- Example 49A LC-MS: m/z 680 (M+H) + .
- Example 49B LC-MS: m/z 680 (M+H) + .
- Example 50-1 Two isomers Example 50A and Example 50B were obtained by chiral separation:
- Example 50A LC-MS: m/z 701 (M+H) + .
- Example 50B LC-MS: m/z 701 (M+H) + .
- 2,6-Dichloro-5-fluoronicotinamide (420 mg, 2.0 mmol) was dissolved in dry tetrahydrofuran (7 mL), and to this solution was slowly added dropwise oxalyl chloride (1.7 mL, 20.0 mmol) in dichloromethane ( 2mL) solution. After the dropwise addition, the mixture was stirred at 75°C under reflux for 2 h, and then concentrated to dryness under reduced pressure. The residue was diluted with anhydrous tetrahydrofuran (7 mL) and cooled to 0°C.
- the ethyl acetate layers were combined, dried, and concentrated.
- Step 5 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2 Preparation of -(methylsulfonyl)phenyl)pyridin[2,3-d]pyrimidin-2(1H)-one
- Example 53-1 Two isomers Example 53A and Example 53B were obtained by chiral separation:
- Example 53A LC-MS: m/z 596 (M+H) + .
- Example 53B LC-MS: m/z 596 (M+H) + .
- Example 62-1 Two isomers Example 62A and Example 62B were obtained by chiral separation:
- Example 62A LC-MS: m/z 692 (M+H) + .
- Example 62B LC-MS: m/z 692 (M+H) + .
- Example 63 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-1-(2-cyclobutyl-6-(methylsulfonyl)benzene yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
- Zinc powder 52 g, 800 mmol, Acros
- tetrahydrofuran 100 mL
- trimethylsilyl chloride 8.7 g, 80 mmol
- bromocyclobutane 54g, 400mmol
- 2-bromo-6-(methylsulfonyl)aniline 10g, 40mmol
- [1,1'-bis(diphenylphosphine) were added
- ferrocene] palladium dichloride dichloromethane complex 3.3 g, 4 mmol
- 2,6-Dichloro-5-fluoronicotinamide (7.7 g, 37 mmol) was dissolved in 100 mL of dry tetrahydrofuran, and oxalyl chloride (47 g, 370 mmol) was slowly added dropwise to this solution. After the dropwise addition, the mixture was stirred at 75°C under reflux for 2 hours, and then concentrated to dryness under reduced pressure. The residue was diluted with 100 mL of anhydrous tetrahydrofuran and cooled to zero. 2-Cyclobutyl-6-(methylsulfonyl)aniline (8.8 g, 39 mmol) was dissolved in 50 mL of dry tetrahydrofuran and added dropwise to the above solution.
- reaction solution was stirred at zero degrees for 2 hours, quenched with saturated ammonium chloride/saturated brine (1:1, 100 mL), and then extracted twice with ethyl acetate (50 mL).
- the combined organic phases were dried, concentrated, and the residual solid was slurried with petroleum ether/ethyl acetate (5:1, 200 mL), suction filtered, and dried to obtain the target product (12.7 g, yield: 75%).
- Step 6 4-((2S,5R)-4-Acryloyl-2,5-dimethylpiperazin-1-yl)-7-chloro-1-(2-cyclobutyl-6-(methyl) Preparation of sulfonyl)phenyl)-6-fluoropyridin[2,3-d]pyrimidin-2(1H)-one
- Step 7 4-((2S,5R)-4-Acryloyl-2,5-dimethylpiperazin-1-yl)-1-(2-cyclobutyl-6-(methylsulfonyl) Preparation of phenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
- Example 63-1 obtained two isomers Examples 63A and 63B by chiral separation:
- Example 76 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-7-(1,4-dimethyl-1H-imidazol-5-yl)-6-fluoro -1-(2-Isopropyl-6-(methylsulfonyl)phenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
- Example 78 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-1-(2-isopropyl-6-(methylsulfonyl)benzene yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
- Example 78-1 Two isomers Examples 78A and 78B were obtained by chiral separation:
- Example 79-1 Two isomers Examples 79A and 79B were obtained by chiral separation:
- Example 80 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2- Isopropyl-6-(isopropylsulfonyl)phenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
- Example 80-1 Two isomers Examples 80A and 80B were obtained by chiral separation:
- Example 81 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-1-(2-cyclopropyl-6-(methylsulfonyl)benzene yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
- Example 81-1 Two isomers Examples 81A and 81B were obtained by chiral separation:
- Example 82 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-1-(2-ethyl-6-(isopropylsulfonyl)benzene yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
- Example 82-1 Two isomers Examples 82A and 82B were obtained by chiral separation:
- Example 83 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-1-(2-ethyl-6-(isopropylsulfonyl)phenyl)-6- Fluoro-7-(2-Fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
- Example 83-1 Two isomer Examples 83A and 83B were obtained by chiral separation:
- Example 84 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-6-chloro-1-(2-ethyl-6-(methylsulfonyl) Acyl)phenyl)-7-(2-fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
- Example 84-1 Two isomers Examples 84A and 84B were obtained by chiral separation:
- 2,6-Dichloro-5-fluoronicotinamide (420 mg, 2.0 mmol) was dissolved in dry tetrahydrofuran (7 mL), and to this solution was slowly added dropwise oxalyl chloride (1.7 mL, 20.0 mmol) in dichloromethane ( 2mL) solution. After the dropwise addition, the mixture was stirred at 75°C under reflux for 2 h, and then concentrated to dryness under reduced pressure. The residue was diluted with anhydrous tetrahydrofuran (7 mL) and cooled to 0°C.
- the ethyl acetate layers were combined, dried, and concentrated.
- Step 5 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2 Preparation of -(methylsulfonyl)phenyl)pyridin[2,3-d]pyrimidin-2(1H)-one
- Example 87-1 Two isomers Example 87A and Example 87B were obtained by chiral separation:
- Example 87A LC-MS: m/z 596 (M+H) + .
- Example 87B LC-MS: m/z 596 (M+H) + .
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Abstract
Provided are an aryl or heteroaryl pyridone or pyrimidone derivative and a preparation method therefor and an application thereof. Specifically, the compound has a structure as shown in formula (I). Also disclosed are a preparation method for the compound and an application of the compound as a KRASG12C inhibitor. The compound has a good selective inhibition effect on KRASG12C and has better pharmacodynamic and pharmacokinetic performance and lower toxic and lower side effects.
Description
本发明属于药物领域,具体涉及一种芳基或杂芳基并吡啶酮或嘧啶酮类衍生物及其制备方法和应用。The invention belongs to the field of medicine, in particular to an aryl or heteroaryl pyridone or pyrimidone derivative and a preparation method and application thereof.
肺癌是人类癌症致死的重要原因之一。按照细胞类型肺癌可以分为小细胞肺癌(SCLC)和非小细胞肺癌(NSCLC),其中NSCLC占所有肺癌患者的85%。据统计2016年全球NSCLC的市场约为209亿美元,其中美国市场占据一半,其次是日本、德国和中国。从现有趋势来看,非小细胞肺癌市场保持着持续增长,预计2023年全球市场将达到540亿美元(Nature,2018;553(7689):446-454)。Lung cancer is one of the important causes of human cancer death. Lung cancer can be divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) according to cell type, and NSCLC accounts for 85% of all lung cancer patients. According to statistics, the global NSCLC market in 2016 was approximately US$20.9 billion, of which the US market accounted for half, followed by Japan, Germany and China. Judging from the existing trends, the non-small cell lung cancer market has maintained continuous growth, and the global market is expected to reach US$54 billion in 2023 (Nature, 2018;553(7689):446-454).
目前NSCLC的主要治疗用药分为化疗药物、分子靶向药物以及肿瘤免疫疗法等。其中化疗药物主要包括吉西他滨、紫杉醇以及铂类药物等,但是这类药物普遍具有选择性差、毒性大从而导致比较强烈的毒副作用。近年来,分子靶向药物因其选择性较高、毒副作用相对较小,能够实现精准治疗等明显优势从而逐渐成为研究热点。现有的NSCLC分子靶向药物包括EGFR抑制剂(如阿法替尼、吉非替尼、厄洛替尼、拉帕替尼、达克替尼、埃克替尼、吡咯替尼、诺司替尼(Rociletinib)、奥希替尼等)、ALK抑制剂(如色瑞替尼、艾乐替尼、布加替尼、劳拉替尼、奥卡替尼等),以及VEGFR抑制剂(索拉非尼、瑞戈非尼、卡博替尼、舒尼替尼、多纳非尼等)。At present, the main treatment drugs for NSCLC are divided into chemotherapy drugs, molecular targeted drugs and tumor immunotherapy. Among them, chemotherapy drugs mainly include gemcitabine, paclitaxel and platinum drugs, but these drugs generally have poor selectivity and high toxicity, resulting in relatively strong side effects. In recent years, molecularly targeted drugs have gradually become a research hotspot due to their obvious advantages such as high selectivity, relatively small toxic and side effects, and the ability to achieve precise treatment. Existing NSCLC molecularly targeted drugs include EGFR inhibitors (such as afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, pyrotinib, Rociletinib, osimertinib, etc.), ALK inhibitors (such as ceritinib, alectinib, brigatinib, lorlatinib, ocaltinib, etc.), and VEGFR inhibitors ( Sorafenib, Regorafenib, Cabozantinib, Sunitinib, Donafenib, etc.).
在肺癌病患里面,经常检测到KRAS突变,约占所有致癌基因突变的32%。其中KRAS
G12C突变在NSCLC里面占所有致癌基因突变的44%。到目前为止,市场上仍然没有针对KRAS
G12C突变的药物被批准上市。
In lung cancer patients, KRAS mutations are frequently detected, accounting for about 32% of all oncogene mutations. Among them, the KRAS G12C mutation accounts for 44% of all oncogene mutations in NSCLC. So far, there are still no drugs on the market that target the KRAS G12C mutation.
由于KRAS
G12C靶蛋白在病理学上与多种疾病相关,因此目前还需要新型的KRAS
G12C抑制剂用于临床治疗。高选择性高活性的KRAS
G12C抑制剂可以对KRAS
G12C突变导致的癌症等疾病更有效治疗,以及减少脱靶效应的潜力,因而具有更迫切的临床需求。
Since KRAS G12C target proteins are pathologically associated with various diseases, novel KRAS G12C inhibitors are still needed for clinical treatment. Highly selective and highly active KRAS G12C inhibitors can be more effective in the treatment of diseases such as cancer caused by KRAS G12C mutations, and have the potential to reduce off-target effects, so there is a more urgent clinical need.
发明内容SUMMARY OF THE INVENTION
本发明的目的在于提供一类新型的对KRAS
G12C有选择性抑制作用和/或更好药效学性能的化合物及其用途。
The purpose of the present invention is to provide a new class of compounds with selective inhibitory effect on KRAS G12C and/or better pharmacodynamic properties and uses thereof.
本发明的第一方面,提供一种式(I)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药:The first aspect of the present invention provides a compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug:
式中:where:
A、B相同或者不同,各自独立地选自下组:CH、CR
5或N;
A and B are the same or different, and are each independently selected from the group consisting of CH, CR 5 or N;
X选自下组:4-14元饱和或不饱和杂环基、C
4-C
14环烷基、C
6-C
14芳基或5-14元杂芳基,其中,所述的杂环基、环烷基、芳基或杂芳基可以任选地被一个或多个(如2、3或4)R
8所取代;
X is selected from the group consisting of 4-14 membered saturated or unsaturated heterocyclic group, C 4 -C 14 cycloalkyl group, C 6 -C 14 aryl group or 5-14 membered heteroaryl group, wherein said heterocyclic group radical, cycloalkyl, aryl or heteroaryl can be optionally substituted with one or more (eg 2, 3 or 4) R8 ;
U、V、W和Q相同或者不同,各自独立地选自下组:CH、CR
3或N;
U, V, W and Q are the same or different and are each independently selected from the group consisting of CH, CR or N;
R
1选自下组:
其中,
代表双键“=”或三键“≡”;
R 1 is selected from the following group: in, Represents a double bond "=" or a triple bond "≡";
R
A为不存在,或者独立地选自下组:氢、氘、氟、氰基或者C
1-C
3烷基;各R
B独立地选自下组:氢、氘、氰基或者C
1-C
3烷基;其中,所述烷基可以被选自下组的一个或多个(如2、3或4)取代基取代:氘、卤素、氰基、胺基、C
3-C
7环烷基、4-7元杂环基、NHR
9或NR
9R
10;R
9和R
10各自独立地为C
1-C
3烷基;或R
9,R
10与其连接的N原子一起构成取代或未取代的4-8元杂环基;
RA is absent, or independently selected from the group consisting of hydrogen, deuterium, fluorine, cyano, or C1 - C3 alkyl; each R B is independently selected from the group consisting of hydrogen, deuterium, cyano, or C1 -C 3 alkyl; wherein the alkyl may be substituted with one or more (eg 2, 3 or 4) substituents selected from the group consisting of deuterium, halogen, cyano, amine, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclyl, NHR 9 or NR 9 R 10 ; R 9 and R 10 are each independently C 1 -C 3 alkyl; or R 9 , R 10 together with the N atom to which it is attached constitutes substituted or unsubstituted 4-8 membered heterocyclyl;
p为1或2的整数;p is an integer of 1 or 2;
R
2选自取代的下组基团:C
6-C
14芳基、5-14元杂芳基,其中,所述取代是指被选自下组的一个或多个基团取代:R'、-SR'、-SOR'、-SO
2R'、-SO
2NR'R”、-NR'SO
2R”、-P(=O)R'R”;限定条件是所述C
6-C
14芳基、5-14元杂芳基至少含有一个取代基选自:-SR'、-SOR'、-SO
2R'、-SO
2NR'R”、-NR'SO
2R”、或-P(=O)R'R”;R'、R”相同或不同,各自独立地选自取代或未取代的下组基团:氢、氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
6烷基、C
3-C
8环烷基、C
4-C
10环烯基、4-8元杂环基、C
6-C
14芳基、5-14元杂芳基;或当R'和R”连接于同一个N原子时,R'、R”与其连接的N原子一起构成取代或未取代的4-8元杂环基;
R 2 is selected from the group of substituted groups: C 6 -C 14 aryl, 5-14-membered heteroaryl, wherein the substitution refers to being substituted by one or more groups selected from the group: R' , -SR', -SOR', -SO 2 R', -SO 2 NR'R", -NR'SO 2 R", -P(=O)R'R"; the qualification is that the C 6 - C 14 aryl, 5-14-membered heteroaryl group contains at least one substituent selected from: -SR', -SOR', -SO 2 R', -SO 2 NR'R", -NR'SO 2 R", or -P(=O)R'R";R',R" are the same or different, each independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, halogen, nitro, hydroxyl, cyano, Ester group, amine group, amide group, C 1 -C 6 alkyl group, C 3 -C 8 cycloalkyl group, C 4 -C 10 cycloalkenyl group, 4-8 membered heterocyclic group, C 6 -C 14 aryl group , 5-14-membered heteroaryl; or when R' and R" are connected to the same N atom, R', R" together with the N atom to which they are connected constitute a substituted or unsubstituted 4-8-membered heterocyclic group;
R
3选自取代或未取代的下组基团:氢、氘、C
1-C
18烷基、氘代C
1-C
18烷基、卤代C
1-C
18烷基、C
3-C
20环烷基、C
1-C
18烷氧基、氘代C
1-C
18烷氧基、卤代C
1-C
18烷氧基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基、脲基、4-20元杂环基、C
6-C
14芳基、5-14元杂芳基;
R 3 is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, halogen, nitro, hydroxyl, cyano, ester, amine group, amide group, sulfonamide group, urea group, 4-20-membered heterocyclic group, C 6 -C 14 aryl group, 5-14-membered heteroaryl group;
L选自下组:键、-C(O)-、C
1-C
3亚烷基;
L is selected from the group consisting of a bond, -C(O)-, C 1 -C 3 alkylene;
R
4选自取代或未取代的下组基团:氢、氘、C
1-C
18烷基、氘代C
1-C
18烷基、卤代C
1-C
18烷基、C
3-C
20环烷基、C
1-C
18烷氧基、氘代C
1-C
18烷氧基、卤代C
1-C
18烷氧基、胺基、羟基、4-20元杂环基、C
6-C
14芳基、5-14元杂芳基;
R 4 is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, amino, hydroxyl, 4-20-membered heterocyclic group, C 6 -C 14 -aryl, 5-14-membered heteroaryl;
R
5选自取代或未取代的下组基团:氢、氘、C
1-C
18烷基、氘代C
1-C
18烷基、卤代C
1-C
18烷基、C
3-C
20环烷基、C
1-C
18烷氧基、氘代C
1-C
18烷氧基、卤代C
1-C
18烷氧基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基、脲基、4-20元杂环基、C
6-C
14芳基、5-14元杂芳基;
R 5 is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, halogen, nitro, hydroxyl, cyano, ester, amine group, amide group, sulfonamide group, urea group, 4-20-membered heterocyclic group, C 6 -C 14 aryl group, 5-14-membered heteroaryl group;
R
6选自取代或未取代的下组基团:氢、氘、C
1-C
18烷基、氘代C
1-C
18烷基、卤代C
1-C
18烷基、C
3-C
20环烷基、C
1-C
18烷氧基、氘代C
1-C
18烷氧基、卤代C
1-C
18烷氧基、4-20元杂环基、C
6-C
14芳基、5-14元杂芳基;
R 6 is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, 4-20 membered heterocyclic group, C 6 -C 14 aryl base, 5-14-membered heteroaryl;
R
8独立地选自取代或未取代的下组基团:氢、氘、C
1-C
18烷基、氘代C
1-C
18烷基、卤代C
1-C
18烷基、C
3-C
20环烷基、C
1-C
18烷氧基、氘代C
1-C
18烷氧基、卤代C
1-C
18烷氧基、氨基、羟基、4-20元杂环基、C
6-C
14芳基、5-14元杂芳基;
R 8 is independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, amino, hydroxyl, 4-20-membered heterocyclic group, C 6 -C 14 aryl, 5-14 membered heteroaryl;
其中,所述“取代”未特别说明的情况下,均是指被选自下组的一个或多个基团取代:氢、氘、C
1-C
18烷基、氘代C
1-C
18烷基、卤代C
1-C
18烷基、C
3-C
20环烷基、C
1-C
18烷氧基、氘代C
1-C
18烷氧基、卤代C
1-C
18烷氧基、C
6-C
14芳基、5-14元杂芳基、4-20元杂环基、卤素、硝基、羟基、氰基、酯基、胺基、NR
bC(=O)OR
e、OC(=O)R
e、OC(=O)NR
bR
c、酰胺基、磺酰胺基或脲基;R
b、R
c可以独立表示氢、氘、C1-C6烷基、C3-C8环烷基、4-8元杂环基、5-14元杂芳基或C6-C14芳环,或者说R
b和R
c与N原子一起可以形成4-8元杂环基;R
e可以独立表示氢、C1-C6烷基、C3-C8环烷基、C2-C6烯基、C3-C6环烯基、C2-C6炔基、4-8元杂环基、5-14元杂芳基或C6-C14芳环;
Wherein, the “substituted” refers to being substituted by one or more groups selected from the following group unless otherwise specified: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 Alkyl, halogenated C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy Oxy, C 6 -C 14 aryl, 5-14-membered heteroaryl, 4-20-membered heterocyclyl, halogen, nitro, hydroxyl, cyano, ester, amine, NR b C(=O) OR e , OC(=O)R e , OC(=O)NR b R c , amide group, sulfonamide group or urea group; R b , R c can independently represent hydrogen, deuterium, C1-C6 alkyl, C3 -C8 cycloalkyl, 4-8 membered heterocyclyl, 5-14 membered heteroaryl or C6-C14 aromatic ring, or Rb and Rc together with N atom can form 4-8 membered heterocyclyl; R e can independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl, 4-8 membered heterocyclyl, 5-14 membered Heteroaryl or C6-C14 aromatic ring;
限定条件为:The qualifications are:
当B为CH或CR
5时,R
1选自下组:
其中,p为2;
When B is CH or CR 5 , R 1 is selected from the group consisting of: Among them, p is 2;
当V为C(Cl)时,R
2不选自:
When V is C(Cl ) , R is not selected from:
在另一优选例中,本发明化合物不包含如下化合物:In another preferred embodiment, the compound of the present invention does not include the following compounds:
在另一优选例中,所述化合物不包含如下化合物:In another preferred embodiment, the compound does not include the following compounds:
在另一优选例中,R
8各自独立地选自取代或未取代的下组基团:氢、氘、C
1-C
6烷基、氘代C
1-C
6烷基、卤代C
1-C
6烷基、C
3-C
8环烷基、C
1-C
6烷氧基、氘代C
1-C
6烷氧基、卤代C
1-C
6烷氧基、氨基、羟基、4-8元杂环基;所述取代是指被选自下组的一个或多个基团取代:氢、氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。
In another preferred embodiment, each R 8 is independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, amino, hydroxyl, 4-8 membered heterocyclyl; the substitution refers to substitution by one or more groups selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, Sulfonamide group or urea group.
另一优选例中,R
8各自独立地选自取代或未取代的下组基团:氢、氘、C
1-C
18烷基、氘代C
1-C
18烷基、卤代C
1-C
18烷基;其中,所述取代是指被氰基取代。
In another preferred embodiment, R 8 is each independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 - C 18 alkyl; wherein, the substitution refers to substitution by cyano.
在另一优选例中,R
1选自下组:-C(O)C(R
A)=C(R
B)
2、-S(O)
2C(R
A)=C(R
B)
2、-NR
6C(O)C(R
A)=C(R
B)
2或-NR
6S(O)
2C(R
A)=C(R
B)
2;
In another preferred embodiment, R 1 is selected from the following group: -C(O)C(R A )=C(R B ) 2 , -S(O) 2 C(R A )=C(R B ) 2 , -NR 6 C(O)C( RA )=C( RB ) 2 or -NR 6 S(O) 2 C( RA )=C( RB ) 2 ;
其中,R
A独立地选自下组:氢、氘、氟、氰基或者C
1-C
3烷基;各R
B相同或不同,且独立地选自下组:氢、氘、氰基或者C
1-C
3烷基;其中,所述烷基可以被选自下组的一个或多个取代基取代:氘、卤素、氰基、胺基、C
3-C
7环烷基、4-7元杂环基、NHR
9或NR
9R
10;R
9和R
10各自独立地为C
1-C
3烷基;或R
9,R
10与其连接的N原子一起构成取代或未取代的4-8元杂环基;
wherein, R A is independently selected from the group consisting of hydrogen, deuterium, fluorine, cyano, or C 1 -C 3 alkyl; each R B is the same or different, and is independently selected from the group consisting of hydrogen, deuterium, cyano or C 1 -C 3 alkyl; wherein the alkyl may be substituted with one or more substituents selected from the group consisting of deuterium, halogen, cyano, amino, C 3 -C 7 cycloalkyl, 4- 7-membered heterocyclyl, NHR 9 or NR 9 R 10 ; R 9 and R 10 are each independently C 1 -C 3 alkyl; or R 9 , R 10 together with the N atom to which it is attached constitutes a substituted or unsubstituted 4 -8-membered heterocyclyl;
R
6选自取代或未取代的下组基团:氢、氘、C
1-C
6烷基、氘代C
1-C
6烷基、卤代C
1-C
6烷基、C
3-C
8环烷基、C
1-C
6烷氧基、氘代C
1-C
6烷氧基、卤代C
1-C
6烷氧基、4-8元杂环基、C
6-C
14芳基、5-14元杂芳基;
R 6 is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 3 -C 8 -cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, 4-8 membered heterocyclic group, C 6 -C 14 aryl base, 5-14-membered heteroaryl;
其中,所述“取代”未特别说明的情况下,均是指被选自下组的一个或多个基团取代:氢、氘、C
1-C
6烷基、氘代C
1-C
6烷基、卤代C
1-C
6烷基、C
3-C
8环烷基、C
1-C
6烷氧基、氘代C
1-C
6烷氧基、卤代C
1-C
6烷氧基、C
6-C
10芳基、5-10元杂芳基、4-8元杂环基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基;
Wherein, the "substituted" refers to being substituted by one or more groups selected from the following group unless otherwise specified: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 Alkyl, halogenated C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy oxy, C 6 -C 10 aryl, 5-10 membered heteroaryl, 4-8 membered heterocyclyl, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamido or Urea group;
限定条件为:The qualifications are:
当B为N时,R
1选自下组:-C(O)C(R
A)=C(R
B)
2或-S(O)
2C(R
A)=C(R
B)
2;
When B is N, R1 is selected from the group consisting of -C(O)C( RA )=C( RB ) 2 or -S(O) 2C ( RA )=C( RB ) 2 ;
当B为CH或CR
5时,R
1选自下组:-NR
6C(O)C(R
A)=C(R
B)
2或-NR
6S(O)
2C(R
A)=C(R
B)
2。
When B is CH or CR5 , R1 is selected from the group consisting of -NR6C (O)C( RA )=C( RB ) 2 or -NR6S (O) 2C ( RA )= C(R B ) 2 .
在另一优选例中,R
1为-C(O)C(R
A)=C(R
B)
2,其中,R
A独立地选自下组:氢、氟;各R
B相同或不同,且独立地选自下组:氢或C
1-C
3烷基,其中,所述烷基可以被选自下组 的一个或多个取代基取代:氘、卤素、氰基、胺基、C
3-C
7环烷基、4-7元杂环基、NHR
9或NR
9R
10;R
9和R
10各自独立地为C
1-C
3烷基;或R
9,R
10与其连接的N原子一起构成4-8元杂环基。
In another preferred embodiment, R 1 is -C(O)C( RA )=C( RB ) 2 , wherein, RA is independently selected from the following group: hydrogen, fluorine; each R B is the same or different, and independently selected from the group consisting of hydrogen or C 1 -C 3 alkyl groups, wherein the alkyl group may be substituted with one or more substituents selected from the group consisting of deuterium, halogen, cyano, amino, C 3 -C 7 cycloalkyl, 4-7 membered heterocyclyl, NHR 9 or NR 9 R 10 ; R 9 and R 10 are each independently C 1 -C 3 alkyl; or R 9 , to which R 10 is attached The N atoms together constitute a 4-8 membered heterocyclic group.
在另一优选例中,R
2选自取代的下组基团:苯基、5-6元杂芳基,其中,R
2中所述取代是指被选自下组的一个或多个基团取代:R'、-SO
2R'、-SO
2NR'R”、-NR'SO
2R”、-P(=O)R'R”;R'、R”相同或不同,各自独立地选自取代或未取代的下组基团:氢、氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
6烷基、C
3-C
6环烷基、C
4-C
6环烯基、4-8元杂环基、C
6-C
10芳基、5-10元杂芳基;或当R'和R”连接于同一个N原子时,R'、R”与其连接的N原子一起构成取代或未取代的4-6元杂环基;其中,R'和R”中所述取代是指被选自下组的一个或多个基团取代:氢、氘、C
1-C
6烷基、氘代C
1-C
6烷基、卤代C
1-C
6烷基、C
3-C
8环烷基、C
1-C
6烷氧基、氘代C
1-C
6烷氧基、卤代C
1-C
6烷氧基、C
6-C
10芳基、5-10元杂芳基、4-8元杂环基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。
In another preferred example, R 2 is selected from the group of substituted groups: phenyl, 5-6-membered heteroaryl, wherein the substitution in R 2 refers to one or more groups selected from the group below Group substitution: R', -SO 2 R', -SO 2 NR'R", -NR'SO 2 R", -P(=O)R'R";R',R" are the same or different, each independently is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C1 - C6 alkyl, C3 - C6 ring Alkyl, C 4 -C 6 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 10 membered aryl, 5-10 membered heteroaryl; or when R' and R" are attached to the same N atom , R', R" together with the N atom connected to form a substituted or unsubstituted 4-6-membered heterocyclic group; wherein, the substitution described in R' and R" refers to one or more groups selected from the following group Group substitution: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkyl Oxy group, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 10 aryl, 5-10 membered heteroaryl, 4-8 membered heterocyclyl, halogen , nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or urea groups.
在另一优选例中,R
3为卤素。
In another preferred embodiment, R 3 is halogen.
在另一优选例中,R
4选自取代或未取代的下组基团:苯基或5-6元杂芳基,其中,所述取代是指被选自下组的一个或多个基团取代:氢、氘、卤素、酯基、NR
bC(=O)OR
e、OC(=O)R
e、OC(=O)NR
bR
c、胺基、卤代C
1-C
18烷基(优选卤代C
1-C
6烷基,更优选卤代C
1-C
3烷基)、羟基;R
b、R
c可以独立表示氢、氘、C1-C6烷基、C3-C8环烷基、4-8元杂环基、5-14元杂芳基或C6-C14芳环,或者说R
b和R
c与N原子一起可以形成4-8元杂环基;R
e可以独立表示氢、C1-C6烷基、C3-C8环烷基、C2-C6烯基、C3-C6环烯基、C2-C6炔基、4-8元杂环基、5-14元杂芳基或C6-C14芳环。
In another preferred example, R 4 is selected from the group consisting of substituted or unsubstituted groups: phenyl or 5-6-membered heteroaryl, wherein the substitution refers to one or more groups selected from the group below Group substitution: hydrogen, deuterium, halogen, ester, NR b C(=O)OR e , OC(=O)R e , OC(=O)NR b R c , amine group, halogenated C 1 -C 18 Alkyl (preferably halogenated C 1 -C 6 alkyl, more preferably halogenated C 1 -C 3 alkyl), hydroxyl; R b and R c can independently represent hydrogen, deuterium, C1-C6 alkyl, C3-C8 Cycloalkyl, 4-8-membered heterocyclic group, 5-14-membered heteroaryl or C6-C14 aromatic ring, or R b and R c together with N atom can form a 4-8-membered heterocyclic group; R e can Independently represents hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl, 4-8 membered heterocyclyl, 5-14 membered heteroaryl base or C6-C14 aromatic ring.
在另一优选例中,A、B相同或者不同,各自独立地为CH或N。In another preferred example, A and B are the same or different, and are each independently CH or N.
在另一优选例中,Q为N。In another preferred embodiment, Q is N.
在另一优选例中,U为N。In another preferred embodiment, U is N.
在另一优选例中,V、W各自独立地为CR
3,R
3为H或卤素。
In another preferred example, V and W are each independently CR 3 , and R 3 is H or halogen.
在另一优选例中,所述的式(I)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其具有式(II-A)或(II-B)所示的结构:In another preferred embodiment, the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, has The structure represented by formula (II-A) or (II-B):
式中:where:
R
1、R
2、R
4、A、B、L、X、U、V、W、Q的定义如上所述。
R 1 , R 2 , R 4 , A, B, L, X, U, V, W, Q are defined as described above.
在另一优选例中,所述的式(I)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其具有式(III)所示结构:In another preferred embodiment, the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, has The structure shown in formula (III):
R
1、R
2、R
4、X、L、U、V、W、Q的定义如上所述。
The definitions of R 1 , R 2 , R 4 , X, L, U, V, W, and Q are as described above.
在另一优选例中,所述的式(I)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其具有式(IV)所示结构:In another preferred embodiment, the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, has The structure shown in formula (IV):
式中:where:
R
1、R
2、R
4、R
8、L、U、V、W、Q的定义如上所述。
R 1 , R 2 , R 4 , R 8 , L, U, V, W, Q are defined as above.
在另一优选例中,所述的式(I)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其具有式(V)所示结构:In another preferred embodiment, the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, has The structure shown in formula (V):
式中:where:
R
1、R
2、R
4、R
8、U、V、W、Q的定义如上所述。
R 1 , R 2 , R 4 , R 8 , U, V, W, Q are defined as described above.
在另一优选例中,所述的式(I)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其具有式(VI)所示结构:In another preferred embodiment, the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, has The structure shown in formula (VI):
式中:where:
R
1、R
2、R
4、R
8、U、V、Q的定义如上所述。
The definitions of R 1 , R 2 , R 4 , R 8 , U, V, and Q are as described above.
在另一优选例中,所述的式(I)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其特征在于,其具有式(VII)所示的结构:In another preferred embodiment, the compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, is characterized by In that it has the structure shown in formula (VII):
式中:where:
R
1、R
2、R
4、R
8、V、Q的定义如上所述。
The definitions of R 1 , R 2 , R 4 , R 8 , V and Q are as described above.
在另一优选例中,所述的式(I)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其具有式(VIII)所示的结构:In another preferred embodiment, the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, has The structure shown by formula (VIII):
式中,In the formula,
R”'选自取代或未取代的下组基团:氢、氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
6烷基、C
3-C
8环烷基、C
4-C
10环烯基、4-8元杂环基、C
6-C
14芳基、5-14元杂芳基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
6烷基、C
3-C
8环烷基、C
4-C
10环烯基、4-8元杂环基、C
6-C
14芳基、5-14元杂芳基;
R"' is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 -C 8 -cycloalkyl, C 4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl, wherein the substitution refers to being selected from the group Substituted with one or more groups of: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amido, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 4 - C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl;
q选自:1、2、3或4;q is selected from: 1, 2, 3 or 4;
R
1、R
4、R
8、R'、V、Q的定义如上所述。
The definitions of R 1 , R 4 , R 8 , R′, V, and Q are as described above.
在另一优选例中,
部分中,R
8可以是1、2、3或4个,或者两个相邻的R
8可以与其相连的C原子共同形成C
3-C
6环烷基。
In another preferred embodiment, moiety, R 8 may be 1, 2, 3 or 4, or two adjacent R 8 may together form a C 3 -C 6 cycloalkyl group with the C atom to which it is attached.
在另一优选例中,所述的化合物具有式(VIII-A)所示的结构:In another preferred example, the compound has the structure shown in formula (VIII-A):
式中,In the formula,
R”'各自独立地选自取代或未取代的下组基团:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
6烷基、C
3-C
8环烷基、C
4-C
10环烯基、4-8元杂环基、C
6-C
14芳基、5-14元杂芳基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
6烷基、C
3-C
8环烷基、C
4-C
10环烯基、4-8元杂环基、C
6-C
14芳基、5-14元杂芳基;
R"' is each independently selected from the group consisting of substituted or unsubstituted groups: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 - C 8 cycloalkyl, C 4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl, wherein the substitution refers to being selected from the following Substituted with one or more groups of the group: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amido, C1 - C6 alkyl, C3 - C8 cycloalkyl, C4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl;
q选自:1、2、3或4;q is selected from: 1, 2, 3 or 4;
R
1、R
4、R
8、R'、V、Q的定义如上所述。
The definitions of R 1 , R 4 , R 8 , R′, V, and Q are as described above.
在另一优选例中,R
8各自独立地选自取代或未取代的下组基团:氢、氘、C
1-C
6烷基、氘代C
1-C
6烷基、卤代C
1-C
6烷基,其中,所述取代是指被氰基取代。
In another preferred embodiment, each R 8 is independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, wherein the substitution refers to substitution by cyano.
在另一优选例中,各R
8独立地为取代或未取代的C
1-C
3烷基,其中,所述取代是指被氰基取代。
In another preferred embodiment, each R 8 is independently a substituted or unsubstituted C 1 -C 3 alkyl group, wherein the substitution refers to being substituted by a cyano group.
在另一优选例中,各R
8为甲基。
In another preferred embodiment, each R 8 is methyl.
在另一优选例中,所述的式(I)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其具有式(IX)所示的结构:In another preferred embodiment, the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, has The structure shown by formula (IX):
式中,In the formula,
R
1选自:
其中,R
A选自:H、D、卤素或氰基;R
B、R
B’相同或不同,各自独立地选自:H、D、卤素、氰基、取代或未取代的C
1-C
3烷基;其中,所述取代是指被选自下组的一个或多个基团取代:D、卤素、氰基、C
1-C
3烷基、C
3-C
6环烷基、4-6元杂环基或NR
IVR
V;R
IV、R
V相同或不同,各自独立地选自:H、C
1-C
3烷基、C
3-C
6环烷基或4-6元杂环基;或者R
IV、R
V和相邻的N一起环合形成4-6元杂环基;
R1 is selected from : Wherein, R A is selected from: H, D, halogen or cyano; R B and R B' are the same or different, each independently selected from: H, D, halogen, cyano, substituted or unsubstituted C 1 -C 3 alkyl; wherein, the substitution refers to being substituted by one or more groups selected from the group consisting of D, halogen, cyano, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 4 -6-membered heterocyclyl or NR IV R V ; R IV and R V are the same or different, each independently selected from: H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl or 4-6 membered Heterocyclyl; or R IV , R V and adjacent N are cyclized together to form a 4-6 membered heterocyclyl;
R
4、R'、V、Q、R”'和q的定义如上所述。
R4 , R', V, Q, R"' and q are as defined above.
在另一优选例中,R”'选自取代或未取代的下组基团:C
1-C
6烷基、C
3-C
8环烷基、C
4-C
10环烯基、4-8元杂环基、C
6-C
10芳基、5-10元杂芳基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
6烷基、C
3-C
8环烷基、4-8元杂环基。
In another preferred example, R"' is selected from the group consisting of substituted or unsubstituted groups: C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 4 -C 10 cycloalkenyl, 4- 8-membered heterocyclyl, C 6 -C 10 aryl, 5-10-membered heteroaryl, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of deuterium, halogen, nitro, Hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 4-8 membered heterocyclic group.
在另一优选例中,R”'选自取代或未取代的下组基团:C
1-C
6烷基、C
3-C
6环烷基、C
4-C
6环烯基、4-6元杂环基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
3烷基。
In another preferred example, R"' is selected from the group consisting of substituted or unsubstituted groups: C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 6 cycloalkenyl, 4- 6-membered heterocyclic group, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 3 alkyl.
在另一优选例中,R”'选自取代或未取代的下组基团:C
3-C
8环烷基、4-8元杂环基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
3烷基。
In another preferred embodiment, R"' is selected from the group consisting of substituted or unsubstituted groups: C 3 -C 8 cycloalkyl, 4-8 membered heterocyclyl, wherein the substitution refers to being selected from the group consisting of Substituted with one or more groups of the group: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C1 - C3 alkyl.
在另一优选例中,R”'选自取代或未取代的下组基团:乙基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、环丙氨基、氮杂环丁烷基、氮杂环戊烷基、氮杂环己烷基、环氧乙烷基、氧杂环丁烷基、氧杂环戊烷基、氧杂环己烷基,其中,所述取代是指被选自下组的一个或多个(如2、3、4)基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
3烷基。
In another preferred example, R"' is selected from the group consisting of substituted or unsubstituted groups: ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl amino, azetidinyl, azepanyl, azetidinyl, oxiranyl, oxetanyl, oxolane, oxanyl, Wherein, the substitution refers to being substituted by one or more (such as 2, 3, 4) groups selected from the group consisting of deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 3 alkyl.
在另一优选例中,q为1。In another preferred embodiment, q is 1.
在另一优选例中,R
2选自:
In another preferred embodiment, R 2 is selected from:
K=O、S、CH
2或NH;f=0、1或2。
K=O, S, CH2 or NH; f=0, 1 or 2.
在另一优选例中,R
2选自下组:
In another preferred embodiment, R 2 is selected from the following group:
K独立地为O、S、CH2或NH;e和f各自独立地为0、1或2,优选地上述基团中的H可任选地被氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
3烷基取代。
K is independently O, S, CH2 or NH; e and f are each independently 0, 1 or 2, preferably H in the above groups can be optionally deuterium, halogen, nitro, hydroxyl, cyano, Ester group, amine group, amide group, C 1 -C 3 alkyl substitution.
K独立地为O、S、CH2或NH;e和f各自独立地为0、1或2,优选地上述基团中的H可任选地被氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
3烷基取代。
K is independently O, S, CH2 or NH; e and f are each independently 0, 1 or 2, preferably H in the above groups can be optionally deuterium, halogen, nitro, hydroxyl, cyano, Ester group, amine group, amide group, C 1 -C 3 alkyl substitution.
在另一优选例中,所述的化合物具有式(VIII-1)或(VIII-2)所示的结构:In another preferred example, the compound has the structure represented by formula (VIII-1) or (VIII-2):
式中,In the formula,
Rx选自:F或Cl;Rx is selected from: F or Cl;
R
4选自取代或未取代苯基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、酯基、氰基、NR
bC(=O)OR
e、OC(=O)R
e、OC(=O)NR
bR
c、胺基、C
1-C
6烷基、卤代C
1-C
6烷基、C
1-C
6烷氧基、羟基;R
b、R
c可以独立表示氢、氘、C
1-C
6烷基、C
3-C
8环烷基、4-8元杂环基、5-14元杂芳基或C
6-C
14芳环,或者说R
b和R
c与N原子一起可以形成4-8元杂环基;R
e可以独立表示氢、C1-C
6烷基、C
3-C
8环烷基、C
2-C
6烯基、C
3-C
6环烯基、C
2-C
6炔基、4-8元杂环基、5-14元杂芳基或C6-C14芳环;
R 4 is selected from substituted or unsubstituted phenyl, wherein the substitution refers to substitution by one or more groups selected from the group consisting of deuterium, halogen, ester, cyano, NR b C(=O)OR e , OC(=O)R e , OC(=O)NR b R c , amine group, C 1 -C 6 alkyl group, halogenated C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, Hydroxyl; R b , R c can independently represent hydrogen, deuterium, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 4-8-membered heterocyclyl, 5-14-membered heteroaryl or C 6 - C 14 aromatic ring, or R b and R c together with N atom can form a 4-8 membered heterocyclic group; R e can independently represent hydrogen, C1-C 6 alkyl, C 3 -C 8 cycloalkyl, C 2 - C6 alkenyl, C3 - C6 cycloalkenyl, C2 - C6 alkynyl, 4-8-membered heterocyclyl, 5-14-membered heteroaryl or C6-C14 aromatic ring;
Rm选自取代或未取代的下组基团:胺基、C
1-C
6烷基、C
3-C
6环烷基、4-6元杂环基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
3烷基、C
3-C
6环烷基、4-6元杂环基;
Rm is selected from the group consisting of substituted or unsubstituted groups: amine group, C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, 4-6 membered heterocyclic group, wherein the substitution refers to the selected Substituted with one or more groups from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl, C3 - C6 cycloalkyl, 4-6 membered heterocyclyl;
Rn选自取代或未取代的下组基团:胺基、C
1-C
6烷基、C
1-C
6烷氧基、C
3-C
6环烷基、-O-C
3-C
6环烷基、C
1-C
6烷基C
3-C
6环烷基、-O-C
1-C
6烷基C
3-C
6环烷基、4-6元杂环基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
3烷基、C
1-C
3卤代烷基、C
3-C
6环烷基、4-6元杂环基;
Rn is selected from the group consisting of substituted or unsubstituted groups: amine, C1 - C6alkyl , C1 - C6alkoxy , C3 - C6cycloalkyl, -OC3 - C6cycloalkane base, C 1 -C 6 alkyl C 3 -C 6 cycloalkyl, -OC 1 -C 6 alkyl C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group, wherein the substitution refers to Substituted with one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl, C1 - C3 haloalkyl , C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group;
R
1的定义如上所述。
R 1 is defined as above.
在另一优选例中,所述的式(I)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其具有式(X)或(XI)所示的结构:In another preferred embodiment, the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, has The structure represented by formula (X) or (XI):
式中,In the formula,
R
4选自取代或未取代C
6-C
14芳基或5-10元杂芳基,其中,所述取代是指被选自下组的一个或多个(如2、3、4或5个)基团取代:氘、卤素、酯基、氰基、NR
bC(=O)OR
e、OC(=O)R
e、OC(=O)NR
bR
c、胺基、C
1-C
6烷基、卤代C
1-C
6烷基、羟基;R
b、R
c可以独立表示氢、氘、C
1-C
6烷基、C
3-C8环烷基、4-8元杂环基、5-14元杂芳基或C
6-C
14芳环,或者说R
b和R
c与N原子一起可以形成4-8元杂环基;R
e可以独立表示氢、C
1-C
6烷基、C
3-C
8环烷基、C
2-C
6烯基、C
3-C
6环烯基、C
2-C
6炔基、4-8元杂环基、5-14元杂芳基或C
6-C
14芳环;
R 4 is selected from substituted or unsubstituted C 6 -C 14 aryl or 5-10 membered heteroaryl, wherein the substitution refers to one or more (such as 2, 3, 4 or 5) selected from the group ) group substitution: deuterium, halogen, ester, cyano, NR b C(=O)OR e , OC(=O)R e , OC(=O)NR b R c , amine group, C 1 - C 6 alkyl, halogenated C 1 -C 6 alkyl, hydroxyl; R b and R c can independently represent hydrogen, deuterium, C 1 -C 6 alkyl, C 3 -C8 cycloalkyl, 4-8-membered heteroalkyl Ring group, 5-14-membered heteroaryl or C 6 -C 14 aromatic ring, or R b and R c together with N atom can form a 4-8-membered heterocyclic group; R e can independently represent hydrogen, C 1 - C 6 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkynyl, 4-8 membered heterocyclyl, 5-14 A membered heteroaryl group or a C 6 -C 14 aromatic ring;
Rm选自取代或未取代的下组基团:胺基、C
1-C
6烷基、C
3-C
6环烷基、4-6元杂环基,其中,所述取代是指被选自下组的一个或多个(如2、3、4)基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
3烷基、C3-C6环烷基、4-6元杂环基;
Rm is selected from the group consisting of substituted or unsubstituted groups: amine group, C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, 4-6 membered heterocyclic group, wherein the substitution refers to the selected Substituted with one or more (eg 2, 3, 4) groups from the following group: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C1 - C3 alkyl, C3 -C6 cycloalkyl, 4-6 membered heterocyclyl;
Rn选自取代或未取代的下组基团:胺基、C
1-C
6烷基、C
1-C
6烷氧基、C
3-C
6环烷基、-O-C
3-C
6环烷基、C
1-C
6烷基C
3-C
6环烷基、-O-C
1-C
6烷基C
3-C
6环烷基、4-6元杂环基,其中,所述取代是指被选自下组的一个或多个(如2、3、4)基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
3烷基、C
1-C
3卤代烷基、C
3-C
6环烷基、4-6元杂环基;
Rn is selected from the group consisting of substituted or unsubstituted groups: amine, C1 - C6alkyl , C1 - C6alkoxy , C3 - C6cycloalkyl, -OC3 - C6cycloalkane base, C 1 -C 6 alkyl C 3 -C 6 cycloalkyl, -OC 1 -C 6 alkyl C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group, wherein the substitution refers to Substituted with one or more (eg 2, 3, 4) groups selected from the group consisting of deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amido, C1 - C3 alkyl , C 1 -C 3 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group;
Rx选自:F或Cl;Rx is selected from: F or Cl;
R
A选自:H、D、卤素,优选地R
A选自:H或F。
R A is selected from: H, D, halogen, preferably R A is selected from: H or F.
R”'的定义如上所述;R"' is as defined above;
q'选自0、1、2、或3。q' is selected from 0, 1, 2, or 3.
在另一优选例中,所述化合物具有式(XII)或(XIII)所示的结构:In another preferred example, the compound has the structure represented by formula (XII) or (XIII):
R
4a、R
4b、R
4c、R
4d、R
4e相同或不同,各自独立地选自:H、氘、卤素、酯基、氰基、NR
bC(=O)OR
e、OC(=O)R
e、OC(=O)NR
bR
c、胺基、C
1-C
6烷基、卤代C
1-C
6烷基、羟基;R
b、R
c可以独立表示氢、氘、C
1-C
6烷基、C
3-C
8环烷基、4-8元杂环基、5-14元杂芳基或C
6-C
14芳环,或者说R
b和R
c与N原子一起可以形成4-8元杂环基;R
e可以独立表示氢、C1-C
6烷基、C
3-C
8环烷基、C
2-C
6烯基、C
3-C
6环烯基、C
2-C
6炔基、4-8元杂环基、5-14元杂芳基或C6-C14 芳环;
R 4a , R 4b , R 4c , R 4d , R 4e are the same or different, each independently selected from: H, deuterium, halogen, ester, cyano, NR b C(=O)OR e , OC(=O ) R e , OC(=O)NR b R c , amino group, C 1 -C 6 alkyl group, halogenated C 1 -C 6 alkyl group, hydroxyl; R b , R c can independently represent hydrogen, deuterium, C 1 - C6 alkyl, C3 - C8 cycloalkyl, 4-8 membered heterocyclyl, 5-14 membered heteroaryl or C6 - C14 aromatic ring, or Rb and Rc and N atom Together they can form a 4-8 membered heterocyclic group; R e can independently represent hydrogen, C1- C6 alkyl, C3 - C8 cycloalkyl, C2 - C6 alkenyl, C3 - C6 cycloalkenyl , C 2 -C 6 alkynyl, 4-8-membered heterocyclic group, 5-14-membered heteroaryl or C6-C14 aromatic ring;
Rm、Rn、Rx、R
A、q'、R”'如上所述。
Rm, Rn, Rx, R A , q', R"' are as described above.
在另一优选例中,q'为0。In another preferred embodiment, q' is 0.
在另一优选例中,所述化合物具有式(XIV)或(XV)所示的结构:In another preferred example, the compound has the structure represented by formula (XIV) or (XV):
式中,In the formula,
R
4a、R
4b、R
4c、R
4d、R
4e各自独立地选自:H、氘、卤素、羟基、胺基、C
1-C
3烷基、卤代C
1-C
3烷基、NR
bC(=O)OR
e、OC(=O)R
e、OC(=O)NR
bR
c;其中,R
b、R
c可以独立表示氢、氘、C
1-C
6烷基;R
e可以独立表示氢、C
1-C
6烷基、C
3-C
8环烷基、4-8元杂环基;
R 4a , R 4b , R 4c , R 4d , R 4e are each independently selected from: H, deuterium, halogen, hydroxy, amino, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, NR b C(=O)OR e , OC(=O)R e , OC(=O)NR b R c ; wherein, R b and R c can independently represent hydrogen, deuterium, C 1 -C 6 alkyl; R e can independently represent hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 4-8 membered heterocyclic group;
Rm、Rn、Rx、R
A如上所述。
Rm, Rn, Rx, RA are as described above.
在另一优选例中,Rn选自取代或未取代的下组基团:乙基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、环丙氨基、氮杂环丁烷基、氮杂环戊烷基、氮杂环己烷基、环氧乙烷基、氧杂环丁烷基、氧杂环戊烷基、氧杂环己烷基,其中,所述取代是指被选自下组的一个或多个(如2、3、4)基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
3烷基。
In another preferred example, Rn is selected from the group consisting of substituted or unsubstituted groups: ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylamino, azetidinyl, azepanyl, azetidine, oxiranyl, oxetanyl, oxolane, oxanyl, wherein, The substitution refers to substitution with one or more (eg 2, 3, 4) groups selected from the group consisting of deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 3 alkyl.
在另一优选例中,Rm选自取代或未取代的下组基团:甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、环丙氨基、氮杂环丁烷基、氮杂环戊烷基、氮杂环己烷基、环氧乙烷基、氧杂环丁烷基、氧杂环戊烷基、氧杂环己烷基,其中,所述取代是指被选自下组的一个或多个(如2、3、4)基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
3烷基。
In another preferred example, Rm is selected from the group consisting of substituted or unsubstituted groups: methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo Propylamino, azetidinyl, azepanyl, azetidinyl, oxiranyl, oxetanyl, oxolane, oxanyl , wherein the substitution refers to being substituted by one or more (eg 2, 3, 4) groups selected from the group consisting of deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide , C 1 -C 3 alkyl.
在另一优选例中,Rn选自取代或未取代的下组基团:乙基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、环丙氨基、氮杂环丁烷基、氮杂环戊烷基、氮杂环己烷基、环氧乙烷基、氧杂环丁烷基、氧杂环戊烷基、氧杂环己烷基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
3烷基;
In another preferred example, Rn is selected from the group consisting of substituted or unsubstituted groups: ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylamino, azetidinyl, azepanyl, azetidine, oxiranyl, oxetanyl, oxolane, oxanyl, wherein, The substitution refers to substitution with one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C1 - C3 alkyl;
Rm选自取代或未取代的下组基团:甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、环丙氨基、氮杂环丁烷基、氮杂环戊烷基、氮杂环己烷基、环氧乙烷基、氧杂环丁烷基、氧杂环戊烷基、氧杂环己烷基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
3烷基。
Rm is selected from the group consisting of substituted or unsubstituted groups: methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylamino, azetidine alkyl, azepanyl, azepanyl, oxiranyl, oxetanyl, oxolane, oxetanyl, wherein the substitution is means substituted with one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl.
在另一优选例中,R
4b、R
4c和R
4d为H。
In another preferred embodiment, R 4b , R 4c and R 4d are H.
在另一优选例中,Rx选自:F或Cl。In another preferred embodiment, Rx is selected from: F or Cl.
在另一优选例中,R
A选自:H、D、卤素,优选地R
A选自:H或F。
In another preferred example, RA is selected from: H, D, halogen, preferably RA is selected from: H or F.
在另一优选例中,所述化合物具有式(XVI)所示的结构:In another preferred example, the compound has the structure shown in formula (XVI):
式中,In the formula,
R”'各自独立地选自取代或未取代的下组基团:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
6烷基、C
3-C
8环烷基、C
4-C
10环烯基、4-8元杂环基、C
6-C
14芳基、5-14元杂芳基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
6烷基、C
3-C
8环烷基、C
4-C
10环烯基、4-8元杂环基、C
6-C
14芳基、5-14元杂芳基;
R"' is each independently selected from the group consisting of substituted or unsubstituted groups: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 - C 8 cycloalkyl, C 4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl, wherein the substitution refers to being selected from the following Substituted with one or more groups of the group: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amido, C1 - C6 alkyl, C3 - C8 cycloalkyl, C4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl;
q选自:1、2、3或4;q is selected from: 1, 2, 3 or 4;
R
1、R
4、R
8、R'、V、Q的定义如上所述。
The definitions of R 1 , R 4 , R 8 , R′, V, and Q are as described above.
