WO2024037668A1 - 2-nitrogen-substituted pyrimidine compound, preparation method therefor, and application thereof - Google Patents
2-nitrogen-substituted pyrimidine compound, preparation method therefor, and application thereof Download PDFInfo
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- WO2024037668A1 WO2024037668A1 PCT/CN2023/124994 CN2023124994W WO2024037668A1 WO 2024037668 A1 WO2024037668 A1 WO 2024037668A1 CN 2023124994 W CN2023124994 W CN 2023124994W WO 2024037668 A1 WO2024037668 A1 WO 2024037668A1
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- Prior art keywords
- group
- saturated
- unsaturated
- alkyl
- substituted
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- -1 pyrimidine compound Chemical class 0.000 title claims abstract description 78
- 238000002360 preparation method Methods 0.000 title claims description 51
- 150000003839 salts Chemical class 0.000 claims abstract description 34
- 230000003287 optical effect Effects 0.000 claims abstract description 21
- 239000000651 prodrug Substances 0.000 claims abstract description 21
- 229940002612 prodrug Drugs 0.000 claims abstract description 21
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 14
- 239000003112 inhibitor Substances 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 239000000126 substance Substances 0.000 claims abstract description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 270
- 125000000217 alkyl group Chemical group 0.000 claims description 124
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical class [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 118
- 125000005842 heteroatom Chemical group 0.000 claims description 111
- 229910052736 halogen Inorganic materials 0.000 claims description 92
- 150000002367 halogens Chemical class 0.000 claims description 92
- 229910052760 oxygen Inorganic materials 0.000 claims description 91
- 229910052717 sulfur Inorganic materials 0.000 claims description 90
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 87
- 125000003118 aryl group Chemical group 0.000 claims description 68
- 150000001875 compounds Chemical class 0.000 claims description 67
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 65
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 59
- 229910052805 deuterium Inorganic materials 0.000 claims description 59
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 54
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 47
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 43
- 125000001424 substituent group Chemical group 0.000 claims description 42
- 125000003545 alkoxy group Chemical group 0.000 claims description 35
- 125000001072 heteroaryl group Chemical group 0.000 claims description 34
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 30
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 25
- XTFIVUDBNACUBN-UHFFFAOYSA-N 1,3,5-trinitro-1,3,5-triazinane Chemical group [O-][N+](=O)N1CN([N+]([O-])=O)CN([N+]([O-])=O)C1 XTFIVUDBNACUBN-UHFFFAOYSA-N 0.000 claims description 24
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 23
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 21
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 20
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 18
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 16
- 125000003277 amino group Chemical group 0.000 claims description 16
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
- 238000011282 treatment Methods 0.000 claims description 13
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 10
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 10
- 238000006467 substitution reaction Methods 0.000 claims description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 8
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 8
- 125000002252 acyl group Chemical group 0.000 claims description 8
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 150000003230 pyrimidines Chemical class 0.000 claims description 7
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 6
- 125000005157 alkyl carboxy group Chemical group 0.000 claims description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
- 125000005915 C6-C14 aryl group Chemical group 0.000 claims description 3
- 125000006823 (C1-C6) acyl group Chemical group 0.000 claims description 2
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 2
- 125000006584 (C3-C10) heterocycloalkyl group Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 7
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims 2
- 150000001335 aliphatic alkanes Chemical group 0.000 claims 1
- 229940041181 antineoplastic drug Drugs 0.000 claims 1
- 210000004027 cell Anatomy 0.000 abstract description 16
- 201000011510 cancer Diseases 0.000 abstract description 8
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- 206010027476 Metastases Diseases 0.000 abstract description 2
- 230000005907 cancer growth Effects 0.000 abstract description 2
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- 230000035755 proliferation Effects 0.000 abstract description 2
- 230000019491 signal transduction Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 66
- 239000000543 intermediate Substances 0.000 description 54
- 102000003984 Aryl Hydrocarbon Receptors Human genes 0.000 description 44
- 108090000448 Aryl Hydrocarbon Receptors Proteins 0.000 description 44
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 125000004432 carbon atom Chemical group C* 0.000 description 29
- 238000003756 stirring Methods 0.000 description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- 239000012141 concentrate Substances 0.000 description 26
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- 229910052757 nitrogen Inorganic materials 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
- 239000000284 extract Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
- 125000000623 heterocyclic group Chemical group 0.000 description 12
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 9
- 239000000047 product Substances 0.000 description 9
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- 239000012046 mixed solvent Substances 0.000 description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 7
- 230000014509 gene expression Effects 0.000 description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 7
- 239000001301 oxygen Chemical group 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 239000011593 sulfur Chemical group 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000000556 agonist Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 6
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
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- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 3
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- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- JXIWJBWMQXDALU-UHFFFAOYSA-N phenyl-[2-(trifluoromethyl)phenyl]methanone Chemical compound FC(F)(F)C1=CC=CC=C1C(=O)C1=CC=CC=C1 JXIWJBWMQXDALU-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 239000013600 plasmid vector Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 239000010318 polygalacturonic acid Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000004850 protein–protein interaction Effects 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 230000010473 stable expression Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 1
- 239000012414 tert-butyl nitrite Substances 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/04—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Definitions
- the invention belongs to the technical field of biopharmaceuticals, and in particular relates to a 2-nitrogen-substituted pyrimidine compound and its pharmaceutically acceptable salt, as well as its preparation method and application.