在另一优选例中,所述化合物具有式(XVI-A)所示的结构:In another preferred embodiment, the compound has the structure shown in formula (XVI-A):
式中,In the formula,
R”'各自独立地选自取代或未取代的下组基团:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
6烷基、C
3-C
8环烷基、C
4-C
10环烯基、4-8元杂环基、C
6-C
14芳基、5-14元杂芳基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
6烷基、C
3-C
8环烷基、C
4-C
10环烯基、4-8元杂环基、 C
6-C
14芳基、5-14元杂芳基;
R"' is each independently selected from the group consisting of substituted or unsubstituted groups: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 - C 8 cycloalkyl, C 4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl, wherein the substitution refers to being selected from the following Substituted with one or more groups of the group: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amido, C1 - C6 alkyl, C3 - C8 cycloalkyl, C4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl;
q选自:1、2、3或4;q is selected from: 1, 2, 3 or 4;
R
1、R
4、R
8、R'、V、Q的定义如上所述。
The definitions of R 1 , R 4 , R 8 , R′, V, and Q are as described above.
在另一优选例中,所述化合物具有式(XVII)所示的结构:In another preferred embodiment, the compound has the structure represented by formula (XVII):
式中,In the formula,
R
1选自:
其中,R
A选自:H、D、卤素或氰基;R
B、R
B’相同或不同,各自独立地选自:H、D、卤素、氰基、取代或未取代的C
1-C
3烷基;其中,所述取代是指被选自下组的一个或多个基团取代:D、卤素、氰基、C
1-C
3烷基、C
3-C
6环烷基、4-6元杂环基或NR
IVR
V;R
IV、R
V相同或不同,各自独立地选自:H、C
1-C
3烷基、C
3-C
6环烷基或4-6元杂环基;或者R
IV、R
V和相邻的N一起环合形成4-6元杂环基;
R1 is selected from : Wherein, R A is selected from: H, D, halogen or cyano; R B and R B' are the same or different, each independently selected from: H, D, halogen, cyano, substituted or unsubstituted C 1 -C 3 alkyl; wherein, the substitution refers to being substituted by one or more groups selected from the group consisting of D, halogen, cyano, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 4 -6-membered heterocyclyl or NR IV R V ; R IV and R V are the same or different, each independently selected from: H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl or 4-6 membered Heterocyclyl; or R IV , R V and adjacent N are cyclized together to form a 4-6 membered heterocyclyl;
R
4、R'、V、Q、R”'及q的定义如上所述。
R4 , R', V, Q, R"' and q are as defined above.
在另一优选例中,所述化合物具有式(XVIII-1)或(XVIII-2)所示的结构:In another preferred example, the compound has a structure represented by formula (XVIII-1) or (XVIII-2):
式中,In the formula,
Rx选自:F或Cl;Rx is selected from: F or Cl;
R
4选自取代或未取代苯基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、酯基、氰基、NR
bC(=O)OR
e、OC(=O)R
e、OC(=O)NR
bR
c、胺基、C
1-C
6烷基、卤代C
1-C
6烷基、C
1-C
6烷氧基、羟基;R
b、R
c可以独立表示氢、氘、C
1-C
6烷基、C
3-C
8环烷基、4-8元杂环基、5-14元杂芳基或C
6-C
14芳环,或者说R
b和R
c与N原子一起可以形成4-8元杂环基;R
e可以独立表示氢、C1-C
6烷基、C
3-C
8环烷基、C
2-C
6烯基、C
3-C
6环烯基、C
2-C
6炔基、4-8元杂环基、5-14元杂芳基或C6-C14芳环;
R 4 is selected from substituted or unsubstituted phenyl, wherein the substitution refers to substitution by one or more groups selected from the group consisting of deuterium, halogen, ester, cyano, NR b C(=O)OR e , OC(=O)R e , OC(=O)NR b R c , amine group, C 1 -C 6 alkyl group, halogenated C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, Hydroxyl; R b , R c can independently represent hydrogen, deuterium, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 4-8-membered heterocyclyl, 5-14-membered heteroaryl or C 6 - C 14 aromatic ring, or R b and R c together with N atom can form a 4-8 membered heterocyclic group; R e can independently represent hydrogen, C1-C 6 alkyl, C 3 -C 8 cycloalkyl, C 2 - C6 alkenyl, C3 - C6 cycloalkenyl, C2 - C6 alkynyl, 4-8-membered heterocyclyl, 5-14-membered heteroaryl or C6-C14 aromatic ring;
Rm选自取代或未取代的下组基团:胺基、C
1-C
6烷基、C
3-C
6环烷基、4-6元杂环基, 其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
3烷基、C
3-C
6环烷基、4-6元杂环基;
Rm is selected from the group consisting of substituted or unsubstituted groups: amine group, C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, 4-6 membered heterocyclic group, wherein the substitution refers to the selected Substituted with one or more groups from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl, C3 - C6 cycloalkyl, 4-6 membered heterocyclyl;
Rn选自取代或未取代的下组基团:胺基、C
1-C
6烷基、C
1-C
6烷氧基、C
3-C
6环烷基、-O-C
3-C
6环烷基、C
1-C
6烷基C
3-C
6环烷基、-O-C
1-C
6烷基C
3-C
6环烷基、4-6元杂环基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
3烷基、C
1-C
3卤代烷基、C
3-C
6环烷基、4-6元杂环基;
Rn is selected from the group consisting of substituted or unsubstituted groups: amine, C1 - C6alkyl , C1 - C6alkoxy , C3 - C6cycloalkyl, -OC3 - C6cycloalkane base, C 1 -C 6 alkyl C 3 -C 6 cycloalkyl, -OC 1 -C 6 alkyl C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group, wherein the substitution refers to Substituted with one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl, C1 - C3 haloalkyl , C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group;
R
1的定义如上所述。
R 1 is defined as above.
在另一优选例中,所述化合物具有式(XIX)或(XX)所示的结构:In another preferred embodiment, the compound has the structure represented by formula (XIX) or (XX):
式中,In the formula,
R
4选自取代或未取代C
6-C
14芳基或5-10元杂芳基,其中,所述取代是指被选自下组的一个或多个(如2、3、4或5个)基团取代:氘、卤素、酯基、氰基、NR
bC(=O)OR
e、OC(=O)R
e、OC(=O)NR
bR
c、胺基、C
1-C
6烷基、卤代C
1-C
6烷基、羟基;R
b、R
c可以独立表示氢、氘、C
1-C
6烷基、C
3-C
8环烷基、4-8元杂环基、5-14元杂芳基或C
6-C
14芳环,或者说R
b和R
c与N原子一起可以形成4-8元杂环基;R
e可以独立表示氢、C1-C
6烷基、C
3-C
8环烷基、C
2-C
6烯基、C
3-C
6环烯基、C
2-C
6炔基、4-8元杂环基、5-14元杂芳基或C6-C14芳环;
R 4 is selected from substituted or unsubstituted C 6 -C 14 aryl or 5-10 membered heteroaryl, wherein the substitution refers to one or more (such as 2, 3, 4 or 5) selected from the group ) group substitution: deuterium, halogen, ester, cyano, NR b C(=O)OR e , OC(=O)R e , OC(=O)NR b R c , amine group, C 1 - C 6 alkyl, halogenated C 1 -C 6 alkyl, hydroxyl; R b and R c can independently represent hydrogen, deuterium, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 4-8 membered Heterocyclic group, 5-14-membered heteroaryl group or C 6 -C 14 aromatic ring, or R b and R c together with N atom can form a 4-8-membered heterocyclic group; R e can independently represent hydrogen, C1- C 6 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkynyl, 4-8 membered heterocyclyl, 5-14 A membered heteroaryl group or a C6-C14 aromatic ring;
Rm选自取代或未取代的下组基团:胺基、C
1-C
6烷基、C
3-C
6环烷基、4-6元杂环基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
3烷基、C
3-C
6环烷基、4-6元杂环基;
Rm is selected from the group consisting of substituted or unsubstituted groups: amine group, C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, 4-6 membered heterocyclic group, wherein the substitution refers to the selected Substituted with one or more groups from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl, C3 - C6 cycloalkyl, 4-6 membered heterocyclyl;
Rn选自取代或未取代的下组基团:胺基、C
1-C
6烷基、C
1-C
6烷氧基、C
3-C
6环烷基、-O-C
3-C
6环烷基、C
1-C
6烷基C
3-C
6环烷基、-O-C
1-C
6烷基C
3-C
6环烷基、4-6元杂环基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
3烷基、C
1-C
3卤代烷基、C
3-C
6环烷基、4-6元杂环基;
Rn is selected from the group consisting of substituted or unsubstituted groups: amine, C1 - C6alkyl , C1 - C6alkoxy , C3 - C6cycloalkyl, -OC3 - C6cycloalkane base, C 1 -C 6 alkyl C 3 -C 6 cycloalkyl, -OC 1 -C 6 alkyl C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group, wherein the substitution refers to Substituted with one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl, C1 - C3 haloalkyl , C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group;
Rx选自:F或Cl;Rx is selected from: F or Cl;
R
A选自:H、D、卤素;
R A is selected from: H, D, halogen;
q'选自0、1、2或3;q' is selected from 0, 1, 2 or 3;
R”'选自取代或未取代的下组基团:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
6烷基、C
3-C
8环烷基、C
4-C
10环烯基、4-8元杂环基、C
6-C
14芳基、5-14元杂芳基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
6烷基、C
3-C
8环烷基、C
4-C
10环烯基、4-8元杂环基、C
6-C
14 芳基、5-14元杂芳基。
R"' is selected from the group consisting of substituted or unsubstituted groups: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 -C 8 ring Alkyl, C 4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl, wherein the substitution refers to one selected from the group or multiple groups substituted: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 4 -C 10 Cycloalkenyl, 4-8 membered heterocyclyl, C6 - C14 aryl, 5-14 membered heteroaryl.
在另一优选例中,所述化合物具有式(XXI)或(XXII)所示的结构:In another preferred example, the compound has a structure represented by formula (XXI) or (XXII):
R
4a、R
4b、R
4c、R
4d、R
4e相同或不同,各自独立地选自:H、氘、卤素、酯基、氰基、NR
bC(=O)OR
e、OC(=O)R
e、OC(=O)NR
bR
c、胺基、C
1-C
6烷基、卤代C
1-C
6烷基、羟基;R
b、R
c可以独立表示氢、氘、C
1-C
6烷基、C
3-C
8环烷基、4-8元杂环基、5-14元杂芳基或C
6-C
14芳环,或者说R
b和R
c与N原子一起可以形成4-8元杂环基;R
e可以独立表示氢、C
1-C
6烷基、C
3-C
8环烷基、C
2-C
6烯基、C
3-C
6环烯基、C
2-C
6炔基、4-8元杂环基、5-14元杂芳基或C6-C14芳环;
R 4a , R 4b , R 4c , R 4d , R 4e are the same or different, each independently selected from: H, deuterium, halogen, ester, cyano, NR b C(=O)OR e , OC(=O ) R e , OC(=O)NR b R c , amino group, C 1 -C 6 alkyl group, halogenated C 1 -C 6 alkyl group, hydroxyl; R b , R c can independently represent hydrogen, deuterium, C 1 - C6 alkyl, C3 - C8 cycloalkyl, 4-8 membered heterocyclyl, 5-14 membered heteroaryl or C6 - C14 aromatic ring, or Rb and Rc and N atom Together they can form a 4-8 membered heterocyclic group; R e can independently represent hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkene base, C 2 -C 6 alkynyl, 4-8 membered heterocyclyl, 5-14 membered heteroaryl or C6-C14 aromatic ring;
Rm、Rn、Rx、R
A、q'、R”'如上所述。
Rm, Rn, Rx, R A , q', R"' are as described above.
在另一优选例中,所述化合物具有式(XXIII)或(XXIV)所示的结构:In another preferred example, the compound has the structure represented by formula (XXIII) or (XXIV):
式中,In the formula,
R
4a、R
4b、R
4c、R
4d、R
4e各自独立地选自:H、氘、卤素、羟基、胺基、C
1-C
3烷基、卤代C
1-C
3烷基、NR
bC(=O)OR
e、OC(=O)R
e、OC(=O)NR
bR
c;其中,R
b、R
c可以独立表示氢、氘、C
1-C
6烷基;R
e可以独立表示氢、C
1-C
6烷基、C
3-C
8环烷基、4-8元杂环基;
R 4a , R 4b , R 4c , R 4d , R 4e are each independently selected from: H, deuterium, halogen, hydroxy, amino, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, NR b C(=O)OR e , OC(=O)R e , OC(=O)NR b R c ; wherein, R b and R c can independently represent hydrogen, deuterium, C 1 -C 6 alkyl; R e can independently represent hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 4-8 membered heterocyclic group;
Rm、Rn、Rx、R
A如上所述。在另一优选例中,R
1、R
2、R
4、R
8、L、U、V、W、Q、p、A、B、X、Rn、Rm、Rx、R
A、R”'、R
4a、R
4b、R
4c、R
4d、R
4e、q和q'为实施例中各具体化合物相对应的具体基团。
Rm, Rn, Rx, RA are as described above. In another preferred example, R 1 , R 2 , R 4 , R 8 , L, U, V, W, Q, p, A, B, X, Rn, Rm, Rx, R A , R"', R 4a , R 4b , R 4c , R 4d , R 4e , q and q' are specific groups corresponding to the specific compounds in the examples.
在另一优选例中,所述的式(I)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,所述化合物选自下组:In another preferred embodiment, the compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, the The compound is selected from the group consisting of:
在另一优选例中,所述式(I)化合物、其立体异构体、互变异构体、晶型、药学上可 接受的盐、水合物、溶剂合物或前药不包含
In another preferred embodiment, the compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs do not contain
在另一优选例中,所述式(I)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药选自实施例中所示化合物。In another preferred embodiment, the compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs are selected from the examples compounds shown in.
本发明第二方面,提供一种制备式(I)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药的方法,包括步骤:The second aspect of the present invention provides a method for preparing a compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, Include steps:
(i)在惰性溶剂(如四氢呋喃)中,式P-1化合物先与草酰氯反应,然后与胺基化合物R
2-NH
2反应,得到式P-2化合物;
(i) in an inert solvent (such as tetrahydrofuran), the compound of formula P-1 is first reacted with oxalyl chloride, and then reacted with the amino compound R 2 -NH 2 to obtain the compound of formula P-2;
(ii)在惰性溶剂(如四氢呋喃)中,在第一种碱存在下,式P-2化合物关环,得到式P-3化合物;(ii) in an inert solvent (such as tetrahydrofuran), in the presence of a first base, the compound of formula P-2 is ring-closed to obtain a compound of formula P-3;
(iii)在惰性溶剂(如乙腈)中,式P-3化合物与三氯氧磷在第二种碱存在下,得到式P-4化合物;(iii) in an inert solvent (such as acetonitrile), the compound of formula P-3 and phosphorus oxychloride in the presence of a second base to obtain the compound of formula P-4;
(iv)在惰性溶剂(如乙腈)中,碱(如N,N-二异丙基乙胺)存在下,式P-4化合物与
通过偶联或者取代反应,得到式P-5化合物;
(iv) in an inert solvent (such as acetonitrile) in the presence of a base (such as N,N-diisopropylethylamine), the compound of formula P-4 with Through coupling or substitution reaction, the compound of formula P-5 is obtained;
(v)在惰性溶剂(如二氯甲烷)中,酸(如三氟乙酸)存在下,式P-5化合物脱保护,得到式P-6化合物;(v) deprotecting the compound of formula P-5 in the presence of an acid (such as trifluoroacetic acid) in an inert solvent (such as dichloromethane) to obtain a compound of formula P-6;
(vi)在惰性溶剂(如二氯甲烷)中,碱(如N,N-二异丙基乙胺)存在下,式P-6化合物与R
1E通过偶联、取代或酰化反应,得到式P-7化合物;
(vi) reacting a compound of formula P-6 with R 1 E by coupling, substitution or acylation in the presence of a base (such as N,N-diisopropylethylamine) in an inert solvent (such as dichloromethane), to obtain the compound of formula P-7;
(vii)在惰性溶剂(如二氧六环/水)中,碱(如乙酸钾)和催化剂(如[1,1'-双(二苯基膦)二茂铁]二氯化钯)存在下,式P-7与R
4-L-E
1通过偶联、取代或者酰化反应,得到式(I)化合物;
(vii) in an inert solvent (eg dioxane/water) in the presence of a base (eg potassium acetate) and a catalyst (eg [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride) Next, the compound of formula (I) is obtained by coupling, substitution or acylation reaction between formula P-7 and R 4 -LE 1 ;
式中,In the formula,
E为卤素、OH、OCOR
1、OCO(
iBu)等;
E is halogen, OH, OCOR 1 , OCO( i Bu), etc.;
PG为氨基保护基,所述保护基选自下组:Boc、Bn、Cbz或Fmoc;PG is an amino protecting group selected from the group consisting of Boc, Bn, Cbz or Fmoc;
Y和Z为离去基团,所述离去基团选自下组:卤素或者OTf;Y and Z are leaving groups selected from the group consisting of halogen or OTf;
所述第一种碱选自下组:KHMDS、NaHMDS、LiHMDS、NaH、NaOMe、NaOEt或
tBuONa;
The first base is selected from the group consisting of KHMDS, NaHMDS, LiHMDS, NaH, NaOMe, NaOEt or tBuONa ;
所述第二种碱选自下组:TEA、DIPEA、DMAP或N,N-二甲基苯胺;The second base is selected from the group consisting of TEA, DIPEA, DMAP or N,N-dimethylaniline;
R
1、R
2、R
4、L、A、B、X、U、V、W和Q的定义如第一方面所述。
R 1 , R 2 , R 4 , L, A, B, X, U, V, W and Q are as defined in the first aspect.
本发明第三方面,提供一种药物组合物,所述药物组合物包含一种或多种第一方面所述的式(I)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药;和药学上可接受的载体。A third aspect of the present invention provides a pharmaceutical composition comprising one or more compounds of formula (I), stereoisomers, tautomers and crystal forms thereof according to the first aspect , a pharmaceutically acceptable salt, hydrate, solvate or prodrug; and a pharmaceutically acceptable carrier.
在另一优选例中,所述药物组合物还包含选自下组的药物:PD-1抑制剂(如纳武单抗、派姆单抗、pidilizumab、cemiplimab、JS-001、SHR-120、BGB-A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10、BAT1306、AK105、LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如度伐单抗、阿特珠单抗、阿维鲁单抗(avelumab)、CS1001、KN035、HLX20、SHR-1316、BGB-A333、JS003、CS1003、KL-A167、F 520、GR1405、MSB2311或上述药物的生物类似药等)、CD20抗体(如利妥昔单抗、奥滨尤妥珠单抗、奥法木单抗、veltuzumab,托西莫单抗、131I-托西莫单抗、替伊莫单抗、90Y-替伊莫单抗、90In-替伊莫单抗、替伊莫单抗(ibritumomab tiuxetan)等)、CD47抗体(如Hu5F9-G4、CC-90002、TTI-621、TTI-622、OSE-172、SRF-231、ALX-148、NI-1701、SHR-1603、IBI188、IMM01)、ALK抑制剂(如色瑞替尼、艾乐替尼、布加替尼、劳拉替尼、奥卡替尼)、PI3K抑制剂(如艾代拉里斯、Duvelisib、Dactolisib、Taselisib、Bimiralisib、Omipalisib、Buparlisib等)、BTK抑制剂(如依鲁替尼、Tirabrutinib、阿卡替尼、赞布替尼、Vecabrutinib等)、EGFR抑制剂(如阿法替尼、吉非替尼、厄洛替尼、拉帕替尼、达克替尼、埃克替尼、卡奈替尼、沙普替尼、Naquotinib、吡咯替尼、罗乐替尼、奥希替尼等)、VEGFR抑制剂(如索拉非尼、帕唑帕尼、瑞戈非尼、司曲替尼、Ningetinib、卡博替尼、舒尼替尼、多纳非尼等)、HDAC抑制剂(如Givinostat、Tucidinostat、伏立诺他、Fimepinostat、Droxinostat、恩替诺特、达西司特、Quisinostat、泰克地那林等)、CDK抑制剂(如帕博西尼、瑞博西尼、Abemaciclib、Milciclib、Trilaciclib、Lerociclib等)、MEK抑制剂(如司美替尼(AZD6244)、曲美替尼(GSK1120212)、PD0325901、U0126、Pimasertib(AS-703026)、PD184352(CI-1040)等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068、TNO155等),或其组合。In another preferred embodiment, the pharmaceutical composition further comprises a drug selected from the group consisting of PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, Atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumumab, 131I-tositumumab, tiimumab, 90Y - tiimumab, 90In-tiimumab, ibritumomab tiuxetan, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172 , SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as ceritinib, alectinib, brigatinib, lorlatinib, ocartinib) Nitrogen), PI3K inhibitors (such as Ideraris, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipalisib, Buparlisib, etc.), BTK inhibitors (such as ibrutinib, Tirabrutinib, acalatinib, zabrutinib, Vecabrutinib) etc.), EGFR inhibitors (such as afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, canetinib, sapritinib, Naquotinib, Pyrotinib, Roletinib, Osimertinib, etc.), VEGFR inhibitors (such as Sorafenib, Pazopanib, Regorafenib, Seletinib, Ningetinib, Cabozantinib, Suni tinib, donafenib, etc.), HDAC inhibitors (such as Givinostat, Tucidinostat, vorinostat, Fimepinostat, Droxinostat, entinostat, darxilast, Quisinostat, tycodinaline, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, Milciclib, Trilaciclib, Lerociclib, etc.), MEK inhibitors (such as selumetinib (AZD6244), trametinib (GSK11) 20212), PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040, etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.), or its combination.
在另一优选例中,提供一种药物组合物的制备方法,包括步骤:将药学上可接受的载 体与本发明第一方面所述式(I)化合物、立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药进行混合,从而形成药物组合物。In another preferred embodiment, a preparation method of a pharmaceutical composition is provided, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of formula (I), stereoisomer, tautomer described in the first aspect of the present invention The form, pharmaceutically acceptable salt, hydrate, solvate or prodrug are mixed to form a pharmaceutical composition.
本发明第四方面,提供第一方面所述的式(I)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,或第三方面所述的药物组合物的用途,用于制备预防和/或治疗与KRAS
G12C的活性或表达量相关的疾病的药物组合物。
The fourth aspect of the present invention provides the compound of formula (I) described in the first aspect, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs , or the use of the pharmaceutical composition described in the third aspect, for preparing a pharmaceutical composition for preventing and/or treating diseases related to the activity or expression of KRAS G12C .
本发明第五方面,提供一种预防和/或治疗与KRAS
G12C的活性或表达量相关疾病的方法,它包括步骤:向所需患者施用有效量的第一方面所述的式(I)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,或施用第三方面所述的药物组合物。
The fifth aspect of the present invention provides a method for preventing and/or treating a disease related to the activity or expression level of KRAS G12C , comprising the step of: administering an effective amount of the compound of formula (I) described in the first aspect to a patient in need , a stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, or administer the pharmaceutical composition of the third aspect.
在另一优选例中,所述的疾病是肿瘤或失调性疾病。In another preferred embodiment, the disease is a tumor or a disordered disease.
在另一优选例中,所述疾病选自下组:肺癌、乳腺癌、前列腺癌、食道癌、结直肠癌、骨癌、肾癌、胃癌、肝癌、大肠癌、黑色素瘤、淋巴瘤、血癌、脑瘤、骨髓瘤、软组织肉瘤、胰腺癌、皮肤癌。In another preferred embodiment, the disease is selected from the group consisting of lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, stomach cancer, liver cancer, colorectal cancer, melanoma, lymphoma, blood cancer , brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer.
本发明第六方面,提供一种非诊断性、非治疗性地抑制KRAS
G12C的方法,它包括步骤:向所需患者施用有效量的第一方面所述的式(I)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,或施用第三方面所述的药物组合物。
The sixth aspect of the present invention provides a non-diagnostic and non-therapeutic method for inhibiting KRAS G12C , which comprises the steps of: administering to a patient in need an effective amount of the compound of formula (I) described in the first aspect, its stereoisomeric isomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or administer the pharmaceutical composition of the third aspect.
本发明第七方面,提供一种体外抑制抑制KRAS
G12C的方法,包括步骤:将第一方面所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药或第三方面所述的组合物,与体细胞接触。
A seventh aspect of the present invention provides a method for inhibiting KRAS G12C in vitro, comprising the steps of: adding the compound described in the first aspect, its stereoisomer, tautomer, crystal form and pharmaceutically acceptable salt , hydrate, solvate or prodrug, or the composition of the third aspect, in contact with a somatic cell.
在另一优选例中,所述体细胞来自灵长动物(如人)。In another preferred embodiment, the somatic cells are derived from primates (eg, humans).
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (eg, the embodiments) can be combined with each other to constitute new or preferred technical solutions. Due to space limitations, it is not repeated here.
本发明人经过长期而深入的研究,意外地制备了一类新型的KRAS
G12C有选择性抑制作用和/或更好药效学性能的化合物。在此基础上,发明人完成了本发明。
After long-term and in-depth research, the present inventors unexpectedly prepared a new class of compounds with selective inhibition of KRAS G12C and/or better pharmacodynamic properties. On this basis, the inventors have completed the present invention.
术语the term
在本发明中,除非特别指出,所用术语具有本领域技术人员公知的一般含义。In the present invention, unless otherwise specified, the terms used have the ordinary meanings known to those skilled in the art.
通过从左向右书写的常规化学式描述取代基时,该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言,-CH
2O-等同于-OCH
2-。
Where substituents are described by conventional chemical formulae written from left to right, such substituents also include chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2- .
术语“烷基”是指直链或支链烷烃基,其可包括任何数量的碳原子,其中,“C
1-C
18烷基”是指包括1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或18个碳原 子,优选例如C
1-C
2、C
1-C
3、C
1-C
4、C
1-C
5、C
1-C
6、C
1-C
7、C
1-C
8、C
1-C
9、C
1-C
10、C
2-C
3、C
2-C
4、C
2-C
5、C
2-C
6、C
3-C
4、C
3-C
5、C
3-C
6、C
4-C
5、C
4-C
6或C
5-6。典型的“烷基”包括但不限于甲基、乙基、丙基、异丙基、正丁基、叔丁基、异丁基、
戊基、异戊基、庚基、4,4–二甲基戊基、辛基、2,2,4-三甲基戊基、壬基、癸基、十一烷基,十二烷基等等。本发明中,烷基还包括取代烷基。“取代烷基”是指烷基中的一个或多个位置被取代,尤其是1-4个取代基,可在任何位置上取代。
The term "alkyl" refers to a straight or branched chain alkane group, which may include any number of carbon atoms, wherein "C 1 -C 18 alkyl" refers to a group including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms, preferably for example C 1 -C 2 , C 1 -C 3 , C 1 -C 4 , C 1 - C 5 , C 1 -C 6 , C 1 -C 7 , C 1 -C 8 , C 1 -C 9 , C 1 -C 10 , C 2 -C 3 , C 2 -C 4 , C 2 -C 5 , C 2 -C 6 , C 3 -C 4 , C 3 -C 5 , C 3 -C 6 , C 4 -C 5 , C 4 -C 6 or C 5-6 . Typical "alkyl" include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, Pentyl, isopentyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and many more. In the present invention, the alkyl group also includes a substituted alkyl group. "Substituted alkyl" means that one or more positions in the alkyl group are substituted, especially 1-4 substituents, which may be substituted at any position.
术语“环烷基”是指完全饱和的环状烃类化合物基团,其中,“C
3-C
20环烷基”是指包含3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个碳原子的完全饱和的环状烃类化合物基团,包括1-4个环,每个环中含有3-8个碳原子。优选地为C
3-C
4、C
3-C
5、C
3-C
6、C
3-C
7、C
3-C
8、C
3-C
9、C
3-C
10。“取代环烷基”是指环烷基中的一个或多个位置被取代,尤其是1-4个取代基,可在任何位置上取代。本发明中,“环烷基”意在包含“取代环烷基”。
The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon compound group, wherein "C 3 -C 20 cycloalkyl" refers to a group containing 3, 4, 5, 6, 7, 8, 9, 10, Fully saturated cyclic hydrocarbon groups of 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, including 1-4 rings, each containing 3-8 carbon atom. Preferably C 3 -C 4 , C 3 -C 5 , C 3 -C 6 , C 3 -C 7 , C 3 -C 8 , C 3 -C 9 , C 3 -C 10 . "Substituted cycloalkyl" means that one or more positions in the cycloalkyl group are substituted, especially 1-4 substituents, which may be substituted at any position. In the present invention, "cycloalkyl" is intended to include "substituted cycloalkyl".
术语“杂环基”是指完全饱和的或部分不饱和的环状基团,其中,“3-20元杂环基”是指包含3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个环原子的完全饱和的或部分不饱和的环状基团(包含但不限于如3-7元单环,6-11元双环,或8-16元三环系统),其中至少有一个杂原子存在于至少有一个碳原子的环中。每个含有杂原子的杂环可以带有1、2、3或4个杂原子,这些杂原子选自氮、氧或硫,其中氮或硫可以被氧化,氮也可以被季铵化。杂环基团可以连接到环或环系分子的任何杂原子或碳原子的残基上。典型的单环杂环基包括但不限于氮杂环丁烷基、吡咯烷基、氧杂环丁烷基、吡唑啉基、咪唑啉基、咪唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基、四氢呋喃基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、六氢吖庚因基、4-哌啶酮基、四氢吡喃基、吗啡啉基、硫代吗啡啉基、硫代吗啡啉亚砜基、硫代吗啡啉砜基、1,3-二噁烷基和四氢-1,1-二氧噻吩等。多环杂环基包括螺环、稠环和桥环的杂环基;其中涉及到的螺环、稠环和桥环的杂环基任选与其他基团通过单键相连接,或者通过环上的任意两个或两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接;杂环基团可以是取代的或者未取代的。The term "heterocyclyl" refers to a fully saturated or partially unsaturated cyclic group, wherein "3-20 membered heterocyclyl" refers to a group containing 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ring atoms fully saturated or partially unsaturated cyclic groups (including but not limited to, such as 3-7 membered monocyclic, 6 -11 membered bicyclic ring, or 8-16 membered tricyclic ring system), in which at least one heteroatom is present in the ring having at least one carbon atom. Each heteroatom-containing heterocycle may carry 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen or sulfur, wherein nitrogen or sulfur may be oxidized or nitrogen may be quaternized. A heterocyclic group can be attached to the residue of any heteroatom or carbon atom of the ring or ring system molecule. Typical monocyclic heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazole Alkyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroacridine Heptinyl, 4-piperidinone, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinosulfoxide, thiomorpholinone sulfone, 1,3-dioxanyl And tetrahydro-1,1-dioxythiophene, etc. Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups are optionally connected with other groups through a single bond, or through a ring Any two or more atoms above are further cyclolinked to other cycloalkyl, heterocyclyl, aryl, and heteroaryl groups; heterocyclyl groups may be substituted or unsubstituted.
术语“芳基”是指芳香环状烃类化合物基团,其中,“C6-C14芳基”是指包含6、7、8、9、10、11、12、13或14个环碳原子的芳香环状烃类化合物基团,具有1-5个环,尤其指单环和双环基团,如苯基、联苯基或萘基。凡含有两个或两个以上芳香环(双环等),芳基基团的芳香环可由单键联接(如联苯),或稠合(如萘、蒽等等)。“取代芳基”是指芳基中的一个或多个位置被取代,尤其是1-3个取代基,可在任何位置上取代。The term "aryl" refers to an aromatic cyclic hydrocarbon compound group, wherein "C6-C14 aryl" refers to a group containing 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring carbon atoms. Aromatic cyclic hydrocarbon group, having 1 to 5 rings, especially monocyclic and bicyclic groups, such as phenyl, biphenyl or naphthyl. Where there are two or more aromatic rings (bicyclic rings, etc.), the aromatic rings of the aryl group can be linked by a single bond (eg, biphenyl), or fused (eg, naphthalene, anthracene, etc.). "Substituted aryl" means that one or more positions in the aryl group are substituted, especially 1-3 substituents, which may be substituted at any position.
术语“杂芳基”指包含1-4个杂原子芳香环状烃类化合物基团,其中,杂原子选自氧、氮和硫。其中,“5-14元杂芳基”是指包含5、6、7、8、9、10、11、12、13或14个环原子的芳香环状烃类化合物基团,其中环原子中含有1-4个选自N、O、S的杂原子。杂芳基优选5至10元环,更优选为5元或6元,杂芳基包括但不限于吡咯基、吡唑基、咪唑基、噁唑 基、异噁唑基、噻唑基、噻二唑基、异噻唑基、呋喃基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三氮嗪基、三氮唑基及四氮唑基等。The term "heteroaryl" refers to an aromatic cyclic hydrocarbon group containing 1-4 heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen and sulfur. Wherein, "5-14 membered heteroaryl" refers to an aromatic cyclic hydrocarbon compound group containing 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, wherein Contains 1-4 heteroatoms selected from N, O, S. Heteroaryl is preferably a 5- to 10-membered ring, more preferably 5- or 6-membered, heteroaryl includes but is not limited to pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadi azolyl, isothiazolyl, furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl and tetrazolyl, etc.
术语“烷氧基”是指具有直链或支链或环状烷氧基,其中,“C1-C18烷氧基”是指具有1至18个碳原子的直链或支链或环状烷氧基,包含C1-C18烷基-O-、-C1-C6烷基-O-C1-C6烷基,优选为C1-C8烷氧基,更优选C1-C6烷氧基,烷氧基包括但不限于甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。The term "alkoxy" refers to a straight chain or branched chain or cyclic alkoxy group, wherein "C1-C18 alkoxy" refers to a straight chain or branched chain or cyclic alkoxy group having 1 to 18 carbon atoms Oxy group, including C1-C18 alkyl-O-, -C1-C6 alkyl-O-C1-C6 alkyl, preferably C1-C8 alkoxy, more preferably C1-C6 alkoxy, alkoxy includes But not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy and the like.
“环烯基”是指具有一个或多个双键的环状烃基,其中,“C
4-C
10环烯基”是指具有一个或多个双键,包含4、5、6、7、8、9或10个碳原子的环状烃基,优选地为C
4-C
6环烯基,环烯基包括但不限于:环丁烯基、环戊烯基、环戊二烯基、环己烯基、环己二烯基等。
"Cycloalkenyl" refers to a cyclic hydrocarbon group with one or more double bonds, wherein, "C 4 -C 10 cycloalkenyl" refers to one or more double bonds, including 4, 5, 6, 7, A cyclic hydrocarbon group of 8, 9 or 10 carbon atoms, preferably C 4 -C 6 cycloalkenyl, cycloalkenyl includes but is not limited to: cyclobutenyl, cyclopentenyl, cyclopentadienyl, cycloalkenyl Hexenyl, cyclohexadienyl, etc.
术语“酯基”是指带有结构-COOR的基团,其中R代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂芳基或取代的杂芳基、杂环基或取代的杂环基。其中,烷基、环烷基、环烯基、芳基、杂芳基、杂环基具有如上所述的定义。The term "ester" refers to a group with the structure -COOR, where R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl. Among them, the alkyl group, the cycloalkyl group, the cycloalkenyl group, the aryl group, the heteroaryl group, and the heterocyclic group have the above-mentioned definitions.
术语“胺基”是指带有结构-NRR'的基团,其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂芳基或取代的杂芳基、杂环基或取代的杂环基。其中,烷基、环烷基、环烯基、芳基、杂芳基、杂环基具有如上所述的定义。R和R'可以相同或不同,R和R'同时为H时,胺基为-NH
2。胺基的实例包括但不限于甲胺基、二甲胺基、乙胺基、二乙胺基、丙胺基、异丙胺基、丁胺基等。
The term "amino" refers to a group bearing the structure -NRR', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or Substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl. Among them, the alkyl group, the cycloalkyl group, the cycloalkenyl group, the aryl group, the heteroaryl group, and the heterocyclic group have the above-mentioned definitions. R and R' may be the same or different, and when both R and R' are H, the amine group is -NH 2 . Examples of amine groups include, but are not limited to, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, isopropylamine, butylamine, and the like.
术语“酰胺基”是指带有结构-CONRR'的基团,其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂芳基或取代的杂芳基、杂环基或取代的杂环基。其中,烷基、环烷基、环烯基、芳基、杂芳基、杂环基具有如上所述的定义。R和R'可以相同或不同。The term "amido" refers to a group with the structure -CONRR', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or Substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl. Among them, the alkyl group, the cycloalkyl group, the cycloalkenyl group, the aryl group, the heteroaryl group, and the heterocyclic group have the above-mentioned definitions. R and R' can be the same or different.
术语“磺酰胺基”是指带有结构-SO
2NRR'的基团,其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂芳基或取代的杂芳基、杂环基或取代的杂环基。其中,烷基、环烷基、环烯基、芳基、杂芳基、杂环基具有如上所述的定义。R和R'可以相同或不同。
The term "sulfonamido" refers to a group with the structure -SO2NRR ', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cyclo Alkenyl or substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl. Among them, the alkyl group, the cycloalkyl group, the cycloalkenyl group, the aryl group, the heteroaryl group, and the heterocyclic group have the above-mentioned definitions. R and R' can be the same or different.
术语“胺基磺酰基”是指带有结构-NRSO
2R'的基团,其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂芳基或取代的杂芳基、杂环基或取代的杂环基。其中,烷基、环烷基、环烯基、芳基、杂芳基、杂环基具有如上所述的定义。R和R'可以相同或不同。
The term "aminosulfonyl" refers to a group with the structure -NRSO2R ', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, Cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl. Among them, the alkyl group, the cycloalkyl group, the cycloalkenyl group, the aryl group, the heteroaryl group, and the heterocyclic group have the above-mentioned definitions. R and R' can be the same or different.
术语“脲基”是指带有结构-NRCONR'R"的基团,其中R、R'和R"可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂芳基或取代的杂芳基、杂环基或取代的杂环基。其中,烷基、环烷基、环烯基、芳基、杂芳基、杂环基具有如上所述的定义。R、R'和R"可以相同或不同。The term "ureido" refers to a group having the structure -NRCONR'R", where R, R' and R" can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl , cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl. Among them, the alkyl group, the cycloalkyl group, the cycloalkenyl group, the aryl group, the heteroaryl group, and the heterocyclic group have the above-mentioned definitions. R, R' and R" can be the same or different.
当取代基为非末端取代基或者相关基团脱掉一个H原子时,其为相应基团的亚基,通常为二价基团,例如烷基脱掉一个H原子后为亚烷基(例如:亚甲基、亚乙基、亚丙基、亚异丙基(如
)、亚丁基(如
)、亚戊基(如
)、亚己基(如
)、亚庚基(如
)等)、环烷基对应亚环烷基(如:
等)、杂环基对应亚杂环基(如如:
)、环烷基对应亚杂环基(如:
等)、烷氧基对应亚烷氧基(-CH
2O-、-CH
2CH
2-O-CH
2-、-CH
2OCH
2CH
2CH
2-)等。
When the substituent is a non-terminal substituent or a related group has one H atom removed, it is a subunit of the corresponding group, usually a divalent group, for example, an alkyl group is an alkylene group after one H atom is removed (such as : methylene, ethylene, propylene, isopropylidene (such as ), butylene (such as ), pentylene (such as ), ahexyl (such as ), heptidene (such as ), etc.), cycloalkyl corresponds to cycloalkylene (such as: etc.), the heterocyclic group corresponds to the heterocyclic group (such as: ), cycloalkyl corresponds to heterocyclylene (such as: etc.), alkoxy corresponds to alkyleneoxy (-CH 2 O-, -CH 2 CH 2 -O-CH 2 -, -CH 2 OCH 2 CH 2 CH 2 -) and the like.
术语“卤素”或“卤”是指氯、溴、氟、碘。The term "halogen" or "halo" refers to chlorine, bromine, fluorine, iodine.
术语“卤代”是指基团中的H被卤素取代。The term "halo" means that the H in the group is replaced by a halogen.
术语“氘代”是指基团中的H被氘取代。The term "deuterated" refers to the replacement of an H in a group with deuterium.
术语“羟基”是指带有结构OH的基团。The term "hydroxyl" refers to a group with the structure OH.
术语“硝基”是指带有结构NO
2的基团。
The term "nitro" refers to a group with the structure NO2.
术语“氰基”是指带有结构CN的基团。The term "cyano" refers to a group with the structure CN.
术语“选自取代或未取代的下组基团”是指所选基团的H原子被取代或未被取代,而所选基团不含H原子则不会被取代。The term "selected from the group consisting of substituted or unsubstituted" means that the H atom of the selected group is substituted or unsubstituted, and the selected group does not contain an H atom and will not be substituted.
除非另外说明,假定任何不满价态的杂原子有足够的氢原子补充其价态。Unless otherwise stated, it is assumed that any heteroatom that is not in a valence state has enough hydrogen atoms to replenish its valence state.
如本文所述,本发明中的化合物可与任何数量取代基或官能团取而扩大其包涵范围。通常,术语“取代”不论在术语“可选”前面或后面出现,在本发明配方中包括取代基的通式,是指用指定结构取代基,代替氢自由基。当特定结构中的多个位置被多个特定的取代基取代时,取代基每一个位置可以是相同或不同。本文中所使用的术语“取代”包括所有允许有机化合物取代。从广义上讲,允许的取代基包括非环状的、环状的、支链的非支链的、碳环的和杂环的,芳环的和非芳环的有机化合物。在本发明中,如杂原子氮可以有氢取代基或任何允许的上文所述的有机化合物来补充其价态。此外,本发明是无意以任何方式限制允许取代有机化合物。本发明认为取代基和可变基团的组合在以稳定化合物形式在疾病的治疗上是很好的,例如传染病或增生性疾病。此处术语“稳定”是指具有稳定的化合物,在足够长的时间内检测足以维持化合物结构的完整性,最好是在足够长的时间内都在效,本文在此用于上述目的。As described herein, the compounds of the present invention may be taken with any number of substituents or functional groups to extend their encompassing scope. Generally, whether the term "substituted" appears before or after the term "optional", the general formula for including substituents in the formulations of the present invention refers to the replacement of a hydrogen radical with a specified structural substituent. When multiple positions in a particular structure are substituted with multiple specified substituents, the substituents may be the same or different at each position. The term "substituted" as used herein includes all permissible substitutions of organic compounds. In a broad sense, permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, eg heteroatom nitrogen may have hydrogen substituents or any permissible organic compound as described above to supplement its valence. Furthermore, the present invention is not intended to limit in any way the permissible substituted organic compounds. The present invention contemplates that combinations of substituents and variable groups are well suited for the treatment of diseases, such as infectious or proliferative diseases, in the form of stable compounds. As used herein, the term "stable" refers to a compound that is stable enough to be detected for a sufficient period of time to maintain the structural integrity of the compound, preferably for a sufficient period of time, and is used herein for the above-mentioned purposes.
在本发明中,术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基,或各实施例中所出现的取代基。除非特别说明,某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基,所述的取代基在各个位置上可以是相同或不同的。本发明中,未特别说明的情况下,所述 基团包含相应的取代基团及亚基,例如:烷基包含取代烷基、环烷基包含取代的环烷基、芳基包含取代芳基、杂芳基包含取代杂芳基、杂环基包含取代杂环基等。本领域技术人员应理解,本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。典型的取代包括但不限于一个或多个以下基团:如氢、氘、卤素(例如,单卤素取代基或多卤素取代基,后者如三氟甲基或包含Cl
3的烷基)、腈基、硝基、氧(如=O)、三氟甲基、三氟甲氧基、环烷基、C2-C6烯基、C4-C10环烯基、C2-C6炔基、杂环基、芳基、杂芳基、OR
a、SR
a、S(=O)R
e、S(=O)
2R
e、P(=O)
2R
e、S(=O)
2OR
e、P(=O)
2OR
e、NR
bR
c、NR
bS(=O)
2R
e、NR
bP(=O)
2R
e、S(=O)
2NR
bR
c、P(=O)
2NR
bR
c、C(=O)OR
d、C(=O)R
a、C(=O)NR
bR
c、OC(=O)R
a、OC(=O)NR
bR
c、NR
bC(=O)OR
e、NR
dC(=O)NR
bR
c、NR
dS(=O)
2NR
bR
c、NR
dP(=O)
2NR
bR
c、NR
bC(=O)R
a、或NR
bP(=O)
2R
e,其中在此出现的R
a可以独立表示氢、氘、C1-C6烷基、C3-C8环烷基、C2-C6烯基、C3-C10环烯基、C2-C6炔基、4-8元杂环基、5-14元杂芳基或C6-C14芳基,R
b、R
c和R
d可以独立表示氢、氘、C1-C6烷基、C3-C8环烷基、4-8元杂环基、5-14元杂芳基或C6-C14芳环,或者说R
b和R
c与N原子一起可以形成杂环;R
e可以独立表示氢、C1-C6烷基、C3-C8环烷基、C2-C6烯基、C3-C6环烯基、C2-C6炔基、4-8元杂环基、5-14元杂芳基或C6-C14芳环。上述典型的取代基,如烷基、环烷基、烯基、环烯基、炔基、杂环基、杂芳基或芳基及其相应的取代基团和亚基可以任选取代,其中,所述的烷基、环烷基、环烯基、杂环基、杂芳基或芳基具有如上所述的定义。
In the present invention, the term "substituted" refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent. Particular substituents are those described correspondingly in the preceding paragraphs, or the substituents appearing in the various examples. Unless otherwise specified, a substituted group may have at any substitutable position of the group a substituent selected from a particular group, which may be the same or different at each position. In the present invention, unless otherwise specified, the groups include corresponding substituted groups and subgroups, for example, alkyl groups include substituted alkyl groups, cycloalkyl groups include substituted cycloalkyl groups, and aryl groups include substituted aryl groups , a heteroaryl group includes a substituted heteroaryl group, a heterocyclic group includes a substituted heterocyclic group, and the like. It will be understood by those skilled in the art that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (eg, a monohalogen substituent or a polyhalogen substituent such as trifluoromethyl or an alkyl group containing Cl ), Nitrile, nitro, oxygen (eg =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, C2-C6 alkenyl, C4-C10 cycloalkenyl, C2-C6 alkynyl, heterocyclyl , aryl, heteroaryl, OR a , SR a , S(=O)R e , S(=O) 2 R e , P(=O) 2 R e , S(=O) 2 OR e , P (=O) 2 OR e , NR b R c , NR b S(=O) 2 Re , NR b P(=O) 2 Re , S(=O) 2 NR b R c , P(=O ) 2 NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , NR b C(=O)OR e , NR d C(=O)NR b R c , NR d S(=O) 2 NR b R c , NR d P(=O) 2 NR b R c , NR b C(=O)R a , or NR b P(=O) 2 R e , where R a appearing here may independently represent hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, C2- C6 alkenyl, C3-C10 cycloalkenyl, C2-C6 alkynyl, 4-8-membered heterocyclyl, 5-14-membered heteroaryl or C6-C14 aryl, R b , R c and R d can be independently represented Hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, 5-14 membered heteroaryl or C6-C14 aromatic ring, or Rb and Rc together with N atom Heterocycle can be formed; R e can independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl, 4-8 membered heterocycle base, 5-14 membered heteroaryl or C6-C14 aromatic ring. The above typical substituents such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclyl, heteroaryl or aryl and their corresponding substituent groups and subunits may be optionally substituted, wherein , the alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl or aryl groups have the above definitions.
活性成分Active ingredient
如本文所用,术语“本发明的化合物”或“本发明的活性成分”可互换使用,指式(I)化合物、或其药学上可接受的盐、水合物、溶剂化物、同位素化合物(如氘代化合物)或前药。该术语还包括外消旋体、光学异构体。As used herein, the terms "compound of the present invention" or "active ingredient of the present invention" are used interchangeably to refer to a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound (such as deuterated compounds) or prodrugs. The term also includes racemates, optical isomers.
所述式(I)化合物具有如下结构:The compound of formula (I) has the following structure:
其中,R
1、R
2、R
4、L、U、V、W、Q、A、B、X的定义如上所述。
The definitions of R 1 , R 2 , R 4 , L, U, V, W, Q, A, B, and X are as described above.
优选地,所述的式(I)化合物具有式(II-A)或(II-B)所示的结构:Preferably, the compound of formula (I) has the structure shown in formula (II-A) or (II-B):
式中:where:
R
1、R
2、R
4、A、B、L、X、U、V、W、Q的定义如上所述。
R 1 , R 2 , R 4 , A, B, L, X, U, V, W, Q are defined as described above.
优选地,所述的式(I)化合物具有式(III)所示结构:Preferably, the compound of formula (I) has the structure shown in formula (III):
R
1、R
2、R
4、X、L、U、V、W、Q的定义如上所述。
The definitions of R 1 , R 2 , R 4 , X, L, U, V, W, and Q are as described above.
优选地,所述的式(I)化合物具有式(IV)所示结构:Preferably, the compound of formula (I) has the structure shown in formula (IV):
式中:where:
R
1、R
2、R
4、R
8、L、U、V、W、Q的定义如上所述。
R 1 , R 2 , R 4 , R 8 , L, U, V, W, Q are defined as above.
优选地,所述的式(I)化合物具有式(V)所示结构:Preferably, the compound of formula (I) has the structure shown in formula (V):
式中:where:
R
1、R
2、R
4、R
8、U、V、W、Q的定义如上所述。
R 1 , R 2 , R 4 , R 8 , U, V, W, Q are defined as described above.
优选地,所述的式(I)化合物具有式(VI)所示结构:Preferably, the compound of formula (I) has the structure shown in formula (VI):
式中:where:
R
1、R
2、R
4、R
8、U、V、Q的定义如上所述。
The definitions of R 1 , R 2 , R 4 , R 8 , U, V, and Q are as described above.
优选地,所述的式(I)化合物具有式(VII)所示的结构:Preferably, the compound of formula (I) has the structure shown in formula (VII):
式中:where:
R
1、R
2、R
4、R
8、V、Q的定义如上所述。
The definitions of R 1 , R 2 , R 4 , R 8 , V and Q are as described above.
优选地,R
1选自下组:-C(O)C(R
A)=C(R
B)
2、-S(O)
2C(R
A)=C(R
B)
2、-NR
6C(O)C(R
A)=C(R
B)
2或-NR
6S(O)
2C(R
A)=C(R
B)
2;
Preferably, R 1 is selected from the group consisting of: -C(O)C( RA )=C( RB ) 2 , -S(O) 2 C( RA )=C( RB ) 2 , -NR 6 C(O)C( RA )=C( RB ) 2 or -NR6S (O) 2C ( RA )=C( RB ) 2 ;
其中,R
A独立地选自下组:氢、氘、氟、氰基或者C
1-C
3烷基;各R
B相同或不同,且独立地选自下组:氢、氘、氰基或者C
1-C
3烷基;其中,所述烷基可以被选自下组的一个或多个(如2、3、4或5个)取代基取代:氘、卤素、氰基、胺基、C
3-C
7环烷基、4-7元杂环基、NHR
9或NR
9R
10;R
9和R
10各自独立地为C
1-C
3烷基;或R
9,R
10与其连接的N原子一起构成取代或未取代的4-8元杂环基;
wherein, R A is independently selected from the group consisting of hydrogen, deuterium, fluorine, cyano, or C 1 -C 3 alkyl; each R B is the same or different, and is independently selected from the group consisting of hydrogen, deuterium, cyano or C 1 -C 3 alkyl; wherein, the alkyl may be substituted with one or more (eg 2, 3, 4 or 5) substituents selected from the group consisting of deuterium, halogen, cyano, amine, C 3 -C 7 cycloalkyl, 4-7 membered heterocyclyl, NHR 9 or NR 9 R 10 ; R 9 and R 10 are each independently C 1 -C 3 alkyl; or R 9 to which R 10 is attached The N atoms together form a substituted or unsubstituted 4-8 membered heterocyclic group;
R
6选自取代或未取代的下组基团:氢、氘、C
1-C
6烷基、氘代C
1-C
6烷基、卤代C
1-C
6烷基、C
3-C
8环烷基、C
1-C
6烷氧基、氘代C
1-C
6烷氧基、卤代C
1-C
6烷氧基、4-8元杂环基、C
6-C
14芳基、5-14元杂芳基;
R 6 is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 3 -C 8 -cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, 4-8 membered heterocyclic group, C 6 -C 14 aryl base, 5-14-membered heteroaryl;
其中,所述“取代”未特别说明的情况下,均是指被选自下组的一个或多个基团取代:氢、氘、C
1-C
6烷基、氘代C
1-C
6烷基、卤代C
1-C
6烷基、C
3-C
8环烷基、C
1-C
6烷氧基、氘代C
1-C
6烷氧基、卤代C
1-C
6烷氧基、C
6-C
10芳基、5-10元杂芳基、4-8元杂环基、卤素、硝基、羟基、氰基、酯基、胺基、NR
bC(=O)OR
e、OC(=O)NR
bR
c、酰胺基、磺酰胺基或脲基;R
b、R
c可以独立表示氢、氘、C1-C6烷基、C3-C8环烷基、4-8元杂环基、5-14元杂芳基或C6-C14芳环,或者说R
b和R
c与N原子一起可以形成4-8元杂环基;R
e可以独立表示氢、C1-C6烷基、C3-C8环烷基、C2-C6烯基、C3-C6环烯基、C2-C6炔基、4-8元杂环基、5-14元杂芳基或C6-C14芳环;
Wherein, the "substituted" refers to being substituted by one or more groups selected from the following group unless otherwise specified: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 Alkyl, halogenated C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy Oxy, C 6 -C 10 aryl, 5-10 membered heteroaryl, 4-8 membered heterocyclyl, halogen, nitro, hydroxyl, cyano, ester, amine, NR b C(=O) OR e , OC(=O)NR b R c , amide group, sulfonamide group or urea group; R b , R c can independently represent hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, 4- 8-membered heterocyclic group, 5-14-membered heteroaryl group or C6-C14 aromatic ring, or R b and R c together with N atom can form a 4-8-membered heterocyclic group; R e can independently represent hydrogen, C1- C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl, 4-8 membered heterocyclyl, 5-14 membered heteroaryl or C6-C14 aryl ring;
限定条件为:The qualifications are:
当B为N时,R
1选自下组:-C(O)C(R
A)=C(R
B)
2或-S(O)
2C(R
A)=C(R
B)
2;
When B is N, R1 is selected from the group consisting of -C(O)C( RA )=C( RB ) 2 or -S(O) 2C ( RA )=C( RB ) 2 ;
当B为CH或CR
5时,R
1选自下组:-NR
6C(O)C(R
A)=C(R
B)
2或-NR
6S(O)
2C(R
A)=C(R
B)
2,更优选地,R
1为-C(O)C(R
A)=C(R
B)
2,其中,R
A独立地选自下组:氢、氟;各R
B相同或不同,且独立地选自下组:氢或C
1-C
3烷基,其中,所述烷基可以被选自下组的一个或多个取代基取代:氘、卤素、氰基、胺基、C
3-C
7环烷基、4-7元杂环基、NHR
9或NR
9R
10;R
9和R
10各自独立地为C
1-C
3烷基;或R
9,R
10与其连接的N原子一起构成4-8元杂环基。
When B is CH or CR5 , R1 is selected from the group consisting of -NR6C (O)C( RA )=C( RB ) 2 or -NR6S (O) 2C ( RA )= C(R B ) 2 , more preferably, R 1 is -C(O)C( RA )=C(R B ) 2 , wherein R A is independently selected from the group consisting of hydrogen, fluorine; each R B identical or different, and independently selected from the group consisting of hydrogen or C1 - C3 alkyl, wherein the alkyl may be substituted with one or more substituents selected from the group consisting of deuterium, halogen, cyano, Amino, C 3 -C 7 cycloalkyl, 4-7 membered heterocyclyl, NHR 9 or NR 9 R 10 ; R 9 and R 10 are each independently C 1 -C 3 alkyl; or R 9 , R 10 together with the N atom to which it is attached constitutes a 4-8 membered heterocyclyl group.