- Aryl hydrocarbon receptor is a member of the subfamily bHLH-PAS (bHLH-PER-ARNT-SIM) of the basic helix-loop-helix ⁇ basic helix-loop-helix (bHLH-PAS) ⁇ superfamily.
- bHLH-PAS basic helix-loop-helix ⁇ basic helix-loop-helix
- One of them is the only receptor in the bHLH-PAS family that can be activated by ligands [Nat.Rev.Cancer, 2014, 14(12), 801; Nat.Rev.Cancer, 2013, 13(12), 827].
- AHR existing in the cytoplasm can sense the stimulation of aromatic hydrocarbons (xenobiotics) in the external environment, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and then move in The cell nucleus forms a heterodimer with the aryl hydrocarbon receptor nuclear transporter (ARNT).
- the AHR/ARNT complex then interacts with the XRE (xenobiotic response element) of the AHR corresponding gene to regulate their transcription;
- AHR can also activate non- XRE-dependent protein-protein interaction pathway.
- AHR is the best understood enzyme that binds environmental toxins and induces metabolic machinery, such as cytochrome CYP450 enzymes (e.g., CYP1A1, CYP1A2, and CYP1B1), which can eliminate environmental toxins (Reyes et al., Science, 1992, 256(5060), 1193- 5; Murray et al., Nat Rev Cancer, 2015, 14(12), 801-14).
- cytochrome CYP450 enzymes e.g., CYP1A1, CYP1A2, and CYP1B1
- Activation of AHR by environmental toxins has demonstrated the role of AHR in numerous cellular processes, such as embryogenesis, tumorigenesis, and inflammation.
- AHR is expressed in many cells of the immune system, including dendritic cells, macrophages, T-cells and NK cells, and plays an important role in immune regulation (Nguyen et al., Front Immunol. 2014, 5, 511).
- Classic exogenous AHR ligands such as TCDD induce profound immunosuppression, promote cancer and induce tumor growth (Oncogene, 2009, 28(28), 2593-2605, Oncogene, 2009, 28(41), 3642-51, Trends Immunol,2009,30,447-454).
- AHR regulates many key innate and adaptive immune responses. Among these responses, AHR agonists promote the production of IL-17 from Th17 cells (T-helper cells) and Treg cells (regulatory T-cells). Activation of AHR further induces the lateral differentiation of Th17 cells and Treg cells and enhances the suppressive activity of Treg.
- AHR activation can inhibit the innate inflammatory response regulated by macrophages (such as reducing the expression of IL-1b, IL-6, IL-12 and TNFa induced by LPS), and inhibit dendritic cells (the expression of dendritic cells Activate and promote the expression of IL-10) (Clin Exp Immunol, 2014, 177 (2), 521-30; J Immunol, 2010, 185 ( ⁇ ), 3190-8; Lab Invest, 2014, 94 (5), 528 -35; PNAS, 2010, 107(46), 19961-6).
- antigen presenting cells In order to establish an effective anti-tumor immune response, antigen presenting cells (APCs) need to be processed, presented, and subsequently activated to helper CD4+T-cells (Th) and cytotoxic CD8+T- cells (cytotoxic CD8+T-cells, Tc), these cells work together to effectively dissolve tumor cells.
- APCs antigen presenting cells
- Th helper CD4+T-cells
- cytotoxic CD8+T- cells cytotoxic CD8+T-cells, Tc
- Tumor cells have developed several mechanisms to escape Th and Tc cytolytic regulation of immunity. One of them is the release of high concentrations of kynurenine and other potential AHR ligands in the tumor microenvironment (TME).
- AHR inhibitors can block the AHR-dependent immune escape pathways used by malignant tumor cells, thereby restoring anti-tumor immunity.
- AHR immune mechanisms regulated by AHR are related to autoimmune and inflammatory diseases, such as multiple sclerosis and inflammatory bowel disease. sick. Therefore, activating the AHR pathway through AHR agonists may be beneficial in the treatment of autoimmune and inflammatory diseases.
- AHR agonists have been described in the art, there remains a need for improvement in immunomodulatory components and methods for treating autoimmune and inflammatory diseases by modulating the AHR.
- an object of the present invention is to provide a class of 2-nitrogen-substituted pyrimidine compounds represented by the following formula I, each of which is an optical isomer, a deuterated product, a prodrug or a pharmaceutically acceptable compound. Salt accepted:
- Ring A is a C 6-10 aryl group or a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S heteroatoms;
- R 3 is selected from deuterium, halogen, nitro, cyano, carboxyl, hydroxyl, -NR d R e , -OR g , -CO 2 R g , -S(O) m R c , or is replaced by 1 to 3 R h -substituted C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 3-8 cycloalkoxy, C 1-8 alkoxycarbonyl, C 1-8 alkyl Carbonyl group, C 1-8 alkylcarboxyl group, 3-10 membered cycloalkyl group, 3-10 membered heterocycloalkyl group, 6-10 membered aryl group, 5-10 membered heteroaryl group.
- R 4 is H or D.
- L is a chemical bond or -NHR i .
- R a and R b are each independently selected from saturated or unsaturated substituted or unsubstituted C 3 -C 8 cycloalkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted Substituted 6- to 10-membered aryl groups or substituted or unsubstituted 4- to 10-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S, wherein the "substituted” refers to selectively substituted by 1 to 10 deuterium substitutions, or optionally containing 1 to 4 selected from hydroxyl, halogen, cyano, -S(O) mRc , -NRdRe , saturated or unsaturated C1 - C8 Alkyl, saturated or unsaturated C 3 -C 8 cycloalkyl, saturated or unsaturated C 1 -C 8 alkoxy, saturated or unsaturated C 3 -C 8 cycloal
- n is an integer of 0, 1, 2, 3, 4 or 5.
- n1 is an integer of 0, 1 or 2.
- n is an integer of 0, 1 or 2.
- R d and R e are each independently selected from hydrogen, halogen, cyano, hydroxyl, saturated or unsaturated C 1 to C 3 alkyl, C 3 to C 6 cycloalkyl, saturated or unsaturated halogen or hydroxyl Substituted C 1 to C 3 alkyl, C 3 to C 6 cycloalkyl substituted by halogen or hydroxyl, saturated or unsaturated C 1 to C 3 alkoxy, C 3 to C 6 cycloalkoxy, saturated or Unsaturated C 1 to C 3 alkoxy group substituted by halogen or hydroxyl group, C 3 to C 6 cycloalkoxy group substituted by halogen or hydroxyl group.
- ring A is a C 6-10 aryl group or a 5-8 membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S heteroatoms.
- the group is a saturated or unsaturated halogenated or unhal
- R 3 is selected from deuterium, halogen, nitro, cyano, carboxyl, hydroxyl, -NR d R e , -OR g , -CO 2 R g , -S(O) m R c , or is replaced by 1 to 3 R h substituted C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 1-6 alkoxycarbonyl, C 1- 6- alkylcarbonyl, C 1-6 alkylcarboxyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl.
- R 3 is selected from deuterium, halogen, nitro, cyano, carboxyl, hydroxyl, -NR d R e , -OR g , -CO 2 R g , -S(O) m R c , or is replaced by 1 To 3 R h substituted C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 3-6 cycloalkoxy, C 1-4 alkoxycarbonyl, C 1 -4 alkylcarbonyl, C 1-4 alkylcarboxyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl.
- R a and R b are each independently selected from saturated or unsaturated substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 6 alkyl, Substituted or unsubstituted 6- to 10-membered aryl groups or substituted or unsubstituted 5- to 8-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S heteroatoms, wherein the "substituted” refers to 1 to 10 deuterium substitutions, or optionally containing 1 to 3 selected from hydroxyl, halogen, cyano, -S(O) mRc , -NRdRe , saturated or unsaturated C1 - C6 Alkyl, saturated or unsaturated C 3 -C 6 cycloalkyl, saturated or unsaturated C 1 -C 6 alkoxy, saturated or unsaturated C 3 -C 6 cycloal
- R a and R b are each independently selected from saturated or unsaturated substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 4 alkyl.
- R f is selected from deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 6 alkyl, saturated or unsaturated C 3 to C 6 cycloalkyl, -S(O) m R c , NR d Re , saturated or unsaturated C 1 to C 6 alkyl group substituted by deuterium, halogen, hydroxyl or amino group, C 3 to C 6 cycloalkyl group substituted by deuterium, halogen, hydroxyl group or amino group, Saturated or unsaturated C 1 to C 6 alkoxy group, C 3 to C 6 cycloalkoxy group, saturated or unsaturated C 1 to C 6 alkoxy group substituted by deuterium, halogen, hydroxyl or amino group, substituted by deuterium, Halogen, hydroxyl or amino substituted C 3 to C 6 cycloalkoxy group.