优选地,R
2选自取代的下组基团:苯基、5-6元杂芳基,其中,所述取代是指被选自下组的一个或多个(如2、3、4或5个)基团取代:R'、-SO
2R'、-SO
2NR'R”、-NR'SO
2R”、 -P(=O)R'R”;R'、R”相同或不同,各自独立地选自取代或未取代的下组基团:氢、氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
6烷基、C
3-C
6环烷基、C
4-C
6环烯基、4-8元杂环基、C
6-C
10芳基、5-10元杂芳基;或当R'和R”连接于同一个N原子时,R'、R”与其连接的N原子一起构成取代或未取代的4-6元杂环基;其中,所述取代是指被选自下组的一个或多个(如2、3、4或5个)基团取代:氢、氘、C
1-C
6烷基、氘代C
1-C
6烷基、卤代C
1-C
6烷基、C
3-C
8环烷基、C
1-C
6烷氧基、氘代C
1-C
6烷氧基、卤代C
1-C
6烷氧基、C
6-C
10芳基、5-10元杂芳基、4-8元杂环基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。
Preferably, R 2 is selected from the group of substituted groups: phenyl, 5-6 membered heteroaryl, wherein the substitution refers to one or more selected from the group (such as 2, 3, 4 or 5) group substitution: R', -SO 2 R', -SO 2 NR'R", -NR'SO 2 R", -P(=O)R'R";R',R" are the same or different, each independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C1 - C6 alkyl, C3 -C 6 cycloalkyl, C 4 -C 6 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl; or when R' and R" are attached to the same In the case of one N atom, R', R" together with the N atom to which they are attached constitute a substituted or unsubstituted 4-6 membered heterocyclic group; wherein, the substitution refers to one or more (such as 2) selected from the following group. , 3, 4 or 5) group substitution: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 3 -C 8 ring Alkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 10 aryl, 5-10 membered heteroaryl, 4-8 membered heterocyclic group, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or urea group.
优选地,R
4选自取代或未取代的下组基团:苯基或5-6元杂芳基,其中,所述取代是指被选自下组的一个或多个(如2、3、4或5个)基团取代:氢、氘、卤素、酯基、氰基、NR
bC(=O)OR
e、OC(=O)R
e、OC(=O)NR
bR
c、胺基、C
1-C
18烷基(优选C
1-C
6烷基、更优选C
1-C
3烷基)、卤代C
1-C
18烷基(优选卤代C
1-C
6烷基、更优选卤代C
1-C
3烷基)、羟基;R
b、R
c可以独立表示氢、氘、C1-C6烷基、C3-C8环烷基、4-8元杂环基、5-14元杂芳基或C6-C14芳环,或者说R
b和R
c与N原子一起可以形成4-8元杂环基;R
e可以独立表示氢、C1-C6烷基、C3-C8环烷基、C2-C6烯基、C3-C6环烯基、C2-C6炔基、4-8元杂环基、5-14元杂芳基或C6-C14芳环。
Preferably, R 4 is selected from the group consisting of substituted or unsubstituted groups: phenyl or 5-6 membered heteroaryl, wherein the substitution refers to one or more selected from the group (such as 2, 3 , 4 or 5) group substitution: hydrogen, deuterium, halogen, ester, cyano, NR b C(=O)OR e , OC(=O)R e , OC(=O)NR b R c , Amine group, C 1 -C 18 alkyl group (preferably C 1 -C 6 alkyl group, more preferably C 1 -C 3 alkyl group), halogenated C 1 -C 18 alkyl group (preferably halogenated C 1 -C 6 alkyl group) group, more preferably halogenated C 1 -C 3 alkyl), hydroxyl; R b , R c can independently represent hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, 5-14-membered heteroaryl group or C6-C14 aromatic ring, or R b and R c together with N atom can form 4-8-membered heterocyclic group; R e can independently represent hydrogen, C1-C6 alkyl, C3- C8 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl, 4-8 membered heterocyclyl, 5-14 membered heteroaryl or C6-C14 aromatic ring.
优选地,Q为N。Preferably, Q is N.
优选地,V、W各自独立地为CR
3,R
3为H或卤素;优选地,R
3为卤素。
Preferably, V and W are each independently CR 3 , and R 3 is H or halogen; preferably, R 3 is halogen.
优选地,R
8独立地选自取代或未取代的下组基团:氢、氘、C
1-C
6烷基、氘代C
1-C
6烷基、卤代C
1-C
6烷基、C
3-C
8环烷基、C
1-C
6烷氧基、氘代C
1-C
6烷氧基、卤代C
1-C
6烷氧基、氨基、羟基、4-8元杂环基;所述取代是指被选自下组的一个或多个(如2、3、4或5个)基团取代:氢、氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基;更优选地,R
8独立地选自取代或未取代的下组基团:氢、氘、C
1-C
6烷基、氘代C
1-C
6烷基、卤代C
1-C
6烷基,更优选地,各R
8独立地为取代或未取代的C
1-C
3烷基,其中,所述取代是指被氰基取代。
Preferably, R 8 is independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl , C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, amino, hydroxyl, 4-8 membered hetero Cyclic; said substitution means substitution with one or more (eg, 2, 3, 4, or 5) groups selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amido, sulfonamide or ureido; more preferably, R8 is independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C1 - C6 alkyl, deuterated C1- C 6 alkyl, halogenated C 1 -C 6 alkyl, more preferably, each R 8 is independently a substituted or unsubstituted C 1 -C 3 alkyl, wherein the substitution refers to substitution by cyano.
优选地,各R
8为甲基。
Preferably, each R8 is methyl.
优选地,所述的化合物具有式(VIII)所示的结构:Preferably, the compound has the structure shown in formula (VIII):
式中,In the formula,
R”'各自独立地选自取代或未取代的下组基团:氢、氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
6烷基、C
3-C
8环烷基、C
4-C
10环烯基、4-8元杂环基、C
6-C
14芳 基、5-14元杂芳基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
6烷基、C
3-C
8环烷基、C
4-C
10环烯基、4-8元杂环基、C
6-C
14芳基、5-14元杂芳基;
R"' is each independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl, wherein the substitution refers to the selected Substituted with one or more groups from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C6 alkyl, C3 - C8 cycloalkyl, C 4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl;
q选自:1、2、3、或4;q is selected from: 1, 2, 3, or 4;
R
1、R
4、R
8、R'、V、Q的定义如上所述。
The definitions of R 1 , R 4 , R 8 , R′, V, and Q are as described above.
优选地,所述的化合物具有式(IX)所示的结构:Preferably, the compound has the structure shown in formula (IX):
式中,In the formula,
R
1、R
4、R'、V、R”'、Q和q的定义如上所述。
R 1 , R 4 , R', V, R"', Q and q are as defined above.
优选地,
部分为
其中,Rx选自:氢、氘、C
1-C
3烷基、氘代C
1-C
3烷基、卤代C
1-C
3烷基、C
3-C
6环烷基、C
1-C
3烷氧基、卤素、硝基、羟基、氰基、酯基、4-6元杂环基,优选地,
部分为
Preferably, part of Wherein, Rx is selected from: hydrogen, deuterium, C 1 -C 3 alkyl, deuterated C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 1 -C C 3 alkoxy, halogen, nitro, hydroxyl, cyano, ester, 4-6 membered heterocyclic group, preferably, part of
优选地,
部分为
其中,Rx选自:氢、氘、C
1-C
3烷基、氘代C
1-C
3烷基、卤代C
1-C
3烷基、C
3-C
6环烷基、C
1-C
3烷氧基、卤素、硝基、羟基、氰基、酯基、4-6元杂环基,优选地,
部分为
Preferably, part of Wherein, Rx is selected from: hydrogen, deuterium, C 1 -C 3 alkyl, deuterated C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 1 -C C 3 alkoxy, halogen, nitro, hydroxyl, cyano, ester, 4-6 membered heterocyclic group, preferably, part of
优选地,R
2选自下组:
Preferably, R is selected from the group consisting of :
K独立地为O、S、CH2或NH;e和f各自独立地为0、1或2,优选地上述基团中的H可任选地被氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
3烷基取代。
K is independently O, S, CH2 or NH; e and f are each independently 0, 1 or 2, preferably H in the above groups can be optionally deuterium, halogen, nitro, hydroxyl, cyano, Ester group, amine group, amide group, C 1 -C 3 alkyl substitution.
优选地,所述的化合物具有式(VIII)所示的结构:Preferably, the compound has the structure shown in formula (VIII):
式中,In the formula,
R”'选自取代或未取代的下组基团:氢、氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
6烷基、C
3-C
8环烷基、C
4-C
10环烯基、4-8元杂环基、C
6-C
14芳基、5-14元杂芳基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
6烷基、C
3-C
8环烷基、C
4-C
10环烯基、4-8元杂环基、C
6-C
14芳基、5-14元杂芳基;
R"' is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 -C 8 -cycloalkyl, C 4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl, wherein the substitution refers to being selected from the group Substituted with one or more groups of: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amido, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 4 - C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl;
R
1、R
4、R
8、R'、V、Q、和q的定义如上所述。
R 1 , R 4 , R 8 , R', V, Q, and q are as defined above.
优选地,R”'选自取代或未取代的下组基团:C
1-C
6烷基、C
3-C
8环烷基、C
4-C
10环烯基、4-8元杂环基、C
6-C
10芳基、5-10元杂芳基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
6烷基、C
3-C
8环烷基、4-8元杂环基。
Preferably, R"' is selected from the group consisting of substituted or unsubstituted groups: C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 4 -C 10 cycloalkenyl, 4-8 membered heterocycle base, C 6 -C 10 aryl, 5-10 membered heteroaryl, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxyl, cyano , ester group, amine group, amide group, C 1 -C 6 alkyl group, C 3 -C 8 cycloalkyl group, 4-8 membered heterocyclic group.
优选地,R”'选自取代或未取代的下组基团:C
1-C
6烷基、C
3-C
6环烷基、C
4-C
6环烯基、4-6元杂环基,更优选地,R”'选自取代或未取代的下组基团:基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、环丙氨基、氮杂环丁烷基、氮杂环戊烷基、氮杂环己烷基、环氧乙烷基、氧杂环丁烷基、氧杂环戊烷基、氧杂环己烷基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
3烷基。
Preferably, R"' is selected from the group consisting of substituted or unsubstituted groups: C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 6 cycloalkenyl, 4-6 membered heterocycle group, more preferably, R"' is selected from the group consisting of substituted or unsubstituted groups: radical, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylamino, azetidinyl, azepanyl, azetidine, oxiranyl, oxetanyl, oxolane, oxanyl, wherein, The substitution refers to substitution with one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl.
K独立地为O、S、CH2或NH;e和f各自独立地为0、1或2,优选地上述基团中的H可任选地被氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
3烷基取代。
K is independently O, S, CH2 or NH; e and f are each independently 0, 1 or 2, preferably H in the above groups can be optionally deuterium, halogen, nitro, hydroxyl, cyano, Ester group, amine group, amide group, C 1 -C 3 alkyl substitution.
优选地,所述的化合物具有式(X)或(XI)所示的结构:Preferably, the compound has a structure represented by formula (X) or (XI):
式中,In the formula,
R
4选自取代或未取代C
6-C
14芳基或5-10元杂芳基,其中,所述取代是指被选自下组的一个或多个(如2、3、4或5个)基团取代:氘、卤素、酯基、氰基、NR
bC(=O)OR
e、OC(=O)R
e、OC(=O)NR
bR
c、胺基、C
1-C
6烷基、卤代C
1-C
6烷基、羟基;R
b、R
c可以独立表示氢、氘、C1-C6烷基、C3-C8环烷基、4-8元杂环基、5-14元杂芳基或C6-C14芳环,或者说R
b和R
c与N原子一起可以形成4-8元杂环基;R
e可以独立表示氢、C1-C6烷基、C3-C8环烷基、C2-C6烯基、C3-C6环烯基、C2-C6炔基、4-8元杂环基、5-14元杂芳基或C6-C14芳环;
R 4 is selected from substituted or unsubstituted C 6 -C 14 aryl or 5-10 membered heteroaryl, wherein the substitution refers to one or more (such as 2, 3, 4 or 5) selected from the group ) group substitution: deuterium, halogen, ester, cyano, NR b C(=O)OR e , OC(=O)R e , OC(=O)NR b R c , amine group, C 1 - C 6 alkyl, halogenated C 1 -C 6 alkyl, hydroxyl; R b and R c can independently represent hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclic group, 5-14-membered heteroaryl group or C6-C14 aromatic ring, or R b and R c together with N atom can form 4-8-membered heterocyclic group; R e can independently represent hydrogen, C1-C6 alkyl, C3- C8 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl, 4-8 membered heterocyclyl, 5-14 membered heteroaryl or C6-C14 aromatic ring;
Rm选自取代或未取代的下组基团:胺基、C
1-C
6烷基、C
3-C
6环烷基、4-6元杂环基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
3烷基、C3-C6环烷基、4-6元杂环基;
Rm is selected from the group consisting of substituted or unsubstituted groups: amine group, C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, 4-6 membered heterocyclic group, wherein the substitution refers to the selected Substituted with one or more groups from the group consisting of deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C1 - C3 alkyl, C3-C6 cycloalkyl, 4- 6-membered heterocyclic group;
Rn选自取代或未取代的下组基团:胺基、C
1-C
6烷基、C
1-C
6烷氧基、C
3-C
6环烷基、-O-C
3-C
6环烷基、C
1-C
6烷基C
3-C
6环烷基、-O-C
1-C
6烷基C
3-C
6环烷基、4-6元杂环基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
3烷基、C
1-C
3卤代烷基、C3-C6环烷基、4-6元杂环基;
Rn is selected from the group consisting of substituted or unsubstituted groups: amine, C1 - C6alkyl , C1 - C6alkoxy , C3 - C6cycloalkyl, -OC3 - C6cycloalkane base, C 1 -C 6 alkyl C 3 -C 6 cycloalkyl, -OC 1 -C 6 alkyl C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group, wherein the substitution refers to Substituted with one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl, C1 - C3 haloalkyl , C3-C6 cycloalkyl, 4-6 membered heterocyclyl;
Rx选自:F或Cl;Rx is selected from: F or Cl;
R
A选自:H、D、卤素、或氰基,优选地R
A选自:H或F。
R A is selected from: H, D, halogen, or cyano, preferably R A is selected from: H or F.
R”'的定义如上所述;R"' is as defined above;
q'选自0、1、2、或3。q' is selected from 0, 1, 2, or 3.
优选地,所述化合物其具有式(VIII-1)所示的结构:Preferably, the compound has a structure represented by formula (VIII-1):
式中,R
1、Rx、R
4、Rm和Rn的定义如上所述。
In the formula, R 1 , Rx, R 4 , Rm and Rn are defined as described above.
优选地,所述化合物具有式(X)所示的结构Preferably, the compound has a structure represented by formula (X)
式中,R
A、Rx、R
4、Rm、Rn、q”'和q'的定义如上所述。
In the formula, R A , Rx, R 4 , Rm, Rn, q"' and q' are defined as described above.
优选地,所述化合物具有式(XII)所示的结构Preferably, the compound has the structure represented by formula (XII)
式中,R
4a、R
4b、R
4c、R
4d、R
4e、Rm、Rn、Rx、R
A、q'、R”'如上所述。
In the formula, R 4a , R 4b , R 4c , R 4d , R 4e , Rm, Rn, Rx, R A , q' and R"' are as described above.
优选地,所述化合物具有式(XIV)所示的结构:Preferably, the compound has the structure shown in formula (XIV):
式中,R
4a、R
4b、R
4c、R
4d、R
4e、Rm、Rn、Rx、R
A如上所述。
In the formula, R 4a , R 4b , R 4c , R 4d , R 4e , Rm, Rn, Rx and RA are as described above.
优选地,R
4选自取代或未取代苯基或5-6元杂芳基,更优选地,R
4选自取代或未取代苯基,其中,所述取代是指被选自下组的一个或多个(如2、3、4或5个)基团取代:氘、卤素、酯基、氰基、NR
bC(=O)OR
e、OC(=O)R
e、OC(=O)NR
bR
c、胺基、C
1-C
3烷基、卤代 C
1-C
3烷基、羟基;R
b、R
c可以独立表示氢、氘、C1-C3烷基、C3-C6环烷基、4-6元杂环基、5-6元杂芳基或苯基,或者说R
b和R
c与N原子一起可以形成4-6元杂环基;R
e可以独立表示氢、C1-C3烷基、C3-C6环烷基。
Preferably, R 4 is selected from substituted or unsubstituted phenyl or 5-6 membered heteroaryl, more preferably, R 4 is selected from substituted or unsubstituted phenyl, wherein, the substitution refers to being selected from the group One or more (eg 2, 3, 4 or 5) group substitutions: deuterium, halogen, ester, cyano, NRb C(=O) ORe , OC(=O) Re , OC(= O) NR b R c , amino, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, hydroxyl; R b and R c can independently represent hydrogen, deuterium, C1-C3 alkyl, C3- C6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl or phenyl, or R b and R c together with N atom can form a 4-6 membered heterocyclyl; R e can represent independently Hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl.
优选地,Rn选自取代或未取代的下组基团:乙基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、环丙氨基、氮杂环丁烷基、氮杂环戊烷基、氮杂环己烷基、环氧乙烷基、氧杂环丁烷基、氧杂环戊烷基、氧杂环己烷基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
3烷基。
Preferably, Rn is selected from the group consisting of substituted or unsubstituted groups: ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylamino, azetidine alkyl, azepanyl, azepanyl, oxiranyl, oxetanyl, oxolane, oxetanyl, wherein the substitution is means substituted with one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl.
优选地,Rm选自取代或未取代的下组基团:甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、环丙氨基、氮杂环丁烷基、氮杂环戊烷基、氮杂环己烷基、环氧乙烷基、氧杂环丁烷基、氧杂环戊烷基、氧杂环己烷基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C
1-C
3烷基。
Preferably, Rm is selected from the group consisting of substituted or unsubstituted groups: methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylamino, nitrogen cyclobutanyl, azepanyl, azetidinyl, oxiranyl, oxetanyl, oxolane, oxetanyl, wherein the The substitution refers to substitution with one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C1 - C3 alkyl.
本发明中的化合物可能形成的盐也是属于本发明的范围。除非另有说明,本发明中的化合物被理解为包括其盐类。在此使用的术语“盐”,指用无机或有机酸和碱形成酸式或碱式的盐。此外,当本发明中的化合物含一个碱性片段时,它包括但不限于吡啶或咪唑,含一个酸性片段时,包括但不限于羧酸,可能形成的两性离子(“内盐”)包含在术语“盐”的范围内。药学上可接受的(即无毒,生理可接受的)盐是首选,虽然其他盐类也有用,例如可以用在制备过程中的分离或纯化步骤。本发明的化合物可能形成盐,例如,化合物I与一定量如等当量的酸或碱反应,在介质中盐析出来,或在水溶液中冷冻干燥得来。The salts that the compounds of the present invention may form are also within the scope of the present invention. Unless otherwise specified, compounds in the present invention are understood to include their salts. As used herein, the term "salt" refers to salts formed with inorganic or organic acids and bases in the acid or basic form. In addition, when a compound of the present invention contains a basic moiety, which includes, but is not limited to, pyridine or imidazole, and when it contains an acidic moiety, including, but is not limited to, a carboxylic acid, the zwitterion ("inner salt") that may be formed is contained in within the scope of the term "salt". Pharmaceutically acceptable (ie, non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, eg, in isolation or purification steps in the manufacturing process. The compounds of the present invention may form salts, for example, by reacting Compound I with an amount, eg, an equivalent, of an acid or base, salting out in a medium, or lyophilizing in an aqueous solution.
本发明中的化合物含有的碱性片段,包括但不限于胺或吡啶或咪唑环,可能会和有机或无机酸形成盐。可以成盐的典型的酸包括醋酸盐(如用醋酸或三卤代醋酸,如三氟乙酸)、己二酸盐、藻朊酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑盐、樟脑磺酸盐、环戊烷丙酸盐、二甘醇酸盐、十二烷基硫酸盐、乙烷磺酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟基乙磺酸盐(如,2-羟基乙磺酸盐)、乳酸盐、马来酸盐、甲磺酸盐、萘磺酸盐(如,2-萘磺酸盐)、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、苯丙酸盐(如3-苯丙酸盐)、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐,水杨酸盐、琥珀酸盐、硫酸盐(如与硫酸形成的)、磺酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐如对甲苯磺酸盐、十二烷酸盐等等The compounds of the present invention contain basic moieties, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids. Typical acids that can form salts include acetates (eg with acetic acid or trihaloacetic acids such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates , benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentane propionate, diglycolate, lauryl sulfate, Ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodate, isethionate (eg, 2-hydroxyethanesulfonate), lactate, maleate, mesylate, naphthalenesulfonate (eg, 2-naphthalenesulfonate), nicotinate, nitrate, oxalic acid Salts, pectates, persulfates, phenylpropionates (such as 3-phenylpropionate), phosphates, picrates, pivalates, propionates, salicylates, succinates, Sulfates (as formed with sulfuric acid), sulfonates, tartrates, thiocyanates, tosylates such as p-toluenesulfonates, dodecanoates, etc.
本发明的某些化合物可能含有的酸性片段,包括但不限于羧酸,可能会和各种有机或无机碱形成盐。典型的碱形成的盐包括铵盐、碱金属盐如钠、锂、钾盐,碱土金属盐如钙、镁盐,和有机碱形成的盐(如有机胺),如苄星、二环已基胺、海巴胺(与N,N-二(去氢枞基)乙二胺形成的盐)、N-甲基-D-葡糖胺、N-甲基-D-葡糖酰胺、叔丁基胺,以及和氨基酸如精氨酸、赖氨酸等等形成的盐。碱性含氮基团可以与卤化物季铵盐,如小分子烷基卤化物(如甲基、乙基、丙基和丁基的氯化物、溴化物及碘化物),二烷基硫酸盐(如, 硫酸二甲酯、二乙酯,二丁酯和二戊酯),长链卤化物(如癸基、十二烷基、十四烷基和十四烷基的氯化物、溴化物及碘化物),芳烷基卤化物(如苄基和苯基溴化物)等等。Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases. Typical base-formed salts include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts formed from organic bases (such as organic amines) such as benzathine, bicyclohexyl Amine, Hepamine (salt with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucosamide, tert-butyl amines, and salts with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (eg, dimethyl, diethyl, dibutyl, and dipentyl sulfate), long-chain halides (eg, decyl, dodecyl, tetradecyl, and tetradecyl chlorides, bromides) and iodides), aralkyl halides (such as benzyl and phenyl bromides), and the like.
本发明中化合物的前药及溶剂合物也在涵盖的范围之内。此处术语“前药”是指一种化合物,在治疗相关疾病时,经过代谢或化学过程的化学转化而产生本发明中的化合物、盐、或溶剂合物。本发明的化合物包括溶剂合物,如水合物。Prodrugs and solvates of the compounds of the present invention are also contemplated. The term "prodrug" as used herein refers to a compound that undergoes chemical transformation through a metabolic or chemical process to yield the compound, salt, or solvate of the present invention in the treatment of a related disease. The compounds of the present invention include solvates, such as hydrates.
本发明中的化合物、盐或溶剂合物,可能存在的互变异构形式(例如酰胺和亚胺醚)。所有这些互变异构体都是本发明的一部分。The compounds, salts or solvates of the present invention may exist in tautomeric forms (eg amides and imine ethers). All of these tautomers are part of the present invention.
所有化合物的立体异构体(例如,那些由于对各种取代可能存在的不对称碳原子),包括其对映体形式和非对映形式,都属于本发明的设想范围。本发明中的化合物独立的立体异构体可能不与其他异构体同时存在(例如,作为一个纯的或者实质上是纯的光学异构体具有特殊的活性),或者也可能是混合物,如消旋体,或与所有其他立体异构体或其中的一部分形成的混合物。本发明的手性中心有S或R两种构型,由理论与应用化学国际联合会(IUPAC)1974年建议定义。外消旋形式可通过物理方法解决,例如分步结晶,或通过衍生为非对映异构体分离结晶,或通过手性柱色谱法分离。单个的光学异构体可通过合适的方法由外消旋体得到,包括但不限于传统的方法,例如与光学活性酸成盐后再结晶。Stereoisomers of all compounds (eg, those due to asymmetric carbon atoms that may exist for various substitutions), including their enantiomeric and diastereomeric forms, are contemplated by the present invention. Individual stereoisomers of the compounds of the present invention may not exist concurrently with other isomers (eg, as a pure or substantially pure optical isomer with specific activity), or may be mixtures such as Racemates, or mixtures with all other stereoisomers or a part thereof. The chiral center of the present invention has two configurations, S or R, as defined by the 1974 recommendation of the International Union of Theoretical and Applied Chemistry (IUPAC). The racemic form can be resolved by physical methods, such as fractional crystallization, or by derivatization to diastereomer separation crystallization, or by chiral column chromatography. The individual optical isomers can be obtained from the racemates by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by crystallization.
本发明中的化合物,依次通过制备、分离纯化获得的该化合物其重量含量等于或大于90%,例如,等于或大于95%,等于或大于99%(“非常纯”的化合物),在正文描述列出。此处这种“非常纯”本发明的化合物也作为本发明的一部分。The compound of the present invention, the compound obtained by successively preparing, isolating and purifying the compound has a weight content equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compound), described in the text List. Herein such "very pure" compounds of the invention are also intended to be part of the invention.
本发明的化合物所有的构型异构体都在涵盖的范围之内,无论是混合物、纯的或非常纯的形式。在本发明化合物的定义包含顺式(Z)和返式(E)两种烯烃异构体,以及碳环和杂环的顺式和反式异构体。All configurational isomers of the compounds of the present invention are contemplated, whether in admixture, pure or very pure form. The definition of compounds of the present invention includes both cis (Z) and trans (E) olefin isomers, as well as carbocyclic and heterocyclic cis and trans isomers.
在整个说明书中,基团和取代基可以被选择以提供稳定的片段和化合物。Throughout the specification, groups and substituents may be selected to provide stable fragments and compounds.
特定官能团和化学术语定义都详细介绍如下。对本发明来说,化学元素与Periodic Table of the Elements,CAS version,Handbook of Chemistry and Physics,75
th Ed.中定义的一致。特定官能团的定义也在其中描述。此外,有机化学的基本原则以及特定官能团和反应性在“Organic Chemistry”,Thomas Sorrell,University Science Books,Sausalito:1999,也有说明,其全部内容纳入参考文献之列。
Specific functional groups and chemical term definitions are detailed below. For the purposes of the present invention, chemical elements are as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Definitions of specific functional groups are also described therein. In addition, basic principles of organic chemistry and specific functional groups and reactivity are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, which is incorporated by reference in its entirety.
本发明的某些化合物可能存在于特定的几何或立体异构体形式。本发明涵盖所有的化合物,包括其顺式和反式异构体、R和S对映异构体、非对映体、(D)型异构体、(L)型异构体、外消旋混合物和其它混合物。另外不对称碳原子可表示取代基,如烷基。所有异构体以及它们的混合物,都包涵在本发明中。Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention covers all compounds including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, Spin mixtures and other mixtures. Additionally asymmetric carbon atoms may represent substituents such as alkyl groups. All isomers, as well as mixtures thereof, are encompassed by the present invention.
按照本发明,同分异构体的混合物含有异构体的比率可以是多样的。例如,在只有两个异构体的混合物可以有以下组合:50:50,60:40,70:30,80:20,90:10,95:5,96:4,97:3,98:2,99:1,或100:0,异构体的所有比率都在本发明范围之内。本专业 内一般技术人员容易理解的类似的比率,及为更复杂的异构体的混合物的比率也在本发明范围之内。In accordance with the present invention, a mixture of isomers may contain isomers in various ratios. For example, in a mixture of only two isomers you can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98: All ratios of 2, 99:1, or 100:0, isomers are within the scope of the present invention. Similar ratios readily understood by those of ordinary skill in the art, as well as ratios that are mixtures of more complex isomers, are also within the scope of the invention.
本发明还包括同位素标记的化合物,等同于原始化合物在此公开。不过实际上对一个或更多的原子被与其原子量或质量序数不同的原子取代通常会出现。可以列为本发明的化合物同位素的例子包括氢、碳、氮、氧、磷、硫、氟和氯同位素,分别如
2H、
3H、
13C、
11C、
14C、
15N、
18O、
17O、
31P、
32P、
35S、
18F和
36Cl。本发明中的化合物,或对映体、非对映体、异构体,或药学上可接受的盐或溶剂化物,其中含有上述化合物的同位素或其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物,例如
3H和
14C的放射性同位素也在其中,在药物和底物的组织分布实验中是有用的。氚,即
3H和碳-14,即
14C,它们的制备和检测比较容易。是同位素中的首选。此外,较重同位素取代如氘,即
2H,由于其很好的代谢稳定性在某些疗法中有优势,例如在体内增加半衰期或减少用量,因此,在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法,通过用易得的同位素标记试剂替换为非同位素的试剂,用批露在示例中的方案可以制备。
The present invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein. In practice, however, it usually occurs that one or more atoms are replaced by atoms with different atomic weights or mass numbers. Examples of isotopes that may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes 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, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotopic atoms of the above compounds are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as radioisotopes of3H and14C , are also among them and are useful in drug and substrate tissue distribution experiments. Tritium, ie 3 H and carbon-14, ie 14 C, are relatively easy to prepare and detect. Is the first choice among isotopes. In addition, heavier isotopic substitutions such as deuterium, ie, 2 H, may be preferred in some cases due to their good metabolic stability in certain therapeutics, such as increased half-life or reduced dosage in vivo. Isotopically-labeled compounds can be prepared by conventional methods by substituting readily available isotopically-labeled reagents for non-isotopically labeled reagents using the protocols disclosed in the Examples.
如果要设计一个本发明的化合物特定的对映体的合成,它可以不对称合成制备,或用手性辅剂衍生化,将所产生的非对映混合物分离,再除去手性辅剂而得到纯的对映体。另外,如果分子中含有一个碱性官能团,如氨基酸,或酸性官能团,如羧基,可以用合适的光学活性的酸或碱的与之形成非对映异构体盐,再通过分离结晶或色谱等常规手段分离,然后就得到了纯的对映体。If a synthesis of a particular enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, separation of the resulting diastereomeric mixture, and removal of the chiral auxiliary to obtain pure enantiomer. In addition, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, a suitable optically active acid or base can be used to form a diastereomeric salt with it, and then the diastereomeric salt can be formed by separation crystallization or chromatography, etc. Separation by conventional means then yields the pure enantiomer.
本申请所涉及的化合物及其药学可接受的盐的代谢产物,以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药,也包含在本申请的权利要求中。The metabolites of the compounds involved in the present application and their pharmaceutically acceptable salts, as well as prodrugs that can be converted into the structures of the compounds involved in the present application and their pharmaceutically acceptable salts in vivo, are also included in the claims of the present application middle.
制备方法Preparation
下面更具体地描述本发明式(I)结构化合物的制备方法,但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得,这样的组合可由本发明所属领域的技术人员容易地进行。The preparation method of the compound of formula (I) of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention pertains.
典型地,本发明化合物的制备工艺流程如下,其中所用原料和试剂如无特殊说明,均可通过商业途径购买或按照已报道的文献合成。Typically, the preparation process of the compound of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels or synthesized according to the reported literature unless otherwise specified.
(i)在惰性溶剂(如四氢呋喃)中,式P-1化合物先与草酰氯反应,然后与胺基化合物R
2-NH
2反应,得到式P-2化合物;
(i) in an inert solvent (such as tetrahydrofuran), the compound of formula P-1 is first reacted with oxalyl chloride, and then reacted with the amino compound R 2 -NH 2 to obtain the compound of formula P-2;
(ii)在惰性溶剂(如四氢呋喃)中,在第一种碱作用下,式P-2化合物关环,得到式P-3化合物;(ii) in an inert solvent (such as tetrahydrofuran), under the action of the first base, the compound of formula P-2 is closed to obtain the compound of formula P-3;
(iii)在惰性溶剂(如乙腈)中,式P-3化合物与三氯氧磷在第二种碱作用下,得到式P-4化合物;(iii) in an inert solvent (such as acetonitrile), the compound of formula P-3 is reacted with phosphorus oxychloride under the action of a second base to obtain the compound of formula P-4;
(iv)在惰性溶剂(如乙腈)中,碱(如N,N-二异丙基乙胺)存在下,式P-4化合物与
通过偶联或者取代反应,得到式P-5化合物;
(iv) in an inert solvent (such as acetonitrile) in the presence of a base (such as N,N-diisopropylethylamine), the compound of formula P-4 with Through coupling or substitution reaction, the compound of formula P-5 is obtained;
(v)在惰性溶剂(如二氯甲烷)中,酸(如三氟乙酸)存在下,式P-5化合物脱保护,得到式P-6化合物;(v) deprotecting the compound of formula P-5 in the presence of an acid (such as trifluoroacetic acid) in an inert solvent (such as dichloromethane) to obtain a compound of formula P-6;
(vi)在惰性溶剂(如二氯甲烷)中,碱(如N,N-二异丙基乙胺)存在下,式P-6化合物与R
1E通过偶联、取代或酰化反应,得到式P-7化合物;
(vi) reacting a compound of formula P-6 with R 1 E by coupling, substitution or acylation in the presence of a base (such as N,N-diisopropylethylamine) in an inert solvent (such as dichloromethane), to obtain the compound of formula P-7;
(vii)在惰性溶剂(如二氧六环/水)中,碱(如乙酸钾)和催化剂(如[1,1'-双(二苯基膦)二茂铁]二氯化钯)存在下,式P-7与R
4-L-E
1通过偶联、取代或者酰化反应,得到式(I)化合物;
(vii) in an inert solvent (eg dioxane/water) in the presence of a base (eg potassium acetate) and a catalyst (eg [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride) Next, the compound of formula (I) is obtained by coupling, substitution or acylation reaction between formula P-7 and R 4 -LE 1 ;
式中,In the formula,
E为卤素、OH、OCOR
1、OCO(
iBu)等;
E is halogen, OH, OCOR 1 , OCO( i Bu), etc.;
PG为氨基保护基,所述保护基选自下组:Boc、Bn、Cbz或Fmoc;PG is an amino protecting group selected from the group consisting of Boc, Bn, Cbz or Fmoc;
Y和Z为离去基团,所述离去基团选自下组:卤素或者OTf;Y and Z are leaving groups selected from the group consisting of halogen or OTf;
所述第一种碱选自下组:KHMDS、NaHMDS、LiHMDS、NaH、NaOMe、NaOEt或
tBuONa;
The first base is selected from the group consisting of KHMDS, NaHMDS, LiHMDS, NaH, NaOMe, NaOEt or tBuONa ;
所述第二种碱选自下组:TEA、DIPEA、DMAP或N,N-二甲基苯胺;The second base is selected from the group consisting of TEA, DIPEA, DMAP or N,N-dimethylaniline;
R
1、R
2、R
4、L、A、B、X、U、V、W和Q的定义如上所述。
R 1 , R 2 , R 4 , L, A, B, X, U, V, W and Q are as defined above.
上述反应步骤中,反应溶剂、反应催化剂、反应所用的碱、反应温度、反应时间等,本领域技术人员可以根据具体的反应物进行选择。In the above reaction steps, the reaction solvent, reaction catalyst, base used in the reaction, reaction temperature, reaction time, etc., can be selected by those skilled in the art according to the specific reactants.
药物组合物和施用方法Pharmaceutical compositions and methods of administration
本发明所述的药物组合物用于预防和/或治疗以下疾病:炎症、癌症、心血管疾病、感染、免疫性疾病、代谢性疾病。The pharmaceutical composition of the present invention is used for preventing and/or treating the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease.
式(I)所述化合物可以与已知的治疗或改进相似病状的其他药物联用。联合给药时,原来药物的给药方式和剂量可以保持不变,而同时或随后服用式(I)的化合物。当式(I)化合物与其它一种或几种药物同时服用时,可以优选使用同时含有一种或几种已知药物和式(I)化合物的药用组合物。药物联用也包括在重叠的时间段服用式(I)化合物与其它一种或几种已知药物。当式(I)化合物与其它一种或几种药物进行药物联用时,式(I)化合物或已知药物的剂量可能比它们单独用药的剂量低。The compounds of formula (I) may be used in combination with other drugs known to treat or ameliorate similar conditions. In the case of combined administration, the mode of administration and dosage of the original drug may remain unchanged, while the compound of formula (I) is administered simultaneously or subsequently. When the compound of formula (I) is administered concomitantly with one or more other drugs, a pharmaceutical composition containing both one or more known drugs and the compound of formula (I) may preferably be used. Drug combinations also include administration of a compound of formula (I) with one or more other known drugs at overlapping time periods. When a compound of formula (I) is administered in combination with one or more other drugs, the doses of the compound of formula (I) or known drugs may be lower than their doses alone.
可以与式(I)所述化合物进行药物联用的药物或活性成分包括但不局限为:PD-1抑制剂(如纳武单抗、派姆单抗、pidilizumab、cemiplimab、JS-001、SHR-120、BGB-A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10、BAT1306、AK105、LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如度伐单抗、阿特珠单抗、阿维鲁单抗(avelumab)、CS1001、KN035、HLX20、SHR-1316、BGB-A333、JS003、CS1003、KL-A167、F 520、GR1405、MSB2311或上述药物的生物类似药等)、CD20抗体(如利妥昔单抗、奥滨尤妥珠单抗、奥法木单抗、veltuzumab,托西莫单抗、131I-托西莫单抗、替伊莫单抗、90Y-替伊莫单抗、90In-替伊莫单抗、替伊莫单抗(ibritumomab tiuxetan)等)、CD47抗体(如Hu5F9-G4、CC-90002、TTI-621、TTI-622、OSE-172、SRF-231、ALX-148、NI-1701、SHR-1603、IBI188、IMM01)、ALK抑制剂(如色瑞替尼、艾乐替尼、布加替尼、劳拉替尼、奥卡替尼)、PI3K抑制剂(如艾代拉里斯、Duvelisib、Dactolisib、Taselisib、Bimiralisib、Omipalisib、Buparlisib等)、BTK抑制剂(如依鲁替尼、Tirabrutinib、阿卡替尼、赞布替尼、Vecabrutinib等)、EGFR抑制剂(如阿法替尼、吉非替尼、厄洛替尼、拉帕替尼、达克替尼、埃克替尼、卡奈替尼、沙普替尼、Naquotinib、吡咯替尼、罗乐替尼、奥希替尼等)、VEGFR抑制剂(如索拉非尼、帕唑帕尼、瑞戈非尼、司曲替尼、Ningetinib、卡博替尼、舒尼替尼、多纳非尼等)、HDAC抑制剂(如Givinostat、Tucidinostat、伏立诺他、Fimepinostat、Droxinostat、恩替诺特、达西司特、Quisinostat、泰克地那林等)、CDK抑制剂(如帕博西尼、瑞博西尼、Abemaciclib、Milciclib、Trilaciclib、Lerociclib等)、MEK抑制剂(如司美替尼(AZD6244)、曲美替尼(GSK1120212)、PD0325901、U0126、Pimasertib(AS-703026)、PD184352(CI-1040)等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068、TNO155等),或其组合。Drugs or active ingredients that can be used in combination with the compound of formula (I) include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR -120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as Duval) Monoclonal antibody, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311, or any of the above Biosimilars, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumumab, 131I-tositumumab, tiimumab Anti-, 90Y-tiimumab, 90In-tiimumab, ibritumomab tiuxetan, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as ceritinib, alectinib, brigatinib, lorlatinib, ocaltinib), PI3K inhibitors (such as idelaris, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipalisib, Buparlisib, etc.), BTK inhibitors (such as ibrutinib, Tirabrutinib, acalatinib, zambrutinib) EGFR inhibitors (such as afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, canetinib, sapritinib, etc.) , Naquotinib, pyrotinib, roletinib, osimertinib, etc.), VEGFR inhibitors (such as sorafenib, pazopanib, regorafenib, sertratinib, Ningetinib, cabozantinib) , Sunitinib, Donafenib, etc.), HDAC inhibitors (such as Givinostat, Tucidinostat, Vorinostat, Fimepinostat, Droxinostat, Entenod, Darxilast, Quisinostat, Tycodinaline, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, Milciclib, Trilaciclib, Lerociclib, etc.), MEK inhibitors (such as selumetinib (AZD6244), Trimet Tini (GSK1120212), PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040, etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.) ), or a combination thereof.
本发明所述药物组合物的剂型包括(但并不限于):注射剂、片剂、胶囊剂、气 雾剂、栓剂、膜剂、滴丸剂、外用擦剂、控释型或缓释型或纳米制剂。The dosage form of the pharmaceutical composition of the present invention includes (but is not limited to): injection, tablet, capsule, aerosol, suppository, film, drop pill, external liniment, controlled-release or sustained-release or nanometer preparation.
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有10-1000mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount. The "safe and effective amount" refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/dose, more preferably, 10-1000 mg of the compound of the present invention/dose. Preferably, the "one dose" is a capsule or tablet.
“药学上可以接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
"Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler or gelling substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility" as used herein means that the components of the composition can be admixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium fatty acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。Besides these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。Suspensions, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
本发明治疗方法可以单独施用,或者与其它治疗手段或者治疗药物联用。The therapeutic methods of the present invention may be administered alone or in combination with other therapeutic means or therapeutic agents.
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选50~1000mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is The administration dose is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
本发明还提供了一种药物组合物的制备方法,包括步骤:将药学上可接受的载体与本发明所述式(I)化合物或其晶型、药学上可接受的盐、水合物或溶剂合物进行混合,从而形成药物组合物。The present invention also provides a method for preparing a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of formula (I) or its crystal form, pharmaceutically acceptable salt, hydrate or solvent of the present invention The compounds are mixed to form a pharmaceutical composition.
本发明还提供了一种治疗方法,它包括步骤:给需要治疗的对象施用本发明中所述式(I)化合物、或其晶型、药学上可接受的盐、水合物或溶剂合物,或施用本发明所述的药物组合物,用于选择性地抑制KRAS
G12C。
The present invention also provides a method of treatment, which comprises the steps of: administering the compound of formula (I) described in the present invention, or a crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof to a subject in need of treatment, Or administer the pharmaceutical composition of the present invention for selectively inhibiting KRAS G12C .
与现有技术相比,本发明具有以下主要优点:Compared with the prior art, the present invention has the following main advantages:
(1)所述化合物对KRAS
G12C具有很好的选择性抑制作用;
(1) The compound has a good selective inhibitory effect on KRAS G12C ;
(2)所述化合物具有更好的药效学、药代动力学性能和更低的毒副作用;其中,实验结果表明,含有苯砜结构的化合物,其药代动力学特性优于其他结构,如吡啶砜结构的化合物,含有二甲基哌嗪结构的化合物相较于单甲基哌嗪具有更好的药效;(2) The compound has better pharmacodynamics, pharmacokinetic properties and lower toxic and side effects; wherein, the experimental results show that the compound containing phenylsulfone structure has better pharmacokinetic properties than other structures, For example, compounds with pyridine sulfone structure, compounds containing dimethylpiperazine structure have better efficacy than monomethylpiperazine;
(3)本发明化合物中,当R
4为苯基时,生物活性较佳,优于杂芳基。
(3) Among the compounds of the present invention, when R 4 is a phenyl group, the biological activity is better than that of a heteroaryl group.
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. In the following examples, the experimental methods without specific conditions are usually in accordance with conventional conditions, or in accordance with the conditions suggested by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be used in the methods of the present invention. Methods and materials for preferred embodiments described herein are provided for illustrative purposes only.
本发明的化合物结构是通过核磁共振(NMR)和液质联用色谱(LC-MS)来确定的。The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).
NMR是使用Bruker AVANCE-400核磁仪检测的,测定溶剂包含氘代二甲亚砜(DMSO-d
6)、氘代丙酮(CD
3COCD
3)、氘代氯仿(CDCl
3)及氘代甲醇(CD
3OD)等,内标采用四甲基硅烷(TMS),化学位移以百万分之一(ppm)的单位计量。
NMR was detected using a Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was determined to include deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated acetone (CD 3 COCD 3 ), deuterated chloroform (CDCl 3 ) and deuterated methanol ( CD 3 OD), etc., tetramethylsilane (TMS) was used as the internal standard, and chemical shifts were measured in units of parts per million (ppm).
液质联用色谱(LC-MS)是使用Waters SQD2质谱仪检测的。HPLC的测定使用Agilent 1100高压色谱仪(Microsorb 5 micron C18 100 x 3.0mm色谱柱)。Liquid chromatography-mass spectrometry (LC-MS) was detected using a Waters SQD2 mass spectrometer. The HPLC assay was performed using an Agilent 1100 high pressure chromatograph (Microsorb 5 micron C18 100 x 3.0 mm column).
薄层层析硅胶板使用青岛GF254硅胶板,TLC采用的是0.15-0.20mm,制备薄层色谱采用的是0.4mm-0.5mm。柱层析一般使用青岛硅胶200-300目硅胶作为载体。TLC silica gel plate used Qingdao GF254 silica gel plate, TLC used 0.15-0.20mm, preparative thin layer chromatography used 0.4mm-0.5mm. Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.
本发明实施例中的起始原料都是已知并有市售的,或者可以采用或按照本领域已报道的文献资料合成的。The starting materials in the examples of the present invention are all known and commercially available, or can be synthesized by adopting or according to the literature data reported in the field.
除特殊说明外,本发明所有反应均在干燥的惰性气体(如氮气或氩气)保护下通过连续磁力搅拌进行,反应温度均为摄氏度。Unless otherwise specified, all the reactions of the present invention are carried out under the protection of dry inert gas (such as nitrogen or argon) by continuous magnetic stirring, and the reaction temperatures are all in degrees Celsius.
实施例Example
实施例1 4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-7-(2-氟-6-羟基苯基)-1-(4-甲基-2-(甲基磺基)吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的制备Example 1 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4- Preparation of methyl-2-(methylsulfo)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one
第1步.4-甲基-2-(甲磺酰基)-3-硝基吡啶的制备Step 1. Preparation of 4-methyl-2-(methylsulfonyl)-3-nitropyridine
将2-氯-4-甲基-3-硝基吡啶(3g,17.4mmol)溶于25毫升二甲亚砜中,向此溶液中加入甲基亚磺酸钠(2.7g,26.2mmol)。将此混合物于120度搅拌1小时,用100毫升水淬灭,然后用100毫升乙酸乙酯萃取3次。合并有机相以50毫升盐水洗涤3次,然后有机相干燥,浓缩。残留固体以乙醇/甲醇/乙酸乙酯(40毫升/5毫升/5毫升)打浆,抽滤、干燥得到目标化合物(2.3g,61%)。2-Chloro-4-methyl-3-nitropyridine (3 g, 17.4 mmol) was dissolved in 25 mL of dimethyl sulfoxide, and to this solution was added sodium methanesulfinate (2.7 g, 26.2 mmol). The mixture was stirred at 120 degrees for 1 hour, quenched with 100 mL of water, and extracted 3 times with 100 mL of ethyl acetate. The combined organic phases were washed three times with 50 mL of brine, then the organic phases were dried and concentrated. The residual solid was slurried with ethanol/methanol/ethyl acetate (40 mL/5 mL/5 mL), suction filtered and dried to obtain the target compound (2.3 g, 61%).
第2步.4-甲基-2-(甲磺酰基)吡啶-3-胺的制备Step 2. Preparation of 4-methyl-2-(methylsulfonyl)pyridin-3-amine
将4-甲基-2-(甲磺酰基)-3-硝基吡啶(2.2g,10.2mmol)溶于110毫升甲醇中,向此溶液中加入10%钯碳(50%w/w,660mg)。将此混合物于氢气氛围中室温搅拌5小时。抽滤除去催化剂,滤液浓缩,硅胶柱分离(石油醚:乙酸乙酯=5:1到2:1)得到目标化合物(820mg,收率:41%)。4-Methyl-2-(methylsulfonyl)-3-nitropyridine (2.2 g, 10.2 mmol) was dissolved in 110 mL of methanol, and to this solution was added 10% palladium on carbon (50% w/w, 660 mg) ). The mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. The catalyst was removed by suction filtration, the filtrate was concentrated, and the silica gel column was separated (petroleum ether:ethyl acetate=5:1 to 2:1) to obtain the target compound (820 mg, yield: 41%).
LC-MS:m/z 187(M+H)
+。
LC-MS: m/z 187 (M+H) + .
第3步.2,6-二氯-5-氟-N-(((4-甲基-2-(甲基磺酰基)吡啶-3-基)氨基甲酰基)烟酰胺的制备Step 3. Preparation of 2,6-dichloro-5-fluoro-N-(((4-methyl-2-(methylsulfonyl)pyridin-3-yl)carbamoyl)nicotinamide
将2,6-二氯-5-氟烟酰胺(873mg,4.2mmol)溶于15毫升无水四氢呋喃中,向此溶液中缓慢滴加草酰氯(3.6mL,42.0mmol)的二氯甲烷(4.5mL)溶液。滴加完毕后,将此混合物于75度回流搅拌2小时,然后减压浓缩至干。残留物以15毫升无水四氢呋喃稀释,冷却至零度。将4-甲基-2-(甲磺酰基)吡啶-3-胺(820mg,4.4mmol)溶于6毫升无水四氢呋喃中,然后滴加进上述溶液中。反应液在零度下搅拌2小时,饱和氯化铵/饱和食盐水(V:V=1:1,30mL)淬灭,然后用二氯甲烷/甲醇(V:V=10:1,30mL)萃取3次。合并有机相干燥,浓缩,残留固体以石油醚/乙酸乙酯(2:1,25mL)打浆,抽滤,干燥,得到目标化合物(1.36g,收率:77%)。2,6-Dichloro-5-fluoronicotinamide (873 mg, 4.2 mmol) was dissolved in 15 mL of dry tetrahydrofuran, and oxalyl chloride (3.6 mL, 42.0 mmol) in dichloromethane (4.5 mL) was slowly added dropwise to this solution. mL) solution. After the dropwise addition, the mixture was stirred at 75°C under reflux for 2 hours, and then concentrated to dryness under reduced pressure. The residue was diluted with 15 mL of dry tetrahydrofuran and cooled to zero. 4-Methyl-2-(methylsulfonyl)pyridin-3-amine (820 mg, 4.4 mmol) was dissolved in 6 mL of dry tetrahydrofuran and added dropwise to the above solution. The reaction solution was stirred at zero temperature for 2 hours, quenched with saturated ammonium chloride/saturated brine (V:V=1:1, 30 mL), and then extracted with dichloromethane/methanol (V:V=10:1, 30 mL) 3 times. The combined organic phases were dried, concentrated, the residual solid was slurried with petroleum ether/ethyl acetate (2:1, 25 mL), suction filtered, and dried to obtain the target compound (1.36 g, yield: 77%).
LC-MS:m/z 421(M+H)
+。
LC-MS: m/z 421 (M+H) + .