- R 1 and R 2 in formula I together with the N atom connecting them is selected from the following groups:
- R a and R b in formula I together with the N atom connecting them is selected from the following groups:
- each of its optical isomers, deuterated products, prodrugs or pharmaceutically acceptable salts is selected from the following compounds:
- another object of the present invention is to provide a pharmaceutical composition, said pharmaceutical composition comprising a therapeutically effective amount of a 2-nitrogen-substituted pyrimidine compound represented by Formula I according to the present invention,
- a pharmaceutical composition comprising a therapeutically effective amount of a 2-nitrogen-substituted pyrimidine compound represented by Formula I according to the present invention,
- another object of the present invention is to provide 2-nitrogen-substituted pyrimidine compounds represented by formula I according to the present invention, each of which is an optical isomer, a deuterated product, a prodrug or a pharmaceutically acceptable compound. Use of the accepted salts in the preparation of inhibitors of AHR disorders.
- another object of the present invention is to provide 2-nitrogen-substituted pyrimidine compounds represented by formula I according to the present invention, each of which is an optical isomer, a deuterated product, a prodrug or a pharmaceutically acceptable compound.
- another object of the present invention is to provide a method for treating tumors associated with AHR disorders, the method comprising administering to a subject in need thereof an effective amount of a compound according to the present invention represented by the formula
- the 2-nitrogen-substituted pyrimidine compound represented by I, each of its optical isomers, deuterated products, prodrugs or pharmaceutically acceptable salts or the pharmaceutical composition according to the present invention are examples of a compound according to the present invention represented by the formula
- the 2-nitrogen-substituted pyrimidine compound represented by I each of its optical isomers, deuterated products, prodrugs or pharmaceutically acceptable salts or the pharmaceutical composition according to the present invention.
- another object of the present invention is to provide 2-nitrogen-substituted pyrimidine compounds represented by formula I according to the present invention, each of which is an optical isomer, a deuterated product, a prodrug or a pharmaceutically acceptable compound.
- the preparation method of the accepted salt, the method is selected from the following reaction formula 1 or reaction formula 2:
- reaction formula 1 the compound of formula III and the compound of formula II undergo an esterification reaction to form a compound represented by formula I, in which the substituents R 1 , R 2 , R 3 , R 4 , R a , R b , ring A,
- the definition of L is the same as in Formula I;
- reaction formula 2 the compound of formula III and the hydrazine compound of formula IV undergo an esterification reaction to form an intermediate compound of formula Ia, and then the intermediate compound Ia reacts with a compound containing substituent R 2 (such as an acid anhydride compound) to form formula I represents a compound in which the definitions of the substituents R 1 , R 2 , R 3 , R 4 , R a , R b , and rings A and L are the same as those in Formula I.
- substituent R 2 such as an acid anhydride compound
- reaction formulas 1 and 2 compound III can be prepared according to one of the following methods, and the following is only an example.
- Dissolve compound VIII in the mixed solvent add lithium hydroxide, stir at room temperature overnight, concentrate under reduced pressure, add ice water, stir, extract with ethyl acetate, adjust the pH of the aqueous phase to 6-7 with hydrochloric acid, filter and dry to obtain compound III , the mixed solvent is THF/MeOH/H 2 O (volume ratio: 1/1/1).
- 2,6-Dichloropyrimidine-4-carboxylic acid ethyl ester and the boric acid compound IX containing the A ring structure are dissolved in dioxane, add saturated sodium carbonate, tetrakis (triphenylphosphorus) palladium, degassed, and protected by nitrogen Heated at room temperature, stirred overnight, cooled to room temperature, concentrated under reduced pressure, added ice water, extracted with ethyl acetate, dried, and purified to obtain compound X;
- Dissolve compound XI in the mixed solvent add lithium hydroxide, stir at room temperature overnight, concentrate under reduced pressure, add ice water, stir, extract with ethyl acetate, adjust the pH of the aqueous phase to 6 ⁇ 7 with hydrochloric acid, filter and dry to obtain compound III , the mixed solvent is THF/MeOH/H 2 O (volume ratio: 1/1/1).
- Dissolve compound XIII in the mixed solvent add lithium hydroxide, stir at room temperature overnight, concentrate under reduced pressure, add ice water, stir, extract with ethyl acetate, adjust the pH of the aqueous phase to 6 ⁇ 7 with hydrochloric acid, filter and dry to obtain compound III , the mixed solvent is THF/MeOH/H 2 O (volume ratio: 1/1/1).
- Alkyl refers to a straight or branched chain saturated hydrocarbon radical having 1 to 8 carbon atoms (“C 1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C 1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 alkyl”).
- an alkyl group has 1 to 2 carbon atoms ("C 1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C 1 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1-6 alkyl”).
- C 1-6 alkyl groups include methyl (C 1 ), ethyl (C 2 ), propyl (C 3 ) (e.g., n-propyl, isopropyl), butyl (C 4 ) (e.g., n-propyl) Butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C 5 ) (for example, n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl group) and hexyl (C 6 ) (e.g., n-hexyl).
- alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents (e.g., halogen, such as F) ("substituted alkyl" ). In certain embodiments, alkyl is unsubstituted C 1-8 alkyl (eg, unsubstituted C 1 alkyl, such as -CH 3 ). In certain embodiments, alkyl is substituted C 1-8 alkyl (eg, substituted C 1 alkyl, such as -CF 3 ).
- Alkoxy means a monovalent -O-alkyl group, wherein the alkyl moiety has the specified number of carbon atoms.
- alkoxy groups generally contain 1-8 carbon atoms ("C1 to C8 alkoxy”), 1-6 carbon atoms ("C1 to C6 alkoxy”), or 1-4 carbon atoms ( “C1-C4 alkoxy”).
- C1-C4 alkoxy groups include methoxy, ethoxy, isopropoxy, tert-butyloxy, etc.
- alkoxy is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkoxy") or substituted with one or more substituents ("substituted alkoxy" ).
- alkoxy is unsubstituted C1 to C6 alkoxy.
- alkoxy is substituted C1 to C6 alkoxy.
- Cycloalkyl refers to a non-aromatic cyclic hydrocarbon group having 3 to 8 ring carbon atoms ("C 3-8 cycloalkyl”) and zero heteroatoms in a non-aromatic ring system.
- a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 cycloalkyl”).
- a cycloalkyl group has 3 to 6 ring carbon atoms (“C 3-6 cycloalkyl”).
- a cycloalkyl group has 5 to 8 ring carbon atoms ("C 5-8 cycloalkyl”).
- Exemplary C 3-6 cycloalkyl groups include, but are not limited to, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl group (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), etc.
- Exemplary C 3-8 cycloalkyl groups include, but are not limited to, the C 3-6 cycloalkyl groups described above as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), etc.
- each instance of cycloalkyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents (“substituted cycloalkyl" ).
- cycloalkyl is unsubstituted C 3-8 cycloalkyl; in certain embodiments, cycloalkyl is substituted C 3-8 cycloalkyl.
- Heterocycloalkyl means a group of 4 to 14 membered non-aromatic ring systems having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen and sulfur (" 4-14 membered heterocyclic group").
- the point of attachment may be a carbon atom or a nitrogen atom, as long as the valency permits.
- Heterocyclic groups may be monocyclic ("monocyclic heterocyclyl”) or fused, bridged or spiro ring systems, such as bicyclic systems (“bicyclic heterocyclyl”), and may be saturated or may be partially Unsaturated.
- Heterocyclic group also includes a heterocyclic group as defined above combined with one or more cyclic A ring system in which an alkyl group is fused (wherein the point of attachment is on a cycloalkyl group or a heterocycle), or in which a heterocycle as defined above is fused with one or more aryl or heteroaryl groups (wherein the attachment point on a heterocyclic ring), and in this case, the number of ring members continues to refer to the number of ring members in the heterocyclic ring system.
- each instance of a heterocyclic group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocycloalkyl") or substituted with one or more substituents ("substituted heterocycloalkyl").
- Cycloalkyl refers to any substituents.
- heterocycloalkyl is unsubstituted 4-14 membered heterocycloalkyl.
- Aryl or “aromatic ring” or “aromatic ring group” refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic ring) having 6 to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system. Ring) A group of 4n+2 aromatic ring systems (eg, having 6, 10, or 14 ⁇ electrons shared in a cyclic array) ("C 6-14 aryl"). In some embodiments, an aryl group has 6 ring carbon atoms (“C 6 aryl”; e.g., phenyl).
- an aryl group has 10 ring carbon atoms ("C 10 aryl”; for example, naphthyl, such as 1-naphthyl and 2-naphthyl).
- an aryl group has 14 ring carbon atoms ("C 14 aryl”; for example, anthracenyl).
- Aryl also includes ring systems in which an aryl ring as defined above is fused to one or more cycloalkyl or heterocyclic groups, wherein the point of attachment is on the aromatic ring, and in this case, the carbon atom The number continues to refer to the number of carbon atoms in the aromatic ring system.
- each instance of aryl is independently optionally substituted, ie, unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl").
- aryl is unsubstituted C 6-14 aryl.
- aryl is substituted C 6-14 aryl.
- Heteroaryl is a 5-10 membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl”).
- heteroaryl is a 5-8 membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen , oxygen and sulfur ("5-8 membered heteroaryl").
- heteroaryl is a 5-6 membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen , oxygen and sulfur ("5-6 membered heteroaryl").
- a 5-6 membered heteroaryl group has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
- a 5-6 membered heteroaryl group has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
- a 5-6 membered heteroaryl group has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
- heteroaryl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl” ).