第4步.7-氯-6-氟-1-(4-甲基-2-(甲基磺酰基)吡啶-3-基)吡啶[2,3-d]嘧啶-2,4(1H,3H)-二酮的制备Step 4. 7-Chloro-6-fluoro-1-(4-methyl-2-(methylsulfonyl)pyridin-3-yl)pyridine[2,3-d]pyrimidine-2,4(1H, Preparation of 3H)-dione
将2,6-二氯-5-氟-N-(((4-甲基-2-(甲基磺酰基)吡啶-3-基)氨基甲酰基)烟酰胺(1.13g,2.7mmol)悬浮于34毫升四氢呋喃中,冰浴下滴加双(三甲基硅烷基)氨基钾(1摩四氢呋喃溶液,6.2mL,6.2mmol)。滴加完毕后反应液变澄清。反应液60度搅拌2小时,40毫升饱和氯化铵淬灭,然后以40毫升乙酸乙酯萃取3次。合并乙酸乙酯层干燥,浓缩。残留固体以石油醚/乙酸乙酯(V:V=1:1,25mL)打浆,抽滤,干燥得到目标化合物(870mg,收率:84%)。2,6-Dichloro-5-fluoro-N-(((4-methyl-2-(methylsulfonyl)pyridin-3-yl)carbamoyl)nicotinamide (1.13 g, 2.7 mmol) was suspended In 34 milliliters of tetrahydrofuran, bis(trimethylsilyl) potassium amide (1 mole of tetrahydrofuran solution, 6.2 mL, 6.2 mmol) was added dropwise under ice bath. The reaction solution became clear after the addition was completed. The reaction solution was stirred at 60 degrees for 2 hours , quenched with 40 mL of saturated ammonium chloride, then extracted three times with 40 mL of ethyl acetate. The ethyl acetate layers were combined, dried, and concentrated. The residual solid was treated with petroleum ether/ethyl acetate (V:V=1:1, 25 mL). Beating, suction filtration, and drying to obtain the target compound (870 mg, yield: 84%).
LC-MS:m/z 385(M+H)
+。
LC-MS: m/z 385 (M+H) + .
第5步.(S)-叔丁基4-(7-氯-6-氟-1-(4-甲基-2-(甲基磺基)吡啶-3-基)-2-氧代-1,2-二氢吡啶[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸酯的制备Step 5. (S)-tert-Butyl 4-(7-Chloro-6-fluoro-1-(4-methyl-2-(methylsulfo)pyridin-3-yl)-2-oxo- Preparation of 1,2-dihydropyridine[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate
将7-氯-6-氟-1-(4-甲基-2-(甲基磺酰基)吡啶-3-基)吡啶[2,3-d]嘧啶-2,4(1H,3H)-二酮(300mg,0.8mmol)悬浮于9毫升乙腈中,滴加N,N-二异丙基乙胺(0.77mL,4.7mmol)和三氯氧磷(0.36mL,3.9mmol),反应液变澄清。将反应液于80度搅拌1小时,减压浓缩至干。残留物溶解在12毫升乙腈中,冷却至零度,加入N,N-二异丙基乙胺(0.4mL,2.3mmol)和(S)-3-甲基哌嗪-1-羧酸叔丁酯(188mg,0.9mmol)。反应液在室温下搅拌1小时,用饱和的碳酸氢钠溶液(20mL)淬灭,再以20毫升乙酸乙酯萃取3次。合并乙酸乙酯层干燥,浓缩,硅胶柱分离(石油醚:乙酸 乙酯=3:1到纯乙酸乙酯)得到目标化合物(328mg,收率:74%)。7-Chloro-6-fluoro-1-(4-methyl-2-(methylsulfonyl)pyridin-3-yl)pyridine[2,3-d]pyrimidine-2,4(1H,3H)- The diketone (300 mg, 0.8 mmol) was suspended in 9 mL of acetonitrile, and N,N-diisopropylethylamine (0.77 mL, 4.7 mmol) and phosphorus oxychloride (0.36 mL, 3.9 mmol) were added dropwise, and the reaction solution became clarify. The reaction solution was stirred at 80 degrees for 1 hour, and concentrated to dryness under reduced pressure. The residue was dissolved in 12 mL of acetonitrile, cooled to zero degrees, and added with N,N-diisopropylethylamine (0.4 mL, 2.3 mmol) and (S)-tert-butyl 3-methylpiperazine-1-carboxylate (188 mg, 0.9 mmol). The reaction was stirred at room temperature for 1 hour, quenched with saturated sodium bicarbonate solution (20 mL), and extracted three times with 20 mL of ethyl acetate. The ethyl acetate layers were combined, dried, concentrated, and separated on a silica gel column (petroleum ether:ethyl acetate=3:1 to pure ethyl acetate) to obtain the title compound (328 mg, yield: 74%).
LC-MS:m/z 567(M+H)
+。
LC-MS: m/z 567 (M+H) + .
第6步.(S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-7-氯-6-氟-1-(4-甲基-2-(甲基磺基)吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的制备Step 6. (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-chloro-6-fluoro-1-(4-methyl-2-(methylsulfonyl) Preparation of pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one
将(S)-叔丁基4-(7-氯-6-氟-1-(4-甲基-2-(甲基磺基)吡啶-3-基)-2-氧代-1,2-二氢吡啶[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸酯(328mg,0.6mmol)溶于4毫升二氯甲烷中,加入1毫升三氟乙酸,反应液室温搅拌2小时,浓缩干,残留物与15毫升二氯甲烷共蒸3次得粗品。将该粗品溶解在6毫升二氯甲烷中,冷却至零度,滴加N,N-二异丙基乙胺(0.38mL,2.3mmol)和丙烯酰氯(63mg,0.7mmol)的二氯甲烷(1mL)溶液。反应液在零度下搅拌30分钟,20毫升饱和碳酸氢钠淬灭,并以20毫升二氯甲烷萃取3次。合并二氯甲烷层,干燥,浓缩,残留物以硅胶柱分离(二氯甲烷:甲醇=60:1)得到目标化合物(200mg,收率:67%)。(S)-tert-butyl 4-(7-chloro-6-fluoro-1-(4-methyl-2-(methylsulfo)pyridin-3-yl)-2-oxo-1,2 - Dihydropyridine[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (328 mg, 0.6 mmol) was dissolved in 4 mL of dichloromethane and 1 mL of trifluoro acetic acid, the reaction solution was stirred at room temperature for 2 hours, concentrated to dryness, and the residue was co-evaporated with 15 ml of dichloromethane for 3 times to obtain a crude product. The crude product was dissolved in 6 mL of dichloromethane, cooled to zero, and N,N-diisopropylethylamine (0.38 mL, 2.3 mmol) and acryloyl chloride (63 mg, 0.7 mmol) in dichloromethane (1 mL) were added dropwise. ) solution. The reaction was stirred at zero for 30 minutes, quenched with 20 mL of saturated sodium bicarbonate, and extracted three times with 20 mL of dichloromethane. The dichloromethane layers were combined, dried, concentrated, and the residue was separated on a silica gel column (dichloromethane:methanol=60:1) to obtain the title compound (200 mg, yield: 67%).
LC-MS:m/z 521(M+H)
+。
LC-MS: m/z 521 (M+H) + .
第7步.4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-7-(2-氟-6-羟基苯基)-1-(4-甲基-2-(甲基磺基)吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的制备Step 7. 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4 Preparation of -methyl-2-(methylsulfo)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one
将(S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-7-氯-6-氟-1-(4-甲基-2-(甲基磺基)吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(126mg,0.24mmol)、(2-氟-6-羟基苯基)硼酸(49mg,0.31mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(20mg,0.024mmol)和乙酸钾(95mg,0.97mmol)悬浮于二氧六环/水(7mL/0.7mL)混合溶剂中,氮气置换3次,并于90度加热搅拌2.5小时。反应液冷却至室温后,加入20毫升半饱和碳酸氢钠溶液,并以20毫升乙酸乙酯萃取3次。合并乙酸乙酯层,干燥,浓缩,残留物以硅胶柱分离(二氯甲烷:甲醇=100:1到60:1)得到目标化合物(45mg,收率:31%)。(S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-chloro-6-fluoro-1-(4-methyl-2-(methylsulfo)pyridine -3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (126 mg, 0.24 mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (49 mg, 0.31 mmol), [1 ,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (20 mg, 0.024 mmol) and potassium acetate (95 mg, 0.97 mmol) were suspended in dioxane/water (7 mL) /0.7mL) mixed solvent, nitrogen was replaced 3 times, and heated and stirred at 90 degrees for 2.5 hours. After the reaction solution was cooled to room temperature, 20 ml of half-saturated sodium bicarbonate solution was added, and the mixture was extracted three times with 20 ml of ethyl acetate. The ethyl acetate layers were combined, dried, concentrated, and the residue was separated on a silica gel column (dichloromethane:methanol=100:1 to 60:1) to obtain the title compound (45 mg, yield: 31%).
LC-MS:m/z 597(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.65-8.63(m,1H),8.57(brs,1H),7.89(t,J=8.8Hz,1H),7.60(d,J=4.4Hz,1H),7.26(m,1H),6.71-6.56(m,3H),6.40(d,J=16.4Hz,1H),5.81(d,J=10.4Hz,1H),5.10-4.50(m,3H),4.10-3.50(m,3H),3.27(d,J=2.4Hz,3H),3.26-3.00(m,1H),2.28(d,J=6.8Hz,3H),1.53(m,3H).
LC-MS: m/z 597 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 8.65-8.63 (m, 1H), 8.57 (brs, 1H), 7.89 (t, J=8.8Hz, 1H), 7.60 (d, J=4.4Hz, 1H) ,7.26(m,1H),6.71-6.56(m,3H),6.40(d,J=16.4Hz,1H),5.81(d,J=10.4Hz,1H),5.10-4.50(m,3H), 4.10-3.50(m, 3H), 3.27(d, J=2.4Hz, 3H), 3.26-3.00(m, 1H), 2.28(d, J=6.8Hz, 3H), 1.53(m, 3H).
按照实施例1的方法以不同的起始原料合成了以下化合物:The following compounds were synthesized according to the method of Example 1 with different starting materials:
实施例2 4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-7-(2-氟-6-羟基苯基)-1-(2-甲基-4-(甲基磺基)吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 2 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2- Methyl-4-(methylsulfo)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 597(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.93(d,J=5.2Hz,1H),8.65(brs,1H),7.95-7.89(m,2H),7.26(m,1H),6.72-6.75(m,3H),6.45-6.39(m,1H),5.85-5.81(m,1H),5.25-4.30(m,3H),4.20-3.50(m,3H),3.30-3.00(m,4H),2.46(d,J=10.0Hz,3H),1.51-1.48(m,3H).
LC-MS: m/z 597 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 8.93(d, J=5.2Hz, 1H), 8.65(brs, 1H), 7.95-7.89(m, 2H), 7.26(m, 1H), 6.72-6.75( m,3H),6.45-6.39(m,1H),5.85-5.81(m,1H),5.25-4.30(m,3H),4.20-3.50(m,3H),3.30-3.00(m,4H), 2.46(d,J=10.0Hz,3H),1.51-1.48(m,3H).
实施例3 2-((2S)-4-丙烯酰-1-(6-氟-7-(2-氟-6-羟基苯基)-1-(2-甲基-6-(甲磺基)苯基)-2-氧代-1,2-二氢吡啶[2,3-d]嘧啶-4-基)哌嗪-2-基)乙腈Example 3 2-((2S)-4-acryloyl-1-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-methyl-6-(methylsulfonyl) )Phenyl)-2-oxo-1,2-dihydropyridine[2,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
LC-MS:m/z 621(M+H)
+。
1H NMR(400MHz,CDCl
3)δ9.01-8.91(m,1H),8.11(t,J=7.2Hz,1H),7.95(brs,1H),7.75(t,J=8.4Hz,1H),7.70-7.64(m,1H),7.26(m,1H),6.71-6.59(m,3H),6.46(d,J=16.4Hz,1H),5.88(d,J=10.4Hz,1H),5.50-5.30(m,1H),4.75-3.40(m,6H),3.10(d,J=4.8Hz,3H),3.05-2.80(m,2H),2.18(d,J=10.8Hz,3H).
LC-MS: m/z 621 (M+H) + . 1 H NMR (400MHz, CDCl 3 )δ9.01-8.91(m,1H),8.11(t,J=7.2Hz,1H),7.95(brs,1H),7.75(t,J=8.4Hz,1H) ,7.70-7.64(m,1H),7.26(m,1H),6.71-6.59(m,3H),6.46(d,J=16.4Hz,1H),5.88(d,J=10.4Hz,1H), 5.50-5.30(m, 1H), 4.75-3.40(m, 6H), 3.10(d, J=4.8Hz, 3H), 3.05-2.80(m, 2H), 2.18(d, J=10.8Hz, 3H) .
实施例4 4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-7-(2-氟-6-羟基苯基)-1-(2-(异丙基磺基)-6-甲基苯基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 4 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2- (Isopropylsulfo)-6-methylphenyl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 624(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.98-8.94(m,1H),8.04(d,J=8.0Hz,1H),7.87(t,J=8.0Hz,1H),7.72(d,J=7.6Hz,1H),7.62(t,J=8.0Hz,1H),7.26(m,1H),6.71-6.54(m,3H),6.44-6.39(m,1H),5.83-5.80(m,1H),5.10-4.30(m,3H),4.10-3.00(m,5H),2.16(d,J=8.4Hz,3H),1.52(brs,3H),1.31-1.28(m,3H),1.16-1.14(m,3H).
LC-MS: m/z 624 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.98-8.94 (m, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.87 (t, J=8.0 Hz, 1H), 7.72 (d, J= 7.6Hz, 1H), 7.62(t, J=8.0Hz, 1H), 7.26(m, 1H), 6.71-6.54(m, 3H), 6.44-6.39(m, 1H), 5.83-5.80(m, 1H) ),5.10-4.30(m,3H),4.10-3.00(m,5H),2.16(d,J=8.4Hz,3H),1.52(brs,3H),1.31-1.28(m,3H),1.16- 1.14(m,3H).
实施例5 4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-1-(2-乙基-6-(甲磺酰)苯基)-6-氟-7-(2-氟-6-羟基苯基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 5 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-1-(2-ethyl-6-(methylsulfonyl)phenyl)-6-fluoro- 7-(2-Fluoro-6-hydroxyphenyl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 610(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.99(s,1H),8.12(d,J=7.6Hz,1H),7.87(dd,J=9.2Hz,3.2Hz,1H),7.78(d,J=7.6Hz,1H),7.71(t,J=7.6Hz,1H),7.26(m,1H),6.69-6.54(m,3H),6.44-6.38(m,1H),5.83-5.80(m,1H),5.10-4.38(m,3H),4.10-3.50(m,3H),3.30-3.00(m,4H),2.59-2.41(m,2H),1.58-1.49(m,3H),1.21-1.16(m,3H).
LC-MS: m/z 610 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 8.99 (s, 1H), 8.12 (d, J=7.6 Hz, 1H), 7.87 (dd, J=9.2 Hz, 3.2 Hz, 1H), 7.78 (d, J =7.6Hz,1H),7.71(t,J=7.6Hz,1H),7.26(m,1H),6.69-6.54(m,3H),6.44-6.38(m,1H),5.83-5.80(m, 1H), 5.10-4.38(m, 3H), 4.10-3.50(m, 3H), 3.30-3.00(m, 4H), 2.59-2.41(m, 2H), 1.58-1.49(m, 3H), 1.21- 1.16(m,3H).
实施例5-1 通过手性分离得到两个异构体实施例5A和实施例5B:Example 5-1 Two isomers Example 5A and Example 5B were obtained by chiral separation:
实施例5A:LC-MS:m/z 610(M+H)
+。
1H NMR(400MHz,CDCl
3)δ9.02(s,1H),8.14(d,J=7.3Hz,1H),7.90(d,J=8.5Hz,1H),7.81(d,J=7.1Hz,1H),7.73(t,J=7.8Hz,1H),7.33–7.23(m,1H),6.76–6.53(m,3H),6.44(d,J=16.3Hz,1H),5.84(d,J=10.0Hz,1H),5.03(m,1H),4.57(m,2H),4.22–3.41(m,3H),3.35–3.00(m,4H),2.48(m,2H),1.51(s,3H),1.21(t,J=6.7Hz,3H).
Example 5A: LC-MS: m/z 610 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 9.02 (s, 1H), 8.14 (d, J=7.3 Hz, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.81 (d, J=7.1 Hz ,1H),7.73(t,J=7.8Hz,1H),7.33-7.23(m,1H),6.76-6.53(m,3H),6.44(d,J=16.3Hz,1H),5.84(d, J=10.0Hz, 1H), 5.03(m, 1H), 4.57(m, 2H), 4.22-3.41(m, 3H), 3.35-3.00(m, 4H), 2.48(m, 2H), 1.51(s ,3H),1.21(t,J=6.7Hz,3H).
实施例5B:LC-MS:m/z 610(M+H)
+。
1H NMR(400MHz,CDCl
3)δ9.01(s,1H),8.21–8.07(m,1H),7.90(d,J=9.3Hz,1H),7.81(d,J=7.0Hz,1H),7.73(t,J=7.8Hz,1H),7.35–7.23(m,1H),6.68(m,3H),6.44(d,J=16.5Hz,1H),5.84(d,J=10.2Hz,1H),5.12–4.29(m,3H),3.99(m,1H),3.69(m,2H),3.22(m,4H),2.69–2.37(m,2H),1.66–1.43(m,3H),1.25–1.12(m,3H).
Example 5B: LC-MS: m/z 610 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 9.01 (s, 1H), 8.21-8.07 (m, 1H), 7.90 (d, J=9.3 Hz, 1H), 7.81 (d, J=7.0 Hz, 1H) ,7.73(t,J=7.8Hz,1H),7.35–7.23(m,1H),6.68(m,3H),6.44(d,J=16.5Hz,1H),5.84(d,J=10.2Hz, 1H), 5.12–4.29 (m, 3H), 3.99 (m, 1H), 3.69 (m, 2H), 3.22 (m, 4H), 2.69–2.37 (m, 2H), 1.66–1.43 (m, 3H) ,1.25–1.12(m,3H).
实施例6 4-((S)-4-丙烯酰基-2-甲基哌嗪-1-基)-1-(2-环丙基-6-(甲基磺酰基)苯基)-6-氟-7-(2-氟-6-羟基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 6 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-1-(2-cyclopropyl-6-(methylsulfonyl)phenyl)-6- Fluoro-7-(2-Fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 622(M+H)
+。
1H NMR(400MHz,CDCl
3)δ9.00(s,1H),8.08(d,J=7.6Hz,1H),7.88(d,J=9.2Hz,1H),7.67-7.63(m,1H),7.46(d,J=7.6Hz,1H),7.29-7.23(m,1H),6.75-6.50(m,3H),6.44-6.39(m,1H),5.83-5.80(m,1H),5.04-4.38(m,3H),4.06-3.55(m,3H),3.24-3.02(m,4H),1.55-1.49(m,4H),0.85-0.56(m,4H).
LC-MS: m/z 622 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 9.00 (s, 1H), 8.08 (d, J=7.6 Hz, 1H), 7.88 (d, J=9.2 Hz, 1H), 7.67-7.63 (m, 1H) ,7.46(d,J=7.6Hz,1H),7.29-7.23(m,1H),6.75-6.50(m,3H),6.44-6.39(m,1H),5.83-5.80(m,1H),5.04 -4.38(m,3H),4.06-3.55(m,3H),3.24-3.02(m,4H),1.55-1.49(m,4H),0.85-0.56(m,4H).
实施例6-1通过手性分离得到两个异构体实施例5A和实施例5B:Example 6-1 obtained two isomers Example 5A and Example 5B by chiral separation:
实施例6A:LC-MS:m/z 622(M+H)
+。
1H NMR(400MHz,CDCl
3)δ9.03(s,1H),8.10(d,J=7.2Hz,1H),7.90(d,J=8.9Hz,1H),7.67(t,J=7.9Hz,1H),7.48(dd,J=7.9,1.0Hz,1H),7.40–7.17(m,1H),6.81–6.54(m,3H),6.43(dd,J=16.7,1.3Hz,1H),5.84(d,J=10.3Hz,1H),5.08(m,1H),4.59(m,2H),4.25–3.44(m,3H),3.31–2.99(m,4H),1.70(m,1H),1.51(s,3H),0.96–0.78(m,2H),0.65(m,2H).
Example 6A: LC-MS: m/z 622 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 9.03 (s, 1H), 8.10 (d, J=7.2 Hz, 1H), 7.90 (d, J=8.9 Hz, 1H), 7.67 (t, J=7.9 Hz) ,1H),7.48(dd,J=7.9,1.0Hz,1H),7.40-7.17(m,1H),6.81-6.54(m,3H),6.43(dd,J=16.7,1.3Hz,1H), 5.84(d, J=10.3Hz, 1H), 5.08(m, 1H), 4.59(m, 2H), 4.25-3.44(m, 3H), 3.31-2.99(m, 4H), 1.70(m, 1H) ,1.51(s,3H),0.96–0.78(m,2H),0.65(m,2H).
实施例6B:LC-MS:m/z 622(M+H)
+。
1H NMR(400MHz,CDCl
3)δ9.02(s,1H),8.10(d,J=7.5Hz,1H),7.91(d,J=9.2Hz,1H),7.67(t,J=7.9Hz,1H),7.47(d,J=7.7Hz,1H),7.36–7.19(m,1H),6.68(m,3H),6.43(d,J=16.6Hz,1H),5.84(d,J=10.3Hz,1H),4.69(m,3H),3.98(m,1H),3.70(m,2H),3.35–3.02(m,4H),1.63(m,4H),0.87(m,2H),0.67(m,2H).
Example 6B: LC-MS: m/z 622 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 9.02 (s, 1H), 8.10 (d, J=7.5 Hz, 1H), 7.91 (d, J=9.2 Hz, 1H), 7.67 (t, J=7.9 Hz) ,1H),7.47(d,J=7.7Hz,1H),7.36–7.19(m,1H),6.68(m,3H),6.43(d,J=16.6Hz,1H),5.84(d,J= 10.3Hz, 1H), 4.69(m, 3H), 3.98(m, 1H), 3.70(m, 2H), 3.35–3.02(m, 4H), 1.63(m, 4H), 0.87(m, 2H), 0.67(m,2H).
实施例7 4-((S)-4-丙烯酰基-2-甲基哌嗪-1-基)-1-(2-(环丙基磺酰基)-6-甲基苯基)-6-氟-7-(2-氟-6-羟基苯基)吡啶基[2,3-d]嘧啶-2(1H)-酮Example 7 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-1-(2-(cyclopropylsulfonyl)-6-methylphenyl)-6- Fluoro-7-(2-Fluoro-6-hydroxyphenyl)pyridyl[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 622(M+H)
+。
1H NMR(400MHz,CDCl
3)δ9.00(s,1H),7.97-7.85(m,2H),7.71(d,J=7.6Hz,1H),7.61(t,J=8.0Hz,1H),7.29-7.23(m,1H),6.69-6.63(m,3H),6.44-6.39(m,1H),5.83-5.80(m,1H),5.05-4.37(m,3H),4.02-3.63(m,3H),3.23-2.78(m,2H),2.19(d,J=10.8Hz,3H),1.41-1.37(m,4H).1.03-0.96(m,3H).
LC-MS: m/z 622 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 9.00 (s, 1H), 7.97-7.85 (m, 2H), 7.71 (d, J=7.6Hz, 1H), 7.61 (t, J=8.0Hz, 1H) ,7.29-7.23(m,1H),6.69-6.63(m,3H),6.44-6.39(m,1H),5.83-5.80(m,1H),5.05-4.37(m,3H),4.02-3.63( m,3H),3.23-2.78(m,2H),2.19(d,J=10.8Hz,3H),1.41-1.37(m,4H).1.03-0.96(m,3H).
实施例8 4-((S)-4-丙烯酰基-2-甲基哌嗪-1-基)-1-(2-氯-6-(甲基磺酰基)苯基)-6-氟-7-(2-氟-6-羟基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 8 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-1-(2-chloro-6-(methylsulfonyl)phenyl)-6-fluoro- 7-(2-Fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 616(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.81(s,1H),8.19(d,J=8.0Hz,1H),7.95-7.85(m,2H),7.70(t,J=8.4Hz,1H),7.33-7.23(m,1H),6.74-6.50(m,3H),6.10(d,J=16.8Hz,1H),6.10(dd,J=10.4Hz,8Hz;1H),5.15-4.30(m,3H),4.15-3.39(m,3H),3.31-2.95(m,4H),1.51(s,3H).
LC-MS: m/z 616 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.81 (s, 1H), 8.19 (d, J=8.0 Hz, 1H), 7.95-7.85 (m, 2H), 7.70 (t, J=8.4 Hz, 1H) ,7.33-7.23(m,1H),6.74-6.50(m,3H),6.10(d,J=16.8Hz,1H),6.10(dd,J=10.4Hz,8Hz;1H),5.15-4.30(m ,3H),4.15-3.39(m,3H),3.31-2.95(m,4H),1.51(s,3H).
实施例9 4-((S)-4-丙烯酰基-2-甲基哌嗪-1-基)-7-(2-(二氟甲基)-6-氟苯基)-6-氟-1-(2-甲基-6-(甲基磺酰基)苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 9 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-7-(2-(difluoromethyl)-6-fluorophenyl)-6-fluoro- 1-(2-Methyl-6-(methylsulfonyl)phenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 630(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.01(d,J=7.6Hz,1H),7.87-7.83(m,1H),7.64-7.62(m,1H),7.56-7.46(m,3H),7.26-7.22(m,1H),6.69-6.30(m,3H),5.82(dd,J=10.4Hz,1.6Hz,1H),5.04-4.36(m,3H),4.05-3.62(m,3H),3.27-3.08(m,4H),2.16-2.13(m,3H),1.60-1.49(m,3H).
LC-MS: m/z 630 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 8.01 (d, J=7.6Hz, 1H), 7.87-7.83 (m, 1H), 7.64-7.62 (m, 1H), 7.56-7.46 (m, 3H), 7.26-7.22(m,1H),6.69-6.30(m,3H),5.82(dd,J=10.4Hz,1.6Hz,1H),5.04-4.36(m,3H),4.05-3.62(m,3H) ,3.27-3.08(m,4H),2.16-2.13(m,3H),1.60-1.49(m,3H).
实施例10 4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-7-(2-氟-6-羟基苯基)-1-(2-异丙基-6-(甲基磺基)苯基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 10 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2- Isopropyl-6-(methylsulfo)phenyl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 624(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.98(s,1H),8.12(dd,J=8.0Hz,1.6Hz,1H),7.89-7.82(m,2H),7.74(t,J=8.0Hz,1H),7.26(m,1H),6.69-6.62(m,3H),6.42(dd,J=16.8Hz,1.6Hz,1H),5.82(dd,J=10.4Hz,1.6Hz,1H),5.15-4.65(m,3H),4.15-3.50(m,3H),3.30-3.00(m,4H),2.85-2.70(m,1H),1.56-1.48(m,3H),1.25(dd,J=6.8Hz,2.4Hz,3H),1.05(t,J=6.4Hz,3H).
LC-MS: m/z 624 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 8.98 (s, 1H), 8.12 (dd, J=8.0Hz, 1.6Hz, 1H), 7.89-7.82 (m, 2H), 7.74 (t, J=8.0Hz) ,1H),7.26(m,1H),6.69-6.62(m,3H),6.42(dd,J=16.8Hz,1.6Hz,1H),5.82(dd,J=10.4Hz,1.6Hz,1H), 5.15-4.65(m, 3H), 4.15-3.50(m, 3H), 3.30-3.00(m, 4H), 2.85-2.70(m, 1H), 1.56-1.48(m, 3H), 1.25(dd, J =6.8Hz,2.4Hz,3H),1.05(t,J=6.4Hz,3H).
实施例10-1 通过手性分离得到两个异构体实施例10A和实施例10B:Example 10-1 Two isomers Example 10A and Example 10B were obtained by chiral separation:
实施例10A:LC-MS:m/z 624(M+H)
+。
1H NMR(400MHz,DMSO)δ10.23(s,1H),8.31(t,J=10.5Hz,1H),7.95–7.75(m,2H),7.66(t,J=7.9Hz,1H),7.26(m,1H),6.98–6.78(m,1H),6.77–6.59(m,2H),6.22(d,J=16.6Hz,1H),5.78(dd,J=10.5,2.1Hz,1H),4.92(s,1H),4.37(m,2H),4.10(m,1H),3.88–3.46(m,2H),3.18(m,1H),2.65(d,J=6.0Hz,1H),1.34(d,J=6.6Hz,3H),1.10(d,J=6.8Hz,3H),1.00(d,J=6.8Hz,3H).
Example 10A: LC-MS: m/z 624 (M+H) + . 1 H NMR(400MHz, DMSO)δ10.23(s,1H),8.31(t,J=10.5Hz,1H),7.95-7.75(m,2H),7.66(t,J=7.9Hz,1H), 7.26 (m, 1H), 6.98–6.78 (m, 1H), 6.77–6.59 (m, 2H), 6.22 (d, J=16.6Hz, 1H), 5.78 (dd, J=10.5, 2.1Hz, 1H) ,4.92(s,1H),4.37(m,2H),4.10(m,1H),3.88–3.46(m,2H),3.18(m,1H),2.65(d,J=6.0Hz,1H), 1.34(d,J=6.6Hz,3H),1.10(d,J=6.8Hz,3H),1.00(d,J=6.8Hz,3H).
实施例10B:LC-MS:m/z 624(M+H)
+。
1H NMR(400MHz,DMSO)δ10.28(s,1H),8.33(t,J=9.2Hz,1H),7.98–7.77(m,2H),7.66(t,J=7.8Hz,1H),7.26m,1H),6.88(m,1H),6.79–6.52(m,2H),6.22(dd,J=16.6,6.0Hz,1H),5.78(dd,J=10.4,2.2Hz,1H),4.89(s,1H),4.55–3.91(m,3H),3.65(m,1H),3.47(m,1H),3.08(m,1H),2.67(m,1H),1.30(s,3H),1.11(d,J=6.8Hz,3H),1.02(m,3H).
Example 10B: LC-MS: m/z 624 (M+H) + . 1 H NMR(400MHz, DMSO)δ10.28(s,1H),8.33(t,J=9.2Hz,1H),7.98-7.77(m,2H),7.66(t,J=7.8Hz,1H), 7.26m, 1H), 6.88 (m, 1H), 6.79–6.52 (m, 2H), 6.22 (dd, J=16.6, 6.0Hz, 1H), 5.78 (dd, J=10.4, 2.2Hz, 1H), 4.89(s, 1H), 4.55–3.91(m, 3H), 3.65(m, 1H), 3.47(m, 1H), 3.08(m, 1H), 2.67(m, 1H), 1.30(s, 3H) ,1.11(d,J=6.8Hz,3H),1.02(m,3H).
实施例11 N-(2-(4-((S)-4-丙烯酰基-2-甲基哌嗪-1-基)-6-氟-7-(2-氟-6-羟基苯基)-2-氧吡喃并[2,3-d]嘧啶-1(2H)-基)-3-甲基苯基)-N-甲基甲磺酰胺Example 11 N-(2-(4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl) -2-Oxypyrano[2,3-d]pyrimidin-1(2H)-yl)-3-methylphenyl)-N-methylmethanesulfonamide
LC-MS:m/z 625(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.64(brs,1H),7.86-7.78(m,1H),7.47(td,J=7.6Hz,1.6Hz;1H),7.40(d,J=7.2Hz,1H),7.32-7.21(m,2H),6.70-6.50(m,3H),6.40(dd,J=16.8Hz,1.6Hz;1H),6.10(dd,J=10.4Hz,1.6Hz;1H),5.05-4.25(m,3H),4.10-3.46(m,3H),3.31-2.99(m,4H),2.85(d,J=2.0Hz,3H),2.17(s,3H),1.54-1.42(m,3H).
LC-MS: m/z 625 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 8.64 (brs, 1H), 7.86-7.78 (m, 1H), 7.47 (td, J=7.6Hz, 1.6Hz; 1H), 7.40 (d, J=7.2Hz) ,1H),7.32-7.21(m,2H),6.70-6.50(m,3H),6.40(dd,J=16.8Hz,1.6Hz;1H),6.10(dd,J=10.4Hz,1.6Hz;1H ), 5.05-4.25(m, 3H), 4.10-3.46(m, 3H), 3.31-2.99(m, 4H), 2.85(d, J=2.0Hz, 3H), 2.17(s, 3H), 1.54- 1.42(m,3H).
实施例12 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-1-(2-乙基-6-(甲基磺酰基)苯基)-6-氟-7-(2-氟-6-羟基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 12 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-1-(2-ethyl-6-(methylsulfonyl)phenyl )-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 624(M+H)
+。
1H NMR(400MHz,CDCl
3)δ9.03(t,J=18.4Hz,1H),8.14-8.10(m,1H),7.89-7.68(m,3H),7.28-7.23(m,1H),6.71-6.36(m,4H),,5.83-5.79(m,1H),5.12-3.47(m,6H),3.14-3.10(m,3H),2.55-2.37(m,2H),1.51-1.16(m,9H).
LC-MS: m/z 624 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 9.03 (t, J=18.4Hz, 1H), 8.14-8.10 (m, 1H), 7.89-7.68 (m, 3H), 7.28-7.23 (m, 1H), 6.71-6.36(m, 4H), 5.83-5.79(m, 1H), 5.12-3.47(m, 6H), 3.14-3.10(m, 3H), 2.55-2.37(m, 2H), 1.51-1.16( m, 9H).
实施例13 (S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-1-(2-环丙基-6-(甲基磺酰基)苯基)-6-氟-7-(2-氟苯基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 13 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-1-(2-cyclopropyl-6-(methylsulfonyl)phenyl)-6- Fluoro-7-(2-fluorophenyl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 606(M+H)
+。
1H NMR(400MHz,CDCl
3)δ7.99(d,J=7.6Hz,1H),7.80-7.77(m,1H),7.55(t,J=8.0Hz,1H),7.42-7.38(m,2H),7.31-7.26(m,1H),7.16-7.08(m,2H),6.70-6.52(m,1H),6.41(dd,J=16.8Hz,1.6Hz,1H),5.81(dd,J=10.4Hz,1.6Hz,1H),5.04-4.36(m,3H),4.05-3.58(m,3H),3.24-3.04(m,4H),1.67-1.60(m,1H),1.54-1.47(m,3H),0.82-0.76(m,2H),0.66-0.53(m,2H).
LC-MS: m/z 606 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.99 (d, J=7.6 Hz, 1H), 7.80-7.77 (m, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.42-7.38 (m, 2H), 7.31-7.26(m, 1H), 7.16-7.08(m, 2H), 6.70-6.52(m, 1H), 6.41(dd, J=16.8Hz, 1.6Hz, 1H), 5.81(dd, J =10.4Hz,1.6Hz,1H),5.04-4.36(m,3H),4.05-3.58(m,3H),3.24-3.04(m,4H),1.67-1.60(m,1H),1.54-1.47( m,3H),0.82-0.76(m,2H),0.66-0.53(m,2H).
实施例14 2-(4-((S)-4-丙烯酰基-2-甲基哌嗪-1-基)-6-氟-7-(2-氟-6-羟基苯基)-2-氧吡喃并[2,3-d]嘧啶-1(2H)-基)-N,N,3-三甲基苯磺酰胺Example 14 2-(4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2- Oxypyrano[2,3-d]pyrimidin-1(2H)-yl)-N,N,3-trimethylbenzenesulfonamide
LC-MS:m/z 625(M+H)
+。
1H NMR(400MHz,CDCl
3)δ9.04(brs,1H),7.96(d,J=8.0Hz,1H),7.89-7.81(m,1H),7.80(d,J=7.6Hz,1H),7.57(t,J=7.6Hz,1H),7.30-7.22(m,1H),6.71-6.51(m,3H),6.41(dd,J=16.4Hz,1.6Hz;1H),5.82(dd,J=10.4Hz,1.6Hz;1H),5.16-2.92(m,7H),2.73(s,6H),2.50(d,J=7.2Hz,3H),1.50-1.41(m,3H).
LC-MS: m/z 625 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 9.04 (brs, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.89-7.81 (m, 1H), 7.80 (d, J=7.6 Hz, 1H) ,7.57(t,J=7.6Hz,1H),7.30-7.22(m,1H),6.71-6.51(m,3H),6.41(dd,J=16.4Hz,1.6Hz;1H),5.82(dd, J=10.4Hz, 1.6Hz; 1H), 5.16-2.92(m, 7H), 2.73(s, 6H), 2.50(d, J=7.2Hz, 3H), 1.50-1.41(m, 3H).
实施例15 (S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-1-(2-环丙基-6-(甲基磺基)苯基)-7-(2,6-二氟苯基)-6-氟吡啶[2,3-d]嘧啶-2(1H)-酮Example 15 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-1-(2-cyclopropyl-6-(methylsulfo)phenyl)-7- (2,6-Difluorophenyl)-6-fluoropyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 624(M+H)
+。
1H NMR(400MHz,CDCl
3)δ7.95(d,J=8.0Hz,1H),7.83-7.78(m,1H),7.50(t,J=8.0Hz,1H),7.42-7.33(m,2H),6.92(t,J=8.4Hz,2H),6.70-6.53(m,1H),6.41(dd,J=16.4Hz,1.6Hz,1H),5.81(dd,J=10.4Hz,2.0Hz,1H),5.08-4.28(m,3H),4.09-3.58(m,3H),3.31-3.07(m,4H),1.65-1.57(m,1H),1.57-1.45(m,3H),0.78-0.74(m,2H),0.66-0.55(m,2H).
LC-MS: m/z 624 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.95 (d, J=8.0 Hz, 1H), 7.83-7.78 (m, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.42-7.33 (m, 2H), 6.92(t, J=8.4Hz, 2H), 6.70-6.53(m, 1H), 6.41(dd, J=16.4Hz, 1.6Hz, 1H), 5.81(dd, J=10.4Hz, 2.0Hz ,1H),5.08-4.28(m,3H),4.09-3.58(m,3H),3.31-3.07(m,4H),1.65-1.57(m,1H),1.57-1.45(m,3H),0.78 -0.74(m,2H),0.66-0.55(m,2H).
实施例16 4-((S)-4-丙烯酰基-2-甲基哌嗪-1-基)-6-氟-7-(2-氟-6-羟基苯基)-1-(4-异丙基-2-(甲基磺酰基)吡啶-3-基)吡啶基[2,3-d]嘧啶-2(1H)-酮Example 16 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4- Isopropyl-2-(methylsulfonyl)pyridin-3-yl)pyridyl[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 625(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.73-8.70(m,1H),8.50-8.41(m,1H),7.89(dd,J=9.2Hz,2.4Hz,1H),7.67(d,J=5.2Hz,1H),7.26(m,1H),6.70-6.50(m,3H),6.40(d,J=16.8Hz,1H),5.81(d,J=10.4Hz,1H),5.10-4.34(m,3H),4.04-3.60(m,3H),3.28-3.09(m,4H),3.00-2.80(m,1H),1.57-1.49(m,3H),1.27(dd,J=6.8Hz,1.6Hz,3H),1.07(t,J=6.4Hz,3H).
LC-MS: m/z 625 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 8.73-8.70 (m, 1H), 8.50-8.41 (m, 1H), 7.89 (dd, J=9.2Hz, 2.4Hz, 1H), 7.67 (d, J= 5.2Hz, 1H), 7.26(m, 1H), 6.70-6.50(m, 3H), 6.40(d, J=16.8Hz, 1H), 5.81(d, J=10.4Hz, 1H), 5.10-4.34( m,3H),4.04-3.60(m,3H),3.28-3.09(m,4H),3.00-2.80(m,1H),1.57-1.49(m,3H),1.27(dd,J=6.8Hz, 1.6Hz, 3H), 1.07(t, J=6.4Hz, 3H).
实施例16-1 通过手性分离得到两个异构体实施例16A和实施例16B:Example 16-1 Two isomers Example 16A and Example 16B were obtained by chiral separation:
实施例16A:LC-MS:m/z 625(M+H)
+。
1H NMR(400MHz,DMSO)δ10.22(s,1H),8.70(d,J=4.7Hz,1H),8.34(d,J=9.3Hz,1H),7.87(d,J=4.8Hz,1H),7.26(dd,J=15.2,7.8Hz,1H),6.85(dd,J=15.8,10.0Hz,1H),6.79–6.56(m,2H),6.21(d,J=16.2Hz,1H),5.77(d,J=10.5Hz,1H),4.97(s,1H),4.22(m,3H),3.61(m,2H),3.30–2.90(m,4H),2.81(m,1H),1.31(d,J=6.3Hz,3H),1.12(d,J=6.6Hz,3H),1.03(d,J=6.5 Hz,3H).
Example 16A: LC-MS: m/z 625 (M+H) + . 1 H NMR(400MHz, DMSO)δ10.22(s,1H),8.70(d,J=4.7Hz,1H),8.34(d,J=9.3Hz,1H),7.87(d,J=4.8Hz, 1H), 7.26(dd, J=15.2, 7.8Hz, 1H), 6.85(dd, J=15.8, 10.0Hz, 1H), 6.79–6.56(m, 2H), 6.21(d, J=16.2Hz, 1H) ), 5.77(d, J=10.5Hz, 1H), 4.97(s, 1H), 4.22(m, 3H), 3.61(m, 2H), 3.30–2.90(m, 4H), 2.81(m, 1H) ,1.31(d,J=6.3Hz,3H),1.12(d,J=6.6Hz,3H),1.03(d,J=6.5Hz,3H).
实施例16B:LC-MS:m/z 625(M+H)
+。
1H NMR(400MHz,DMSO)δ10.22(s,1H),8.70(d,J=5.0Hz,1H),8.31(t,J=10.7Hz,1H),7.87(d,J=5.0Hz,1H),7.26(dd,J=15.4,8.1Hz,1H),7.01–6.77(m,1H),6.76–6.57(m,2H),6.29–6.11(m,1H),5.77(dd,J=10.5,2.0Hz,1H),4.86(s,1H),4.50–3.93(m,3H),3.78–3.40(m,2H),3.30–2.94(m,4H),2.80(m,1H),1.31(d,J=6.5Hz,3H),1.13(d,J=6.8Hz,3H),1.03(d,J=6.7Hz,3H).
Example 16B: LC-MS: m/z 625 (M+H) + . 1 H NMR(400MHz, DMSO)δ10.22(s,1H),8.70(d,J=5.0Hz,1H),8.31(t,J=10.7Hz,1H),7.87(d,J=5.0Hz, 1H), 7.26 (dd, J=15.4, 8.1Hz, 1H), 7.01–6.77 (m, 1H), 6.76–6.57 (m, 2H), 6.29–6.11 (m, 1H), 5.77 (dd, J= 10.5, 2.0Hz, 1H), 4.86 (s, 1H), 4.50–3.93 (m, 3H), 3.78–3.40 (m, 2H), 3.30–2.94 (m, 4H), 2.80 (m, 1H), 1.31 (d, J=6.5Hz, 3H), 1.13 (d, J=6.8Hz, 3H), 1.03 (d, J=6.7Hz, 3H).
实施例17 (S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-7-(2-氯苯基)-1-(2-环丙基-6-(甲基磺酰基)苯基)-6-氟吡啶[2,3-d]嘧啶-2(1H)-酮Example 17 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-(2-chlorophenyl)-1-(2-cyclopropyl-6-(methyl) sulfonyl)phenyl)-6-fluoropyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 622(M+H)
+。
1H NMR(400MHz,CDCl
3)δ7.96(d,J=7.6Hz,1H),7.80-7.77(m,1H),7.51(t,J=8.0Hz,1H),7.41-7.28(m,3H),7.26(m,2H),6.68-6.54(m,1H),6.42(dd,J=16.8Hz,2.0Hz,1H),5.81(dd,J=10.4Hz,1.6Hz,1H),5.08-4.33(m,3H),4.07-3.59(m,3H),3.28-3.09(m,4H),1.69-1.65(m,1H),1.57-1.47(m,3H),0.82-0.76(m,2H),0.67-0.51(m,2H).
LC-MS: m/z 622 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.96 (d, J=7.6 Hz, 1H), 7.80-7.77 (m, 1H), 7.51 (t, J=8.0 Hz, 1H), 7.41-7.28 (m, 3H),7.26(m,2H),6.68-6.54(m,1H),6.42(dd,J=16.8Hz,2.0Hz,1H),5.81(dd,J=10.4Hz,1.6Hz,1H),5.08 -4.33(m, 3H), 4.07-3.59(m, 3H), 3.28-3.09(m, 4H), 1.69-1.65(m, 1H), 1.57-1.47(m, 3H), 0.82-0.76(m, 2H),0.67-0.51(m,2H).
实施例18 4-((S)-4-丙烯酰基-2-甲基哌嗪-1-基)-6-氟-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-(甲基磺酰基)吡啶-3-基)吡啶基[2,3-d]嘧啶-2(1H)-酮Example 18 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2- Isopropyl-4-(methylsulfonyl)pyridin-3-yl)pyridinyl[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 625(M+H)
+。
1H NMR(400MHz,CDCl
3)δ9.02(t,J=8.8Hz,1H),8.67(t,J=4.8Hz,1H),7.93-7.89(m,2H),7.28-7.26(m,1H),6.71-6.40(m,4H),5.84-5.81(m,1H),4.48-3.68(m,7H),3.15(s,3H),2.97-2.93(m,1H),1.59-1.07(m,9H).
LC-MS: m/z 625 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 9.02 (t, J=8.8 Hz, 1H), 8.67 (t, J=4.8 Hz, 1H), 7.93-7.89 (m, 2H), 7.28-7.26 (m, 1H), 6.71-6.40(m, 4H), 5.84-5.81(m, 1H), 4.48-3.68(m, 7H), 3.15(s, 3H), 2.97-2.93(m, 1H), 1.59-1.07( m, 9H).
实施例18-1 通过手性分离得到两个异构体实施例18A和实施例18B:Example 18-1 Two isomers Example 18A and Example 18B were obtained by chiral separation:
实施例18A:LC-MS:m/z 625(M+H)
+。
1H NMR(400MHz,DMSO)δ10.31(s,1H),8.96(d,J=5.0Hz,1H),8.40(t,J=10.2Hz,1H),7.89(d,J=5.0Hz,1H),7.32(dd,J=15.3,8.3Hz,1H),7.02–6.84(m,1H),6.83–6.64(m,2H),6.26(dd,J=16.6,5.1Hz,1H),5.82(dd,J=10.4,2.3Hz,1H),4.96(s,1H),4.29(m,3H),3.58(m,2H),3.36–2.87(m,5H),1.43–1.33(m,3H),1.17(d,J=6.7Hz,3H),1.10–1.00(m,3H).
Example 18A: LC-MS: m/z 625 (M+H) + . 1 H NMR(400MHz, DMSO)δ10.31(s,1H),8.96(d,J=5.0Hz,1H),8.40(t,J=10.2Hz,1H),7.89(d,J=5.0Hz, 1H), 7.32 (dd, J=15.3, 8.3Hz, 1H), 7.02–6.84 (m, 1H), 6.83–6.64 (m, 2H), 6.26 (dd, J=16.6, 5.1Hz, 1H), 5.82 (dd,J=10.4,2.3Hz,1H),4.96(s,1H),4.29(m,3H),3.58(m,2H),3.36–2.87(m,5H),1.43–1.33(m,3H) ), 1.17(d, J=6.7Hz, 3H), 1.10–1.00(m, 3H).
实施例18B:LC-MS:m/z 625(M+H)
+。
1H NMR(400MHz,DMSO)δ10.24(s,1H),8.90(d,J=5.0Hz,1H),8.35(t,J=10.4Hz,1H),7.83(d,J=5.0Hz,1H),7.26(dd,J=15.3,8.2Hz,1H),6.95–6.79(m,1H),6.78–6.57(m,2H),6.21(d,J=16.6Hz,1H),5.77(dd,J=10.5,2.1Hz,1H),4.97(s,1H),4.22(m,3H),3.86–3.43(m,2H),3.29–2.81(m,5H),1.32(t,J=7.0Hz,3H),1.12(t,J=8.2Hz,3H),1.02(d,J=6.6Hz,3H).
Example 18B: LC-MS: m/z 625 (M+H) + . 1 H NMR(400MHz, DMSO)δ10.24(s,1H),8.90(d,J=5.0Hz,1H),8.35(t,J=10.4Hz,1H),7.83(d,J=5.0Hz, 1H), 7.26(dd, J=15.3, 8.2Hz, 1H), 6.95-6.79(m, 1H), 6.78-6.57(m, 2H), 6.21(d, J=16.6Hz, 1H), 5.77(dd , J=10.5, 2.1Hz, 1H), 4.97 (s, 1H), 4.22 (m, 3H), 3.86–3.43 (m, 2H), 3.29–2.81 (m, 5H), 1.32 (t, J=7.0 Hz, 3H), 1.12(t, J=8.2Hz, 3H), 1.02(d, J=6.6Hz, 3H).
实施例19 4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-7-(2-氟-6-甲氧基苯基)-1-(4-异丙基-2-(甲砜基)吡啶-3-基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 19 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-( 4-Isopropyl-2-(methylsulfonyl)pyridin-3-yl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 639(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.66(d,J=5.2Hz,1H),7.79-7.75(m,1H),7.58(d,J=4.4Hz,1H),7.33-7.29(m,1H),6.71-6.60(m,3H),6.41-6.38(m,1H),5.80(d,J=10.4Hz,1H),5.04-4.35(m,3H),4.00-3.60(m,6H),3.18(m,4H),2.92(m,1H),1.48(m,3H),1.23(d,J=6.8Hz,3H),1.09(m,3H).
LC-MS: m/z 639 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.66 (d, J=5.2 Hz, 1H), 7.79-7.75 (m, 1H), 7.58 (d, J=4.4 Hz, 1H), 7.33-7.29 (m, 1H), 6.71-6.60(m, 3H), 6.41-6.38(m, 1H), 5.80(d, J=10.4Hz, 1H), 5.04-4.35(m, 3H), 4.00-3.60(m, 6H) ,3.18(m,4H),2.92(m,1H),1.48(m,3H),1.23(d,J=6.8Hz,3H),1.09(m,3H).
实施例20 (S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-7-(2-氯苯基)-6-氟-1-(4-异丙基-2-(甲砜基)吡啶-3-基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 20 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-(2-chlorophenyl)-6-fluoro-1-(4-isopropyl- 2-(Methylsulfonyl)pyridin-3-yl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 625(M+H)
+。δ8.67-8.65(m,1H),7.81-7.77(m,1H),7.57(d,J=4.8Hz,1H),7.40-7.27(m,4H),6.61(m,1H),6.42-6.38(m,1H),5.80(d,J=10.4Hz,1H),5.16-4.36(m,3H),4.02-3.59(m,3H),3.17(m,4H),2.95(m,1H),1.49(m,3H),1.25(d,J=6.8Hz,3H),1.06(d,J=6.8Hz,3H).
LC-MS: m/z 625 (M+H) + . δ8.67-8.65(m,1H),7.81-7.77(m,1H),7.57(d,J=4.8Hz,1H),7.40-7.27(m,4H),6.61(m,1H),6.42- 6.38(m, 1H), 5.80(d, J=10.4Hz, 1H), 5.16-4.36(m, 3H), 4.02-3.59(m, 3H), 3.17(m, 4H), 2.95(m, 1H) ,1.49(m,3H),1.25(d,J=6.8Hz,3H),1.06(d,J=6.8Hz,3H).
实施例20-1 通过手性分离得到两个异构体实施例20A和实施例20B:Example 20-1 Two isomers Example 20A and Example 20B were obtained by chiral separation:
实施例20A:LC-MS:m/z 625(M+H)
+。
1H NMR(400MHz,DMSO)δ8.71(d,J=5.0Hz,1H),8.41(t,J=9.3Hz,1H),7.88(d,J=5.0Hz,1H),7.56(d,J=7.1Hz,1H),7.50(dd,J=7.4,1.6Hz,1H),7.42(t,J=7.5Hz,1H),7.38–7.25(m,1H),6.86(dd,J=16.6,9.3Hz,1H),6.22(d,J=16.4Hz,1H),5.89–5.69(m,1H),5.02(s,1H),4.23(m,3H),3.93–3.57(m,2H),3.30–3.01(m,4H),2.88(m,1H),1.31(d,J=6.5Hz,3H),1.15(d,J=6.8Hz,3H),1.02(d,J=6.8Hz,3H).
Example 20A: LC-MS: m/z 625 (M+H) + . 1 H NMR (400MHz, DMSO) δ8.71(d, J=5.0Hz, 1H), 8.41(t, J=9.3Hz, 1H), 7.88(d, J=5.0Hz, 1H), 7.56(d, J=7.1Hz, 1H), 7.50 (dd, J=7.4, 1.6Hz, 1H), 7.42 (t, J=7.5Hz, 1H), 7.38–7.25 (m, 1H), 6.86 (dd, J=16.6 ,9.3Hz,1H),6.22(d,J=16.4Hz,1H),5.89-5.69(m,1H),5.02(s,1H),4.23(m,3H),3.93-3.57(m,2H) ,3.30–3.01(m,4H),2.88(m,1H),1.31(d,J=6.5Hz,3H),1.15(d,J=6.8Hz,3H),1.02(d,J=6.8Hz, 3H).
实施例20B:LC-MS:m/z 625(M+H)
+。
1H NMR(400MHz,DMSO)δ8.71(d,J=5.0Hz,1H),8.37(t,J=10.5Hz,1H),7.88(d,J=5.0Hz,1H),7.48(m,3H),7.30(d,J=7.3Hz,1H),6.87(d,J=10.4Hz,1H),6.22(d,J=16.4Hz,1H),5.78(d,J=12.5Hz,1H),4.86(s,1H),4.62–3.99(m,3H),3.58(m,2H),3.11(m,4H),2.94–2.81(m,1H),1.33(d,J=6.6Hz,3H),1.15(d,J=6.8Hz,3H),1.02(d,J=6.8Hz,3H).
Example 20B: LC-MS: m/z 625 (M+H) + . 1 H NMR(400MHz, DMSO)δ8.71(d,J=5.0Hz,1H),8.37(t,J=10.5Hz,1H),7.88(d,J=5.0Hz,1H),7.48(m, 3H), 7.30(d, J=7.3Hz, 1H), 6.87(d, J=10.4Hz, 1H), 6.22(d, J=16.4Hz, 1H), 5.78(d, J=12.5Hz, 1H) ,4.86(s,1H),4.62-3.99(m,3H),3.58(m,2H),3.11(m,4H),2.94-2.81(m,1H),1.33(d,J=6.6Hz,3H ),1.15(d,J=6.8Hz,3H),1.02(d,J=6.8Hz,3H).