- heteroaryl is unsubstituted 5-10 membered heteroaryl.
- heteroaryl is a substituted 5-10 membered heteroaryl.
- Halogen refers to fluorine (fluorine, -F), chlorine (chlorine, -Cl), bromine (bromine, -Br) or iodine (iodine, -I).
- Substituted or “optionally substituted” means that an atom, such as a hydrogen atom, in the group is substituted.
- alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted (e.g., "substituted” alkyl, "substituted” cycloalkyl, “substituted” heterocycloalkyl radical, "substituted” aryl, or "substituted” heteroaryl).
- substituted means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced by a permissible substituent, e.g. Substitution results in the formation of stable compounds, eg, compounds that do not undergo spontaneous transformation (eg, by rearrangement, cyclization, elimination, or other reactions).
- a "substituted” group has a substituent at one or more substitutable positions on the group, and when more than one position in any given structure is substituted, the substituent is present at each The location is the same or different.
- substituted is intended to include substitution with all permissible substituents of organic compounds, any substituent described herein that results in the formation of a stable compound. This disclosure contemplates any and all of these combinations to obtain stable compounds.
- a heteroatom such as nitrogen may have a hydrogen substituent and/or any suitable substituent as described herein that satisfies the valency of the heteroatom and results in the formation of a stable moiety.
- the substituents are carbon atom substituents.
- the substituents are nitrogen atom substituents.
- the substituents are oxygen atom substituents.
- the substituent is a sulfur atom substituent.
- “Unsaturated” or “partially unsaturated” refers to a group containing at least one double or triple bond. “Partially unsaturated” ring systems are also intended to encompass rings having multiple sites of unsaturation, but are not intended to include aromatic groups (eg, aryl or heteroaryl). Likewise, “saturated” refers to a group that contains no double or triple bonds, that is, all single bonds.
- the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- salts refers to salts of compounds of the present invention prepared from compounds having specific substituents found in the present invention and relatively non-toxic acids or bases.
- base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent.
- Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
- acid addition salts examples include inorganic acid salts and organic acid salts
- the inorganic acid includes, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid , hydrogen sulfate, hydriodic acid, phosphorous acid, etc.
- the organic acids include benzoic acid, 2-hydroxyethanesulfonic acid, sulfamic acid, benzenesulfonic acid, phenylacetic acid, mandelic acid, malonic acid, propionic acid, Oxalic acid, p-aminobenzenesulfonic acid, p-toluenesulfonic acid, polygalacturonic acid, pantothenic acid, fumaric acid, glutamic acid, succinic acid, methane sulfonic acid
- the modifier term "about” refers to numerical variations that may occur, e.g., through routine testing and handling; through inadvertent errors in such testing and handling; through variations in the manufacture, source, or purity of the ingredients used in the invention. Difference; etc.
- “about” a particular value also includes that particular value, for example, “about 10%” includes 10%.
- the claims include equivalents of the recited quantities. In one embodiment, the term “about” means within 20% of the reported value.
- the term “treating” means eliminating, alleviating or ameliorating a disease or condition and/or symptoms associated therewith. Although not excluded, treatment of a disease or condition does not require the complete elimination of the disease, condition or symptoms associated with it.
- the term “treatment” and the like may include “preventive treatment” which refers to reducing the recurrence of a disease or condition in a subject who does not have or is at risk of developing or susceptible to the disease or condition or the recurrence of the disease or condition. The possibility of development or recurrence of a previously controlled disease or condition.
- treatment and synonyms contemplate the administration of a therapeutically effective amount of a compound described herein to a subject in need of such treatment.
- the term "effective amount” or “therapeutically effective amount” with respect to a drug or pharmacologically active agent refers to a non-toxic amount of the drug or agent sufficient to achieve the desired effect.
- the "effective amount” of an active substance in the composition refers to the amount required to achieve the desired effect when combined with another active substance in the composition.
- the determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
- the AHR pathway-related diseases according to the present invention include, but are not limited to, tumors related to the AHR pathway.
- the hydrazine in Table 3 below can be prepared according to the same method as compound II-6.
- compound 33 was obtained by reacting intermediate III-J and (S)-N-(2-aminopropyl)-1-methylcyclopropanyl-1-sulfonamide group.
- the test used the human liver cancer HepG2 cell line that endogenously expresses AHR protein (provided by the Stem Cell Bank of the Chinese Academy of Sciences).
- AHR protein provided by the Stem Cell Bank of the Chinese Academy of Sciences.
- CYP1A1 gene expression is regulated by AHR activity. After AHR is activated, it can bind to the CYP1A1 enhancer called The sequence of the xenobiotic response element (XRE) triggers CYP1A1 gene expression.
- XRE xenobiotic response element
- the 1200 bp (-1143 to +57) regulatory sequence upstream of the CYP1A1 gene promoter was synthesized and inserted into a plasmid vector containing firefly luciferase.
- the plasmid was then linearized by single enzyme digestion and transfected into HepG2 cells via lipofectamine 3000.
- the transfected HepG2 cells were screened with puromycin to obtain stable expression cell lines.
- AHR agonists such as L-Kynurenine, Kynurenic acid, indirubin, TCDD, ITE (2-(1H-Indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester
- Expression of firefly luciferase is elicited while cells are treated with different concentrations of compounds, and the inhibition of luciferase expression by the compounds is measured.
- MEM Minimum Eagle's medium
- MEM medium was supplemented with 1mM sodium pyruvate, 2mM GlutaMax, 1 ⁇ non-essential amino acids, 10% Australian fetal calf serum, 100U/mL penicillin and 5ug/mL puromycin.
- HepG2 cells were seeded into 96-well plates at a density of 5 to 8 ⁇ 10 4 /well and grown for 24 to 48 h to reach ⁇ 90% confluence before drug treatment (the culture medium did not contain puromyces white).
- HepG2 cells were lysed by Promega's Steady-Glo luciferase detection system 24 hours after compound treatment, and the luciferase signal was measured using Tecan's InfiniteM1000Pro microplate reader.
- each compound was tested repeatedly for each group.
- the well signal with a compound concentration of 0 was taken as 100%, and the cell signal with untreated agonist was taken as 0.
- the AHR activity inhibition percentage at different compound concentrations was calculated in turn.
- the average value of 2 sets of repeated data is calculated by nonlinear fitting according to the formula Calculate the IC 50 corresponding to the compound, where y is the percent inhibition and x is the concentration of the corresponding compound.
- the IC 50 of each compound is shown in Table 6, where A means IC 50 ⁇ 100nM, B means 100nM ⁇ IC 50 ⁇ 1.0 ⁇ M, C means 1 ⁇ M ⁇ IC 50 ⁇ 5.0 ⁇ M, and D means IC 50 >5.0 ⁇ M.
- the above-mentioned compounds according to the present invention can inhibit those functions and signaling pathways controlled by AHR, thereby affecting the growth and proliferation of cancer cells and the invasiveness of tumor cells. Therefore, 2- represented by Formula I of the present invention Nitrogen-substituted pyrimidine compounds, their respective optical isomers, deuterated products, prodrugs or pharmaceutically acceptable salts can be used to inhibit the growth of cancer cells and inhibit the metastasis and invasion of tumor cells.
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Abstract
Disclosed are a 2-nitrogen-substituted pyrimidine compound represented by formula I, a respective optical isomer, a deuterated substance, a prodrug or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the 2-nitrogen-substituted pyrimidine compound, and a use thereof as an AHR inhibitor. In the present invention, the 2-nitrogen-substituted pyrimidine compound represented by the formula I, the respective optical isomer, deuterated substance, prodrug or pharmaceutically acceptable salt thereof can inhibit AHR and the functions and signal pathways controlled by AHR, so that the growth and proliferation of cancer cells and the invasiveness of tumor cells can be affected. Thus, the 2-nitrogen-substituted pyrimidine compound represented by formula I of the present invention, the respective optical isomer, the deuterated substance, the prodrug or pharmaceutically acceptable salt thereof can be used for inhibiting the growth of cancer cells and inhibiting the metastasis and invasion of tumor cells.
Description
本发明属于生物制药技术领域,尤其涉及一种2-氮取代嘧啶类化合物及其药学上可接受的盐,以及其制备方法和应用。The invention belongs to the technical field of biopharmaceuticals, and in particular relates to a 2-nitrogen-substituted pyrimidine compound and its pharmaceutically acceptable salt, as well as its preparation method and application.
芳香烃受体(AHR,Aryl hydrocarbon receptor)是碱性螺旋-环-螺旋{basic helix-loop-helix(bHLH-PAS)}超家族的亚家族bHLH-PAS(bHLH-PER-ARNT-SIM)成员之一,是bHLH-PAS家族中唯一可以被配体激活的受体[Nat.Rev.Cancer,2014,14(12),801;Nat.Rev.Cancer,2013,13(12),827]。存在于胞浆中的AHR能够感受外界环境中的芳香烃类异质物(xenobiotic),如2,3,7,8-四氯二苯并对二恶英(TCDD)的刺激,然后迁入细胞核与芳香烃受体核转运体(ARNT)形成一个杂二聚体,AHR/ARNT复合物接着与AHR相应基因的XRE(xenobiotic response element)相互作用,从而调控它们的转录;AHR也可以激活非XRE依赖的蛋白-蛋白交互作用通路。Aryl hydrocarbon receptor (AHR) is a member of the subfamily bHLH-PAS (bHLH-PER-ARNT-SIM) of the basic helix-loop-helix {basic helix-loop-helix (bHLH-PAS)} superfamily. One of them is the only receptor in the bHLH-PAS family that can be activated by ligands [Nat.Rev.Cancer, 2014, 14(12), 801; Nat.Rev.Cancer, 2013, 13(12), 827]. AHR existing in the cytoplasm can sense the stimulation of aromatic hydrocarbons (xenobiotics) in the external environment, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and then move in The cell nucleus forms a heterodimer with the aryl hydrocarbon receptor nuclear transporter (ARNT). The AHR/ARNT complex then interacts with the XRE (xenobiotic response element) of the AHR corresponding gene to regulate their transcription; AHR can also activate non- XRE-dependent protein-protein interaction pathway.