实施例21 6-氟-7-(2-氟-6-羟基苯基)-4-((S)-4-(2-氟丙烯酰基)-2-甲基哌嗪-1-基)-1-(2-异丙基-6-(甲砜基)苯基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 21 6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-4-((S)-4-(2-fluoroacryloyl)-2-methylpiperazin-1-yl)- 1-(2-Isopropyl-6-(methylsulfonyl)phenyl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 642(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.97(s,1H),8.13-8.11(m,1H),7.88-7.82(m,2H),7.76-7.72(m,1H),7.28-7.22(m,1H),6.66-6.62(m,2H),5.48-5.35(m,1H),5.26-5.22(m,1H),5.02-4.90(m,1H),4.53-3.65(m,6H),3.11(s,3H),2.82-2.73(m,1H),1.60-1.03(m,9H).
LC-MS: m/z 642 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 8.97(s, 1H), 8.13-8.11(m, 1H), 7.88-7.82(m, 2H), 7.76-7.72(m, 1H), 7.28-7.22(m ,1H),6.66-6.62(m,2H),5.48-5.35(m,1H),5.26-5.22(m,1H),5.02-4.90(m,1H),4.53-3.65(m,6H),3.11 (s,3H),2.82-2.73(m,1H),1.60-1.03(m,9H).
实施例22 (S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-7-(2-氯-4-氟苯基)-6-氟-1-(4-异丙基-2-(甲砜基)吡啶-3-基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 22 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-(2-chloro-4-fluorophenyl)-6-fluoro-1-(4- Isopropyl-2-(methylsulfonyl)pyridin-3-yl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 643(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.68-8.67(m,1H),7.81-7.78(m,1H),7.59(d,J=5.2Hz,1H),7.34(m,1H),7.14(dd,J=4.4,2.4Hz,1H),7.02-6.99(m,1H),6.61-6.58(m,1H),6.4-6.38(m,1H),5.82-5.80(m,1H),5.01-3.62(m,6H),3.18(m,4H),2.96(m,1H),1.48(m,3H),1.26(d,J=6.8Hz,3H),1.07-1.05(m,3H).
LC-MS: m/z 643 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 8.68-8.67 (m, 1H), 7.81-7.78 (m, 1H), 7.59 (d, J=5.2Hz, 1H), 7.34 (m, 1H), 7.14 ( dd,J=4.4,2.4Hz,1H),7.02-6.99(m,1H),6.61-6.58(m,1H),6.4-6.38(m,1H),5.82-5.80(m,1H),5.01- 3.62(m, 6H), 3.18(m, 4H), 2.96(m, 1H), 1.48(m, 3H), 1.26(d, J=6.8Hz, 3H), 1.07-1.05(m, 3H).
实施例23 (S)-7-(2-氯苯基)-6-氟-4-(4-(2-氟丙烯酰)-2-甲基哌嗪-1-基)-1-(2-异丙基-6-(甲砜基)苯基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 23 (S)-7-(2-Chlorophenyl)-6-fluoro-4-(4-(2-fluoroacryloyl)-2-methylpiperazin-1-yl)-1-(2 -Isopropyl-6-(methylsulfonyl)phenyl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 642(M+H)
+。
1H NMR(400MHz,CDCl
3)δ7.98(d,J=6.8Hz,1H),7.79-7.75(m,1H),7.70-7.69(m,1H),7.60-7.56(m,1H),7.39-7.19(m,4H),5.46-5.33(m,1H),5.25-5.20(m,1H),4.93(m,1H),4.65-3.20(m,6H),3.07(s,3H),2.81-2.75(m,1H),1.52(d,J=6.8Hz,3H),1.23(d,J=6.8Hz,3H),1.02-1.00(m,3H).
LC-MS: m/z 642 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.98 (d, J=6.8 Hz, 1H), 7.79-7.75 (m, 1H), 7.70-7.69 (m, 1H), 7.60-7.56 (m, 1H), 7.39-7.19(m, 4H), 5.46-5.33(m, 1H), 5.25-5.20(m, 1H), 4.93(m, 1H), 4.65-3.20(m, 6H), 3.07(s, 3H), 2.81-2.75(m,1H),1.52(d,J=6.8Hz,3H),1.23(d,J=6.8Hz,3H),1.02-1.00(m,3H).
实施例24 2-(4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-1-(4-异丙基-2-(甲砜基)吡啶-3-基)-2-氧-1,2-二氢吡啶[2,3-d]嘧啶-7-基)-3-氟苯基乙酸酯Example 24 2-(4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-1-(4-isopropyl-2-(methylsulfonyl) Pyridin-3-yl)-2-oxo-1,2-dihydropyridine[2,3-d]pyrimidin-7-yl)-3-fluorophenyl acetate
LC-MS:m/z 667(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.68-8.67(m,1H),7.85-7.79(m,1H),7.56(d,J=4.8Hz,1H),7.43-7.37(m,1H),7.02-6.95(m,2H),6.70-6.53(m,1H),6.42-6.38(m,1H),5.81-5.79(m,1H),5.08-3.63(m,6H),3.17(m,4H), 2.76(m,1H),2.02(s,3H),1.46(m,3H),1.20(d,J=6.8Hz,3H),0.99(m,3H).
LC-MS: m/z 667 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 8.68-8.67 (m, 1H), 7.85-7.79 (m, 1H), 7.56 (d, J=4.8Hz, 1H), 7.43-7.37 (m, 1H), 7.02-6.95(m, 2H), 6.70-6.53(m, 1H), 6.42-6.38(m, 1H), 5.81-5.79(m, 1H), 5.08-3.63(m, 6H), 3.17(m, 4H) ), 2.76(m, 1H), 2.02(s, 3H), 1.46(m, 3H), 1.20(d, J=6.8Hz, 3H), 0.99(m, 3H).
实施例25 4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-1-(2-环丁基-6-(甲砜基)苯基)-6-氟-7-(2-氟-6-羟基苯基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 25 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-1-(2-cyclobutyl-6-(methylsulfonyl)phenyl)-6-fluoro -7-(2-Fluoro-6-hydroxyphenyl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 636(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.97(s,1H),8.11(d,J=6.8Hz,1H),8.10-7.70(m,3H),7.28-7.22(m,1H),6.69-6.60(m,3H),6.42-6.39(m,1H),5.83-5.80(m,1H),5.05-3.64(m,6H),3.12(m,5H),2.30-2.25(m,1H),2.11-2.08(m,2H),1.85-1.71(m,3H),1.47(d,J=6.4Hz,3H).
LC-MS: m/z 636 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 8.97(s, 1H), 8.11(d, J=6.8Hz, 1H), 8.10-7.70(m, 3H), 7.28-7.22(m, 1H), 6.69- 6.60(m, 3H), 6.42-6.39(m, 1H), 5.83-5.80(m, 1H), 5.05-3.64(m, 6H), 3.12(m, 5H), 2.30-2.25(m, 1H), 2.11-2.08(m, 2H), 1.85-1.71(m, 3H), 1.47(d, J=6.4Hz, 3H).
实施例25-1 通过手性分离得到两个异构体实施例25A和实施例25B:Example 25-1 Two isomers Example 25A and Example 25B were obtained by chiral separation:
实施例25A:LC-MS:m/z 636(M+H)
+。
1H NMR(400MHz,DMSO)δ10.24(s,1H),8.32(t,J=9.3Hz,1H),7.89(dd,J=7.8,1.1Hz,1H),7.76(d,J=7.3Hz,1H),7.65(m,1H),7.27(m,1H),6.87(m,1H),6.79–6.58(m,2H),6.22(m,1H),5.78(m,1H),4.87(m,1H),4.21(m,3H),3.78–3.42(m,2H),3.31–2.91(m,5H),2.19–1.87(m,3H),1.87–1.57(m,3H),1.33(m,3H).
Example 25A: LC-MS: m/z 636 (M+H) + . 1 H NMR (400MHz, DMSO) δ 10.24 (s, 1H), 8.32 (t, J=9.3Hz, 1H), 7.89 (dd, J=7.8, 1.1Hz, 1H), 7.76 (d, J=7.3 Hz, 1H), 7.65(m, 1H), 7.27(m, 1H), 6.87(m, 1H), 6.79–6.58(m, 2H), 6.22(m, 1H), 5.78(m, 1H), 4.87 (m, 1H), 4.21 (m, 3H), 3.78–3.42 (m, 2H), 3.31–2.91 (m, 5H), 2.19–1.87 (m, 3H), 1.87–1.57 (m, 3H), 1.33 (m,3H).
实施例25B:LC-MS:m/z 636(M+H)
+。
1H NMR(400MHz,DMSO)δ10.24(s,1H),8.33(t,J=10.1Hz,1H),7.89(dd,J=7.8,1.1Hz,1H),7.76(d,J=7.3Hz,1H),7.66(m,1H),7.27(m,1H),6.99–6.79(m,1H),6.79–6.58(m,2H),6.21(m,1H),5.77(m,1H),4.88(s,1H),4.55–3.97(m,3H),3.77–3.42(m,2H),3.30–2.89(m,5H),2.13–1.88(m,3H),1.89–1.57(m,3H),1.29(m,3H).
Example 25B: LC-MS: m/z 636 (M+H) + . 1 H NMR (400MHz, DMSO) δ 10.24 (s, 1H), 8.33 (t, J=10.1 Hz, 1H), 7.89 (dd, J=7.8, 1.1 Hz, 1H), 7.76 (d, J=7.3 Hz, 1H), 7.66 (m, 1H), 7.27 (m, 1H), 6.99–6.79 (m, 1H), 6.79–6.58 (m, 2H), 6.21 (m, 1H), 5.77 (m, 1H) ,4.88(s,1H),4.55–3.97(m,3H),3.77–3.42(m,2H),3.30–2.89(m,5H),2.13–1.88(m,3H),1.89–1.57(m, 3H),1.29(m,3H).
实施例26 (S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-7-(2-氯-3-氟苯基)-6-氟-1-(4-异丙基-2-(甲砜基)吡啶-3-基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 26 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-(2-chloro-3-fluorophenyl)-6-fluoro-1-(4- Isopropyl-2-(methylsulfonyl)pyridin-3-yl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 643(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.67-8.66(m,1H),7.83-7.80(m,1H),7.58(d,J=4.2Hz,1H),7.28-7.13(m,3H),6.61-6.58(m,1H),6.42-6.39(m,1H),5.83-5.80(m,1H),5.34-3.62(m,6H),3.18(m,4H),2.97(m,1H),1.49(m,3H),1.27-1.25(m,3H),1.07-1.06(m,3H).
LC-MS: m/z 643 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 8.67-8.66 (m, 1H), 7.83-7.80 (m, 1H), 7.58 (d, J=4.2Hz, 1H), 7.28-7.13 (m, 3H), 6.61-6.58(m, 1H), 6.42-6.39(m, 1H), 5.83-5.80(m, 1H), 5.34-3.62(m, 6H), 3.18(m, 4H), 2.97(m, 1H), 1.49(m,3H),1.27-1.25(m,3H),1.07-1.06(m,3H).
实施例27 4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-7-(2-氯-6-羟基苯基)-6-氟-1-(4-异丙基-2-(甲砜基)吡啶-3-基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 27 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-7-(2-chloro-6-hydroxyphenyl)-6-fluoro-1-(4- Isopropyl-2-(methylsulfonyl)pyridin-3-yl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 641(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.61(m,1H),7.90-7.86(m,1H),7.61-7.60(m,1H),7.26-7.18(m,1H),6.96(d,J=8.0Hz,1H),6.84(d,J=8.4Hz,1H),6.60-6.57(m,1H),6.42-6.38(m,1H),5.82-5.79(m,1H),5.06-3.61(m,6H),3.30(s,3H),2.95-2.88(m,2H),1.54-1.50(m,3H),1.28-1.26(m,3H),1.02(m,3H).
LC-MS: m/z 641 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 8.61 (m, 1H), 7.90-7.86 (m, 1H), 7.61-7.60 (m, 1H), 7.26-7.18 (m, 1H), 6.96 (d, J =8.0Hz,1H),6.84(d,J=8.4Hz,1H),6.60-6.57(m,1H),6.42-6.38(m,1H),5.82-5.79(m,1H),5.06-3.61( m, 6H), 3.30(s, 3H), 2.95-2.88(m, 2H), 1.54-1.50(m, 3H), 1.28-1.26(m, 3H), 1.02(m, 3H).
实施例28 4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-7-(2-氯-6-氟苯基)-6-氟-1-(4-异丙基-2-(甲砜基)吡啶-3-基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 28 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-7-(2-chloro-6-fluorophenyl)-6-fluoro-1-(4- Isopropyl-2-(methylsulfonyl)pyridin-3-yl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 643(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.66(m,1H),7.87-7.83(m,1H),7.58(d,J=4.8Hz,1H),7.36-7.31(m,1H),7.23-7.21(m,1H),7.03-7.02(m,1H),6.61-6.58(m,1H),6.42-6.38(m,1H),5.82-5.79(m,1H),5.06-3.61(m,6H),3.27-3.12(m,4H),2.92(m,1H),1.53-1.50(m,3H),1.25-1.23(m,3H),1.08(m,3H).
LC-MS: m/z 643 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.66 (m, 1H), 7.87-7.83 (m, 1H), 7.58 (d, J=4.8Hz, 1H), 7.36-7.31 (m, 1H), 7.23- 7.21(m,1H),7.03-7.02(m,1H),6.61-6.58(m,1H),6.42-6.38(m,1H),5.82-5.79(m,1H),5.06-3.61(m,6H ),3.27-3.12(m,4H),2.92(m,1H),1.53-1.50(m,3H),1.25-1.23(m,3H),1.08(m,3H).
实施例29 4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-7-(2-氟-6-羟基苯基)-1-(3-异丙基-5-(甲砜基)嘧啶-4-基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 29 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(3- Isopropyl-5-(methylsulfonyl)pyrimidin-4-yl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 625(M+H)
+。
1H NMR(400MHz,CDCl
3)δ9.25(s,1H),9.06(s,1H),8.58(s,1H),7.90(d,J=9.3Hz,1H),7.32–7.23(m,1H),6.74–6.51(m,3H),6.42(dd,J=16.7,1.6Hz,1H),5.89–5.77(m,1H),5.27–3.45(m,6H),3.17(s,4H),2.83(m,1H),1.56–1.41(m,3H),1.30(m,3H),1.14(t,J=6.5Hz,3H).
LC-MS: m/z 625 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 9.25(s, 1H), 9.06(s, 1H), 8.58(s, 1H), 7.90(d, J=9.3Hz, 1H), 7.32-7.23(m, 1H), 6.74–6.51 (m, 3H), 6.42 (dd, J=16.7, 1.6Hz, 1H), 5.89–5.77 (m, 1H), 5.27–3.45 (m, 6H), 3.17 (s, 4H) ,2.83(m,1H),1.56–1.41(m,3H),1.30(m,3H),1.14(t,J=6.5Hz,3H).
实施例29-1 通过手性分离得到两个异构体实施例29A和实施例29B:Example 29-1 Two isomers Example 29A and Example 29B were obtained by chiral separation:
实施例29A:LC-MS:m/z 625(M+H)
+。
Example 29A: LC-MS: m/z 625 (M+H) + .
实施例29B:LC-MS:m/z 625(M+H)
+。
Example 29B: LC-MS: m/z 625 (M+H) + .
实施例30 (S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-7-(2-氯苯基)-6-氟-1-(2-异丙基-6-(甲砜基)苯基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 30 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-(2-chlorophenyl)-6-fluoro-1-(2-isopropyl- 6-(Methylsulfonyl)phenyl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 624(M+H)
+。
1H NMR(400MHz,CDCl
3)δ7.98(dd,J=7.8,1.3Hz,1H),7.84–7.73(m,1H),7.70(d,J=6.8Hz,1H),7.58(t,J=7.9Hz,1H),7.44–7.30(m,2H),7.28–7.15(m,2H),6.61(m,1H),6.41(dd,J=16.8,1.7Hz,1H),5.81(d,J=10.5Hz,1H),5.13–3.47(m,6H),3.08(m,4H),2.80(m,1H),1.50(m,3H),1.24(t,J=6.4Hz,3H),1.01(d,J=6.8Hz,3H).
LC-MS: m/z 624 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.98 (dd, J=7.8, 1.3 Hz, 1H), 7.84-7.73 (m, 1H), 7.70 (d, J=6.8 Hz, 1H), 7.58 (t, J=7.9Hz, 1H), 7.44–7.30 (m, 2H), 7.28–7.15 (m, 2H), 6.61 (m, 1H), 6.41 (dd, J=16.8, 1.7Hz, 1H), 5.81 (d , J=10.5Hz, 1H), 5.13–3.47(m, 6H), 3.08(m, 4H), 2.80(m, 1H), 1.50(m, 3H), 1.24(t, J=6.4Hz, 3H) ,1.01(d,J=6.8Hz,3H).
实施例30-1 通过手性分离得到两个异构体实施例30A和实施例30B:Example 30-1 Two isomers Example 30A and Example 30B were obtained by chiral separation:
实施例30A:LC-MS:m/z 624(M+H)
+。
1H NMR(400MHz,DMSO)δ8.38(t,J=9.3Hz,1H),7.86(m,2H),7.66(t,J=7.8Hz,1H),7.47(m,3H),7.22(d,J=7.2Hz,1H),6.92–6.74(m,1H),6.22(d,J=16.6Hz,1H),5.77(d,J=10.7Hz,1H),4.96(brs,1H),4.23(m,3H),3.87–3.44(m,2H),3.28–3.07(m,1H),3.01(s,3H),2.71(d,J=6.1Hz,1H),1.30(t,J=14.4Hz,3H),1.11(d,J=6.7Hz,3H),0.94(t,J=28.8Hz,3H).
Example 30A: LC-MS: m/z 624 (M+H) + . 1 H NMR(400MHz, DMSO)δ8.38(t,J=9.3Hz,1H),7.86(m,2H),7.66(t,J=7.8Hz,1H),7.47(m,3H),7.22( d, J=7.2Hz, 1H), 6.92–6.74 (m, 1H), 6.22 (d, J=16.6Hz, 1H), 5.77 (d, J=10.7Hz, 1H), 4.96 (brs, 1H), 4.23(m, 3H), 3.87-3.44(m, 2H), 3.28-3.07(m, 1H), 3.01(s, 3H), 2.71(d, J=6.1Hz, 1H), 1.30(t, J= 14.4Hz, 3H), 1.11 (d, J=6.7Hz, 3H), 0.94 (t, J=28.8Hz, 3H).
实施例30B:LC-MS:m/z 624(M+H)
+。
1H NMR(400MHz,DMSO)δ8.37(m,1H),7.86(m,2H),7.66(t,J=7.5Hz,1H),7.47(m,3H),7.22(d,J=7.0Hz,1H),6.96–6.68(m,1H),6.22(d,J=15.4Hz,1H),5.77(d,J=10.3Hz,1H),4.88(brs,1H),4.53–3.94(m,3H),3.76–3.45(m,2H),3.33–2.60(m,5H),1.30(t,J=15.2Hz,3H),1.09(t,J=15.7Hz,3H),0.95(t,J=27.8Hz,3H).
Example 30B: LC-MS: m/z 624 (M+H) + . 1 H NMR (400MHz, DMSO) δ8.37(m, 1H), 7.86(m, 2H), 7.66(t, J=7.5Hz, 1H), 7.47(m, 3H), 7.22(d, J=7.0 Hz, 1H), 6.96–6.68 (m, 1H), 6.22 (d, J=15.4Hz, 1H), 5.77 (d, J=10.3Hz, 1H), 4.88 (brs, 1H), 4.53–3.94 (m ,3H),3.76–3.45(m,2H),3.33–2.60(m,5H),1.30(t,J=15.2Hz,3H),1.09(t,J=15.7Hz,3H),0.95(t, J=27.8Hz, 3H).
实施例31 2-(4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-1-(2-异丙基-6-(甲砜基)苯基)-2-氧-1,2-二氢吡啶[2,3-d]嘧啶-7-基)-3-氟苯基乙酸酯Example 31 2-(4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-1-(2-isopropyl-6-(methylsulfonyl) Phenyl)-2-oxo-1,2-dihydropyridine[2,3-d]pyrimidin-7-yl)-3-fluorophenyl acetate
LC-MS:m/z 666(M+H)
+。
1H NMR(400MHz,CDCl
3)δ7.91(d,J=7.3Hz,1H),7.76(s,1H),7.60(d,J=7.4Hz,1H),7.52(t,J=7.6Hz,1H),7.32(m,1H),6.99–6.76(m,2H),6.55(m,1H),6.34m,1H),5.75(m,1H),5.23–3.42(m,6H),3.15(m,4H),2.54(s,1H),1.94(s,3H),1.57–1.30(m,3H),1.07(m,3H),0.85(m,3H).
LC-MS: m/z 666 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.91 (d, J=7.3 Hz, 1H), 7.76 (s, 1H), 7.60 (d, J=7.4 Hz, 1H), 7.52 (t, J=7.6 Hz) ,1H),7.32(m,1H),6.99–6.76(m,2H),6.55(m,1H),6.34m,1H),5.75(m,1H),5.23–3.42(m,6H),3.15 (m, 4H), 2.54(s, 1H), 1.94(s, 3H), 1.57–1.30(m, 3H), 1.07(m, 3H), 0.85(m, 3H).
实施例31-1 通过手性分离得到两个异构体实施例31A和实施例31B:Example 31-1 Two isomers Example 31A and Example 31B were obtained by chiral separation:
实施例31A:LC-MS:m/z 666(M+H)
+。
1H NMR(400MHz,DMSO)δ8.38(t,J=9.3 Hz,1H),7.89(dd,J=7.8,1.3Hz,1H),7.80(dt,J=14.3,7.2Hz,1H),7.66(t,J=7.8Hz,1H),7.56(td,J=8.4,6.6Hz,1H),7.25(t,J=8.7Hz,1H),7.12(d,J=7.8Hz,1H),6.87(m,1H),6.22(d,J=16.7Hz,1H),5.78(d,J=10.6Hz,1H),4.93(brs,1H),4.35(m,2H),4.10(m,1H),3.86–3.46(m,2H),3.24(m,1H),2.99(m,3H),2.60(m,1H),2.13–1.86(m,3H),1.35(d,J=6.5Hz,3H),1.09(d,J=6.6Hz,3H),0.90(t,J=12.5Hz,3H).
Example 31A: LC-MS: m/z 666 (M+H) + . 1 H NMR (400MHz, DMSO) δ8.38 (t, J=9.3 Hz, 1H), 7.89 (dd, J=7.8, 1.3 Hz, 1H), 7.80 (dt, J=14.3, 7.2 Hz, 1H), 7.66(t,J=7.8Hz,1H),7.56(td,J=8.4,6.6Hz,1H),7.25(t,J=8.7Hz,1H),7.12(d,J=7.8Hz,1H), 6.87(m,1H),6.22(d,J=16.7Hz,1H),5.78(d,J=10.6Hz,1H),4.93(brs,1H),4.35(m,2H),4.10(m,1H ), 3.86–3.46 (m, 2H), 3.24 (m, 1H), 2.99 (m, 3H), 2.60 (m, 1H), 2.13–1.86 (m, 3H), 1.35 (d, J=6.5Hz, 3H), 1.09(d, J=6.6Hz, 3H), 0.90(t, J=12.5Hz, 3H).
实施例31B:LC-MS:m/z 666(M+H)
+。
1H NMR(400MHz,DMSO)δ8.41(t,J=8.8Hz,1H),7.89(dd,J=7.8,1.4Hz,1H),7.82(dt,J=7.9,3.9Hz,1H),7.66(t,J=7.8Hz,1H),7.56(td,J=8.4,6.6Hz,1H),7.25(t,J=8.8Hz,1H),7.12(d,J=8.0Hz,1H),7.00–6.78(m,1H),6.34–6.09(m,1H),5.78(dd,J=10.4,2.3Hz,1H),4.90(brs,1H),4.56–3.94(m,3H),3.63(m,2H),3.31–2.88(m,4H),2.66(m,1H),2.09–1.87(m,3H),1.31(m,3H),1.09(d,J=6.6Hz,3H),0.93(m,3H).
Example 31B: LC-MS: m/z 666 (M+H) + . 1 H NMR (400MHz, DMSO) δ 8.41 (t, J=8.8Hz, 1H), 7.89 (dd, J=7.8, 1.4Hz, 1H), 7.82 (dt, J=7.9, 3.9Hz, 1H), 7.66(t,J=7.8Hz,1H),7.56(td,J=8.4,6.6Hz,1H),7.25(t,J=8.8Hz,1H),7.12(d,J=8.0Hz,1H), 7.00–6.78 (m, 1H), 6.34–6.09 (m, 1H), 5.78 (dd, J=10.4, 2.3Hz, 1H), 4.90 (brs, 1H), 4.56–3.94 (m, 3H), 3.63 ( m, 2H), 3.31–2.88 (m, 4H), 2.66 (m, 1H), 2.09–1.87 (m, 3H), 1.31 (m, 3H), 1.09 (d, J=6.6Hz, 3H), 0.93 (m,3H).
实施例32 (S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-7-(2-氯-3-氟苯基)-6-氟-1-(2-异丙基-6-(甲砜基)苯基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 32 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-(2-chloro-3-fluorophenyl)-6-fluoro-1-(2- Isopropyl-6-(methylsulfonyl)phenyl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 642(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.03–7.91(m,1H),7.80(dd,J=8.6,5.5Hz,1H),7.70(d,J=7.0Hz,1H),7.59(t,J=7.8Hz,1H),7.21(m,2H),7.02(d,J=7.4Hz,1H),6.61(s,1H),6.41(dd,J=16.8,1.6Hz,1H),5.81(d,J=10.5Hz,1H),5.24–3.42(m,6H),3.08(s,4H),2.80(m,1H),1.47(m,3H),1.25(m,3H),1.06–0.93(m,3H).
LC-MS: m/z 642 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.03-7.91 (m, 1H), 7.80 (dd, J=8.6, 5.5 Hz, 1H), 7.70 (d, J=7.0 Hz, 1H), 7.59 (t, J=7.8Hz, 1H), 7.21(m, 2H), 7.02(d, J=7.4Hz, 1H), 6.61(s, 1H), 6.41(dd, J=16.8, 1.6Hz, 1H), 5.81( d, J=10.5Hz, 1H), 5.24–3.42 (m, 6H), 3.08 (s, 4H), 2.80 (m, 1H), 1.47 (m, 3H), 1.25 (m, 3H), 1.06–0.93 (m,3H).
实施例32-1 通过手性分离得到两个异构体实施例32A和实施例32B:Example 32-1 Two isomers Example 32A and Example 32B were obtained by chiral separation:
实施例32A:LC-MS:m/z 642(M+H)
+。
1H NMR(400MHz,DMSO)δ8.42(t,J=9.4Hz,1H),7.86(m,2H),7.67(t,J=7.8Hz,1H),7.58–7.23(m,2H),7.12(m,1H),6.91(m,1H),6.22(d,J=16.9Hz,1H),5.78(d,J=11.3Hz,1H),4.97(brs,1H),4.23(m,3H),3.90–3.56(m,2H),3.20(m,1H),3.01(s,3H),2.73(m,1H),1.32(d,J=6.4Hz,3H),1.11(d,J=6.7Hz,3H),0.98(d,J=6.7Hz,3H).
Example 32A: LC-MS: m/z 642 (M+H) + . 1 H NMR(400MHz, DMSO)δ8.42(t,J=9.4Hz,1H),7.86(m,2H),7.67(t,J=7.8Hz,1H),7.58-7.23(m,2H), 7.12(m, 1H), 6.91(m, 1H), 6.22(d, J=16.9Hz, 1H), 5.78(d, J=11.3Hz, 1H), 4.97(brs, 1H), 4.23(m, 3H) ), 3.90–3.56(m, 2H), 3.20(m, 1H), 3.01(s, 3H), 2.73(m, 1H), 1.32(d, J=6.4Hz, 3H), 1.11(d, J= 6.7Hz, 3H), 0.98(d, J=6.7Hz, 3H).
实施例32B:LC-MS:m/z 642(M+H)
+。
1H NMR(400MHz,DMSO)δ8.40(t,J=9.9Hz,1H),7.87(m,2H),7.67(t,J=7.8Hz,1H),7.59–7.38(m,2H),7.10(d,J=7.5Hz,1H),6.87(dd,J=26.4,15.8Hz,1H),6.22(d,J=16.5Hz,1H),5.90–5.66(m,1H),4.87(brs,1H),4.24(m,3H),3.82–3.45(m,2H),3.18(m,1H),3.01(s,3H),2.74(m,1H),1.31(t,J=6.4Hz,3H),1.11(d,J=6.8Hz,3H),0.98(d,J=6.8Hz,3H).
Example 32B: LC-MS: m/z 642 (M+H) + . 1 H NMR(400MHz,DMSO)δ8.40(t,J=9.9Hz,1H),7.87(m,2H),7.67(t,J=7.8Hz,1H),7.59-7.38(m,2H), 7.10(d,J=7.5Hz,1H),6.87(dd,J=26.4,15.8Hz,1H),6.22(d,J=16.5Hz,1H),5.90–5.66(m,1H),4.87(brs ,1H),4.24(m,3H),3.82–3.45(m,2H),3.18(m,1H),3.01(s,3H),2.74(m,1H),1.31(t,J=6.4Hz, 3H), 1.11(d, J=6.8Hz, 3H), 0.98(d, J=6.8Hz, 3H).
实施例33 (S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-7-(2-氯苯基)-6-氟-1-(2-异丙基-4-(甲砜基)吡啶-3-基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 33 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-(2-chlorophenyl)-6-fluoro-1-(2-isopropyl- 4-(Methylsulfonyl)pyridin-3-yl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 625(M+H)
+。
LC-MS: m/z 625 (M+H) + .
实施例33-1 通过手性分离得到两个异构体实施例33A和实施例33B:Example 33-1 Two isomers Example 33A and Example 33B were obtained by chiral separation:
实施例33A:LC-MS:m/z 625(M+H)
+。
Example 33A: LC-MS: m/z 625 (M+H) + .
实施例33B:LC-MS:m/z 625(M+H)
+。
Example 33B: LC-MS: m/z 625 (M+H) + .
实施例34 (S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-7-(2-氯-3-氟苯基)-6-氟-1-(2-异丙基-4-(甲砜基)吡啶-3-基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 34 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-(2-chloro-3-fluorophenyl)-6-fluoro-1-(2- Isopropyl-4-(methylsulfonyl)pyridin-3-yl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 643(M+H)
+。
LC-MS: m/z 643 (M+H) + .
实施例34-1 通过手性分离得到两个异构体实施例34A和实施例34B:Example 34-1 Two isomers Example 34A and Example 34B were obtained by chiral separation:
实施例34A:LC-MS:m/z 643(M+H)
+。
Example 34A: LC-MS: m/z 643 (M+H) + .
实施例34B:LC-MS:m/z 643(M+H)
+。
Example 34B: LC-MS: m/z 643 (M+H) + .
实施例35 (S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-7-(2-氯苯基)-1-(2-环丁基-6-(甲砜基)苯基)-6-氟吡啶[2,3-d]嘧啶-2(1H)-酮Example 35 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-(2-chlorophenyl)-1-(2-cyclobutyl-6-(methyl) Sulfonyl)phenyl)-6-fluoropyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 636(M+H)
+。
LC-MS: m/z 636 (M+H) + .
实施例35-1 通过手性分离得到两个异构体实施例35A和实施例35B:Example 35-1 Two isomers Example 35A and Example 35B were obtained by chiral separation:
实施例35A:LC-MS:m/z 636(M+H)
+。
Example 35A: LC-MS: m/z 636 (M+H) + .
实施例35B:LC-MS:m/z 636(M+H)
+。
Example 35B: LC-MS: m/z 636 (M+H) + .
实施例36 (S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-7-(2-氯-3-氟苯基)-1-(2-环丁基-6-(甲砜基)苯基)-6-氟吡啶[2,3-d]嘧啶-2(1H)-酮Example 36 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-(2-chloro-3-fluorophenyl)-1-(2-cyclobutyl- 6-(Methylsulfonyl)phenyl)-6-fluoropyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 654(M+H)
+。
LC-MS: m/z 654 (M+H) + .
实施例36-1 通过手性分离得到两个异构体实施例36A和实施例36B:Example 36-1 Two isomers Example 36A and Example 36B were obtained by chiral separation:
实施例36A:LC-MS:m/z 654(M+H)
+。
Example 36A: LC-MS: m/z 654 (M+H) + .
实施例36B:LC-MS:m/z 654(M+H)
+。
Example 36B: LC-MS: m/z 654 (M+H) + .
实施例37 (S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-7-(2-氯吡啶-3-基)-6-氟-1-(2-异丙基-6-(甲砜基)苯基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 37 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-(2-chloropyridin-3-yl)-6-fluoro-1-(2-iso Propyl-6-(methylsulfonyl)phenyl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 625(M+H)
+。
LC-MS: m/z 625 (M+H) + .
实施例37-1 通过手性分离得到两个异构体实施例37A和实施例37B:Example 37-1 Two isomers Example 37A and Example 37B were obtained by chiral separation:
实施例37A:LC-MS:m/z 625(M+H)
+。
Example 37A: LC-MS: m/z 625 (M+H) + .
实施例37B:LC-MS:m/z 625(M+H)
+。
Example 37B: LC-MS: m/z 625 (M+H) + .
实施例38 (S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-7-(3-氯吡啶-4-基)-6-氟-1-(2-异丙基-6-(甲砜基)苯基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 38 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-(3-chloropyridin-4-yl)-6-fluoro-1-(2-iso Propyl-6-(methylsulfonyl)phenyl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 625(M+H)
+。
LC-MS: m/z 625 (M+H) + .
实施例38-1 通过手性分离得到两个异构体实施例38A和实施例38B:Example 38-1 Two isomers Example 38A and Example 38B were obtained by chiral separation:
实施例38A:LC-MS:m/z 625(M+H)
+。
Example 38A: LC-MS: m/z 625 (M+H) + .
实施例38B:LC-MS:m/z 625(M+H)
+。
Example 38B: LC-MS: m/z 625 (M+H) + .
实施例39 (S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-7-(4-氯吡啶-3-基)-6-氟-1-(2-异丙基-6-(甲砜基)苯基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 39 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-(4-chloropyridin-3-yl)-6-fluoro-1-(2-iso Propyl-6-(methylsulfonyl)phenyl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 625(M+H)
+。
LC-MS: m/z 625 (M+H) + .
实施例39-1 通过手性分离得到两个异构体实施例39A和实施例39B:Example 39-1 Two isomers Example 39A and Example 39B were obtained by chiral separation:
实施例39A:LC-MS:m/z 625(M+H)
+。
Example 39A: LC-MS: m/z 625 (M+H) + .
实施例39B:LC-MS:m/z 625(M+H)
+。
Example 39B: LC-MS: m/z 625 (M+H) + .
实施例40 (S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-7-(3-氯吡啶-2-基)-6-氟-1-(2-异丙基-6-(甲砜基)苯基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 40 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-(3-chloropyridin-2-yl)-6-fluoro-1-(2-iso Propyl-6-(methylsulfonyl)phenyl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 625(M+H)
+。
LC-MS: m/z 625 (M+H) + .
实施例40-1 通过手性分离得到两个异构体实施例39A和实施例39B:Example 40-1 Two isomers Example 39A and Example 39B were obtained by chiral separation:
实施例40A:LC-MS:m/z 625(M+H)
+。
Example 40A: LC-MS: m/z 625 (M+H) + .
实施例40B:LC-MS:m/z 625(M+H)
+。
Example 40B: LC-MS: m/z 625 (M+H) + .
实施例41 (S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-7-(2-氨基吡啶-3-基)-6-氟-1-(2-异丙基-6-(甲砜基)苯基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 41 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-(2-aminopyridin-3-yl)-6-fluoro-1-(2-iso Propyl-6-(methylsulfonyl)phenyl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 606(M+H)
+。
LC-MS: m/z 606 (M+H) + .
实施例41-1 通过手性分离得到两个异构体实施例41A和实施例41B:Example 41-1 Two isomers Example 41A and Example 41B were obtained by chiral separation:
实施例41A:LC-MS:m/z 606(M+H)
+。
Example 41A: LC-MS: m/z 606 (M+H) + .
实施例41B:LC-MS:m/z 606(M+H)
+。
Example 41B: LC-MS: m/z 606 (M+H) + .
实施例42 (S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-7-(3-氨基吡啶-4-基)-6-氟-1-(2-异丙基-6-(甲砜基)苯基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 42 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-(3-aminopyridin-4-yl)-6-fluoro-1-(2-iso Propyl-6-(methylsulfonyl)phenyl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 606(M+H)
+。
LC-MS: m/z 606 (M+H) + .
实施例42-1 通过手性分离得到两个异构体实施例42A和实施例42B:Example 42-1 Two isomers Example 42A and Example 42B were obtained by chiral separation:
实施例42A:LC-MS:m/z 606(M+H)
+。
Example 42A: LC-MS: m/z 606 (M+H) + .
实施例42B:LC-MS:m/z 606(M+H)
+。
Example 42B: LC-MS: m/z 606 (M+H) + .
实施例43 (S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-7-(4-氨基吡啶-3-基)-6-氟-1-(2-异丙基-6-(甲砜基)苯基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 43 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-(4-aminopyridin-3-yl)-6-fluoro-1-(2-iso Propyl-6-(methylsulfonyl)phenyl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 606(M+H)
+。
LC-MS: m/z 606 (M+H) + .
实施例43-1 通过手性分离得到两个异构体实施例43A和实施例43B:Example 43-1 Two isomers Example 43A and Example 43B were obtained by chiral separation:
实施例43A:LC-MS:m/z 606(M+H)
+。
Example 43A: LC-MS: m/z 606 (M+H) + .
实施例43B:LC-MS:m/z 606(M+H)
+。
Example 43B: LC-MS: m/z 606 (M+H) + .
实施例44 (S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-7-(3-氨基吡啶-2-基)-6-氟-1-(2-异丙基-6-(甲砜基)苯基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 44 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-(3-aminopyridin-2-yl)-6-fluoro-1-(2-iso Propyl-6-(methylsulfonyl)phenyl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 606(M+H)
+。
LC-MS: m/z 606 (M+H) + .
实施例44-1 通过手性分离得到两个异构体实施例44A和实施例44B:Example 44-1 Two isomers Example 44A and Example 44B were obtained by chiral separation:
实施例44A:LC-MS:m/z 606(M+H)
+。
Example 44A: LC-MS: m/z 606 (M+H) + .
实施例44B:LC-MS:m/z 606(M+H)
+。
Example 44B: LC-MS: m/z 606 (M+H) + .
实施例45 2-(4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-1-(2-异丙基-6-(甲砜基)苯基)-2-氧-1,2-二氢吡啶[2,3-d]嘧啶-7-基)-3-氟苯基丙酸酯Example 45 2-(4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-1-(2-isopropyl-6-(methylsulfonyl) Phenyl)-2-oxo-1,2-dihydropyridine[2,3-d]pyrimidin-7-yl)-3-fluorophenylpropionate
LC-MS:m/z 680(M+H)
+。
LC-MS: m/z 680 (M+H) + .
实施例45-1 通过手性分离得到两个异构体实施例45A和实施例45B:Example 45-1 Two isomers Example 45A and Example 45B were obtained by chiral separation:
实施例45A:LC-MS:m/z 680(M+H)
+。
Example 45A: LC-MS: m/z 680 (M+H) + .
实施例45B:LC-MS:m/z 680(M+H)
+。
Example 45B: LC-MS: m/z 680 (M+H) + .
实施例46 2-(4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-1-(2-异丙基-6-(甲砜基)苯基)-2-氧-1,2-二氢吡啶[2,3-d]嘧啶-7-基)-3-氟苯基异丁酸酯Example 46 2-(4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-1-(2-isopropyl-6-(methylsulfonyl) Phenyl)-2-oxo-1,2-dihydropyridine[2,3-d]pyrimidin-7-yl)-3-fluorophenyl isobutyrate
LC-MS:m/z 694(M+H)
+。
LC-MS: m/z 694 (M+H) + .
实施例46-1 通过手性分离得到两个异构体实施例46A和实施例46B:Example 46-1 Two isomers Example 46A and Example 46B were obtained by chiral separation:
实施例46A:LC-MS:m/z 694(M+H)
+。
Example 46A: LC-MS: m/z 694 (M+H) + .
实施例46B:LC-MS:m/z 694(M+H)
+。
Example 46B: LC-MS: m/z 694 (M+H) + .
实施例47 2-(4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-1-(2-异丙基-6-(甲砜基)苯基)-2-氧-1,2-二氢吡啶[2,3-d]嘧啶-7-基)-3-氟苯基甲基氨基甲酸酯Example 47 2-(4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-1-(2-isopropyl-6-(methylsulfonyl) Phenyl)-2-oxo-1,2-dihydropyridine[2,3-d]pyrimidin-7-yl)-3-fluorophenylmethylcarbamate
LC-MS:m/z 681(M+H)
+。
LC-MS: m/z 681 (M+H) + .
实施例47-1 通过手性分离得到两个异构体实施例47A和实施例47B:Example 47-1 Two isomers Example 47A and Example 47B were obtained by chiral separation:
实施例47A:LC-MS:m/z 681(M+H)
+。
Example 47A: LC-MS: m/z 681 (M+H) + .
实施例47B:LC-MS:m/z 681(M+H)
+。
Example 47B: LC-MS: m/z 681 (M+H) + .
实施例48 (2-(4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-1-(2-异丙基-6-(甲砜基)苯基)-2-氧-1,2-二氢吡啶[2,3-d]嘧啶-7-基)-3-氟苯基)氨基甲酸甲酯Example 48 (2-(4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-1-(2-isopropyl-6-(methylsulfonyl) )phenyl)-2-oxo-1,2-dihydropyridine[2,3-d]pyrimidin-7-yl)-3-fluorophenyl)carbamate
LC-MS:m/z 681(M+H)
+。
LC-MS: m/z 681 (M+H) + .
实施例48-1 通过手性分离得到两个异构体实施例48A和实施例48B:Example 48-1 Two isomers Example 48A and Example 48B were obtained by chiral separation:
实施例48A:LC-MS:m/z 681(M+H)
+。
Example 48A: LC-MS: m/z 681 (M+H) + .
实施例48B:LC-MS:m/z 681(M+H)
+。
Example 48B: LC-MS: m/z 681 (M+H) + .
实施例49 1-(2-(4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-1-(2-异丙基-6-(甲砜基)苯基)-2-氧-1,2-二氢吡啶[2,3-d]嘧啶-7-基)-3-氟苯基)-3-甲基脲Example 49 1-(2-(4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-1-(2-isopropyl-6-(methyl) Sulfonyl)phenyl)-2-oxo-1,2-dihydropyridine[2,3-d]pyrimidin-7-yl)-3-fluorophenyl)-3-methylurea
LC-MS:m/z 680(M+H)
+。
LC-MS: m/z 680 (M+H) + .
实施例49-1 通过手性分离得到两个异构体实施例49A和实施例49B:Example 49-1 Two isomers Example 49A and Example 49B were obtained by chiral separation:
实施例49A:LC-MS:m/z 680(M+H)
+。
Example 49A: LC-MS: m/z 680 (M+H) + .
实施例49B:LC-MS:m/z 680(M+H)
+。
Example 49B: LC-MS: m/z 680 (M+H) + .
实施例50 N-(2-(4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-1-(2-异丙基-6-(甲砜基)苯基)-2-氧-1,2-二氢吡啶[2,3-d]嘧啶-7-基)-3-氟苯基)-甲磺酰胺Example 50 N-(2-(4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-1-(2-isopropyl-6-(methyl) Sulfonyl)phenyl)-2-oxo-1,2-dihydropyridine[2,3-d]pyrimidin-7-yl)-3-fluorophenyl)-methanesulfonamide
LC-MS:m/z 701(M+H)
+。
LC-MS: m/z 701 (M+H) + .
实施例50-1 通过手性分离得到两个异构体实施例50A和实施例50B:Example 50-1 Two isomers Example 50A and Example 50B were obtained by chiral separation:
实施例50A:LC-MS:m/z 701(M+H)
+。
Example 50A: LC-MS: m/z 701 (M+H) + .
实施例50B:LC-MS:m/z 701(M+H)
+。
Example 50B: LC-MS: m/z 701 (M+H) + .
实施例51 4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-7-(2-氟-6-羟基苯基)-1-(2-(甲磺酰基)苯基)吡啶[2,3-d]嘧啶-2(1H)-酮的制备Example 51 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2- Preparation of (Methylsulfonyl)phenyl)pyridin[2,3-d]pyrimidin-2(1H)-one
第1步.2,6-二氯-5-氟-N-(((2-(甲基磺酰基)苯基)氨基甲酰基)烟酰胺的制备Step 1. Preparation of 2,6-dichloro-5-fluoro-N-(((2-(methylsulfonyl)phenyl)carbamoyl)nicotinamide
将2,6-二氯-5-氟烟酰胺(420mg,2.0mmol)溶于无水四氢呋喃(7mL)中,向此溶液中缓慢滴加草酰氯(1.7mL,20.0mmol)的二氯甲烷(2mL)溶液。滴加完毕后,将此混合物于75℃回流搅拌2h,然后减压浓缩至干。残留物用无水四氢呋喃(7 mL)稀释,冷却至0℃。将2-(甲基磺酰基)苯胺(360mg,2.1mmol)溶于无水四氢呋喃(3mL)中,然后滴加进上述溶液中。反应液在0℃下搅拌2h,饱和氯化铵/饱和食盐水(V/V=1/1,20mL)淬灭,然后用二氯甲烷/甲醇(V/V=10/1,20mL)萃取3次。合并有机相干燥,浓缩,残留固体以石油醚/乙酸乙酯(V/V=3/1,15mL)打浆,抽滤,干燥,得目标产物(645mg,收率:79%)。2,6-Dichloro-5-fluoronicotinamide (420 mg, 2.0 mmol) was dissolved in dry tetrahydrofuran (7 mL), and to this solution was slowly added dropwise oxalyl chloride (1.7 mL, 20.0 mmol) in dichloromethane ( 2mL) solution. After the dropwise addition, the mixture was stirred at 75°C under reflux for 2 h, and then concentrated to dryness under reduced pressure. The residue was diluted with anhydrous tetrahydrofuran (7 mL) and cooled to 0°C. 2-(Methylsulfonyl)aniline (360 mg, 2.1 mmol) was dissolved in dry tetrahydrofuran (3 mL) and added dropwise to the above solution. The reaction solution was stirred at 0 °C for 2 h, quenched with saturated ammonium chloride/saturated brine (V/V=1/1, 20 mL), and then extracted with dichloromethane/methanol (V/V=10/1, 20 mL) 3 times. The combined organic phases were dried, concentrated, and the residual solid was slurried with petroleum ether/ethyl acetate (V/V=3/1, 15 mL), suction filtered, and dried to obtain the target product (645 mg, yield: 79%).
LC-MS:m/z 406(M+H)
+。
LC-MS: m/z 406 (M+H) + .
第2步.7-氯-6-氟-1-(2-(甲基磺酰基)苯基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮的制备Step 2. Preparation of 7-chloro-6-fluoro-1-(2-(methylsulfonyl)phenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione
将2,6-二氯-5-氟-N-(((2-(甲基磺酰基)苯基)氨基甲酰基)烟酰胺(645mg,1.6mmol)悬浮于四氢呋喃(15mL)中,冰浴下滴加双(三甲基硅烷基)氨基钾(1摩四氢呋喃溶液,3.6mL,3.6mmol)。滴加完毕后反应液变澄清。反应液室温搅拌16h,饱和氯化铵(20mL)淬灭,然后以乙酸乙酯(20mL)萃取3次。合并乙酸乙酯层干燥,浓缩。残留固体以石油醚/乙酸乙酯(V/V=3/1,10mL)打浆,抽滤,干燥得得目标产物(500mg,收率:85%)。2,6-Dichloro-5-fluoro-N-(((2-(methylsulfonyl)phenyl)carbamoyl)nicotinamide (645 mg, 1.6 mmol) was suspended in tetrahydrofuran (15 mL), ice bathed Bis(trimethylsilyl) potassium amide (1 mole of tetrahydrofuran solution, 3.6 mL, 3.6 mmol) was added dropwise. The reaction solution became clear after the addition was completed. The reaction solution was stirred at room temperature for 16 h, and quenched with saturated ammonium chloride (20 mL). , then extracted 3 times with ethyl acetate (20 mL). The ethyl acetate layers were combined, dried, and concentrated. The residual solid was slurried with petroleum ether/ethyl acetate (V/V=3/1, 10 mL), filtered with suction, and dried to obtain The target product (500 mg, yield: 85%).
LC-MS:m/z 370(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ12.32(s,1H),8.50(d,J=7.2Hz,1H),8.15(dd,J=8.0Hz,1.2Hz,1H),7.97-7.92(m,1H),7.86-7.81(m,1H),7.66(dd,J=8.0Hz,1.2Hz,1H),3.09(s,3H).
LC-MS: m/z 370 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 12.32 (s, 1H), 8.50 (d, J=7.2Hz, 1H), 8.15 (dd, J=8.0Hz, 1.2Hz, 1H), 7.97-7.92 (m,1H),7.86-7.81(m,1H),7.66(dd,J=8.0Hz,1.2Hz,1H),3.09(s,3H).
第3步.(S)-叔丁基4-(7-氯-6-氟-1-(2-(甲基磺酰基)苯基)-2-氧-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸的制备Step 3. (S)-tert-Butyl 4-(7-Chloro-6-fluoro-1-(2-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyrido[ Preparation of 2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid
将7-氯-6-氟-1-(2-(甲基磺酰基)苯基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(450mg,1.2mmol)悬浮于乙腈(10mL)中,滴加N,N-二异丙基乙胺(1.2mL,7.3mmol)和三氯氧磷(0.6mL,6.1mmol),反应液变澄清。将反应液于80℃搅拌4h,减压浓缩至干。残留物溶解在乙腈(10mL)中,冷却至0℃,加入N,N-二异丙基乙胺(0.6mL,3.7mmol)和(S)-3-甲基哌嗪-1-羧酸叔丁酯(290mg,1.5mmol),反应液在室温下搅拌1h,半饱和的碳酸氢钠溶液(40mL)淬灭,再以乙酸乙酯(30mL)萃取3次。合并乙酸乙酯层干燥,浓缩,硅胶柱纯化(石油醚/乙酸乙酯=3/1到1/2.5),得目标产物(460mg,收率:68%)。7-Chloro-6-fluoro-1-(2-(methylsulfonyl)phenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (450 mg, 1.2 mmol ) was suspended in acetonitrile (10 mL), N,N-diisopropylethylamine (1.2 mL, 7.3 mmol) and phosphorus oxychloride (0.6 mL, 6.1 mmol) were added dropwise, and the reaction solution became clear. The reaction solution was stirred at 80 °C for 4 h, and concentrated to dryness under reduced pressure. The residue was dissolved in acetonitrile (10 mL), cooled to 0 °C, N,N-diisopropylethylamine (0.6 mL, 3.7 mmol) and (S)-3-methylpiperazine-1-carboxylic acid tert. Butyl ester (290 mg, 1.5 mmol), the reaction solution was stirred at room temperature for 1 h, quenched with half-saturated sodium bicarbonate solution (40 mL), and extracted three times with ethyl acetate (30 mL). The combined ethyl acetate layers were dried, concentrated, and purified by silica gel column (petroleum ether/ethyl acetate=3/1 to 1/2.5) to obtain the target product (460 mg, yield: 68%).
LC-MS:m/z 552(M+H)
+。
LC-MS: m/z 552 (M+H) + .
第4步.(S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-7-氯-6-氟-1-(2-(甲基磺基)苯基)吡啶[2,3-d]嘧啶-2(1H)-酮的制备Step 4. (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-chloro-6-fluoro-1-(2-(methylsulfo)phenyl) Preparation of pyrid[2,3-d]pyrimidin-2(1H)-one
将(S)-叔丁基4-(7-氯-6-氟-1-(2-(甲基磺酰基)苯基)-2-氧-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸(500mg,0.9mmol)溶于二氯甲烷(10mL)中,加入三氟乙酸(2mL),反应液室温搅拌2h,浓缩干,残留物与二氯甲烷(15mL)共蒸3次得粗品。将该粗品溶解在二氯甲烷(8mL)中,冷却至0℃,滴加N,N-二异丙基乙胺(0.6mL,3.6mmol)和丙烯酰氯(110mg,1.2mmol)的二氯甲烷溶液(1mL)。 反应液在0℃下搅拌30min,饱和碳酸氢钠(30mL)淬灭,并以二氯甲烷(20mL)萃取3次,合并二氯甲烷层,干燥,浓缩,残留物以硅胶柱纯化(二氯甲烷/甲醇=60/1),得目标产物(380mg,收率:83%)。(S)-tert-butyl 4-(7-chloro-6-fluoro-1-(2-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyrido[2,3 -d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid (500mg, 0.9mmol) was dissolved in dichloromethane (10mL), trifluoroacetic acid (2mL) was added, the reaction solution was stirred at room temperature for 2h, Concentrated to dryness, the residue was co-evaporated with dichloromethane (15 mL) three times to obtain the crude product. The crude product was dissolved in dichloromethane (8 mL), cooled to 0°C, and N,N-diisopropylethylamine (0.6 mL, 3.6 mmol) and acryloyl chloride (110 mg, 1.2 mmol) in dichloromethane were added dropwise solution (1 mL). The reaction solution was stirred at 0 °C for 30 min, quenched with saturated sodium bicarbonate (30 mL), and extracted three times with dichloromethane (20 mL), the dichloromethane layers were combined, dried, concentrated, and the residue was purified by silica gel column (dichloromethane). Methane/methanol=60/1) to obtain the target product (380 mg, yield: 83%).
LC-MS:m/z 506(M+H)
+。
LC-MS: m/z 506 (M+H) + .
第5步.4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-7-(2-氟-6-羟基苯基)-1-(2-(甲磺酰基)苯基)吡啶[2,3-d]嘧啶-2(1H)-酮的制备Step 5. 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2 Preparation of -(methylsulfonyl)phenyl)pyridin[2,3-d]pyrimidin-2(1H)-one
将(S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-7-氯-6-氟-1-(2-(甲基磺基)苯基)吡啶[2,3-d]嘧啶-2(1H)-酮(150mg,0.3mmol)、(2-氟-6-羟基苯基)硼酸(60mg,0.4mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(24mg,0.03mmol)和乙酸钾(120mg,1.2mmol)悬浮于二氧六环/水(7.5mL/0.75mL)混合溶剂中,氮气置换3次,并于90℃加热搅拌2h。反应液冷却至室温后,加入半饱和碳酸氢钠溶液(20mL),并以乙酸乙酯(20mL)萃取3次。合并乙酸乙酯层,干燥,浓缩,残留物以硅胶柱纯化(二氯甲烷/甲醇=100/1到60/1),得目标产物(90mg,收率:52%)。(S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-chloro-6-fluoro-1-(2-(methylsulfo)phenyl)pyridine[2 ,3-d]pyrimidin-2(1H)-one (150 mg, 0.3 mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (60 mg, 0.4 mmol), [1,1'-bis(diphenyl) Phosphine)ferrocene]dichloropalladium dichloromethane complex (24mg, 0.03mmol) and potassium acetate (120mg, 1.2mmol) were suspended in dioxane/water (7.5mL/0.75mL) mixed solvent, Nitrogen was replaced three times, and the mixture was heated and stirred at 90 °C for 2 h. After the reaction solution was cooled to room temperature, half-saturated sodium bicarbonate solution (20 mL) was added, followed by extraction with ethyl acetate (20 mL) three times. The ethyl acetate layers were combined, dried and concentrated, and the residue was purified by silica gel column (dichloromethane/methanol=100/1 to 60/1) to obtain the target product (90 mg, yield: 52%).
LC-MS:m/z 582(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.97-8.94(m,1H),8.27(d,J=8.0Hz,1H),7.90-7.84(m,2H),7.79-7.74(m,1H),7.46-7.42(m,1H),7.29-7.23(m,1H),6.71-6.57(m,3H),6.44-6.38(m,1H),5.82(d,J=11.2Hz,1H),5.12-4.32(m,3H),4.07-3.63(m,3H),3.24-3.01(m,4H),1.50(s,3H).
LC-MS: m/z 582 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 8.97-8.94(m, 1H), 8.27(d, J=8.0Hz, 1H), 7.90-7.84(m, 2H), 7.79-7.74(m, 1H), 7.46-7.42(m, 1H), 7.29-7.23(m, 1H), 6.71-6.57(m, 3H), 6.44-6.38(m, 1H), 5.82(d, J=11.2Hz, 1H), 5.12- 4.32(m,3H),4.07-3.63(m,3H),3.24-3.01(m,4H),1.50(s,3H).
按照实施例51的方法以不同的起始原料合成了以下化合物:The following compounds were synthesized according to the method of Example 51 with different starting materials:
实施例52 4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-7-(2-氟-6-羟基苯基)-1-(2-(异丙磺酰基)苯基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 52 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2- (Isopropylsulfonyl)phenyl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 610(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.91-8.86(m,1H),8.22-8.19(m,1H),7.88-7.82(m,2H),7.75-7.72(m,1H),7.45-7.42(m,1H),7.28-7.23(m,1H),6.71-6.63(m,3H),6.44-6.39(m,1H),5.83-5.80(m,1H),5.04-4.79(m,3H),4.56-3.90(m,4H),3.71-3.48(m,1H),1.50(s,3H),1.33-1.30(m,3H),1.18-1.16(m,3H).
LC-MS: m/z 610 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.91-8.86 (m, 1H), 8.22-8.19 (m, 1H), 7.88-7.82 (m, 2H), 7.75-7.72 (m, 1H), 7.45-7.42 (m,1H),7.28-7.23(m,1H),6.71-6.63(m,3H),6.44-6.39(m,1H),5.83-5.80(m,1H),5.04-4.79(m,3H) ,4.56-3.90(m,4H),3.71-3.48(m,1H),1.50(s,3H),1.33-1.30(m,3H),1.18-1.16(m,3H).
实施例53 4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-7-(2-氟-6-羟基苯基)-1-(2-甲基-6-(甲磺酰基)苯基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 53 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2- Methyl-6-(methylsulfonyl)phenyl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 596(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.12-8.11(m,1H),7.89-7.87(m,1H),7.75-7.63(m,2H),7.26(m,1H),6.69-6.64(m 3H),6.44-6.40(m,1H),5.84-5.81(m,1H),5.00-4.40(m,3H),4.07-3.65(m,3H),3.25-3.16(m,4H),2.20-2.18(m,3H),1.58-1.50(m,3H).
LC-MS: m/z 596 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 8.12-8.11 (m, 1H), 7.89-7.87 (m, 1H), 7.75-7.63 (m, 2H), 7.26 (m, 1H), 6.69-6.64 (m 3H), 6.44-6.40(m, 1H), 5.84-5.81(m, 1H), 5.00-4.40(m, 3H), 4.07-3.65(m, 3H), 3.25-3.16(m, 4H), 2.20- 2.18(m,3H),1.58-1.50(m,3H).
实施例53-1 通过手性分离得到两个异构体实施例53A和实施例53B:Example 53-1 Two isomers Example 53A and Example 53B were obtained by chiral separation:
实施例53A:LC-MS:m/z 596(M+H)
+。
Example 53A: LC-MS: m/z 596 (M+H) + .
实施例53B:LC-MS:m/z 596(M+H)
+。
Example 53B: LC-MS: m/z 596 (M+H) + .
实施例54 4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-7-(2-氟-6-羟基苯基)-1-(2-(甲磺酰基)吡啶-3-基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 54 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2- (Methylsulfonyl)pyridin-3-yl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 583(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.80(dd,J=4.8,1.2Hz,1H),8.37-8.25(m,1H),8.05(dd,J=8.0,1.2Hz,1H),7.90-7.87(m,1H),7.26(dd,J=14.6,7.6Hz,1H),6.92(m,1H),6.82-6.65(m,2H),6.23-6.18(m,1H),5.76(dd,J=6.4,2.4Hz,1H),4.98-4.82(m,1H),4.44-4.00(m,3H),3.81-3.62(m,2H),3.24-3.00(m,4H),1.34-1.29(m,3H).
LC-MS: m/z 583 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.80 (dd, J=4.8, 1.2 Hz, 1H), 8.37-8.25 (m, 1H), 8.05 (dd, J=8.0, 1.2 Hz, 1H), 7.90- 7.87(m, 1H), 7.26(dd, J=14.6, 7.6Hz, 1H), 6.92(m, 1H), 6.82-6.65(m, 2H), 6.23-6.18(m, 1H), 5.76(dd, J=6.4, 2.4Hz, 1H), 4.98-4.82(m, 1H), 4.44-4.00(m, 3H), 3.81-3.62(m, 2H), 3.24-3.00(m, 4H), 1.34-1.29( m,3H).
实施例55 4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-7-(2-氟-6-羟基苯基)-1-(4-(甲磺酰基)吡啶-3-基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 55 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4- (Methylsulfonyl)pyridin-3-yl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 583(M+H)
+。
1H NMR(400MHz,CDCl
3)δ9.06(d,J=4.2Hz),8.75-8.74(m,1H),8.59-8.57(m,1H),8.10(d,J=4.2Hz),7.87(d,J=11.2Hz,1H),7.30-7.25(m,1H),6.72-6.57(m,3H),6.64-6.58(m,1H),5.84-5.82(m,1H),5.29-4.28(m,3H),4.10-3.61(m,3H),3.22-2.92(m,4H0,1.59-1.48(m,3H).
LC-MS: m/z 583 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 9.06 (d, J=4.2 Hz), 8.75-8.74 (m, 1H), 8.59-8.57 (m, 1H), 8.10 (d, J=4.2 Hz), 7.87 (d, J=11.2Hz, 1H), 7.30-7.25(m, 1H), 6.72-6.57(m, 3H), 6.64-6.58(m, 1H), 5.84-5.82(m, 1H), 5.29-4.28 (m,3H),4.10-3.61(m,3H),3.22-2.92(m,4H0,1.59-1.48(m,3H).
实施例56 2-(1-丙烯酰-4-(6-氟-7-(2-氟-6-羟基苯基)-1-(2-(甲磺酰基)苯基)-2-氧-1,2-二氢吡啶[2,3-d]嘧啶-4-基)哌嗪-2-基)乙腈Example 56 2-(1-Acryloyl-4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-(methylsulfonyl)phenyl)-2-oxo- 1,2-Dihydropyridine[2,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
LC-MS:m/z 607(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.29-8.24(m,1H),7.96-7.76(m,3H),7.47-7.43(m,1H),7.29(m,1H),6.70-6.56(m,3H),6.45-6.41(m,1H),5.00(brs,1H),4.56-3.70(m,6H),3.16(m,3H),3.16-3.10(m,1H),2.98-2.79(m,1H).
LC-MS: m/z 607 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 8.29-8.24 (m, 1H), 7.96-7.76 (m, 3H), 7.47-7.43 (m, 1H), 7.29 (m, 1H), 6.70-6.56 (m) ,3H),6.45-6.41(m,1H),5.00(brs,1H),4.56-3.70(m,6H),3.16(m,3H),3.16-3.10(m,1H),2.98-2.79(m , 1H).
实施例57 2-(1-丙烯酰-4-(6-氟-7-(2-氟-6-羟基苯基)-1-(2-甲基-6-(甲磺酰基)苯基)-2-氧-1,2-二氢吡啶[2,3-d]嘧啶-4-基)哌嗪-2-基)乙腈Example 57 2-(1-Acryloyl-4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-methyl-6-(methylsulfonyl)phenyl) -2-Oxo-1,2-dihydropyridine[2,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
LC-MS:m/z 621(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.12-7.97(m,2H),7.76-7.72(m,1H),7.67-7.64(m,1H),7.29(m,1H),6.69-6.46(m,3H),6.42-6.41(m,1H),5.88-5.86(m,1H),5.00(brs,1H),4.54-3.77(m,6H),3.12(m,4H),2.81-2.77(m,1H),2.20-2.17(m,3H).
LC-MS: m/z 621 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 8.12-7.97(m, 2H), 7.76-7.72(m, 1H), 7.67-7.64(m, 1H), 7.29(m, 1H), 6.69-6.46(m ,3H),6.42-6.41(m,1H),5.88-5.86(m,1H),5.00(brs,1H),4.54-3.77(m,6H),3.12(m,4H),2.81-2.77(m ,1H),2.20-2.17(m,3H).
实施例58 2-(1-丙烯酰-4-(6-氟-7-(2-氟-6-羟基苯基)-1-(2-(甲磺酰基)吡啶-3-基)-2-氧-1,2-二氢吡啶[2,3-d]嘧啶-4-基)哌嗪-2-基)乙腈Example 58 2-(1-Acryloyl-4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-(methylsulfonyl)pyridin-3-yl)-2 -Oxy-1,2-dihydropyridine[2,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
LC-MS:m/z 608(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.82-8.81(m,1H),7.99-7.76(m,3H),7.30(m,1H),6.70-6.56(m,3H),6.44-6.40(m,1H),5.87-5.84(m,1H),5.01(brs,1H),4.61-3.60(m,6H),3.29(m,3H),2.96-2.76(m,2H).
LC-MS: m/z 608 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 8.82-8.81 (m, 1H), 7.99-7.76 (m, 3H), 7.30 (m, 1H), 6.70-6.56 (m, 3H), 6.44-6.40 (m ,1H),5.87-5.84(m,1H),5.01(brs,1H),4.61-3.60(m,6H),3.29(m,3H),2.96-2.76(m,2H).
实施例59 4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-7-(2-氯-6-氟苯基)-6-氟-1-(2-甲基-6-(甲砜基)苯基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 59 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-7-(2-chloro-6-fluorophenyl)-6-fluoro-1-(2- Methyl-6-(methylsulfonyl)phenyl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 614(M+H)
+。
1H NMR(400MHz,CDCl
3)δ7.95(d,J=3.6Hz,1H),7.82(t,J=8.4Hz,1H),7.60(d,J=3.2Hz,1H),7.50(t,J=8.4Hz,1H),7.34-7.29(m,1H),7.20(d,J=8Hz,1H),7.02(m,1H),6.60(m,1H),6.39(dd,J=1.6Hz,17.2Hz,1H),5.80(dd,J=1.2Hz,10.4Hz,1H),5.20-4.20(m,3H),4.10-3.55(m,3H),3.40-3.05(m,4H),2.17-2.15(m,3H),1,.51(m,3H).
LC-MS: m/z 614 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.95 (d, J=3.6 Hz, 1H), 7.82 (t, J=8.4 Hz, 1H), 7.60 (d, J=3.2 Hz, 1H), 7.50 (t ,J=8.4Hz,1H),7.34-7.29(m,1H),7.20(d,J=8Hz,1H),7.02(m,1H),6.60(m,1H),6.39(dd,J=1.6 Hz, 17.2Hz, 1H), 5.80(dd, J=1.2Hz, 10.4Hz, 1H), 5.20-4.20(m, 3H), 4.10-3.55(m, 3H), 3.40-3.05(m, 4H), 2.17-2.15(m,3H),1,.51(m,3H).
实施例60 2-(4-丙烯酰-1-(6-氟-7-(2-氟-6-羟基苯基)-1-(2-(甲砜基)苯基)-2-氧-1,2-二氢吡啶[2,3-d]嘧啶-4-基)哌嗪-2-基)乙腈Example 60 2-(4-Acryloyl-1-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-(methylsulfonyl)phenyl)-2-oxo- 1,2-Dihydropyridine[2,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
LC-MS:m/z 607(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.87-8.77(m,1H),8.22-8.19(m,1H),7.86-7.80(m,3H),7.69(m,1H),7.37-7.36(m,1H),7.25(m,1H),6.66-6.53(m,3H),6.39(d,J=17.2Hz,1H),5.81(d,J=10Hz,1H),5.30-5.20(m,1H),4.80-3.95(m,3H),3.90-3.30(m,3H),3.09-2.88(m,5H).
LC-MS: m/z 607 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 8.87-8.77(m,1H), 8.22-8.19(m,1H), 7.86-7.80(m,3H), 7.69(m,1H), 7.37-7.36(m) ,1H),7.25(m,1H),6.66-6.53(m,3H),6.39(d,J=17.2Hz,1H),5.81(d,J=10Hz,1H),5.30-5.20(m,1H) ),4.80-3.95(m,3H),3.90-3.30(m,3H),3.09-2.88(m,5H).
实施例61 2-(4-丙烯酰-1-(6-氟-7-(2-氟-6-羟基苯基)-1-(2-(甲砜基)苯基)-2-氧-1,2-二 氢吡啶[2,3-d]嘧啶-4-基)哌嗪-2-基)乙酰胺Example 61 2-(4-Acryloyl-1-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-(methylsulfonyl)phenyl)-2-oxo- 1,2-Dihydropyridine[2,3-d]pyrimidin-4-yl)piperazin-2-yl)acetamide
LC-MS:m/z 625(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.20-7.75(m,2H),7.60-7.40(m,2H),7.11-7.01(m,2H),6.84-7.53(m,5H),6.36-6.29(m,1H),5.79(m,1H),5.44-5.23(m,1H),5.50-3.98(m,4H),3.81-3.070(m,6H),2.85-2.63(m,2H).
LC-MS: m/z 625 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 8.20-7.75 (m, 2H), 7.60-7.40 (m, 2H), 7.11-7.01 (m, 2H), 6.84-7.53 (m, 5H), 6.36-6.29 (m,1H),5.79(m,1H),5.44-5.23(m,1H),5.50-3.98(m,4H),3.81-3.070(m,6H),2.85-2.63(m,2H).
实施例62 2-(4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-1-(2-异丙基-6-(甲砜基)苯基)-2-氧-1,2-二氢吡啶[2,3-d]嘧啶-7-基)-3-氟苯基环丙酸酯Example 62 2-(4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-1-(2-isopropyl-6-(methylsulfonyl) Phenyl)-2-oxo-1,2-dihydropyridine[2,3-d]pyrimidin-7-yl)-3-fluorophenylcyclopropionate
LC-MS:m/z 692(M+H)
+。
LC-MS: m/z 692 (M+H) + .
实施例62-1 通过手性分离得到两个异构体实施例62A和实施例62B:Example 62-1 Two isomers Example 62A and Example 62B were obtained by chiral separation:
实施例62A:LC-MS:m/z 692(M+H)
+。
Example 62A: LC-MS: m/z 692 (M+H) + .
实施例62B:LC-MS:m/z 692(M+H)
+。
Example 62B: LC-MS: m/z 692 (M+H) + .
实施例63 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-1-(2-环丁基-6-(甲基磺酰基)苯基)-6-氟-7-(2-氟-6-羟基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮的制备Example 63 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-1-(2-cyclobutyl-6-(methylsulfonyl)benzene yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
第1步.2-溴-6-(甲基磺酰基)苯胺的制备Step 1. Preparation of 2-bromo-6-(methylsulfonyl)aniline
将1-溴-3-(甲基磺酰基)-2-硝基苯(44g,158mmol),铁粉(44g,788mmol),氯化铵(83g,1.6mol)悬浮于乙醇/水(600mL/120mL)混合溶剂中,于75度加热搅拌2小时。反应液冷却至室温后,抽滤除去固体,滤液加入500毫升水,并以500毫升乙酸乙酯萃取2次。合并乙酸乙酯层,500毫升盐水洗涤,干燥,浓缩,残留物以硅胶柱分离(石油醚:乙酸乙酯=10:1到2:1)得目标产物(30g,收率:77%)。1-Bromo-3-(methylsulfonyl)-2-nitrobenzene (44g, 158mmol), iron powder (44g, 788mmol), ammonium chloride (83g, 1.6mol) were suspended in ethanol/water (600mL/ 120 mL) mixed solvent, heated and stirred at 75 degrees for 2 hours. After the reaction solution was cooled to room temperature, the solid was removed by suction filtration, 500 ml of water was added to the filtrate, and the mixture was extracted twice with 500 ml of ethyl acetate. The ethyl acetate layers were combined, washed with 500 ml of brine, dried, concentrated, and the residue was separated by silica gel column (petroleum ether:ethyl acetate=10:1 to 2:1) to obtain the target product (30 g, yield: 77%).
第2步.2-环丁基-6-(甲基磺酰基)苯胺的制备Step 2. Preparation of 2-Cyclobutyl-6-(methylsulfonyl)aniline
将锌粉(52g,800mmol,Acros)悬浮于四氢呋喃(100mL)溶剂中,然后加入三甲基氯硅烷(8.7g,80mmol),并于75度加热搅拌半小时。然后加入溴环丁烷(54g,400mmol),反应液冷却至室温,加入2-溴-6-(甲基磺酰基)苯胺(10g,40mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(3.3g,4mmol),并于75度加热搅拌三小时。反应液用1M磷酸30毫升淬灭,乙酸乙酯萃取2次。合并乙酸乙酯层,干燥,浓缩,残留物以硅胶柱分离(石油醚:乙酸乙酯=10:1到2:1)得目标产物(8.1g,收率:90%)。Zinc powder (52 g, 800 mmol, Acros) was suspended in tetrahydrofuran (100 mL) solvent, then trimethylsilyl chloride (8.7 g, 80 mmol) was added, and the mixture was heated and stirred at 75 degrees for half an hour. Then bromocyclobutane (54g, 400mmol) was added, the reaction solution was cooled to room temperature, 2-bromo-6-(methylsulfonyl)aniline (10g, 40mmol) and [1,1'-bis(diphenylphosphine) were added ) ferrocene] palladium dichloride dichloromethane complex (3.3 g, 4 mmol), and heated and stirred at 75 degrees for three hours. The reaction solution was quenched with 30 mL of 1M phosphoric acid, and extracted twice with ethyl acetate. The ethyl acetate layers were combined, dried, concentrated, and the residue was separated on a silica gel column (petroleum ether:ethyl acetate=10:1 to 2:1) to obtain the target product (8.1 g, yield: 90%).
LC-MS:m/z 226(M+H)
+。
LC-MS: m/z 226 (M+H) + .
第3步.2,6-二氯-N-(((2-环丁基-6-(甲基磺酰基)苯基)氨基甲酰基)-5-氟烟酰胺的制备Step 3. Preparation of 2,6-dichloro-N-(((2-cyclobutyl-6-(methylsulfonyl)phenyl)carbamoyl)-5-fluoronicotinamide
将2,6-二氯-5-氟烟酰胺(7.7g,37mmol)溶于100毫升无水四氢呋喃中,向此溶液中缓慢滴加草酰氯(47g,370mmol)。滴加完毕后,将此混合物于75度回流搅拌2小时,然后减压浓缩至干。残留物以100毫升无水四氢呋喃稀释,冷却至零度。将2-环丁基-6-(甲基磺酰基)苯胺(8.8g,39mmol)溶于50毫升无水四氢呋喃中,然后滴加进上述溶液中。反应液在零度下搅拌2小时,饱和氯化铵/饱和食盐水(1:1,100mL)淬灭,然后用乙酸乙酯(50mL)萃取2次。合并有机相干燥,浓缩,残留固体 以石油醚/乙酸乙酯(5:1,200mL)打浆,抽滤,干燥,得目标产物(12.7g,收率:75%)。2,6-Dichloro-5-fluoronicotinamide (7.7 g, 37 mmol) was dissolved in 100 mL of dry tetrahydrofuran, and oxalyl chloride (47 g, 370 mmol) was slowly added dropwise to this solution. After the dropwise addition, the mixture was stirred at 75°C under reflux for 2 hours, and then concentrated to dryness under reduced pressure. The residue was diluted with 100 mL of anhydrous tetrahydrofuran and cooled to zero. 2-Cyclobutyl-6-(methylsulfonyl)aniline (8.8 g, 39 mmol) was dissolved in 50 mL of dry tetrahydrofuran and added dropwise to the above solution. The reaction solution was stirred at zero degrees for 2 hours, quenched with saturated ammonium chloride/saturated brine (1:1, 100 mL), and then extracted twice with ethyl acetate (50 mL). The combined organic phases were dried, concentrated, and the residual solid was slurried with petroleum ether/ethyl acetate (5:1, 200 mL), suction filtered, and dried to obtain the target product (12.7 g, yield: 75%).
LC-MS:m/z 460(M+H)
+。
LC-MS: m/z 460 (M+H) + .
第4步.7-氯-1-(2-环丁基-6-(甲基磺酰基)苯基)-6-氟吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮的制备Step 4. 7-Chloro-1-(2-cyclobutyl-6-(methylsulfonyl)phenyl)-6-fluoropyrido[2,3-d]pyrimidine-2,4(1H,3H )-dione preparation
将2,6-二氯-N-(((2-环丁基-6-(甲基磺酰基)苯基)氨基甲酰基)-5-氟烟酰胺5(37.3g,81.1mmol)溶于550毫升四氢呋喃中,冰浴下滴加双(三甲基硅烷基)氨基钾(1mol/L,186.5mL,186.5mmol)。滴加完毕后反应液25度搅拌16小时,200毫升饱和氯化铵淬灭,然后以1000毫升乙酸乙酯萃取2次。合并乙酸乙酯层干燥,浓缩。残留固体以石油醚/乙酸乙酯(1:1,300mL)打浆,抽滤,干燥得目标产物(23.2g,收率:68%)。2,6-Dichloro-N-(((2-cyclobutyl-6-(methylsulfonyl)phenyl)carbamoyl)-5-fluoronicotinamide 5 (37.3 g, 81.1 mmol) was dissolved in In 550 ml of tetrahydrofuran, bis(trimethylsilyl) potassium amide (1 mol/L, 186.5 mL, 186.5 mmol) was added dropwise under an ice bath. After the dropwise addition, the reaction solution was stirred at 25 degrees for 16 hours, and 200 ml of saturated ammonium chloride were added dropwise. Quenched, then extracted twice with 1000 mL of ethyl acetate. The ethyl acetate layers were combined, dried, and concentrated. The residual solid was slurried with petroleum ether/ethyl acetate (1:1, 300 mL), filtered with suction, and dried to obtain the target product (23.2 g, yield: 68%).
LC-MS:m/z 424(M+H)
+。
LC-MS: m/z 424 (M+H) + .
第5步.(2R,5S)-叔丁基4-(7-氯-1-(2-环丁基-6-(甲基磺酰基)苯基)-6-氟-2-氧代-1,2-二氢吡啶基[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-甲酸酯的制备Step 5. (2R,5S)-tert-Butyl 4-(7-chloro-1-(2-cyclobutyl-6-(methylsulfonyl)phenyl)-6-fluoro-2-oxo- Preparation of 1,2-dihydropyridyl[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate
将7-氯-1-(2-环丁基-6-(甲基磺酰基)苯基)-6-氟吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(23.2g,54.7mmol)悬浮于350毫升乙腈中,滴加N,N-二异丙基乙胺(42.3g,328mmol)和三氯氧磷(33.5g,219mmol),反应液变澄清。将反应液于80度搅拌1小时,减压浓缩至干。残留物溶解在350毫升乙腈中,冷却至零度,加入N,N-二异丙基乙胺(42.3g,328mmol)和2,5-二甲基哌嗪-1-甲酸(2R,5S)-叔丁基酯(14g,65.6mmol)。反应液在室温下搅拌1小时,用半饱和的碳酸氢钠溶液(400mL)淬灭,再以1000毫升乙酸乙酯萃取2次。合并乙酸乙酯层干燥,浓缩,硅胶柱分离(石油醚:乙酸乙酯=5:1到1:1)得目标产物(21.2g,收率:63%)。7-Chloro-1-(2-cyclobutyl-6-(methylsulfonyl)phenyl)-6-fluoropyrido[2,3-d]pyrimidine-2,4(1H,3H)-di The ketone (23.2 g, 54.7 mmol) was suspended in 350 mL of acetonitrile, N,N-diisopropylethylamine (42.3 g, 328 mmol) and phosphorus oxychloride (33.5 g, 219 mmol) were added dropwise, and the reaction solution became clear. The reaction solution was stirred at 80 degrees for 1 hour, and concentrated to dryness under reduced pressure. The residue was dissolved in 350 mL of acetonitrile, cooled to zero, and N,N-diisopropylethylamine (42.3 g, 328 mmol) and 2,5-dimethylpiperazine-1-carboxylic acid (2R,5S)- tert-Butyl ester (14 g, 65.6 mmol). The reaction solution was stirred at room temperature for 1 hour, quenched with half-saturated sodium bicarbonate solution (400 mL), and extracted twice with 1000 mL of ethyl acetate. The ethyl acetate layers were combined, dried, concentrated, and separated on a silica gel column (petroleum ether:ethyl acetate=5:1 to 1:1) to obtain the target product (21.2 g, yield: 63%).
LC-MS:m/z 620(M+H)
+。
LC-MS: m/z 620 (M+H) + .
第6步.4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-7-氯-1-(2-环丁基-6-(甲基磺酰基)苯基)-6-氟吡啶[2,3-d]嘧啶-2(1H)-酮的制备Step 6. 4-((2S,5R)-4-Acryloyl-2,5-dimethylpiperazin-1-yl)-7-chloro-1-(2-cyclobutyl-6-(methyl) Preparation of sulfonyl)phenyl)-6-fluoropyridin[2,3-d]pyrimidin-2(1H)-one
将(2R,5S)-叔丁基4-(7-氯-1-(2-环丁基-6-(甲基磺酰基)苯基)-6-氟-2-氧代-1,2-二氢吡啶基[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-甲酸酯(21.2g,34.2mmol)溶于200毫升二氯甲烷中,加入65毫升三氟乙酸,反应液室温搅拌2小时,浓缩干,残留物与100毫升二氯甲烷共蒸2次得粗品。将该粗品溶解在200毫升二氯甲烷中,冷却至零度,滴加三乙胺(17.3g,171mmol)和丙烯酰氯(4g,44.5mmol)的二氯甲烷(20mL)溶液。反应液在零度下搅拌30分钟,室温下搅拌30分钟。200毫升饱和碳酸氢钠淬灭,并以800毫升二氯甲烷萃取2次。有机相干燥,浓缩,残留物以硅胶柱分离(二氯甲烷:甲醇=60:1)得目标产物(13.6g,收率:69%)。(2R,5S)-tert-butyl 4-(7-chloro-1-(2-cyclobutyl-6-(methylsulfonyl)phenyl)-6-fluoro-2-oxo-1,2 - Dihydropyridyl[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (21.2 g, 34.2 mmol) was dissolved in 200 mL of dichloromethane, 65 ml of trifluoroacetic acid was added, the reaction solution was stirred at room temperature for 2 hours, concentrated to dryness, and the residue was co-evaporated with 100 ml of dichloromethane twice to obtain a crude product. The crude product was dissolved in 200 mL of dichloromethane, cooled to zero, and a solution of triethylamine (17.3 g, 171 mmol) and acryloyl chloride (4 g, 44.5 mmol) in dichloromethane (20 mL) was added dropwise. The reaction solution was stirred at zero for 30 minutes and at room temperature for 30 minutes. Quenched with 200 mL of saturated sodium bicarbonate and extracted twice with 800 mL of dichloromethane. The organic phase was dried, concentrated, and the residue was separated by silica gel column (dichloromethane:methanol=60:1) to obtain the target product (13.6 g, yield: 69%).
LC-MS:m/z 574(M+H)
+。
LC-MS: m/z 574 (M+H) + .
第7步.4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-1-(2-环丁基-6-(甲 基磺酰基)苯基)-6-氟-7-(2-氟-6-羟基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮的制备Step 7. 4-((2S,5R)-4-Acryloyl-2,5-dimethylpiperazin-1-yl)-1-(2-cyclobutyl-6-(methylsulfonyl) Preparation of phenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
将4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-7-氯-1-(2-环丁基-6-(甲基磺酰基)苯基)-6-氟吡啶[2,3-d]嘧啶-2(1H)-酮(13.6g,23.7mmol),(2-氟-6-羟基苯基)硼酸(5.2g,33.1mmol),[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(1.94g,2.4mmol)和乙酸钾(9.3g,95mmol)悬浮于二氧六环/水(200mL/20mL)混合溶剂中,氮气置换3次,并于90度加热搅拌4小时。反应液冷却至室温后,加入200毫升半饱和碳酸氢钠溶液,并以500毫升乙酸乙酯萃取2次。合并乙酸乙酯层,干燥,浓缩,残留物用硅胶柱分离(二氯甲烷:甲醇=100:1到50:1)得到目标产物(8.6g,收率:56%)。4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-chloro-1-(2-cyclobutyl-6-(methylsulfonyl) )phenyl)-6-fluoropyridin[2,3-d]pyrimidin-2(1H)-one (13.6 g, 23.7 mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (5.2 g, 33.1 mmol) ), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (1.94 g, 2.4 mmol) and potassium acetate (9.3 g, 95 mmol) were suspended in dioxane In a mixed solvent of ring/water (200 mL/20 mL), nitrogen was replaced three times, and the mixture was heated and stirred at 90 degrees for 4 hours. After the reaction solution was cooled to room temperature, 200 mL of half-saturated sodium bicarbonate solution was added, and the mixture was extracted twice with 500 mL of ethyl acetate. The ethyl acetate layers were combined, dried, concentrated, and the residue was separated with a silica gel column (dichloromethane:methanol=100:1 to 50:1) to obtain the target product (8.6 g, yield: 56%).
LC-MS:m/z 650(M+H)
+。
1H NMR(400MHz,CDCl
3)δ9.07-8.93(m,1H),8.14-8.09(m,1H),7.90-7.67(m,3H),7.29-7.23(m,1H),6.71-6.52(m,3H),6.40(m,1H),5.80(m,1H),5.23-3.30(m,6H),3.15-3.08(m,3H),2.33-2.20(m,1H),2.17-2.05(m,1H),1.96-1.65(m,3H),1.60-1.32(m,8H).
LC-MS: m/z 650 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 9.07-8.93 (m, 1H), 8.14-8.09 (m, 1H), 7.90-7.67 (m, 3H), 7.29-7.23 (m, 1H), 6.71-6.52 (m,3H),6.40(m,1H),5.80(m,1H),5.23-3.30(m,6H),3.15-3.08(m,3H),2.33-2.20(m,1H),2.17-2.05 (m,1H),1.96-1.65(m,3H),1.60-1.32(m,8H).
实施例63-1通过手性分离得到两个异构体实施例63A和63B:Example 63-1 obtained two isomers Examples 63A and 63B by chiral separation:
化合物63ACompound 63A
LC-MS:m/z 650(M+H)
+。
1H NMR(400MHz,DMSO)δ10.21(s,1H),8.32(d,J=9.1Hz,1H),7.88(d,J=7.7Hz,1H),7.75–7.59(m,2H),7.27(m,1H),6.93–6.60(m,3H),6.19(m,1H),5.74(m,1H),4.93–4.38(m,2H),4.23–3.40(m,3H),3.30–3.23(m,1H),2.99(s,3H),2.18–1.87(m,3H),1.85–1.52(m,3H),1.38–1.10(m,7H).
LC-MS: m/z 650 (M+H) + . 1 H NMR (400MHz, DMSO) δ10.21(s, 1H), 8.32(d, J=9.1Hz, 1H), 7.88(d, J=7.7Hz, 1H), 7.75-7.59(m, 2H), 7.27 (m, 1H), 6.93–6.60 (m, 3H), 6.19 (m, 1H), 5.74 (m, 1H), 4.93–4.38 (m, 2H), 4.23–3.40 (m, 3H), 3.30– 3.23 (m, 1H), 2.99 (s, 3H), 2.18–1.87 (m, 3H), 1.85–1.52 (m, 3H), 1.38–1.10 (m, 7H).
化合物63BCompound 63B
LC-MS:m/z 650(M+H)
+。
1H NMR(400MHz,DMSO)δ10.23(s,1H),8.34(m,1H),7.89(d,J=7.7Hz,1H),7.77(m,1H),7.66(t,J=7.8Hz,1H),7.27(m,1H),6.95–6.60(m,3H),6.19(m,1H),5.75(m,1H),4.93–4.38(m,2H),4.18–3.45(m,3H),3.28(m,1H),2.96(s,3H),2.15–1.86(m,3H),1.86–1.56(m,3H),1.35–0.98(m,7H).
LC-MS: m/z 650 (M+H) + . 1 H NMR (400MHz, DMSO) δ 10.23 (s, 1H), 8.34 (m, 1H), 7.89 (d, J=7.7Hz, 1H), 7.77 (m, 1H), 7.66 (t, J=7.8 Hz, 1H), 7.27 (m, 1H), 6.95–6.60 (m, 3H), 6.19 (m, 1H), 5.75 (m, 1H), 4.93–4.38 (m, 2H), 4.18–3.45 (m, 3H), 3.28 (m, 1H), 2.96 (s, 3H), 2.15–1.86 (m, 3H), 1.86–1.56 (m, 3H), 1.35–0.98 (m, 7H).
按照实施例63的方法以不同的起始原料合成了以下化合物:The following compounds were synthesized according to the method of Example 63 with different starting materials:
实施例64(S)-3-(4-(4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-1-(2-异丙基-6-(甲基磺酰基)苯基)-2-氧代-1,2-二氢吡啶[2,3-d]嘧啶-7-基)-4-氯苯甲腈Example 64 (S)-3-(4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-1-(2-isopropyl-6-(methylsulfonyl) )phenyl)-2-oxo-1,2-dihydropyridine[2,3-d]pyrimidin-7-yl)-4-chlorobenzonitrile
LC-MS:m/z 649(M+H)
+。
1H NMR(400MHz,CDCl
3)δ7.99(d,J=7.6Hz,1H),7.84(dd,J=8.8Hz,6.4Hz,1H),7.72(d,J=7.6Hz,1H),7.64-7.60(m,2H),7.53-7.48(m,2H),6.61(s,1H),6.40(d,J=16.8Hz,1H),5.80(d,J=12.0Hz,1H),5.06-3.62(m,6H),3.33-3.01(m,4H),2.80(s,1H),1.51(s,3H),1.24(d,J=6.8Hz,3H),1.03(d,J=6.8Hz,1H).
LC-MS: m/z 649 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 7.99 (d, J=7.6Hz, 1H), 7.84 (dd, J=8.8Hz, 6.4Hz, 1H), 7.72 (d, J=7.6Hz, 1H), 7.64-7.60(m, 2H), 7.53-7.48(m, 2H), 6.61(s, 1H), 6.40(d, J=16.8Hz, 1H), 5.80(d, J=12.0Hz, 1H), 5.06 -3.62(m, 6H), 3.33-3.01(m, 4H), 2.80(s, 1H), 1.51(s, 3H), 1.24(d, J=6.8Hz, 3H), 1.03(d, J=6.8 Hz, 1H).
实施例65 (S)-3-(4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-氟-1-(2-异丙基-6-(甲基磺酰基)苯基)-2-氧-1,2-二氢吡啶并[2,3-d]嘧啶-7-基)-2-氯苄腈Example 65 (S)-3-(4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-1-(2-isopropyl-6-(methylsulfonyl) )phenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-7-yl)-2-chlorobenzonitrile
LC-MS:m/z 649(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.34(d,J=2.4Hz,1H),8.07-7.98(m,2H),7.91-7.63(m,5H),7.43(t,J=7.6Hz,1H),7.03-6.81(m,1H),5.10-3.51(m,6H),3.44-3.14(m,1H),3.06(s,3H),2.78-2.58(m,1H),1.56-1.45(m,3H),1.26-1.18(m,3H),1.13-1.05(m,3H).
LC-MS: m/z 649 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 8.34 (d, J=2.4Hz, 1H), 8.07-7.98 (m, 2H), 7.91-7.63 (m, 5H), 7.43 (t, J=7.6Hz, 1H), 7.03-6.81(m, 1H), 5.10-3.51(m, 6H), 3.44-3.14(m, 1H), 3.06(s, 3H), 2.78-2.58(m, 1H), 1.56-1.45( m,3H),1.26-1.18(m,3H),1.13-1.05(m,3H).
实施例66 (S)-4-(4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-氟-1-(2-异丙基-6-(甲基磺酰基)苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-7-基)-3-氯苄腈Example 66 (S)-4-(4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-1-(2-isopropyl-6-(methylsulfonyl) )phenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-7-yl)-3-chlorobenzonitrile
LC-MS:m/z 649(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.34(d,J=2.0Hz,1H),8.07-7.99(m,2H),7.82-7.77(m,1H),7.76-7.64(m,4H),7.59(d,J=8.4Hz,1H),7.05-6.84(m,1H),5.10-3.12(m,7H),3.06(s,3H),2.79-2.58(m,1H),1.56-1.41(m,3H),1.26-1.18(m,3H),1.13-1.05(m,3H).
LC-MS: m/z 649 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.34 (d, J=2.0 Hz, 1H), 8.07-7.99 (m, 2H), 7.82-7.77 (m, 1H), 7.76-7.64 (m, 4H), 7.59(d, J=8.4Hz, 1H), 7.05-6.84(m, 1H), 5.10-3.12(m, 7H), 3.06(s, 3H), 2.79-2.58(m, 1H), 1.56-1.41( m,3H),1.26-1.18(m,3H),1.13-1.05(m,3H).
实施例67 2-(4-((S)-4-丙烯酰基-2-甲基哌嗪-1-基)-6-氟-1-(2-异丙基-6-(甲基磺酰基)苯基)-2-氧-1,2-二氢吡啶并[2,3-d]嘧啶-7-基)-3-氯苄腈Example 67 2-(4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-1-(2-isopropyl-6-(methylsulfonyl) )phenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-7-yl)-3-chlorobenzonitrile
LC-MS:m/z 649(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.34(d,J=2.4Hz,1H),8.03(d,J=8.0Hz,1H),7.94(d,J=15.6Hz,1H),7.79(d,J=7.2Hz,1H),7.76-7.63(m,4H),7.41(t,J=8.0Hz,1H),7.25-7.16(m,1H),5.01-3.60(m,6H),3.38-3.10(m,1H),3.07(s,3H),2.78-2.62(m,1H),1.56-1.46(m,3H),1.26-1.18(m,3H),1.13-1.05(m,3H).
LC-MS: m/z 649 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.34 (d, J=2.4 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.94 (d, J=15.6 Hz, 1H), 7.79 (d , J=7.2Hz, 1H), 7.76-7.63(m, 4H), 7.41(t, J=8.0Hz, 1H), 7.25-7.16(m, 1H), 5.01-3.60(m, 6H), 3.38- 3.10(m, 1H), 3.07(s, 3H), 2.78-2.62(m, 1H), 1.56-1.46(m, 3H), 1.26-1.18(m, 3H), 1.13-1.05(m, 3H).
实施例68 (S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-1-(2-异丙基-6-(甲基磺酰基)苯基)-7-(1-甲基-1H-吡唑-5-基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 68 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-1-(2-isopropyl-6-(methylsulfonyl)phenyl )-7-(1-methyl-1H-pyrazol-5-yl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 594(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.05(d,J=7.8Hz,1H),7.82-7.78(m,2H),7.73(t,J=7.8Hz,1H),7.47(d,J=1.8Hz,1H),6.94(s,1H),6.59(d,J=17.9Hz,1H),6.42(dd,J=16.7,1.6Hz,1H),5.81(d,J=10.4Hz,1H),5.01-3.67(m,7H),3.61(s,3H),3.19(s,3H),2.75(s,1H),1.52(s,3H),1.28-1.23(m,3H),1.04(d,J=5.8Hz,3H).
LC-MS: m/z 594 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.05 (d, J=7.8 Hz, 1H), 7.82-7.78 (m, 2H), 7.73 (t, J=7.8 Hz, 1H), 7.47 (d, J= 1.8Hz,1H),6.94(s,1H),6.59(d,J=17.9Hz,1H),6.42(dd,J=16.7,1.6Hz,1H),5.81(d,J=10.4Hz,1H) ,5.01-3.67(m,7H),3.61(s,3H),3.19(s,3H),2.75(s,1H),1.52(s,3H),1.28-1.23(m,3H),1.04(d ,J=5.8Hz,3H).
实施例69 (S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-1-(2-异丙基-6-(甲基磺酰基)苯基)-7-(1H-吡唑-5-基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 69 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-1-(2-isopropyl-6-(methylsulfonyl)phenyl )-7-(1H-pyrazol-5-yl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 580(M+H)
+。H NMR(400MHz,CDCl
3)δ8.07(d,J=7.8Hz,1H),7.86-7.77(m,2H),7.73(t,J=7.8Hz,1H),7.61(d,J=1.8Hz,1H),6.83(s,1H),6.58(d,J=17.9Hz,1H),6.40(dd,J=16.7Hz,1.6Hz,1H),5.81(d,J=10.4Hz,1H),5.01-3.67(m,6H),3.09(s,4H),2.75(s,1H),1.52(s,3H),1.28-1.23(m,3H),1.04(d,J=5.8Hz,3H).
LC-MS: m/z 580 (M+H) + . H NMR (400MHz, CDCl 3 ) δ 8.07 (d, J=7.8Hz, 1H), 7.86-7.77 (m, 2H), 7.73 (t, J=7.8Hz, 1H), 7.61 (d, J=1.8 Hz,1H),6.83(s,1H),6.58(d,J=17.9Hz,1H),6.40(dd,J=16.7Hz,1.6Hz,1H),5.81(d,J=10.4Hz,1H) ,5.01-3.67(m,6H),3.09(s,4H),2.75(s,1H),1.52(s,3H),1.28-1.23(m,3H),1.04(d,J=5.8Hz,3H ).
实施例70 (S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-氟-1-(2-异丙基-6-(甲基 磺酰基)苯基)-7-(1-甲基-1H-咪唑-5-基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 70 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-1-(2-isopropyl-6-(methylsulfonyl)phenyl )-7-(1-methyl-1H-imidazol-5-yl)pyrido[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 594(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.34(d,J=2.4Hz,1H),8.03(d,J=8.0Hz,1H),7.79(d,J=7.6Hz,1H),7.76-7.60(m,3H),7.57-7.45(m,2H),6.86-6.63(m,1H),5.06-3.12(m,10H),3.07(s,3H),2.78-2.59(m,1H),1.56-1.41(m,3H),1.26-1.18(m,3H),1.13-1.05(m,3H).
LC-MS: m/z 594 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.34 (d, J=2.4 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.76-7.60 (m,3H),7.57-7.45(m,2H),6.86-6.63(m,1H),5.06-3.12(m,10H),3.07(s,3H),2.78-2.59(m,1H),1.56 -1.41(m,3H),1.26-1.18(m,3H),1.13-1.05(m,3H).
实施例71 (S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-氟-1-(2-异丙基-6-(甲基磺酰基)苯基)-7-(2-氧代-1,2-二氢吡啶-3-基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 71 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-1-(2-isopropyl-6-(methylsulfonyl)phenyl )-7-(2-oxo-1,2-dihydropyridin-3-yl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 607(M+H)
+。
1H NMR(400MHz,CDCl
3)δ11.34(s,1H),8.33(d,J=2.8Hz,1H),8.06-7.88(m,2H),7.79(d,J=7.6Hz,1H),7.76-7.60(m,3H),7.56(d,J=15.2Hz,1H),7.37(d,J=6.0Hz,1H),6.39(t,J=6.4Hz,1H),5.01-3.52(m,7H),3.07(s,3H),2.78-2.62(m,1H),1.56-1.46(m,3H),1.26-1.18(m,3H),1.13-1.05(m,3H).
LC-MS: m/z 607 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 11.34 (s, 1H), 8.33 (d, J=2.8Hz, 1H), 8.06-7.88 (m, 2H), 7.79 (d, J=7.6Hz, 1H) ,7.76-7.60(m,3H),7.56(d,J=15.2Hz,1H),7.37(d,J=6.0Hz,1H),6.39(t,J=6.4Hz,1H),5.01-3.52( m, 7H), 3.07(s, 3H), 2.78-2.62(m, 1H), 1.56-1.46(m, 3H), 1.26-1.18(m, 3H), 1.13-1.05(m, 3H).
实施例72 (S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-1-(2-异丙基-6-(甲基磺酰基)苯基)-7-(6-氧代-1,6-二氢吡啶-2-基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 72 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-1-(2-isopropyl-6-(methylsulfonyl)phenyl )-7-(6-oxo-1,6-dihydropyridin-2-yl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 607(M+H)
+。
1H NMR(400MHz,CDCl
3)δ13.26(brs,1H),8.35(d,J=2.4Hz,1H),8.04(d,J=8.0Hz,1H),7.87-7.66(m,4H),7.56-7.52(m,1H),7.42-7.37(m,1H),6.52(d,J=9.2Hz,1H),6.46(d,J=6.8Hz,1H),5.14-4.24(m,4H),3.80-3.66(m,2H),3.33-3.08(m,4H),2.73-2.68(m,1H),1.56-1.50(m,3H),1.26-1.18(m,3H),1.13-1.05(m,3H).
LC-MS: m/z 607 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 13.26 (brs, 1H), 8.35 (d, J=2.4Hz, 1H), 8.04 (d, J=8.0Hz, 1H), 7.87-7.66 (m, 4H) ,7.56-7.52(m,1H),7.42-7.37(m,1H),6.52(d,J=9.2Hz,1H),6.46(d,J=6.8Hz,1H),5.14-4.24(m,4H ),3.80-3.66(m,2H),3.33-3.08(m,4H),2.73-2.68(m,1H),1.56-1.50(m,3H),1.26-1.18(m,3H),1.13-1.05 (m,3H).
实施例73 (S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-氟-1-(2-异丙基-6-(甲基磺酰基)苯基)-7-(1-甲基-2-氧代-1,2-二氢吡啶-3-基)吡啶[2,3-d]嘧啶-2(1H)- 酮Example 73 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-1-(2-isopropyl-6-(methylsulfonyl)phenyl )-7-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 621(M+H)
+.
1H NMR(400MHz,CDCl
3)δ8.33(d,J=2.4Hz,1H),8.11-7.94(m,2H),7.90(d,J=8.0Hz,1H),7.75-7.63(m,2H),7.59-7.51(m,2H),7.38(d,J=6.4Hz,1H),6.30(t,J=6.8Hz,1H),4.99-4.02(m,4H),3.77-3.48(m,5H),3.31-3.10(m,1H),3.07(s,3H),2.78-2.62(m,1H),1.55-1.43(m,3H),1.26-1.18(m,3H),1.13-1.05(m,3H).
LC-MS: m/z 621 (M+H) + .1 H NMR (400 MHz, CDCl 3 ) δ 8.33 (d, J=2.4 Hz, 1 H), 8.11-7.94 (m, 2H), 7.90 (d ,J=8.0Hz,1H),7.75-7.63(m,2H),7.59-7.51(m,2H),7.38(d,J=6.4Hz,1H),6.30(t,J=6.8Hz,1H) ,4.99-4.02(m,4H),3.77-3.48(m,5H),3.31-3.10(m,1H),3.07(s,3H),2.78-2.62(m,1H),1.55-1.43(m, 3H), 1.26-1.18(m, 3H), 1.13-1.05(m, 3H).
实施例74 (S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-氟-1-(2-异丙基-6-(甲基磺酰基)苯基)-7-(1-甲基-6-氧代-1,6-二氢吡啶-2-基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 74 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-1-(2-isopropyl-6-(methylsulfonyl)phenyl )-7-(1-methyl-6-oxo-1,6-dihydropyridin-2-yl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 621(M+H)
+.
1H NMR(400MHz,CDCl
3)δ8.35(d,J=2.4Hz,1H),8.03(d,J=7.6Hz,1H),7.80(d,J=7.2Hz,1H),7.76-7.65(m,3H),7.31(t,J=8.0Hz,1H),6.94-6.74(m,1H),6.63(d,J=9.2Hz,1H),6.46-6.35(m,1H),5.10-3.64(m,6H),3.60(s,3H),3.45-3.09(m,1H),3.06(s,3H),2.78-2.62(m,1H),1.59-1.43(m,3H),1.23(d,J=6.8Hz,3H),1.10(d,J=5.6Hz,3H).
LC-MS: m/z 621 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.35 (d, J=2.4 Hz, 1H), 8.03 (d, J=7.6 Hz, 1H), 7.80(d,J=7.2Hz,1H),7.76-7.65(m,3H),7.31(t,J=8.0Hz,1H),6.94-6.74(m,1H),6.63(d,J=9.2Hz ,1H),6.46-6.35(m,1H),5.10-3.64(m,6H),3.60(s,3H),3.45-3.09(m,1H),3.06(s,3H),2.78-2.62(m ,1H),1.59-1.43(m,3H),1.23(d,J=6.8Hz,3H),1.10(d,J=5.6Hz,3H).
实施例75 4-((S)-4-丙烯酰基-2-甲基哌嗪-1-基)-7-(6-氯-1H-吲唑-7-基)-6-氟-1-(2-异丙基-6-(甲基磺酰基)苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 75 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-7-(6-chloro-1H-indazol-7-yl)-6-fluoro-1- (2-Isopropyl-6-(methylsulfonyl)phenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 664(M+H)
+.
1H NMR(400MHz,CDCl
3)δ12.99(brs,1H),8.57-8.20(m,3H),8.02(d,J=7.2Hz,1H),7.86-7.72(m,2H),7.67(t,J=8.0Hz,1H),7.59(d,J=7.6Hz,1H),7.23-7.03(m,2H),5.19-3.24(m,7H),3.06(s,3H),2.78-2.58(m,1H), 1.60-1.42(m,3H),1.30-1.15(m,3H),1.14-0.99(m,3H).
LC-MS: m/z 664 (M+H) + .1 H NMR (400 MHz, CDCl 3 ) δ 12.99 (brs, 1H), 8.57-8.20 (m, 3H), 8.02 (d, J=7.2Hz ,1H),7.86-7.72(m,2H),7.67(t,J=8.0Hz,1H),7.59(d,J=7.6Hz,1H),7.23-7.03(m,2H),5.19-3.24( m, 7H), 3.06(s, 3H), 2.78-2.58(m, 1H), 1.60-1.42(m, 3H), 1.30-1.15(m, 3H), 1.14-0.99(m, 3H).
实施例76 4-((S)-4-丙烯酰基-2-甲基哌嗪-1-基)-7-(1,4-二甲基-1H-咪唑-5-基)-6-氟-1-(2-异丙基-6-(甲基磺酰基)苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 76 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-7-(1,4-dimethyl-1H-imidazol-5-yl)-6-fluoro -1-(2-Isopropyl-6-(methylsulfonyl)phenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 608(M+H)
+.
1H NMR(400MHz,CDCl
3)δ8.34(d,J=2.4Hz,1H),8.03(d,J=8.0Hz,1H),7.79(d,J=6.8Hz,1H),7.76-7.64(m,3H),7.43(s,1H),6.61-6.44(m,1H),5.10-3.37(m,10H),3.07(s,3H),2.78-2.59(m,1H),2.42(s,3H),1.56-1.41(m,3H),1.28-1.18(m,3H),1.16-1.02(m,3H).
LC-MS: m/z 608 (M+H) + .1 H NMR (400 MHz, CDCl 3 ) δ 8.34 (d, J=2.4 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.79(d, J=6.8Hz, 1H), 7.76-7.64(m, 3H), 7.43(s, 1H), 6.61-6.44(m, 1H), 5.10-3.37(m, 10H), 3.07(s, 3H), 2.78-2.59(m, 1H), 2.42(s, 3H), 1.56-1.41(m, 3H), 1.28-1.18(m, 3H), 1.16-1.02(m, 3H).
实施例77 2-(4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-1-(2-异丙基-6-(甲基磺酰基)苯基)-2-氧代-1,2-二氢吡啶[2,3-d]嘧啶-7-基)-3-氟苯甲酸甲酯Example 77 2-(4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-1-(2-isopropyl-6-(methylsulfonyl) )phenyl)-2-oxo-1,2-dihydropyridine[2,3-d]pyrimidin-7-yl)-3-fluorobenzoic acid methyl ester
LC-MS:m/z 666(M+H)
+.
1H NMR(400MHz,CDCl
3)δ8.34(d,J=2.4Hz,1H),8.04-7.96(m,2H),7.80-7.65(m,4H),7.41-7.36(m,1H),7.33-7.26(m,1H),7.00-6.87(m,1H),4.97-4.14(m,4H),3.94(s,3H),3.76-3.65(m,2H),3.30-3.07(m,4H),2.71(s,1H),1.55-1.49(m,3H),1.29-1.23(m,3H),1.11-1.08(m,3H).
LC-MS: m/z 666 (M+H) + .1H NMR (400MHz, CDCl3 ) δ 8.34 (d, J=2.4Hz, 1H), 8.04-7.96 (m, 2H), 7.80-7.65 (m,4H),7.41-7.36(m,1H),7.33-7.26(m,1H),7.00-6.87(m,1H),4.97-4.14(m,4H),3.94(s,3H),3.76 -3.65(m, 2H), 3.30-3.07(m, 4H), 2.71(s, 1H), 1.55-1.49(m, 3H), 1.29-1.23(m, 3H), 1.11-1.08(m, 3H) .
实施例78 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-1-(2-异丙基-6-(甲基磺酰基)苯基)-6-氟-7-(2-氟-6-羟基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮的制备Example 78 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-1-(2-isopropyl-6-(methylsulfonyl)benzene yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 638(M+H)
+.
LC-MS: m/z 638 (M+H) + .
实施例78-1 通过手性分离得到两个异构体实施例78A和78B:Example 78-1 Two isomers Examples 78A and 78B were obtained by chiral separation:
实施例78AExample 78A
LC-MS:m/z 638(M+H)
+.
1H NMR(400MHz,DMSO)δ10.21(brs,1H),8.28(m,1H),7.85(m,2H),7.65(t,J=7.8Hz,1H),7.26(m,1H),6.95–6.58(m,3H),6.19(m,1H),5.82–5.69(m,1H),4.96–4.41(m,2H),4.30–3.38(m,4H),2.95(s,3H),2.72–2.55(m,1H),1.40–0.93(m,12H).
LC-MS: m/z 638 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 10.21 (brs, 1H), 8.28 (m, 1H), 7.85 (m, 2H), 7.65 (t, J=7.8Hz, 1H), 7.26 (m, 1H), 6.95–6.58 (m, 3H), 6.19 (m, 1H), 5.82–5.69 (m, 1H), 4.96–4.41 (m, 2H), 4.30 –3.38(m,4H),2.95(s,3H),2.72–2.55(m,1H),1.40–0.93(m,12H).
实施例78BExample 78B
LC-MS:m/z 638(M+H)
+.
1H NMR(400MHz,DMSO)δ10.28(brs,1H),8.51–8.33(m,1H),8.00–7.81(m,2H),7.70(t,J=7.8Hz,1H),7.31(m,1H),7.00–6.65(m,3H),6.24(m,1H),5.80(m,1H),5.02–4.46(m,2H),4.27–3.57(m,4H),2.97(s,3H),2.70–2.58(m,1H),1.43–0.97(m,12H).
LC-MS: m/z 638 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 10.28 (brs, 1H), 8.51–8.33 (m, 1H), 8.00–7.81 (m, 2H), 7.70(t,J=7.8Hz,1H),7.31(m,1H),7.00-6.65(m,3H),6.24(m,1H),5.80(m,1H),5.02-4.46(m,2H) ,4.27–3.57(m,4H),2.97(s,3H),2.70–2.58(m,1H),1.43–0.97(m,12H).
实施例79 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-6-氯-7-(2-氟-6-羟基苯基)-1-(2-异丙基-6-(甲基磺酰基)苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 79 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-6-chloro-7-(2-fluoro-6-hydroxyphenyl)- 1-(2-Isopropyl-6-(methylsulfonyl)phenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 654(M+H)
+.
LC-MS: m/z 654 (M+H) + .
实施例79-1 通过手性分离得到两个异构体实施例79A和79B:Example 79-1 Two isomers Examples 79A and 79B were obtained by chiral separation:
实施例79AExample 79A
LC-MS:m/z 638(M+H)
+.
1H NMR(400MHz,CDCl
3)δ8.11(t,J=7.0Hz,2H),7.78(d,J=6.8Hz,1H),7.68(t,J=7.8Hz,1H),7.26–7.20(m,1H),6.78–6.49(m,3H),6.40(m,1H),5.81(m,1H),5.11(m,2H),4.53–4.19(m,1H),4.17–3.80(m,2H),3.61 (m,1H),3.13(d,J=5.6Hz,3H),2.81–2.61(m,1H),1.52–0.94(m,12H).
LC-MS: m/z 638 (M+H) + .1 H NMR (400 MHz, CDCl 3 ) δ 8.11 (t, J=7.0 Hz, 2H), 7.78 (d, J=6.8 Hz, 1H), 7.68(t,J=7.8Hz,1H),7.26-7.20(m,1H),6.78-6.49(m,3H),6.40(m,1H),5.81(m,1H),5.11(m,2H) , 4.53–4.19 (m, 1H), 4.17–3.80 (m, 2H), 3.61 (m, 1H), 3.13 (d, J=5.6Hz, 3H), 2.81–2.61 (m, 1H), 1.52–0.94 (m,12H).
实施例79BExample 79B
LC-MS:m/z 638(M+H)
+.
1H NMR(400MHz,DMSO)δ10.12(brs,1H),8.48(s,1H),7.92–7.75(m,2H),7.65(t,J=7.8Hz,1H),7.22(m,1H),6.92–6.53(m,3H),6.19(m,1H),5.84–5.69(m,1H),4.70(m,2H),4.19–3.47(m,4H),2.90(s,3H),2.57(m,1H),1.37–0.90(m,12H).
LC-MS: m/z 638(M+H) + .1H NMR (400MHz, DMSO) δ 10.12(brs,1H), 8.48(s,1H), 7.92–7.75(m,2H), 7.65( t, J = 7.8Hz, 1H), 7.22 (m, 1H), 6.92–6.53 (m, 3H), 6.19 (m, 1H), 5.84–5.69 (m, 1H), 4.70 (m, 2H), 4.19 –3.47(m,4H),2.90(s,3H),2.57(m,1H),1.37–0.90(m,12H).
实施例80 4-((S)-4-丙烯酰基-2-甲基哌嗪-1-基)-6-氟-7-(2-氟-6-羟基苯基)-1-(2-异丙基-6-(异丙基磺酰基)苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 80 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2- Isopropyl-6-(isopropylsulfonyl)phenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 652(M+H)
+.
1H NMR(400MHz,CDCl
3)δ8.91(brs,1H),8.04(d,J=7.2Hz,1H),7.87(dd,J=9.2Hz,3.2Hz,1H),7.81(dd,J=8.0Hz,1.2Hz,1H),7.72-7.67(m,1H),7.26(overlap,1H),6.69-6.54(m,3H),6.42(dd,J=16.8Hz,1.6Hz,1H),5.81(dd,J=10.8Hz,1.6Hz,1H),5.10-3.40(m,7H),3.30-3.00(m,1H),2.75-2.60(m,1H),1.50-1.48(m,3H),1.31-1.24(m,6H),1.17-1.15(m,3H),1.02-0.99(m,3H).
LC-MS: m/z 652 (M+H) + .1 H NMR (400 MHz, CDCl 3 ) δ 8.91 (brs, 1H), 8.04 (d, J=7.2 Hz, 1H), 7.87 (dd, J =9.2Hz,3.2Hz,1H),7.81(dd,J=8.0Hz,1.2Hz,1H),7.72-7.67(m,1H),7.26(overlap,1H),6.69-6.54(m,3H), 6.42(dd,J=16.8Hz,1.6Hz,1H),5.81(dd,J=10.8Hz,1.6Hz,1H),5.10-3.40(m,7H),3.30-3.00(m,1H),2.75- 2.60(m, 1H), 1.50-1.48(m, 3H), 1.31-1.24(m, 6H), 1.17-1.15(m, 3H), 1.02-0.99(m, 3H).
实施例80-1 通过手性分离得到两个异构体实施例80A和80B:Example 80-1 Two isomers Examples 80A and 80B were obtained by chiral separation:
实施例80AExample 80A
LC-MS:m/z 652(M+H)
+.
1H NMR(400MHz,DMSO)δ10.19(brs,1H),8.28(t,J=9.7Hz,1H),7.90–7.76(m,2H),7.64(t,J=7.8Hz,1H),7.26(m,1H),6.97–6.58(m,3H),6.21(m,1H),5.77(m,1H),4.86(m,1H),4.49–3.96(m,3H),3.83–3.48(m,2H),3.28–3.02(m,2H),2.59(m,1H),1.34(m,3H),1.18–0.89(m,12H).
LC-MS: m/z 652 (M+H) + . 1 H NMR (400MHz, DMSO) δ 10.19 (brs, 1H), 8.28 (t, J=9.7Hz, 1H), 7.90–7.76 (m, 2H), 7.64(t, J=7.8Hz, 1H), 7.26(m, 1H), 6.97–6.58(m, 3H), 6.21(m, 1H), 5.77(m, 1H), 4.86(m, 1H) ), 4.49–3.96 (m, 3H), 3.83–3.48 (m, 2H), 3.28–3.02 (m, 2H), 2.59 (m, 1H), 1.34 (m, 3H), 1.18–0.89 (m, 12H) ).
实施例80BExample 80B
LC-MS:m/z 652(M+H)
+.
1H NMR(400MHz,DMSO)δ10.21(brs,1H),8.38(s,1H),7.82(m,2H),7.74–7.58(m,1H),7.26(m,1H),7.05–6.58(m,3H),6.22(m,1H),5.88–5.67(m,1H),4.92(m,1H),4.63–3.95(m,3H),3.74(m,2H),3.29(m,1H),3.05 (m,1H),2.62(m,1H),1.35–1.19(m,3H),1.18–0.82(m,12H).
LC-MS: m/z 652 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 10.21 (brs, 1H), 8.38 (s, 1H), 7.82 (m, 2H), 7.74–7.58 ( m, 1H), 7.26 (m, 1H), 7.05–6.58 (m, 3H), 6.22 (m, 1H), 5.88–5.67 (m, 1H), 4.92 (m, 1H), 4.63–3.95 (m, 3H), 3.74 (m, 2H), 3.29 (m, 1H), 3.05 (m, 1H), 2.62 (m, 1H), 1.35–1.19 (m, 3H), 1.18–0.82 (m, 12H).
实施例81 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-1-(2-环丙基-6-(甲基磺酰基)苯基)-6-氟-7-(2-氟-6-羟基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 81 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-1-(2-cyclopropyl-6-(methylsulfonyl)benzene yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 636(M+H)
+.
1H NMR(400MHz,CDCl
3)δ9.16-8.90(m,1H),8.14-8.02(m,1H),7.92-7.82(m,1H),7.65(t,J=8.0Hz,1H),7.54-7.41(m,1H),7.30-7.21(m,1H),6.73-6.50(m,3H),6.40(t,J=15.2Hz,1H),5.81(t,J=8.8Hz,1H),5.18-3.67(m,6H),3.18-3.07(m,3H),1.53-1.19(m,7H),0.93-0.53(m,4H).
LC-MS: m/z 636 (M+H) + .1 H NMR (400 MHz, CDCl 3 ) δ 9.16-8.90 (m, 1H), 8.14-8.02 (m, 1H), 7.92-7.82 (m, 1H), 7.65(t, J=8.0Hz, 1H), 7.54-7.41(m, 1H), 7.30-7.21(m, 1H), 6.73-6.50(m, 3H), 6.40(t, J=15.2Hz ,1H),5.81(t,J=8.8Hz,1H),5.18-3.67(m,6H),3.18-3.07(m,3H),1.53-1.19(m,7H),0.93-0.53(m,4H ).
实施例81-1 通过手性分离得到两个异构体实施例81A和81B:Example 81-1 Two isomers Examples 81A and 81B were obtained by chiral separation:
实施例81AExample 81A
LC-MS:m/z 636(M+H)
+.
1H NMR(400MHz,DMSO)δ10.22(brs,1H),8.31(d,J=9.0Hz,1H),7.86(d,J=7.6Hz,1H),7.58(t,J=7.8Hz,1H),7.54–7.44(m,1H),7.26(dd,J=15.3,8.0Hz,1H),6.96–6.52(m,3H),6.19(m,1H),5.79–5.65(m,1H),4.97–4.36(m,2H),4.16(m,1H),3.95–3.41(m,3H),3.00(s,3H),1.67–1.46(m,1H),1.24(m,6H),0.75–0.43(m,4H).
LC-MS: m/z 636 (M+H) + .1 H NMR (400MHz, DMSO) δ 10.22 (brs, 1H), 8.31 (d, J=9.0 Hz, 1H), 7.86 (d, J= 7.6Hz, 1H), 7.58 (t, J=7.8Hz, 1H), 7.54–7.44 (m, 1H), 7.26 (dd, J=15.3, 8.0Hz, 1H), 6.96–6.52 (m, 3H), 6.19 (m, 1H), 5.79–5.65 (m, 1H), 4.97–4.36 (m, 2H), 4.16 (m, 1H), 3.95–3.41 (m, 3H), 3.00 (s, 3H), 1.67– 1.46(m,1H),1.24(m,6H),0.75–0.43(m,4H).
实施例81BExample 81B
LC-MS:m/z 636(M+H)
+.
1H NMR(400MHz,DMSO)δ10.29(brs,1H),8.34(dd,J=8.9,4.0Hz,1H),7.85(d,J=7.5Hz,1H),7.58(t,J=7.8Hz,1H),7.43(d,J=7.7Hz,1H),7.26(dd,J=15.4,8.0Hz,1H),6.95–6.55(m,3H),6.19(m,1H),5.75(m,1H),4.74(m,2H),4.22–3.51(m,4H),2.96(s,3H),1.64–1.48(m,1H),1.25(m,6H),0.63(m,4H).
LC-MS: m/z 636 (M+H) + .1H NMR (400MHz, DMSO) δ 10.29 (brs, 1H), 8.34 (dd, J=8.9, 4.0Hz, 1H), 7.85 (d, J=7.5Hz, 1H), 7.58(t, J=7.8Hz, 1H), 7.43(d, J=7.7Hz, 1H), 7.26(dd, J=15.4, 8.0Hz, 1H), 6.95–6.55( m, 3H), 6.19 (m, 1H), 5.75 (m, 1H), 4.74 (m, 2H), 4.22–3.51 (m, 4H), 2.96 (s, 3H), 1.64–1.48 (m, 1H) ,1.25(m,6H),0.63(m,4H).
实施例82 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-1-(2-乙基-6-(异丙基磺酰基)苯基)-6-氟-7-(2-氟-6-羟基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 82 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-1-(2-ethyl-6-(isopropylsulfonyl)benzene yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 652(M+H)
+.
1H NMR(400MHz,CDCl
3)δ9.10-8.09(m,1H),8.06-8.03(m,1H),7.88-7.85(m,1H),7.80-7.76(m,1H),7.70-7.65(m,1H),7.28-7.22(m,1H),6.70-6.55(m,3H),6.39(t,J=13.6Hz,1H),5.80-5.78(m,1H),5.07-3.40(m,7H),2.52-2.49(m,1H),2.36-2.33(m,1H),1.50-1.41(m,3H),1.40-1.29(m,6H),1.27-1.17(m,6H).
LC-MS: m/z 652 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 9.10-8.09 (m, 1H), 8.06-8.03 (m, 1H), 7.88-7.85 (m, 1H), 7.80-7.76(m, 1H), 7.70-7.65(m, 1H), 7.28-7.22(m, 1H), 6.70-6.55(m, 3H), 6.39(t, J=13.6Hz, 1H) ,5.80-5.78(m,1H),5.07-3.40(m,7H),2.52-2.49(m,1H),2.36-2.33(m,1H),1.50-1.41(m,3H),1.40-1.29( m,6H),1.27-1.17(m,6H).
实施例82-1 通过手性分离得到两个异构体实施例82A和82B:Example 82-1 Two isomers Examples 82A and 82B were obtained by chiral separation:
实施例82AExample 82A
LC-MS:m/z 652(M+H)
+.
1H NMR(400MHz,DMSO)δ10.16(brs,1H),8.29–8.11(m,1H),7.78(t,J=7.0Hz,2H),7.63(t,J=7.8Hz,1H),7.27(m,1H),6.96–6.58(m,3H),6.19(m,1H),5.75(m,1H),4.66(m,2H),4.46–4.13(m,2H),3.94–3.57(m,2H),3.23(m,1H),2.31(dd,J=14.7,7.2Hz,2H),1.38(d,J=6.5Hz,3H),1.22(m,3H),1.10–0.86(m,9H).
LC-MS: m/z 652 (M+H) + . 1 H NMR (400MHz, DMSO) δ 10.16 (brs, 1H), 8.29–8.11 (m, 1H), 7.78 (t, J=7.0Hz, 2H), 7.63(t, J=7.8Hz, 1H), 7.27(m, 1H), 6.96-6.58(m, 3H), 6.19(m, 1H), 5.75(m, 1H), 4.66(m, 2H) ), 4.46–4.13 (m, 2H), 3.94–3.57 (m, 2H), 3.23 (m, 1H), 2.31 (dd, J=14.7, 7.2Hz, 2H), 1.38 (d, J=6.5Hz, 3H), 1.22(m, 3H), 1.10–0.86(m, 9H).
实施例82BExample 82B
LC-MS:m/z 652(M+H)
+.
1H NMR(400MHz,DMSO)δ10.13(brs,1H),8.37(t,J=8.2Hz,1H),7.79(t,J=6.4Hz,2H),7.64(t,J=7.7Hz,1H),7.26(m,1H),6.93–6.57(m,3H),6.19(m,1H),5.75(m,1H),5.05–4.31(m,2H),4.21–3.52(m,4H),3.17–2.99(m,1H),2.30(d,J=6.9Hz,2H),1.40–0.84(m,15H).
LC-MS: m/z 652 (M+H) + .1 H NMR (400MHz, DMSO) δ 10.13 (brs, 1H), 8.37 (t, J=8.2Hz, 1H), 7.79 (t, J= 6.4Hz, 2H), 7.64 (t, J=7.7Hz, 1H), 7.26 (m, 1H), 6.93–6.57 (m, 3H), 6.19 (m, 1H), 5.75 (m, 1H), 5.05– 4.31 (m, 2H), 4.21–3.52 (m, 4H), 3.17–2.99 (m, 1H), 2.30 (d, J=6.9Hz, 2H), 1.40–0.84 (m, 15H).
实施例83 4-((S)-4-丙烯酰基-2-甲基哌嗪-1-基)-1-(2-乙基-6-(异丙基磺酰基)苯基)-6-氟-7-(2-氟-6-羟基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 83 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-1-(2-ethyl-6-(isopropylsulfonyl)phenyl)-6- Fluoro-7-(2-Fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 638(M+H)
+.
1H NMR(400MHz,CDCl
3)δ8.96(brs,1H),8.05(d,J=7.6Hz,1H),7.89-7.85(m,1H),7.78(d,J=8Hz,1H),7.70-7.68(m,1H),7.28-7.22(m,1H),6.70-6.61(m,3H),6.43-6.39(m,1H),5.83-5.80(m,1H),5.00-3.06(m,8H),2.58-2.50(m,1H),2.39-2.35(m,1H),1.33-1.28(m,6H),1.26-1.15(m,6H).
LC-MS: m/z 638 (M+H) + .1 H NMR (400 MHz, CDCl 3 ) δ 8.96 (brs, 1H), 8.05 (d, J=7.6 Hz, 1H), 7.89-7.85 (m ,1H),7.78(d,J=8Hz,1H),7.70-7.68(m,1H),7.28-7.22(m,1H),6.70-6.61(m,3H),6.43-6.39(m,1H) ,5.83-5.80(m,1H),5.00-3.06(m,8H),2.58-2.50(m,1H),2.39-2.35(m,1H),1.33-1.28(m,6H),1.26-1.15( m,6H).
实施例83-1 通过手性分离得到两个异构体实施例83A和83B:Example 83-1 Two isomer Examples 83A and 83B were obtained by chiral separation:
实施例83AExample 83A
LC-MS:m/z 638(M+H)
+.
1H NMR(400MHz,DMSO)δ10.19(brs,1H),8.28(d,J=8.8Hz,1H),7.78(t,J=6.9Hz,2H),7.63(t,J=7.7Hz,1H),7.26(m,1H),6.75(m,3H),6.21(m,1H),5.77(m,1H),4.84(s,1H),4.57–3.99(m,3H),3.78–3.49(m,2H),3.19(m,2H),2.41–2.18(m,2H),1.36(d,J=6.4Hz,3H),1.12–0.81(m,9H).
LC-MS: m/z 638 (M+H) + .1 H NMR (400MHz, DMSO) δ 10.19 (brs, 1H), 8.28 (d, J=8.8Hz, 1H), 7.78 (t, J= 6.9Hz, 2H), 7.63(t, J=7.7Hz, 1H), 7.26(m, 1H), 6.75(m, 3H), 6.21(m, 1H), 5.77(m, 1H), 4.84(s, 1H), 4.57–3.99 (m, 3H), 3.78–3.49 (m, 2H), 3.19 (m, 2H), 2.41–2.18 (m, 2H), 1.36 (d, J=6.4Hz, 3H), 1.12 –0.81(m,9H).
实施例83BExample 83B
LC-MS:m/z 638(M+H)
+.
1H NMR(400MHz,DMSO)δ9.31(br,1H),8.35(s,1H),7.84–7.70(m,2H),7.63(t,J=7.8Hz,1H),7.25(m,1H),6.96–6.55(m,3H),6.21(m,1H),5.77(m,1H),4.90(m,1H),4.59–3.94(m,3H),3.66(m,2H),3.07(m,2H),2.39–2.23(m,2H),1.31–1.15(m,3H),1.15–0.89(m,9H).
LC-MS: m/z 638 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 9.31 (br, 1H), 8.35 (s, 1H), 7.84–7.70 (m, 2H), 7.63 ( t, J=7.8Hz, 1H), 7.25 (m, 1H), 6.96–6.55 (m, 3H), 6.21 (m, 1H), 5.77 (m, 1H), 4.90 (m, 1H), 4.59–3.94 (m, 3H), 3.66 (m, 2H), 3.07 (m, 2H), 2.39–2.23 (m, 2H), 1.31–1.15 (m, 3H), 1.15–0.89 (m, 9H).
实施例84 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-6-氯-1-(2-乙基-6-(甲基磺酰基)苯基)-7-(2-氟-6-羟基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 84 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-6-chloro-1-(2-ethyl-6-(methylsulfonyl) Acyl)phenyl)-7-(2-fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 640(M+H)
+.
1H NMR(400MHz,CDCl
3)δ8.19-8.06(m,2H),8.06-7.83(m,1H),7.75(t,J=8.0Hz,1H),7.66(dt,J=8.0Hz,2.0Hz,1H),7.26-7.20(m,1H),6.77-6.50(m,3H),6.40(t,J=15.2Hz,1H),5.81(t,J=8.8Hz,1H),5.21-3.64(m,6H),3.17-3.05(m,3H),2.60-2.31(m,2H),1.55-1.34(m,6H),1.22-1.11(m,3H).
LC-MS: m/z 640 (M+H) + .1 H NMR (400 MHz, CDCl 3 ) δ 8.19-8.06 (m, 2H), 8.06-7.83 (m, 1H), 7.75 (t, J= 8.0Hz,1H),7.66(dt,J=8.0Hz,2.0Hz,1H),7.26-7.20(m,1H),6.77-6.50(m,3H),6.40(t,J=15.2Hz,1H) ,5.81(t,J=8.8Hz,1H),5.21-3.64(m,6H),3.17-3.05(m,3H),2.60-2.31(m,2H),1.55-1.34(m,6H),1.22 -1.11(m,3H).
实施例84-1 通过手性分离得到两个异构体实施例84A和84B:Example 84-1 Two isomers Examples 84A and 84B were obtained by chiral separation:
实施例84AExample 84A
LC-MS:m/z 640(M+H)
+.
1H NMR(400MHz,DMSO)δ10.20(brs,1H),8.42(d,J=10.9Hz,1H),7.88(d,J=7.7Hz,1H),7.73(s,1H),7.60m,1H),7.22(m,1H),6.94–6.52(m,3H),6.19(m,1H),5.85–5.69(m,1H),4.65(m,2H),4.37–4.05(m,2H),3.74(m,2H),2.97(s,3H),2.33(m,2H),1.45–0.86(m,9H).
LC-MS: m/z 640 (M+H) + .1 H NMR (400MHz, DMSO) δ 10.20 (brs, 1H), 8.42 (d, J=10.9 Hz, 1H), 7.88 (d, J= 7.7Hz, 1H), 7.73 (s, 1H), 7.60m, 1H), 7.22 (m, 1H), 6.94–6.52 (m, 3H), 6.19 (m, 1H), 5.85–5.69 (m, 1H) ,4.65(m,2H),4.37–4.05(m,2H),3.74(m,2H),2.97(s,3H),2.33(m,2H),1.45–0.86(m,9H).
实施例84BExample 84B
LC-MS:m/z 640(M+H)
+.
1H NMR(400MHz,DMSO)δ10.21(brs,1H),8.48(m,1H),7.88(d,J=7.7Hz,1H),7.74(s,1H),7.63(t,J=7.8Hz,1H),7.23(dd,J=15.4,8.0Hz,1H),6.82(dt,J=16.8,10.0Hz,1H),6.74–6.54(m,2H),6.19(m,1H),5.85–5.64(m,1H),4.71(m,2H),3.95(m,4H),2.95(s,3H),2.31(m,2H),1.39–0.97(m,9H).
LC-MS: m/z 640 (M+H) + .1 H NMR (400MHz, DMSO) δ 10.21 (brs, 1H), 8.48 (m, 1H), 7.88 (d, J=7.7Hz, 1H) ,7.74(s,1H),7.63(t,J=7.8Hz,1H),7.23(dd,J=15.4,8.0Hz,1H),6.82(dt,J=16.8,10.0Hz,1H),6.74– 6.54(m, 2H), 6.19(m, 1H), 5.85–5.64(m, 1H), 4.71(m, 2H), 3.95(m, 4H), 2.95(s, 3H), 2.31(m, 2H) ,1.39–0.97(m,9H).
实施例85 4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-7-(2-氟-6-羟基苯基)-1-(2-(甲磺酰基)苯基)吡啶[2,3-d]嘧啶-2(1H)-酮的制备Example 85 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2- Preparation of (Methylsulfonyl)phenyl)pyridin[2,3-d]pyrimidin-2(1H)-one
第1步.2,6-二氯-5-氟-N-(((2-(甲基磺酰基)苯基)氨基甲酰基)烟酰胺的制备Step 1. Preparation of 2,6-dichloro-5-fluoro-N-(((2-(methylsulfonyl)phenyl)carbamoyl)nicotinamide
将2,6-二氯-5-氟烟酰胺(420mg,2.0mmol)溶于无水四氢呋喃(7mL)中,向此溶液中缓慢滴加草酰氯(1.7mL,20.0mmol)的二氯甲烷(2mL)溶液。滴加完毕后,将此混合物于75℃回流搅拌2h,然后减压浓缩至干。残留物用无水四氢呋喃(7mL)稀释,冷却至0℃。将2-(甲基磺酰基)苯胺(360mg,2.1mmol)溶于无水四氢呋喃(3mL)中,然后滴加进上述溶液中。反应液在0℃下搅拌2h,饱和氯化铵/饱和食盐水(V/V=1/1,20mL)淬灭,然后用二氯甲烷/甲醇(V/V=10/1,20mL)萃取3次。合并有机相干燥,浓缩,残留固体以石油醚/乙酸乙酯(V/V=3/1,15mL)打浆,抽滤,干燥,得目标产物(645mg,收率:79%)。2,6-Dichloro-5-fluoronicotinamide (420 mg, 2.0 mmol) was dissolved in dry tetrahydrofuran (7 mL), and to this solution was slowly added dropwise oxalyl chloride (1.7 mL, 20.0 mmol) in dichloromethane ( 2mL) solution. After the dropwise addition, the mixture was stirred at 75°C under reflux for 2 h, and then concentrated to dryness under reduced pressure. The residue was diluted with anhydrous tetrahydrofuran (7 mL) and cooled to 0°C. 2-(Methylsulfonyl)aniline (360 mg, 2.1 mmol) was dissolved in dry tetrahydrofuran (3 mL) and added dropwise to the above solution. The reaction solution was stirred at 0 °C for 2 h, quenched with saturated ammonium chloride/saturated brine (V/V=1/1, 20 mL), and then extracted with dichloromethane/methanol (V/V=10/1, 20 mL) 3 times. The combined organic phases were dried, concentrated, and the residual solid was slurried with petroleum ether/ethyl acetate (V/V=3/1, 15 mL), suction filtered, and dried to obtain the target product (645 mg, yield: 79%).
LC-MS:m/z 406(M+H)
+。
LC-MS: m/z 406 (M+H) + .
第2步.7-氯-6-氟-1-(2-(甲基磺酰基)苯基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮的制备Step 2. Preparation of 7-chloro-6-fluoro-1-(2-(methylsulfonyl)phenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione
将2,6-二氯-5-氟-N-(((2-(甲基磺酰基)苯基)氨基甲酰基)烟酰胺(645mg,1.6mmol)悬浮于四氢呋喃(15mL)中,冰浴下滴加双(三甲基硅烷基)氨基钾(1摩四氢呋喃溶液,3.6mL,3.6mmol)。滴加完毕后反应液变澄清。反应液室温搅拌16h,饱和氯化铵(20mL)淬灭,然后以乙酸乙酯(20mL)萃取3次。合并乙酸乙酯层干燥,浓缩。残留固体以石油醚/乙酸乙酯(V/V=3/1,10mL)打浆,抽滤,干燥得得目标产物(500mg,收率:85%)。2,6-Dichloro-5-fluoro-N-(((2-(methylsulfonyl)phenyl)carbamoyl)nicotinamide (645 mg, 1.6 mmol) was suspended in tetrahydrofuran (15 mL), ice bathed Bis (trimethylsilyl) potassium amide (1 mole of tetrahydrofuran solution, 3.6 mL, 3.6 mmol) was added dropwise. The reaction solution became clear after the addition was completed. The reaction solution was stirred at room temperature for 16 h, and quenched with saturated ammonium chloride (20 mL). , and then extracted 3 times with ethyl acetate (20 mL). The ethyl acetate layers were combined, dried, and concentrated. The residual solid was slurried with petroleum ether/ethyl acetate (V/V=3/1, 10 mL), filtered with suction, and dried to obtain The target product (500 mg, yield: 85%).
LC-MS:m/z 370(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ12.32(s,1H),8.50(d,J=7.2Hz,1H),8.15(dd,J=8.0Hz,1.2Hz,1H),7.97-7.92(m,1H),7.86-7.81(m,1H),7.66(dd,J=8.0Hz,1.2Hz,1H),3.09(s,3H).
LC-MS: m/z 370 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 12.32 (s, 1H), 8.50 (d, J=7.2Hz, 1H), 8.15 (dd, J=8.0Hz, 1.2Hz, 1H), 7.97-7.92 (m,1H),7.86-7.81(m,1H),7.66(dd,J=8.0Hz,1.2Hz,1H),3.09(s,3H).
第3步.(S)-叔丁基4-(7-氯-6-氟-1-(2-(甲基磺酰基)苯基)-2-氧-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸的制备Step 3. (S)-tert-Butyl 4-(7-Chloro-6-fluoro-1-(2-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyrido[ Preparation of 2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid
将7-氯-6-氟-1-(2-(甲基磺酰基)苯基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(450mg,1.2mmol)悬浮于乙腈(10mL)中,滴加N,N-二异丙基乙胺(1.2mL,7.3mmol)和三氯氧磷(0.6mL,6.1mmol),反应液变澄清。将反应液于80℃搅拌4h,减压浓缩至干。残留物溶解在乙腈(10mL)中,冷却至0℃,加入N,N-二异丙基乙胺(0.6mL,3.7mmol)和(S)-3-甲基哌嗪-1-羧酸叔丁酯(290mg,1.5mmol),反应液在室温下搅拌1h,半饱和的碳酸氢钠溶液(40mL)淬灭,再以乙酸乙酯(30mL)萃取3次。合并乙酸乙酯层干燥,浓缩,硅胶柱纯化(石油醚/乙酸乙酯=3/1到1/2.5),得目标产物(460mg,收率:68%)。7-Chloro-6-fluoro-1-(2-(methylsulfonyl)phenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (450 mg, 1.2 mmol ) was suspended in acetonitrile (10 mL), N,N-diisopropylethylamine (1.2 mL, 7.3 mmol) and phosphorus oxychloride (0.6 mL, 6.1 mmol) were added dropwise, and the reaction solution became clear. The reaction solution was stirred at 80 °C for 4 h, and concentrated to dryness under reduced pressure. The residue was dissolved in acetonitrile (10 mL), cooled to 0 °C, N,N-diisopropylethylamine (0.6 mL, 3.7 mmol) and (S)-3-methylpiperazine-1-carboxylic acid tert. Butyl ester (290 mg, 1.5 mmol), the reaction solution was stirred at room temperature for 1 h, quenched with half-saturated sodium bicarbonate solution (40 mL), and extracted three times with ethyl acetate (30 mL). The combined ethyl acetate layers were dried, concentrated, and purified by silica gel column (petroleum ether/ethyl acetate=3/1 to 1/2.5) to obtain the target product (460 mg, yield: 68%).
LC-MS:m/z 552(M+H)
+。
LC-MS: m/z 552 (M+H) + .
第4步.(S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-7-氯-6-氟-1-(2-(甲基磺基)苯基)吡啶[2,3-d]嘧啶-2(1H)-酮的制备Step 4. (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-chloro-6-fluoro-1-(2-(methylsulfo)phenyl) Preparation of pyrid[2,3-d]pyrimidin-2(1H)-one
将(S)-叔丁基4-(7-氯-6-氟-1-(2-(甲基磺酰基)苯基)-2-氧-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸(500mg,0.9mmol)溶于二氯甲烷(10mL)中,加入三氟乙酸(2mL),反应液室温搅拌2h,浓缩干,残留物与二氯甲烷(15mL)共蒸3次得粗品。将该粗品溶解在二氯甲烷(8mL)中,冷却至0℃,滴加N,N-二异丙基乙胺(0.6mL,3.6mmol)和丙烯酰氯(110mg,1.2mmol)的二氯甲烷溶液(1mL)。反应液在0℃下搅拌30min,饱和碳酸氢钠(30mL)淬灭,并以二氯甲烷(20mL)萃取3次,合并二氯甲烷层,干燥,浓缩,残留物以硅胶柱纯化(二氯甲烷/甲醇=60/1),得目标产物(380mg,收率:83%)。(S)-tert-butyl 4-(7-chloro-6-fluoro-1-(2-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyrido[2,3 -d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid (500mg, 0.9mmol) was dissolved in dichloromethane (10mL), trifluoroacetic acid (2mL) was added, the reaction solution was stirred at room temperature for 2h, Concentrated to dryness, the residue was co-evaporated with dichloromethane (15 mL) three times to obtain the crude product. The crude product was dissolved in dichloromethane (8 mL), cooled to 0°C, and N,N-diisopropylethylamine (0.6 mL, 3.6 mmol) and acryloyl chloride (110 mg, 1.2 mmol) in dichloromethane were added dropwise solution (1 mL). The reaction solution was stirred at 0 °C for 30 min, quenched with saturated sodium bicarbonate (30 mL), and extracted three times with dichloromethane (20 mL), the dichloromethane layers were combined, dried, concentrated, and the residue was purified by silica gel column (dichloromethane). Methane/methanol=60/1) to obtain the target product (380 mg, yield: 83%).
LC-MS:m/z 506(M+H)
+。
LC-MS: m/z 506 (M+H) + .
第5步.4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-7-(2-氟-6-羟基苯基)-1-(2-(甲磺酰基)苯基)吡啶[2,3-d]嘧啶-2(1H)-酮的制备Step 5. 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2 Preparation of -(methylsulfonyl)phenyl)pyridin[2,3-d]pyrimidin-2(1H)-one
将(S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-7-氯-6-氟-1-(2-(甲基磺基)苯基)吡啶[2,3-d]嘧啶-2(1H)-酮(150mg,0.3mmol)、(2-氟-6-羟基苯基)硼酸(60mg,0.4mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(24mg,0.03mmol)和乙酸钾(120mg,1.2mmol)悬浮于二氧六环/水(7.5mL/0.75mL)混合溶剂中,氮气置换3次,并于90℃加热搅拌2h。反应液冷却至室温后,加入半饱和碳酸氢钠溶液(20mL),并以乙酸乙酯(20mL)萃取3次。合并乙酸乙酯层,干燥,浓缩,残留物以硅胶柱纯化(二氯甲烷/甲醇=100/1到60/1),得目标产物(90mg,收率:52%)。(S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-chloro-6-fluoro-1-(2-(methylsulfo)phenyl)pyridine[2 ,3-d]pyrimidin-2(1H)-one (150 mg, 0.3 mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (60 mg, 0.4 mmol), [1,1'-bis(diphenyl) Phosphine)ferrocene]dichloropalladium dichloromethane complex (24mg, 0.03mmol) and potassium acetate (120mg, 1.2mmol) were suspended in dioxane/water (7.5mL/0.75mL) mixed solvent, Nitrogen was replaced three times, and the mixture was heated and stirred at 90 °C for 2 h. After the reaction solution was cooled to room temperature, half-saturated sodium bicarbonate solution (20 mL) was added, followed by extraction with ethyl acetate (20 mL) three times. The ethyl acetate layers were combined, dried and concentrated, and the residue was purified by silica gel column (dichloromethane/methanol=100/1 to 60/1) to obtain the target product (90 mg, yield: 52%).
LC-MS:m/z 582(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.97-8.94(m,1H),8.27(d, J=8.0Hz,1H),7.90-7.84(m,2H),7.79-7.74(m,1H),7.46-7.42(m,1H),7.29-7.23(m,1H),6.71-6.57(m,3H),6.44-6.38(m,1H),5.82(d,J=11.2Hz,1H),5.12-4.32(m,3H),4.07-3.63(m,3H),3.24-3.01(m,4H),1.50(s,3H).
LC-MS: m/z 582 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.97-8.94 (m, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.90-7.84 (m, 2H), 7.79-7.74 (m, 1H), 7.46-7.42(m, 1H), 7.29-7.23(m, 1H), 6.71-6.57(m, 3H), 6.44-6.38(m, 1H), 5.82(d, J=11.2Hz, 1H), 5.12- 4.32(m,3H),4.07-3.63(m,3H),3.24-3.01(m,4H),1.50(s,3H).
按照实施例85的方法以不同的起始原料合成了以下化合物:The following compounds were synthesized according to the method of Example 85 with different starting materials:
实施例86 4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-7-(2-氟-6-羟基苯基)-1-(2-(异丙磺酰基)苯基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 86 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2- (Isopropylsulfonyl)phenyl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 610(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.91-8.86(m,1H),8.22-8.19(m,1H),7.88-7.82(m,2H),7.75-7.72(m,1H),7.45-7.42(m,1H),7.28-7.23(m,1H),6.71-6.63(m,3H),6.44-6.39(m,1H),5.83-5.80(m,1H),5.04-4.79(m,3H),4.56-3.90(m,4H),3.71-3.48(m,1H),1.50(s,3H),1.33-1.30(m,3H),1.18-1.16(m,3H).
LC-MS: m/z 610 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.91-8.86 (m, 1H), 8.22-8.19 (m, 1H), 7.88-7.82 (m, 2H), 7.75-7.72 (m, 1H), 7.45-7.42 (m,1H),7.28-7.23(m,1H),6.71-6.63(m,3H),6.44-6.39(m,1H),5.83-5.80(m,1H),5.04-4.79(m,3H) ,4.56-3.90(m,4H),3.71-3.48(m,1H),1.50(s,3H),1.33-1.30(m,3H),1.18-1.16(m,3H).
实施例87 4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-7-(2-氟-6-羟基苯基)-1-(2-甲基-6-(甲磺酰基)苯基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 87 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2- Methyl-6-(methylsulfonyl)phenyl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 596(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.12-8.11(m,1H),7.89-7.87(m,1H),7.75-7.63(m,2H),7.26(m,1H),6.69-6.64(m 3H),6.44-6.40(m,1H),5.84-5.81(m,1H),5.00-4.40(m,3H),4.07-3.65(m,3H),3.25-3.16(m,4H),2.20-2.18(m,3H),1.58-1.50(m,3H).
LC-MS: m/z 596 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 8.12-8.11 (m, 1H), 7.89-7.87 (m, 1H), 7.75-7.63 (m, 2H), 7.26 (m, 1H), 6.69-6.64 (m 3H), 6.44-6.40(m, 1H), 5.84-5.81(m, 1H), 5.00-4.40(m, 3H), 4.07-3.65(m, 3H), 3.25-3.16(m, 4H), 2.20- 2.18(m,3H),1.58-1.50(m,3H).
实施例87-1 通过手性分离得到两个异构体实施例87A和实施例87B:Example 87-1 Two isomers Example 87A and Example 87B were obtained by chiral separation:
实施例87A:LC-MS:m/z 596(M+H)
+。
Example 87A: LC-MS: m/z 596 (M+H) + .
实施例87B:LC-MS:m/z 596(M+H)
+。
Example 87B: LC-MS: m/z 596 (M+H) + .
实施例88 4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-7-(2-氟-6-羟基苯基)-1-(2-(甲磺酰基)吡啶-3-基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 88 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2- (Methylsulfonyl)pyridin-3-yl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 583(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.80(dd,J=4.8,1.2Hz,1H),8.37-8.25(m,1H),8.05(dd,J=8.0,1.2Hz,1H),7.90-7.87(m,1H),7.26(dd,J=14.6,7.6Hz,1H),6.92(m,1H),6.82-6.65(m,2H),6.23-6.18(m,1H),5.76(dd,J=6.4,2.4Hz,1H),4.98-4.82(m,1H),4.44-4.00(m,3H),3.81-3.62(m,2H),3.24-3.00(m,4H),1.34-1.29(m,3H).
LC-MS: m/z 583 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.80 (dd, J=4.8, 1.2 Hz, 1H), 8.37-8.25 (m, 1H), 8.05 (dd, J=8.0, 1.2 Hz, 1H), 7.90- 7.87(m, 1H), 7.26(dd, J=14.6, 7.6Hz, 1H), 6.92(m, 1H), 6.82-6.65(m, 2H), 6.23-6.18(m, 1H), 5.76(dd, J=6.4, 2.4Hz, 1H), 4.98-4.82(m, 1H), 4.44-4.00(m, 3H), 3.81-3.62(m, 2H), 3.24-3.00(m, 4H), 1.34-1.29( m,3H).
实施例89 4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-7-(2-氟-6-羟基苯基)-1-(4-(甲磺酰基)吡啶-3-基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 89 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4- (Methylsulfonyl)pyridin-3-yl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 583(M+H)
+。
1H NMR(400MHz,CDCl
3)δ9.06(d,J=4.2Hz),8.75-8.74(m,1H),8.59-8.57(m,1H),8.10(d,J=4.2Hz),7.87(d,J=11.2Hz,1H),7.30-7.25(m,1H),6.72-6.57(m,3H),6.64-6.58(m,1H),5.84-5.82(m,1H),5.29-4.28(m,3H),4.10-3.61(m,3H),3.22-2.92(m,4H0,1.59-1.48(m,3H).
LC-MS: m/z 583 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 9.06 (d, J=4.2Hz), 8.75-8.74 (m, 1H), 8.59-8.57 (m, 1H), 8.10 (d, J=4.2Hz), 7.87 (d, J=11.2Hz, 1H), 7.30-7.25(m, 1H), 6.72-6.57(m, 3H), 6.64-6.58(m, 1H), 5.84-5.82(m, 1H), 5.29-4.28 (m,3H),4.10-3.61(m,3H),3.22-2.92(m,4H0,1.59-1.48(m,3H).
实施例90 2-(1-丙烯酰-4-(6-氟-7-(2-氟-6-羟基苯基)-1-(2-(甲磺酰基)苯基)-2-氧-1,2-二氢吡啶[2,3-d]嘧啶-4-基)哌嗪-2-基)乙腈Example 90 2-(1-Acryloyl-4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-(methylsulfonyl)phenyl)-2-oxo- 1,2-Dihydropyridine[2,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
LC-MS:m/z 607(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.29-8.24(m,1H),7.96-7.76(m,3H),7.47-7.43(m,1H),7.29(m,1H),6.70-6.56(m,3H),6.45-6.41(m,1H),5.00(brs,1H),4.56-3.70(m,6H),3.16(m,3H),3.16-3.10(m,1H),2.98-2.79(m,1H).
LC-MS: m/z 607 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 8.29-8.24 (m, 1H), 7.96-7.76 (m, 3H), 7.47-7.43 (m, 1H), 7.29 (m, 1H), 6.70-6.56 (m) ,3H),6.45-6.41(m,1H),5.00(brs,1H),4.56-3.70(m,6H),3.16(m,3H),3.16-3.10(m,1H),2.98-2.79(m , 1H).
实施例91 2-(1-丙烯酰-4-(6-氟-7-(2-氟-6-羟基苯基)-1-(2-甲基-6-(甲磺酰基)苯基)-2-氧-1,2-二氢吡啶[2,3-d]嘧啶-4-基)哌嗪-2-基)乙腈Example 91 2-(1-Acryloyl-4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-methyl-6-(methylsulfonyl)phenyl) -2-Oxo-1,2-dihydropyridine[2,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
LC-MS:m/z 621(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.12-7.97(m,2H),7.76-7.72(m,1H),7.67-7.64(m,1H),7.29(m,1H),6.69-6.46(m,3H),6.42-6.41(m,1H),5.88-5.86(m,1H),5.00(brs,1H),4.54-3.77(m,6H),3.12(m,4H),2.81-2.77(m,1H),2.20-2.17(m,3H).
LC-MS: m/z 621 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 8.12-7.97(m, 2H), 7.76-7.72(m, 1H), 7.67-7.64(m, 1H), 7.29(m, 1H), 6.69-6.46(m ,3H),6.42-6.41(m,1H),5.88-5.86(m,1H),5.00(brs,1H),4.54-3.77(m,6H),3.12(m,4H),2.81-2.77(m ,1H),2.20-2.17(m,3H).
实施例92 2-(1-丙烯酰-4-(6-氟-7-(2-氟-6-羟基苯基)-1-(2-(甲磺酰基)吡啶-3-基)-2-氧-1,2-二氢吡啶[2,3-d]嘧啶-4-基)哌嗪-2-基)乙腈Example 92 2-(1-Acryloyl-4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-(methylsulfonyl)pyridin-3-yl)-2 -Oxy-1,2-dihydropyridine[2,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
LC-MS:m/z 608(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.82-8.81(m,1H),7.99-7.76(m,3H),7.30(m,1H),6.70-6.56(m,3H),6.44-6.40(m,1H),5.87-5.84(m,1H),5.01(brs,1H),4.61-3.60(m,6H),3.29(m,3H),2.96-2.76(m,2H).
LC-MS: m/z 608 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 8.82-8.81 (m, 1H), 7.99-7.76 (m, 3H), 7.30 (m, 1H), 6.70-6.56 (m, 3H), 6.44-6.40 (m ,1H),5.87-5.84(m,1H),5.01(brs,1H),4.61-3.60(m,6H),3.29(m,3H),2.96-2.76(m,2H).
实施例93 4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-7-(2-氯-6-氟苯基)-6-氟-1-(2-甲基-6-(甲砜基)苯基)吡啶[2,3-d]嘧啶-2(1H)-酮Example 93 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-7-(2-chloro-6-fluorophenyl)-6-fluoro-1-(2- Methyl-6-(methylsulfonyl)phenyl)pyridin[2,3-d]pyrimidin-2(1H)-one
LC-MS:m/z 614(M+H)
+。
1H NMR(400MHz,CDCl
3)δ7.95(d,J=3.6Hz,1H),7.82(t,J=8.4Hz,1H),7.60(d,J=3.2Hz,1H),7.50(t,J=8.4Hz,1H),7.34-7.29(m,1H),7.20(d,J=8Hz,1H),7.02(m,1H),6.60(m,1H),6.39(dd,J=1.6Hz,17.2Hz,1H),5.80(dd,J=1.2Hz,10.4Hz,1H),5.20-4.20(m,3H),4.10-3.55(m,3H),3.40-3.05(m,4H),2.17-2.15(m,3H),1,.51(m,3H).
LC-MS: m/z 614 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.95 (d, J=3.6 Hz, 1H), 7.82 (t, J=8.4 Hz, 1H), 7.60 (d, J=3.2 Hz, 1H), 7.50 (t ,J=8.4Hz,1H),7.34-7.29(m,1H),7.20(d,J=8Hz,1H),7.02(m,1H),6.60(m,1H),6.39(dd,J=1.6 Hz, 17.2Hz, 1H), 5.80(dd, J=1.2Hz, 10.4Hz, 1H), 5.20-4.20(m, 3H), 4.10-3.55(m, 3H), 3.40-3.05(m, 4H), 2.17-2.15(m,3H),1,.51(m,3H).
实施例95 2-(4-丙烯酰-1-(6-氟-7-(2-氟-6-羟基苯基)-1-(2-(甲砜基)苯基)-2-氧-1,2-二氢吡啶[2,3-d]嘧啶-4-基)哌嗪-2-基)乙腈Example 95 2-(4-Acryloyl-1-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-(methylsulfonyl)phenyl)-2-oxo- 1,2-Dihydropyridine[2,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile
LC-MS:m/z 607(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.87-8.77(m,1H),8.22-8.19(m,1H),7.86-7.80(m,3H),7.69(m,1H),7.37-7.36(m,1H),7.25(m,1H),6.66-6.53(m,3H),6.39(d,J=17.2Hz,1H),5.81(d,J=10Hz,1H),5.30-5.20(m,1H),4.80-3.95(m,3H),3.90-3.30(m,3H),3.09-2.88(m,5H).
LC-MS: m/z 607 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 8.87-8.77(m,1H), 8.22-8.19(m,1H), 7.86-7.80(m,3H), 7.69(m,1H), 7.37-7.36(m) ,1H),7.25(m,1H),6.66-6.53(m,3H),6.39(d,J=17.2Hz,1H),5.81(d,J=10Hz,1H),5.30-5.20(m,1H) ),4.80-3.95(m,3H),3.90-3.30(m,3H),3.09-2.88(m,5H).
实施例96 2-(4-丙烯酰-1-(6-氟-7-(2-氟-6-羟基苯基)-1-(2-(甲砜基)苯基)-2-氧-1,2-二氢吡啶[2,3-d]嘧啶-4-yl)哌嗪-2-基)乙酰胺Example 96 2-(4-Acryloyl-1-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-(methylsulfonyl)phenyl)-2-oxo- 1,2-Dihydropyridine[2,3-d]pyrimidine-4-yl)piperazin-2-yl)acetamide
LC-MS:m/z 625(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.20-7.75(m,2H),7.60-7.40(m,2H),7.11-7.01(m,2H),6.84-7.53(m,5H),6.36-6.29(m,1H),5.79(m,1H),5.44-5.23(m,1H),5.50-3.98(m,4H),3.81-3.070(m,6H),2.85-2.63(m,2H).
LC-MS: m/z 625 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 8.20-7.75 (m, 2H), 7.60-7.40 (m, 2H), 7.11-7.01 (m, 2H), 6.84-7.53 (m, 5H), 6.36-6.29 (m,1H),5.79(m,1H),5.44-5.23(m,1H),5.50-3.98(m,4H),3.81-3.070(m,6H),2.85-2.63(m,2H).
生物学测试评价Biological Test Evaluation
以下生物学测试例进一步描述解释本发明,但这些实例并非意味着限制本发明的范围。The following biological test examples are further described to illustrate the present invention, but these examples are not meant to limit the scope of the present invention.
化合物对NCI-H358(KRAS
G12C突变)细胞的抗增殖活性的细胞实验。
Cellular assay for antiproliferative activity of compounds on NCI-H358 (KRAS G12C mutant) cells.
实验步骤Experimental procedure
向384微孔板的外围孔中加入40μL磷酸盐缓冲液,随后向其他孔中加入40μL待测细胞悬浮液,然后将微孔板置于二氧化碳培养箱中培养过夜。40 μL of phosphate buffer was added to the peripheral wells of the 384 microwell plate, followed by 40 μL of the cell suspension to be tested to other wells, and then the microplates were incubated in a carbon dioxide incubator overnight.
对待测化合物进行梯度稀释,将每个化合物稀释10个浓度梯度(从50μM稀释到0.003μM)并分别加100nL到微孔板的对应孔中。加药以后,在A、P行及1、24列每孔加入40μL磷酸盐缓冲液,然后将微孔板置于二氧化碳培养箱中培养5天。The compounds to be tested were serially diluted, and each compound was diluted with 10 concentration gradients (diluted from 50 μM to 0.003 μM) and added 100 nL to the corresponding wells of the microplate. After dosing, 40 μL of phosphate buffer was added to each well in rows A and P and columns 1 and 24, and then the microplate was incubated in a carbon dioxide incubator for 5 days.
向微孔板每孔中加入20μL的Promega CellTiter-Glo试剂,随后在室温震荡10min使发光信号稳定,然后采用PekinElmer Envision多标记分析仪读数。20 μL of Promega CellTiter-Glo reagent was added to each well of the microplate, followed by shaking at room temperature for 10 min to stabilize the luminescence signal, and then read using a PekinElmer Envision multi-label analyzer.
最后应用GraphPad Prism软件计算化合物的IC
50值,并绘出拟合曲线。
Finally, the IC 50 values of the compounds were calculated by GraphPad Prism software, and the fitting curves were drawn.
本发明中实施例化合物对NCI-H358(KRAS
G12C突变)细胞的抗增殖活性见表1。
Table 1 shows the anti-proliferative activities of the compounds of the examples of the present invention on NCI-H358 (KRAS G12C mutant) cells.
表1本发明中实施例化合物抗增殖活性Table 1 Antiproliferative activity of example compounds in the present invention
IC 50 IC50 | NCI-H358(μM)NCI-H358(μM) |
实施例1Example 1 | 0.090.09 |
实施例2Example 2 | 0.540.54 |
实施例3Example 3 | 0.870.87 |
实施例4Example 4 | 0.420.42 |
实施例5Example 5 | 0.0280.028 |
实施例5AExample 5A | 0.230.23 |
实施例5BExample 5B | 0.0110.011 |
实施例6Example 6 | 0.0280.028 |
实施例6AExample 6A | 0.20.2 |
实施例6BExample 6B | 0.0150.015 |
实施例7Example 7 | 0.240.24 |
实施例8Example 8 | 0.170.17 |
实施例9Example 9 | 0.230.23 |
实施例10Example 10 | 0.0100.010 |
实施例10AExample 10A | 0.280.28 |
实施例10BExample 10B | 0.0050.005 |
实施例11Example 11 | 0.180.18 |
实施例12Example 12 | 0.0410.041 |
实施例13Example 13 | 0.0150.015 |
实施例14Example 14 | 0.360.36 |
实施例15Example 15 | 0.0580.058 |
实施例16Example 16 | 0.0120.012 |
实施例16AExample 16A | 0.720.72 |
实施例16BExample 16B | 0.0070.007 |
实施例17Example 17 | 0.0310.031 |
实施例18Example 18 | 0.0300.030 |
实施例18AExample 18A | 0.0130.013 |
实施例18BExample 18B | 0.460.46 |
实施例19Example 19 | 0.0480.048 |
实施例20Example 20 | 0.0230.023 |
实施例20AExample 20A | 1.51.5 |
实施例20BExample 20B | 0.0130.013 |
实施例21Example 21 | 1.21.2 |
实施例22Example 22 | 0.0390.039 |
实施例23Example 23 | 1.11.1 |
实施例24Example 24 | 0.0280.028 |
实施例25Example 25 | 0.0090.009 |
实施例25AExample 25A | 0.350.35 |
实施例25BExample 25B | 0.0060.006 |
实施例26Example 26 | 0.0180.018 |
实施例27Example 27 | 0.030.03 |
实施例28Example 28 | 0.0260.026 |
实施例29Example 29 | 0.0530.053 |
实施例30Example 30 | 0.0180.018 |
实施例30AExample 30A | 0.740.74 |
实施例30BExample 30B | 0.0110.011 |
实施例31Example 31 | 0.0080.008 |
实施例31AExample 31A | 0.300.30 |
实施例31BExample 31B | 0.0060.006 |
实施例53BExample 53B | 0.0660.066 |
实施例54Example 54 | 2.52.5 |
实施例55Example 55 | 5.35.3 |
实施例56Example 56 | 8.08.0 |
实施例57Example 57 | 1010 |
实施例58Example 58 | 1010 |
实施例59Example 59 | 0.200.20 |
实施例60Example 60 | >10>10 |
实施例61Example 61 | >10>10 |
实施例63AExample 63A | 0.370.37 |
实施例63BExample 63B | 0.0080.008 |
实施例64Example 64 | 0.120.12 |
实施例65Example 65 | >10>10 |
实施例66Example 66 | >10>10 |
实施例67Example 67 | >10>10 |
实施例68Example 68 | 2.22.2 |
实施例69Example 69 | >10>10 |
实施例70Example 70 | >10>10 |
实施例71Example 71 | >10>10 |
实施例72Example 72 | >10>10 |
实施例73Example 73 | >10>10 |
实施例74Example 74 | >10>10 |
实施例75Example 75 | >10>10 |
实施例76Example 76 | >10>10 |
实施例77Example 77 | >10>10 |
实施例78AExample 78A | 0.170.17 |
实施例78BExample 78B | 0.0070.007 |
实施例79AExample 79A | 0.0480.048 |
实施例79BExample 79B | 0.0020.002 |
实施例80BExample 80B | 0.0070.007 |
实施例81BExample 81B | 0.0090.009 |
实施例82BExample 82B | 0.0500.050 |
实施例83BExample 83B | 0.0260.026 |
实施例84BExample 84B | 0.0060.006 |
实施例85Example 85 | 0.620.62 |
实施例86Example 86 | 0.560.56 |
实施例87Example 87 | 0.0370.037 |
实施例87AExample 87A | 0.0290.029 |
实施例87BExample 87B | 0.430.43 |
实施例88Example 88 | 2.52.5 |
实施例89Example 89 | 5.35.3 |
实施例90Example 90 | 3.23.2 |
实施例91Example 91 | 1.51.5 |
实施例92Example 92 | >10>10 |
从表1可以看出:It can be seen from Table 1 that:
本发明实施例化合物对于KRAS
G12C突变型NCI-H358细胞显示出了很好的细胞抗增殖活性。此外,本发明化合物中,当R
4为取代苯基时,活性较佳,优于杂芳基,尤其是含有苯砜结构的化合物。
The compounds of the examples of the present invention showed good cell anti-proliferation activity on KRAS G12C mutant NCI-H358 cells. In addition, in the compounds of the present invention, when R 4 is a substituted phenyl group, the activity is better than that of a heteroaryl group, especially a compound containing a phenylsulfone structure.
药代动力学测试评价Pharmacokinetic Testing Evaluation
小鼠药代动力学测试评价Evaluation of Pharmacokinetic Testing in Mice
雄性ICR小鼠,体重20-30g左右,禁食过夜后,灌胃给予30mg/kg本发明化合物实施例10B、16B、18A、63B、78B的溶液[CMC/TW80为载体]。分别在给于本发明化合物后0.5,1.0,2.0,4.0,6.0,8.0,12和24h采血,用LC/MS/MS测定血浆中本发明化合物的浓度。Male ICR mice, weighing about 20-30 g, were fasted overnight and were given 30 mg/kg solutions of the compounds of the present invention Examples 10B, 16B, 18A, 63B, and 78B by gavage [CMC/TW80 as the carrier]. Blood was collected at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12 and 24 hours after administration of the compound of the present invention, respectively, and the concentration of the compound of the present invention in plasma was determined by LC/MS/MS.
测试结果如表2所示The test results are shown in Table 2
表2药代动力学参数总结(n=4,均值)Table 2 Summary of pharmacokinetic parameters (n=4, mean)
由检测结果看出,具有相似结构的化合物,其中,含有苯砜结构的化合物相对于吡啶砜结构的化合物具有更好的药代动力学特性。It can be seen from the detection results that the compounds with similar structures, among them, the compounds containing the phenylsulfone structure have better pharmacokinetic properties than the compounds with the pyridinesulfone structure.
大鼠药代动力学测试评价Evaluation of Pharmacokinetic Testing in Rats
雄性SD大鼠,体重220g左右,禁食过夜后,灌胃给予15mg/kg本发明化合物或对照化合物AMG510的溶液[DMSO/PEG400为载体]。分别在给于本发明化合物后0.5,1.0,2.0,4.0,6.0,8.0,12和24采血,或者连续给药7天以后0.5,1.0,2.0,4.0,6.0,8.0,12,和24采血,用LC/MS/MS测定血浆中本发明化合物或对照化合物AMG510的浓度。Male SD rats, weighing about 220 g, were fasted overnight and then intragastrically administered a solution of 15 mg/kg of the present compound or the control compound AMG510 [DMSO/PEG400 as carrier]. Blood was collected at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12, and 24 after administration of the compound of the present invention, or at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12, and 24 after administration for 7 consecutive days, respectively, The concentration of the compound of the present invention or the control compound AMG510 in plasma was determined by LC/MS/MS.
检测结果表明,本发明化合物相对于AMG510具有良好的药代动力学特性。The test results show that the compound of the present invention has good pharmacokinetic properties relative to AMG510.
抗肿瘤活性药效学测试评价Pharmacodynamic test evaluation of antitumor activity
1、H358 CDX肿瘤模型1. H358 CDX tumor model
将100uL含5x10
6NCI-H358肿瘤细胞悬液皮下接种到裸鼠右后背部。每天监测小鼠健康状况,当肿瘤生长至可触及时开始测量。肿瘤体积计算公式采用:0.5xLxW2,其中L、W分别代表肿瘤长、宽。肿瘤长至~200mm
3,对小鼠进行随机分组。小鼠每天灌胃给予相应剂量(20mg/Kg)化合物的溶液,同时对其一般状态进行监测。肿瘤每周测量2次,体重每周测量两次。测试结果如表3所示。
100 uL of 5x10 6 NCI-H358 tumor cell suspension was subcutaneously inoculated into the right posterior back of nude mice. Mice health were monitored daily, starting when tumors grew to palpable size. The tumor volume was calculated using the formula: 0.5xLxW2, where L and W represent the length and width of the tumor, respectively. Tumors grew to -200 mm3 and mice were randomized. Mice were given the corresponding dose (20 mg/Kg) of compound solution by gavage every day, and their general status was monitored. Tumors were measured twice a week and body weights were measured twice a week. The test results are shown in Table 3.
表3抗肿瘤活性药效学测试评价Table 3 Pharmacodynamic test evaluation of antitumor activity
结果表明,本发明含有苯砜结构的化合物(如实施例63B和实施例78B)具有比对照化合物AMG510更好的药效。此外,含有二甲基哌嗪结构的实施例63B和实施例78B具有比单甲基哌嗪化合物实施例10B更好的药效。The results show that the compounds of the present invention containing phenylsulfone structure (such as Example 63B and Example 78B) have better efficacy than the control compound AMG510. In addition, Example 63B and Example 78B containing the dimethylpiperazine structure had better efficacy than the monomethylpiperazine compound Example 10B.
2、MIA PaCa-2 CDX肿瘤模型2. MIA PaCa-2 CDX tumor model
将100uL含5x10
6MIA PaCa-2肿瘤细胞悬液皮下接种到裸鼠右后侧腹部。每天监测小鼠健康状况,当肿瘤生长至可触及时开始测量。肿瘤体积计算公式采用:0.5xLxW
2,其中L、W分别代表肿瘤长、宽。肿瘤长至~150mm
3,对小鼠进行随机分组。小鼠每天灌胃给予相应剂量(3、10mg/Kg)化合物的CMC-Na悬液,同时对其一般状态进行监测。肿瘤每周测量3次,体重每周测量两次。
100 uL of 5x10 6 MIA PaCa-2 tumor cell suspension was subcutaneously inoculated into the right hind flank of nude mice. Mice health were monitored daily, starting when tumors grew to palpable size. The tumor volume calculation formula adopts: 0.5×L×W 2 , where L and W represent the length and width of the tumor, respectively. Tumors grew to -150 mm3 and mice were randomized. Mice were given corresponding doses (3, 10 mg/Kg) of compound CMC-Na suspension by gavage every day, and their general status was monitored at the same time. Tumors were measured 3 times a week and body weights were measured twice a week.
由检测结果看出,本发明化合物具有良好的抗肿瘤效果。It can be seen from the detection results that the compound of the present invention has a good anti-tumor effect.
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned herein are incorporated by reference in this application as if each document were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.
Claims (29)
- 式(I)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药:Compounds of formula (I), stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof:式中:where:A、B相同或者不同,各自独立地选自下组:CH、CR 5或N; A and B are the same or different, and are each independently selected from the group consisting of CH, CR 5 or N;X选自下组:4-14元饱和或不饱和杂环基、C 4-C 14环烷基、C 6-C 14芳基或5-14元杂芳基,其中,所述的杂环基、环烷基、芳基或杂芳基可以任选地被一个或多个R 8所取代; X is selected from the group consisting of 4-14 membered saturated or unsaturated heterocyclic group, C 4 -C 14 cycloalkyl group, C 6 -C 14 aryl group or 5-14 membered heteroaryl group, wherein said heterocyclic group radical, cycloalkyl, aryl or heteroaryl may be optionally substituted with one or more R 8 ;U、V、W和Q相同或者不同,各自独立地选自下组:CH、CR 3或N; U, V, W and Q are the same or different and are each independently selected from the group consisting of CH, CR or N;R 1选自下组: 其中, 代表双键 或三键 R 1 is selected from the following group: in, stands for double bond or three keysR A为不存在,或者独立地选自下组:氢、氘、氟、氰基或者C 1-C 3烷基;各R B独立地选自下组:氢、氘、氰基或者C 1-C 3烷基;其中,所述烷基可以被选自下组的一个或多个取代基取代:氘、卤素、氰基、胺基、C 3-C 7环烷基、4-7元杂环基、NHR 9或NR 9R 10;R 9和R 10各自独立地为C 1-C 3烷基;或R 9,R 10与其连接的N原子一起构成取代或未取代的4-8元杂环基; RA is absent, or independently selected from the group consisting of hydrogen, deuterium, fluorine, cyano, or C1 - C3 alkyl; each R B is independently selected from the group consisting of hydrogen, deuterium, cyano, or C1 -C 3 alkyl; wherein, the alkyl may be substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, amine, C 3 -C 7 cycloalkyl, 4-7 membered Heterocyclyl, NHR 9 or NR 9 R 10 ; R 9 and R 10 are each independently C 1 -C 3 alkyl; or R 9 , R 10 together with the N atom to which it is attached constitutes a substituted or unsubstituted 4-8 membered heterocyclic group;p为1或2的整数;p is an integer of 1 or 2;R 2选自取代的下组基团:C 6-C 14芳基、5-14元杂芳基,其中,所述取代是指被选自下组的一个或多个基团取代:R'、-SR'、-SOR'、-SO 2R'、-SO 2NR'R”、-NR'SO 2R”、-P(=O)R'R”;限定条件是所述C 6-C 14芳基、5-14元杂芳基至少含有一个取代基选自:-SR'、-SOR'、-SO 2R'、-SO 2NR'R”、-NR'SO 2R”、或-P(=O)R'R”;R'、R”相同或不同,各自独立地选自取代或未取代的下组基团:氢、氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C 1-C 6烷基、C 3-C 8环烷基、C 4-C 10环烯基、4-8元杂环基、C 6-C 14芳基、5-14元杂芳基;或当R'和R”连接于同一个N原子时,R'、R”与其连接的N原子一起构成取代或未取代的4-8元杂环基; R 2 is selected from the group of substituted groups: C 6 -C 14 aryl, 5-14-membered heteroaryl, wherein the substitution refers to being substituted by one or more groups selected from the group: R' , -SR', -SOR', -SO 2 R', -SO 2 NR'R", -NR'SO 2 R", -P(=O)R'R"; the qualification is that the C 6 - C 14 aryl, 5-14-membered heteroaryl group contains at least one substituent selected from: -SR', -SOR', -SO 2 R', -SO 2 NR'R", -NR'SO 2 R", or -P(=O)R'R";R',R" are the same or different, each independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, halogen, nitro, hydroxyl, cyano, Ester group, amine group, amide group, C 1 -C 6 alkyl group, C 3 -C 8 cycloalkyl group, C 4 -C 10 cycloalkenyl group, 4-8 membered heterocyclic group, C 6 -C 14 aryl group , 5-14-membered heteroaryl; or when R' and R" are connected to the same N atom, R', R" together with the N atom to which they are connected constitute a substituted or unsubstituted 4-8-membered heterocyclic group;R 3选自取代或未取代的下组基团:氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基、脲基、4-20元杂环基、C 6-C 14芳基、5-14元杂芳基; R 3 is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, halogen, nitro, hydroxyl, cyano, ester, amine group, amide group, sulfonamide group, urea group, 4-20-membered heterocyclic group, C 6 -C 14 aryl group, 5-14-membered heteroaryl group;L选自下组:键、-C(O)-、C 1-C 3亚烷基; L is selected from the group consisting of a bond, -C(O)-, C 1 -C 3 alkylene;R 4选自取代或未取代的下组基团:氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、胺基、羟基、4-20元杂环基、C 6-C 14芳基、5-14元杂芳基; R 4 is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, amino, hydroxyl, 4-20-membered heterocyclic group, C 6 -C 14 -aryl, 5-14-membered heteroaryl;R 5选自取代或未取代的下组基团:氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基、脲基、4-20元杂环基、C 6-C 14芳基、5-14元杂芳基; R 5 is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, halogen, nitro, hydroxyl, cyano, ester, amine group, amide group, sulfonamide group, urea group, 4-20-membered heterocyclic group, C 6 -C 14 aryl group, 5-14-membered heteroaryl group;R 6选自取代或未取代的下组基团:氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、4-20元杂环基、C 6-C 14芳基、5-14元杂芳基; R 6 is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, 4-20 membered heterocyclic group, C 6 -C 14 aryl base, 5-14-membered heteroaryl;R 8独立地选自取代或未取代的下组基团:氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、氨基、羟基、4-20元杂环基、C 6-C 14芳基、5-14元杂芳基; R 8 is independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, amino, hydroxyl, 4-20-membered heterocyclic group, C 6 -C 14 aryl, 5-14 membered heteroaryl;其中,所述“取代”未特别说明的情况下,均是指被选自下组的一个或多个基团取代:氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、硝基、羟基、氰基、酯基、胺基、NR bC(=O)OR e、OC(=O)R e、OC(=O)NR bR c、酰胺基、磺酰胺基或脲基;R b、R c可以独立表示氢、氘、C1-C6烷基、C3-C8环烷基、4-8元杂环基、5-14元杂芳基或C6-C14芳环,或者说R b和R c与N原子一起可以形成4-8元杂环基;R e可以独立表示氢、C1-C6烷基、C3-C8环烷基、C2-C6烯基、C3-C6环烯基、C2-C6炔基、4-8元杂环基、5-14元杂芳基或C6-C14芳环; Wherein, the "substituted" refers to being substituted by one or more groups selected from the following group unless otherwise specified: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 Alkyl, halogenated C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy Oxy, C 6 -C 14 aryl, 5-14-membered heteroaryl, 4-20-membered heterocyclyl, halogen, nitro, hydroxyl, cyano, ester, amine, NR b C(=O) OR e , OC(=O)R e , OC(=O)NR b R c , amide group, sulfonamide group or urea group; R b , R c can independently represent hydrogen, deuterium, C1-C6 alkyl, C3 -C8 cycloalkyl, 4-8 membered heterocyclyl, 5-14 membered heteroaryl or C6-C14 aromatic ring, or Rb and Rc together with N atom can form 4-8 membered heterocyclyl; R e can independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl, 4-8 membered heterocyclyl, 5-14 membered Heteroaryl or C6-C14 aromatic ring;限定条件为:The qualifications are:当B为CH或CR 5时,R 1选自下组: 其中,p为2; When B is CH or CR 5 , R 1 is selected from the group consisting of: Among them, p is 2;当V为C(Cl)时,R 2不选自: When V is C(Cl ) , R is not selected from:
- 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的 盐、水合物、溶剂合物或前药,其特征在于,其具有式(III)所示结构:The compound of claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that it has the formula (III ) shown in the structure:R 1、R 2、R 4、X、L、U、V、W、Q的定义如权利要求1所述。 The definitions of R 1 , R 2 , R 4 , X, L, U, V, W, and Q are as described in claim 1 .
- 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其特征在于,其具有式(IV)所示结构:The compound of claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that it has the formula (IV ) shown in the structure:式中:where:R 1、R 2、R 4、R 8、L、U、V、W、Q的定义如权利要求1所述。 The definitions of R 1 , R 2 , R 4 , R 8 , L, U, V, W and Q are as described in claim 1 .
- 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其特征在于,其具有式(V)所示结构:The compound of claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that it has the formula (V ) shown in the structure:式中:where:R 1、R 2、R 4、R 8、U、V、W、Q的定义如权利要求1所述。 The definitions of R 1 , R 2 , R 4 , R 8 , U, V, W and Q are as described in claim 1 .
- 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其特征在于,其具有式(VI)所示结构:The compound of claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that it has the formula (VI ) shown in the structure:式中:where:R 1、R 2、R 4、R 8、U、V、Q的定义如权利要求1所述。 The definitions of R 1 , R 2 , R 4 , R 8 , U, V and Q are as described in claim 1 .
- 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其特征在于,其具有式(VII)所示的结构:The compound of claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that it has the formula (VII ) shown in the structure:式中:where:R 1、R 2、R 4、R 8、V、Q的定义如权利要求1所述。 The definitions of R 1 , R 2 , R 4 , R 8 , V and Q are as described in claim 1 .
- 如权利要求1-6中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其特征在于,其具有式(VIII)所示的结构:The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof of any one of claims 1-6, characterized in that , which has the structure shown in formula (VIII):式中,In the formula,R”'各自独立地选自取代或未取代的下组基团:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C 1-C 6烷基、C 3-C 8环烷基、C 4-C 10环烯基、4-8元杂环基、C 6-C 14芳基、5-14元杂芳基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C 1-C 6烷基、C 3-C 8环烷基、C 4-C 10环烯基、4-8元杂环基、C 6-C 14芳基、5-14元杂芳基; R"' is each independently selected from the group consisting of substituted or unsubstituted groups: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 - C 8 cycloalkyl, C 4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl, wherein the substitution refers to being selected from the following Substituted with one or more groups of the group: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amido, C1 - C6 alkyl, C3 - C8 cycloalkyl, C4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl;q选自:1、2、3或4;q is selected from: 1, 2, 3 or 4;R 1、R 4、R 8、R'、V、Q的定义如权利要求1所述。 The definitions of R 1 , R 4 , R 8 , R′, V and Q are as described in claim 1 .
- 如权利要求1-7中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其特征在于,其具有式(VIII-A)所示的结构:The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof of any one of claims 1-7, characterized in that , which has the structure shown in formula (VIII-A):式中,In the formula,R”'各自独立地选自取代或未取代的下组基团:氘、卤素、硝基、羟基、氰基、酯基、 胺基、酰胺基、C 1-C 6烷基、C 3-C 8环烷基、C 4-C 10环烯基、4-8元杂环基、C 6-C 14芳基、5-14元杂芳基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C 1-C 6烷基、C 3-C 8环烷基、C 4-C 10环烯基、4-8元杂环基、C 6-C 14芳基、5-14元杂芳基; R"' is each independently selected from the group consisting of substituted or unsubstituted groups: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C1 - C6 alkyl, C3- C 8 cycloalkyl, C 4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl, wherein the substitution refers to being selected from the following Substituted with one or more groups of the group: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amido, C1 - C6 alkyl, C3 - C8 cycloalkyl, C4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl;q选自:1、2、3或4;q is selected from: 1, 2, 3 or 4;R 1、R 4、R 8、R'、V、Q的定义如权利要求1所述。 The definitions of R 1 , R 4 , R 8 , R′, V and Q are as described in claim 1 .
- 如权利要求1-8中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其特征在于,R 8各自独立地选自取代或未取代的下组基团:氢、氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基,其中,所述取代是指被氰基取代。 The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof of any one of claims 1-8, characterized in that , R 8 are each independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, Wherein, the substitution refers to substitution by a cyano group.
- 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其特征在于,其具有式(IX)所示的结构:The compound of claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that it has the formula (IX ) shown in the structure:式中,In the formula,R 1选自: 其中,R A选自:H、D、卤素或氰基;R B、R B’相同或不同,各自独立地选自:H、D、卤素、氰基、取代或未取代的C 1-C 3烷基;其中,所述取代是指被选自下组的一个或多个基团取代:D、卤素、氰基、C 1-C 3烷基、C 3-C 6环烷基、4-6元杂环基或NR IVR V;R IV、R V相同或不同,各自独立地选自:H、C 1-C 3烷基、C 3-C 6环烷基或4-6元杂环基;或者R IV、R V和相邻的N一起环合形成4-6元杂环基; R1 is selected from : Wherein, R A is selected from: H, D, halogen or cyano; R B and R B' are the same or different, each independently selected from: H, D, halogen, cyano, substituted or unsubstituted C 1 -C 3 alkyl; wherein, the substitution refers to being substituted by one or more groups selected from the group consisting of D, halogen, cyano, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 4 -6-membered heterocyclyl or NR IV R V ; R IV and R V are the same or different, each independently selected from: H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl or 4-6 membered Heterocyclyl; or R IV , R V and adjacent N are cyclized together to form a 4-6 membered heterocyclyl;R 4、R'、V、Q、R”'及q的定义如权利要求7所述。 The definitions of R 4 , R′, V, Q, R″′ and q are as described in claim 7 .
- 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其特征在于,其具有式(VIII-1)或(VIII-2)所示的结构:The compound of claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that it has the formula (VIII -1) or the structure shown in (VIII-2):式中,In the formula,Rx选自:F或Cl;Rx is selected from: F or Cl;R 4选自取代或未取代苯基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、酯基、氰基、NR bC(=O)OR e、OC(=O)R e、OC(=O)NR bR c、胺基、C 1-C 6烷基、卤代C 1-C 6烷基、C 1-C 6烷氧基、羟基;R b、R c可以独立表示氢、氘、C 1-C 6烷基、C 3-C 8环烷基、4-8元杂环基、5-14元杂芳基或C 6-C 14芳环,或者说R b和R c与N原子一起可以形成4-8元杂环基;R e可以独立表示氢、C1-C 6烷基、C 3-C 8环烷基、C 2-C 6烯基、C 3-C 6环烯基、C 2-C 6炔基、4-8元杂环基、5-14元杂芳基或C6-C14芳环; R 4 is selected from substituted or unsubstituted phenyl, wherein the substitution refers to substitution by one or more groups selected from the group consisting of deuterium, halogen, ester, cyano, NR b C(=O)OR e , OC(=O)R e , OC(=O)NR b R c , amine group, C 1 -C 6 alkyl group, halogenated C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, Hydroxyl; R b , R c can independently represent hydrogen, deuterium, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 4-8-membered heterocyclyl, 5-14-membered heteroaryl or C 6 - C 14 aromatic ring, or R b and R c together with N atom can form a 4-8 membered heterocyclic group; R e can independently represent hydrogen, C1-C 6 alkyl, C 3 -C 8 cycloalkyl, C 2 - C6 alkenyl, C3 - C6 cycloalkenyl, C2 - C6 alkynyl, 4-8-membered heterocyclyl, 5-14-membered heteroaryl or C6-C14 aromatic ring;Rm选自取代或未取代的下组基团:胺基、C 1-C 6烷基、C 3-C 6环烷基、4-6元杂环基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C 1-C 3烷基、C 3-C 6环烷基、4-6元杂环基; Rm is selected from the group consisting of substituted or unsubstituted groups: amine group, C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, 4-6 membered heterocyclic group, wherein the substitution refers to the selected Substituted with one or more groups from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl, C3 - C6 cycloalkyl, 4-6 membered heterocyclyl;Rn选自取代或未取代的下组基团:胺基、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基、-O-C 3-C 6环烷基、C 1-C 6烷基C 3-C 6环烷基、-O-C 1-C 6烷基C 3-C 6环烷基、4-6元杂环基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C 1-C 3烷基、C 1-C 3卤代烷基、C 3-C 6环烷基、4-6元杂环基; Rn is selected from the group consisting of substituted or unsubstituted groups: amine, C1 - C6alkyl , C1 - C6alkoxy , C3 - C6cycloalkyl, -OC3 - C6cycloalkane base, C 1 -C 6 alkyl C 3 -C 6 cycloalkyl, -OC 1 -C 6 alkyl C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group, wherein the substitution refers to Substituted with one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl, C1 - C3 haloalkyl , C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group;R 1的定义如权利要求1所述。 R 1 is as defined in claim 1 .
- 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其特征在于,其具有式(X)或(XI)所示的结构:The compound of claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that it has the formula (X ) or the structure shown in (XI):式中,In the formula,R 4选自取代或未取代C 6-C 14芳基或5-10元杂芳基,其中,所述取代是指被选自下组的一个或多个(如2、3、4或5个)基团取代:氘、卤素、酯基、氰基、NR bC(=O)OR e、OC(=O)R e、 OC(=O)NR bR c、胺基、C 1-C 6烷基、卤代C 1-C 6烷基、羟基;R b、R c可以独立表示氢、氘、C 1-C 6烷基、C 3-C 8环烷基、4-8元杂环基、5-14元杂芳基或C 6-C 14芳环,或者说R b和R c与N原子一起可以形成4-8元杂环基;R e可以独立表示氢、C1-C 6烷基、C 3-C 8环烷基、C 2-C 6烯基、C 3-C 6环烯基、C 2-C 6炔基、4-8元杂环基、5-14元杂芳基或C6-C14芳环; R 4 is selected from substituted or unsubstituted C 6 -C 14 aryl or 5-10 membered heteroaryl, wherein the substitution refers to one or more (such as 2, 3, 4 or 5) selected from the group ) group substitution: deuterium, halogen, ester, cyano, NR b C(=O)OR e , OC(=O)R e , OC(=O)NR b R c , amine group, C 1 - C 6 alkyl, halogenated C 1 -C 6 alkyl, hydroxyl; R b and R c can independently represent hydrogen, deuterium, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 4-8 membered Heterocyclic group, 5-14-membered heteroaryl group or C 6 -C 14 aromatic ring, or R b and R c together with N atom can form a 4-8-membered heterocyclic group; R e can independently represent hydrogen, C1- C 6 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkynyl, 4-8 membered heterocyclyl, 5-14 A membered heteroaryl group or a C6-C14 aromatic ring;Rm选自取代或未取代的下组基团:胺基、C 1-C 6烷基、C 3-C 6环烷基、4-6元杂环基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C 1-C 3烷基、C 3-C 6环烷基、4-6元杂环基; Rm is selected from the group consisting of substituted or unsubstituted groups: amine group, C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, 4-6 membered heterocyclic group, wherein the substitution refers to the selected Substituted with one or more groups from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl, C3 - C6 cycloalkyl, 4-6 membered heterocyclyl;Rn选自取代或未取代的下组基团:胺基、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基、-O-C 3-C 6环烷基、C 1-C 6烷基C 3-C 6环烷基、-O-C 1-C 6烷基C 3-C 6环烷基、4-6元杂环基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C 1-C 3烷基、C 1-C 3卤代烷基、C 3-C 6环烷基、4-6元杂环基; Rn is selected from the group consisting of substituted or unsubstituted groups: amine, C1 - C6alkyl , C1 - C6alkoxy , C3 - C6cycloalkyl, -OC3 - C6cycloalkane base, C 1 -C 6 alkyl C 3 -C 6 cycloalkyl, -OC 1 -C 6 alkyl C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group, wherein the substitution refers to Substituted with one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl, C1 - C3 haloalkyl , C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group;Rx选自:F或Cl;Rx is selected from: F or Cl;R A选自:H、D、卤素; R A is selected from: H, D, halogen;q'选自0、1、2或3;q' is selected from 0, 1, 2 or 3;R”'选自取代或未取代的下组基团:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C 1-C 6烷基、C 3-C 8环烷基、C 4-C 10环烯基、4-8元杂环基、C 6-C 14芳基、5-14元杂芳基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C 1-C 6烷基、C 3-C 8环烷基、C 4-C 10环烯基、4-8元杂环基、C 6-C 14芳基、5-14元杂芳基。 R"' is selected from the group consisting of substituted or unsubstituted groups: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 -C 8 ring Alkyl, C 4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl, wherein the substitution refers to one selected from the group or multiple groups substituted: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 4 -C 10 Cycloalkenyl, 4-8 membered heterocyclyl, C6 - C14 aryl, 5-14 membered heteroaryl.
- 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其特征在于,其具有式(XII)或(XIII)所示的结构:The compound of claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that it has the formula (XII ) or the structure shown in (XIII):R 4a、R 4b、R 4c、R 4d、R 4e相同或不同,各自独立地选自:H、氘、卤素、酯基、氰基、NR bC(=O)OR e、OC(=O)R e、OC(=O)NR bR c、胺基、C 1-C 6烷基、卤代C 1-C 6烷基、羟基;R b、R c可以独立表示氢、氘、C 1-C 6烷基、C 3-C 8环烷基、4-8元杂环基、5-14元杂芳基或C 6-C 14芳环,或者说R b和R c与N原子一起可以形成4-8元杂环基;R e可以独立表示氢、C 1-C 6烷基、C 3-C 8环烷基、C 2-C 6烯基、C 3-C 6环烯基、C 2-C 6炔基、4-8元杂环基、5-14元杂芳基或C6-C14芳环; R 4a , R 4b , R 4c , R 4d , R 4e are the same or different, each independently selected from: H, deuterium, halogen, ester, cyano, NR b C(=O)OR e , OC(=O ) R e , OC(=O)NR b R c , amino group, C 1 -C 6 alkyl group, halogenated C 1 -C 6 alkyl group, hydroxyl; R b , R c can independently represent hydrogen, deuterium, C 1 - C6 alkyl, C3 - C8 cycloalkyl, 4-8 membered heterocyclyl, 5-14 membered heteroaryl or C6 - C14 aromatic ring, or Rb and Rc and N atom Together they can form a 4-8 membered heterocyclic group; R e can independently represent hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkene base, C 2 -C 6 alkynyl, 4-8 membered heterocyclyl, 5-14 membered heteroaryl or C6-C14 aromatic ring;Rm、Rn、Rx、R A、q'、R”'如权利要求13所述。 Rm, Rn, Rx, R A , q', R"' are as described in claim 13.
- 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其特征在于,其具有式(XIV)或(XV)所示的结构:The compound of claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that it has the formula (XIV ) or the structure shown in (XV):式中,In the formula,R 4a、R 4b、R 4c、R 4d、R 4e各自独立地选自:H、氘、卤素、羟基、胺基、C 1-C 3烷基、卤代C 1-C 3烷基、NR bC(=O)OR e、OC(=O)R e、OC(=O)NR bR c;其中,R b、R c可以独立表示氢、氘、C 1-C 6烷基;R e可以独立表示氢、C 1-C 6烷基、C 3-C 8环烷基、4-8元杂环基; R 4a , R 4b , R 4c , R 4d , R 4e are each independently selected from: H, deuterium, halogen, hydroxy, amino, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, NR b C(=O)OR e , OC(=O)R e , OC(=O)NR b R c ; wherein, R b and R c can independently represent hydrogen, deuterium, C 1 -C 6 alkyl; R e can independently represent hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 4-8 membered heterocyclic group;Rm、Rn、Rx、R A如权利要求13所述。 Rm, Rn, Rx, RA are as described in claim 13.
- 如权利要求1-6中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其特征在于,其具有式(XVI)所示的结构:The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof of any one of claims 1-6, characterized in that , which has the structure shown in formula (XVI):式中,In the formula,R”'各自独立地选自取代或未取代的下组基团:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C 1-C 6烷基、C 3-C 8环烷基、C 4-C 10环烯基、4-8元杂环基、C 6-C 14芳基、5-14元杂芳基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C 1-C 6烷基、C 3-C 8环烷基、C 4-C 10环烯基、4-8元杂环基、C 6-C 14芳基、5-14元杂芳基; R"' is each independently selected from the group consisting of substituted or unsubstituted groups: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 - C 8 cycloalkyl, C 4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl, wherein the substitution refers to being selected from the following Substituted with one or more groups of the group: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amido, C1 - C6 alkyl, C3 - C8 cycloalkyl, C4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl;q选自:1、2、3或4;q is selected from: 1, 2, 3 or 4;R 1、R 4、R 8、R'、V、Q的定义如权利要求1所述。 The definitions of R 1 , R 4 , R 8 , R′, V and Q are as described in claim 1 .
- 如权利要求1-7中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其特征在于,其具有式(XVI-A)所示的结构:The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof of any one of claims 1-7, characterized in that , which has the structure shown in formula (XVI-A):式中,In the formula,R”'各自独立地选自取代或未取代的下组基团:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C 1-C 6烷基、C 3-C 8环烷基、C 4-C 10环烯基、4-8元杂环基、C 6-C 14芳基、5-14 元杂芳基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C 1-C 6烷基、C 3-C 8环烷基、C 4-C 10环烯基、4-8元杂环基、C 6-C 14芳基、5-14元杂芳基; R"' is each independently selected from the group consisting of substituted or unsubstituted groups: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 - C 8 cycloalkyl, C 4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl, wherein the substitution refers to being selected from the following Substituted with one or more groups of the group: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amido, C1 - C6 alkyl, C3 - C8 cycloalkyl, C4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl;q选自:1、2、3或4;q is selected from: 1, 2, 3 or 4;R 1、R 4、R 8、R'、V、Q的定义如权利要求1所述。 The definitions of R 1 , R 4 , R 8 , R′, V and Q are as described in claim 1 .
- 如权利要求16-17中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其特征在于,R 8各自独立地选自取代或未取代的下组基团:氢、氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基,其中,所述取代是指被氰基取代。 The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof of any one of claims 16-17, characterized in that , R 8 are each independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, Wherein, the substitution refers to substitution by a cyano group.
- 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其特征在于,其具有式(XVII)所示的结构:The compound of claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that it has the formula (XVII ) shown in the structure:式中,In the formula,R 1选自: 其中,R A选自:H、D、卤素或氰基;R B、R B’相同或不同,各自独立地选自:H、D、卤素、氰基、取代或未取代的C 1-C 3烷基;其中,所述取代是指被选自下组的一个或多个基团取代:D、卤素、氰基、C 1-C 3烷基、C 3-C 6环烷基、4-6元杂环基或NR IVR V;R IV、R V相同或不同,各自独立地选自:H、C 1-C 3烷基、C 3-C 6环烷基或4-6元杂环基;或者R IV、R V和相邻的N一起环合形成4-6元杂环基; R1 is selected from : Wherein, R A is selected from: H, D, halogen or cyano; R B and R B' are the same or different, each independently selected from: H, D, halogen, cyano, substituted or unsubstituted C 1 -C 3 alkyl; wherein, the substitution refers to being substituted by one or more groups selected from the group consisting of D, halogen, cyano, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 4 -6-membered heterocyclyl or NR IV R V ; R IV and R V are the same or different, each independently selected from: H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl or 4-6 membered Heterocyclyl; or R IV , R V and adjacent N are cyclized together to form a 4-6 membered heterocyclyl;R 4、R'、V、Q、R”'及q的定义如权利要求16所述。 The definitions of R 4 , R', V, Q, R"' and q are as described in claim 16 .
- 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其特征在于,其具有式(XVIII-1)或(XVIII-2)所示的结构:The compound of claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that it has the formula (XVIII -1) or the structure shown in (XVIII-2):式中,In the formula,Rx选自:F或Cl;Rx is selected from: F or Cl;R 4选自取代或未取代苯基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、酯基、氰基、NR bC(=O)OR e、OC(=O)R e、OC(=O)NR bR c、胺基、C 1-C 6烷基、卤代C 1-C 6烷基、C 1-C 6烷氧基、羟基;R b、R c可以独立表示氢、氘、C 1-C 6烷基、C 3-C 8环烷基、4-8元杂环基、5-14元杂芳基或C 6-C 14芳环,或者说R b和R c与N原子一起可以形成4-8元杂环基;R e可以独立表示氢、C1-C 6烷基、C 3-C 8环烷基、C 2-C 6烯基、C 3-C 6环烯基、C 2-C 6炔基、4-8元杂环基、5-14元杂芳基或C6-C14芳环; R 4 is selected from substituted or unsubstituted phenyl, wherein the substitution refers to substitution by one or more groups selected from the group consisting of deuterium, halogen, ester, cyano, NR b C(=O)OR e , OC(=O)R e , OC(=O)NR b R c , amine group, C 1 -C 6 alkyl group, halogenated C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, Hydroxyl; R b , R c can independently represent hydrogen, deuterium, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 4-8-membered heterocyclyl, 5-14-membered heteroaryl or C 6 - C 14 aromatic ring, or R b and R c together with N atom can form a 4-8 membered heterocyclic group; R e can independently represent hydrogen, C1-C 6 alkyl, C 3 -C 8 cycloalkyl, C 2 - C6 alkenyl, C3 - C6 cycloalkenyl, C2 - C6 alkynyl, 4-8-membered heterocyclyl, 5-14-membered heteroaryl or C6-C14 aromatic ring;Rm选自取代或未取代的下组基团:胺基、C 1-C 6烷基、C 3-C 6环烷基、4-6元杂环基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C 1-C 3烷基、C 3-C 6环烷基、4-6元杂环基; Rm is selected from the group consisting of substituted or unsubstituted groups: amine group, C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, 4-6 membered heterocyclic group, wherein the substitution refers to the selected Substituted with one or more groups from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl, C3 - C6 cycloalkyl, 4-6 membered heterocyclyl;Rn选自取代或未取代的下组基团:胺基、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基、-O-C 3-C 6环烷基、C 1-C 6烷基C 3-C 6环烷基、-O-C 1-C 6烷基C 3-C 6环烷基、4-6元杂环基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C 1-C 3烷基、C 1-C 3卤代烷基、C 3-C 6环烷基、4-6元杂环基; Rn is selected from the group consisting of substituted or unsubstituted groups: amine, C1 - C6alkyl , C1 - C6alkoxy , C3 - C6cycloalkyl, -OC3 - C6cycloalkane base, C 1 -C 6 alkyl C 3 -C 6 cycloalkyl, -OC 1 -C 6 alkyl C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group, wherein the substitution refers to Substituted with one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl, C1 - C3 haloalkyl , C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group;R 1的定义如权利要求1所述。 R 1 is as defined in claim 1 .
- 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其特征在于,其具有式(XIX)或(XX)所示的结构:The compound of claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that it has the formula (XIX ) or the structure shown in (XX):式中,In the formula,R 4选自取代或未取代C 6-C 14芳基或5-10元杂芳基,其中,所述取代是指被选自下组的一个或多个(如2、3、4或5个)基团取代:氘、卤素、酯基、氰基、NR bC(=O)OR e、OC(=O)R e、 OC(=O)NR bR c、胺基、C 1-C 6烷基、卤代C 1-C 6烷基、羟基;R b、R c可以独立表示氢、氘、C 1-C 6烷基、C 3-C 8环烷基、4-8元杂环基、5-14元杂芳基或C 6-C 14芳环,或者说R b和R c与N原子一起可以形成4-8元杂环基;R e可以独立表示氢、C1-C 6烷基、C 3-C 8环烷基、C 2-C 6烯基、C 3-C 6环烯基、C 2-C 6炔基、4-8元杂环基、5-14元杂芳基或C6-C14芳环; R 4 is selected from substituted or unsubstituted C 6 -C 14 aryl or 5-10 membered heteroaryl, wherein the substitution refers to one or more (such as 2, 3, 4 or 5) selected from the group ) group substitution: deuterium, halogen, ester, cyano, NR b C(=O)OR e , OC(=O)R e , OC(=O)NR b R c , amine group, C 1 - C 6 alkyl, halogenated C 1 -C 6 alkyl, hydroxyl; R b and R c can independently represent hydrogen, deuterium, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 4-8 membered Heterocyclic group, 5-14-membered heteroaryl group or C 6 -C 14 aromatic ring, or R b and R c together with N atom can form a 4-8-membered heterocyclic group; R e can independently represent hydrogen, C1- C 6 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkynyl, 4-8 membered heterocyclyl, 5-14 A membered heteroaryl group or a C6-C14 aromatic ring;Rm选自取代或未取代的下组基团:胺基、C 1-C 6烷基、C 3-C 6环烷基、4-6元杂环基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C 1-C 3烷基、C 3-C 6环烷基、4-6元杂环基; Rm is selected from the group consisting of substituted or unsubstituted groups: amine group, C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, 4-6 membered heterocyclic group, wherein the substitution refers to the selected Substituted with one or more groups from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl, C3 - C6 cycloalkyl, 4-6 membered heterocyclyl;Rn选自取代或未取代的下组基团:胺基、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基、-O-C 3-C 6环烷基、C 1-C 6烷基C 3-C 6环烷基、-O-C 1-C 6烷基C 3-C 6环烷基、4-6元杂环基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C 1-C 3烷基、C 1-C 3卤代烷基、C 3-C 6环烷基、4-6元杂环基; Rn is selected from the group consisting of substituted or unsubstituted groups: amine, C1 - C6alkyl , C1 - C6alkoxy , C3 - C6cycloalkyl, -OC3 - C6cycloalkane base, C 1 -C 6 alkyl C 3 -C 6 cycloalkyl, -OC 1 -C 6 alkyl C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group, wherein the substitution refers to Substituted with one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl, C1 - C3 haloalkyl , C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group;Rx选自:F或Cl;Rx is selected from: F or Cl;R A选自:H、D、卤素; R A is selected from: H, D, halogen;q'选自0、1、2或3;q' is selected from 0, 1, 2 or 3;R”'选自取代或未取代的下组基团:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C 1-C 6烷基、C 3-C 8环烷基、C 4-C 10环烯基、4-8元杂环基、C 6-C 14芳基、5-14元杂芳基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C 1-C 6烷基、C 3-C 8环烷基、C 4-C 10环烯基、4-8元杂环基、C 6-C 14芳基、5-14元杂芳基。 R"' is selected from the group consisting of substituted or unsubstituted groups: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 -C 8 ring Alkyl, C 4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl, wherein the substitution refers to one selected from the group or multiple groups substituted: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 4 -C 10 Cycloalkenyl, 4-8 membered heterocyclyl, C6 - C14 aryl, 5-14 membered heteroaryl.
- 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其特征在于,其具有式(XXI)或(XXII)所示的结构:The compound of claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that it has the formula (XXI ) or the structure shown in (XXII):R 4a、R 4b、R 4c、R 4d、R 4e相同或不同,各自独立地选自:H、氘、卤素、酯基、氰基、NR bC(=O)OR e、OC(=O)R e、OC(=O)NR bR c、胺基、C 1-C 6烷基、卤代C 1-C 6烷基、羟基;R b、R c可以独立表示氢、氘、C 1-C 6烷基、C 3-C 8环烷基、4-8元杂环基、5-14元杂芳基或C 6-C 14芳环,或者说R b和R c与N原子一起可以形成4-8元杂环基;R e可以独立表示氢、C 1-C 6烷基、C 3-C 8环烷基、C 2-C 6烯基、C 3-C 6环烯基、C 2-C 6炔基、4-8元杂环基、5-14元杂芳基或C6-C14芳环; R 4a , R 4b , R 4c , R 4d , R 4e are the same or different, each independently selected from: H, deuterium, halogen, ester, cyano, NR b C(=O)OR e , OC(=O ) R e , OC(=O)NR b R c , amino group, C 1 -C 6 alkyl group, halogenated C 1 -C 6 alkyl group, hydroxyl; R b , R c can independently represent hydrogen, deuterium, C 1 - C6 alkyl, C3 - C8 cycloalkyl, 4-8 membered heterocyclyl, 5-14 membered heteroaryl or C6 - C14 aromatic ring, or Rb and Rc and N atom Together they can form a 4-8 membered heterocyclic group; R e can independently represent hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkene base, C 2 -C 6 alkynyl, 4-8 membered heterocyclyl, 5-14 membered heteroaryl or C6-C14 aromatic ring;Rm、Rn、Rx、R A、q'、R”'如权利要求22所述。 Rm, Rn, Rx, R A , q', R"' are as claimed in claim 22.
- 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其特征在于,其具有式(XXIII)或(XXIV)所示的结构:The compound of claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that it has the formula (XXIII ) or the structure shown in (XXIV):式中,In the formula,R 4a、R 4b、R 4c、R 4d、R 4e各自独立地选自:H、氘、卤素、羟基、胺基、C 1-C 3烷基、卤代C 1-C 3烷基、NR bC(=O)OR e、OC(=O)R e、OC(=O)NR bR c;其中,R b、R c可以独立表示氢、氘、C 1-C 6烷基;R e可以独立表示氢、C 1-C 6烷基、C 3-C 8环烷基、4-8元杂环基; R 4a , R 4b , R 4c , R 4d , R 4e are each independently selected from: H, deuterium, halogen, hydroxy, amino, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, NR b C(=O)OR e , OC(=O)R e , OC(=O)NR b R c ; wherein, R b and R c can independently represent hydrogen, deuterium, C 1 -C 6 alkyl; R e can independently represent hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 4-8 membered heterocyclic group;Rm、Rn、Rx、R A如权利要求22所述。 Rm, Rn, Rx, RA are as claimed in claim 22.
- 如权利要求11-24中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,Rn选自取代或未取代的下组基团:乙基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、环丙氨基、氮杂环丁烷基、氮杂环戊烷基、氮杂环己烷基、环氧乙烷基、氧杂环丁烷基、氧杂环戊烷基、氧杂环己烷基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C 1-C 3烷基; The compound of any one of claims 11-24, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, Rn is selected from Substituted or unsubstituted groups of the following groups: ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylamino, azetidinyl, azetidine pentyl, azepanyl, oxiranyl, oxetanyl, oxolane, oxanyl, wherein the substitution means being selected from the group One or more groups are substituted with: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 3 alkyl;Rm选自取代或未取代的下组基团:甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、环丙氨基、氮杂环丁烷基、氮杂环戊烷基、氮杂环己烷基、环氧乙烷基、氧杂环丁烷基、氧杂环戊烷基、氧杂环己烷基,其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、C 1-C 3烷基。 Rm is selected from the group consisting of substituted or unsubstituted groups: methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylamino, azetidine alkyl, azepanyl, azepanyl, oxiranyl, oxetanyl, oxolane, oxetanyl, wherein the substitution is means substituted with one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl.
- 一种制备如权利要求1所述的式(I)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药的方法,其特征在于,包括步骤:A method for preparing a compound of formula (I) as claimed in claim 1, a stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, It is characterized in that, comprises the steps:(i)在惰性溶剂中,式P-1化合物先与草酰氯反应,然后与胺基化合物R 2-NH 2反应,得到式P-2化合物; (i) in an inert solvent, the compound of formula P-1 is first reacted with oxalyl chloride, and then reacted with the amino compound R 2 -NH 2 to obtain the compound of formula P-2;(ii)在惰性溶剂中,在第一种碱作用下,式P-2化合物关环,得到式P-3化合物;(ii) in an inert solvent, under the action of the first base, the compound of formula P-2 is closed to obtain the compound of formula P-3;(iii)在惰性溶剂中,式P-3化合物与三氯氧磷在第二种碱作用下,得到式P-4化合物;(iii) in an inert solvent, the compound of formula P-3 and phosphorus oxychloride are under the action of the second base to obtain the compound of formula P-4;(iv)在惰性溶剂中,碱存在下,式P-4化合物与 通过偶联或者取代反应,得到式P-5化合物; (iv) in an inert solvent, in the presence of a base, the compound of formula P-4 with Through coupling or substitution reaction, the compound of formula P-5 is obtained;(v)在惰性溶剂中,酸存在下,式P-5化合物脱保护,得到式P-6化合物;(v) in an inert solvent, in the presence of an acid, the compound of formula P-5 is deprotected to obtain a compound of formula P-6;(vi)在惰性溶剂中,碱存在下,式P-6化合物与R 1E通过偶联、取代或酰化反应,得到式P-7化合物; (vi) in an inert solvent, in the presence of a base, the compound of formula P-6 is reacted with R 1 E through coupling, substitution or acylation to obtain the compound of formula P-7;(vii)在惰性溶剂中,碱和催化剂存在下,式P-7与R 4-L-E 1通过偶联、取代或者酰化反应,得到式(I)化合物; (vii) in an inert solvent, in the presence of a base and a catalyst, the compound of formula (I) is obtained by coupling, substitution or acylation reaction between formula P-7 and R 4 -LE 1 ;式中,In the formula,E选自:卤素、OH、OCOR 1、OCO( iBu); E is selected from: halogen, OH, OCOR 1 , OCO( i Bu);PG为氨基保护基,所述保护基选自下组:Boc、Bn、Cbz或Fmoc;PG is an amino protecting group selected from the group consisting of Boc, Bn, Cbz or Fmoc;Y和Z为离去基团,所述离去基团选自下组:卤素或者OTf;Y and Z are leaving groups selected from the group consisting of halogen or OTf;所述第一种碱选自下组:KHMDS、NaHMDS、LiHMDS、NaH、NaOMe、NaOEt或 tBuONa; The first base is selected from the group consisting of KHMDS, NaHMDS, LiHMDS, NaH, NaOMe, NaOEt or tBuONa ;所述第二种碱选自下组:TEA、DIPEA、DMAP或N,N-二甲基苯胺;The second base is selected from the group consisting of TEA, DIPEA, DMAP or N,N-dimethylaniline;R 1、R 2、R 4、L、A、B、X、U、V、W和Q的定义如权利要求1所述。 R 1 , R 2 , R 4 , L, A, B, X, U, V, W and Q are as defined in claim 1 .
- 一种药物组合物,其特征在于,包含一种或多种权利要求1-26中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药;和药学上可接受的载体。A pharmaceutical composition, characterized in that, comprising one or more compounds according to any one of claims 1-26, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable a salt, hydrate, solvate or prodrug; and a pharmaceutically acceptable carrier.
- 一种权利要求1-26中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,或权利要求28所述的药物组合物的用途, 其特征在于,用于制备预防和/或治疗与KRAS G12C的活性或表达量相关的疾病的药物组合物。 A compound of any one of claims 1-26, a stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, or a claim The use of the pharmaceutical composition according to claim 28, characterized in that it is used to prepare a pharmaceutical composition for preventing and/or treating diseases related to the activity or expression level of KRAS G12C .
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