AHR是了解最多的结合环境毒素并且诱导代谢机器,如细胞色素CYP450酶(如CYP1A1,CYP1A2和CYP1B1),这些酶可以消除环境毒素(Reyes et al.,Science,1992,256(5060),1193-5;Murray et al.,Nat Rev Cancer,2015,14(12),801-14)。通过环境毒素对AHR的激活已经证明AHR在众多细胞过程中的作用,例如胚胎、肿瘤发生及炎症。AHR在免疫系统许多细胞中都有表达,包括树突细胞、巨噬细胞、T-细胞和NK细胞,而且在免疫调节中起重要作用(Nguyen et al.,Front Immunol.2014,5,511)。经典的外源性AHR配体TCDD等诱导深度免疫抑制、促进癌症发生及诱导肿瘤生长(Oncogene,2009,28(28),2593-2605,Oncogene,2009,28(41),3642-51,Trends Immunol,2009,30,447-454)。AHR is the best understood enzyme that binds environmental toxins and induces metabolic machinery, such as cytochrome CYP450 enzymes (e.g., CYP1A1, CYP1A2, and CYP1B1), which can eliminate environmental toxins (Reyes et al., Science, 1992, 256(5060), 1193- 5; Murray et al., Nat Rev Cancer, 2015, 14(12), 801-14). Activation of AHR by environmental toxins has demonstrated the role of AHR in numerous cellular processes, such as embryogenesis, tumorigenesis, and inflammation. AHR is expressed in many cells of the immune system, including dendritic cells, macrophages, T-cells and NK cells, and plays an important role in immune regulation (Nguyen et al., Front Immunol. 2014, 5, 511). Classic exogenous AHR ligands such as TCDD induce profound immunosuppression, promote cancer and induce tumor growth (Oncogene, 2009, 28(28), 2593-2605, Oncogene, 2009, 28(41), 3642-51, Trends Immunol,2009,30,447-454).
通过XRE-依赖性或非依赖性活性,AHR调节许多关键的先天和自适应免疫反应。这些反应中,AHR激动剂促进产生Th17细胞(T-helper cells)和Treg细胞(regulatory T-cells)的IL-17。AHR的激活进一步诱导Th17细胞想Treg细胞的横向分化,加强Treg的抑制活性。研究证明AHR激活可对巨噬细胞调控的先天炎症反应产生抑制(例如减少LPS诱导的IL-1b,IL-6,IL-12及TNFa表达),及对树突细胞的抑制(树突细胞的活化及促进IL-10的表达)(Clin Exp Immunol,2014,177(2),521-30;J Immunol,2010,185(^),3190-8;Lab Invest,2014,94(5),528-35;PNAS,2010,107(46),19961-6)。Through XRE-dependent or -independent activities, AHR regulates many key innate and adaptive immune responses. Among these responses, AHR agonists promote the production of IL-17 from Th17 cells (T-helper cells) and Treg cells (regulatory T-cells). Activation of AHR further induces the lateral differentiation of Th17 cells and Treg cells and enhances the suppressive activity of Treg. Studies have shown that AHR activation can inhibit the innate inflammatory response regulated by macrophages (such as reducing the expression of IL-1b, IL-6, IL-12 and TNFa induced by LPS), and inhibit dendritic cells (the expression of dendritic cells Activate and promote the expression of IL-10) (Clin Exp Immunol, 2014, 177 (2), 521-30; J Immunol, 2010, 185 (^), 3190-8; Lab Invest, 2014, 94 (5), 528 -35; PNAS, 2010, 107(46), 19961-6).
为了建立有效的抗肿瘤免疫反应,抗原呈递细胞(antigen presenting cells,APCs)需要处理、呈递,接着激活帮助器CD4+T-细胞(helper CD4+T-cells,Th)和细胞毒CD8+T-细胞(cytotoxic CD8+T-cells,Tc),这些细胞协同作用有效溶解肿瘤细胞。肿瘤细胞以及发展了几种机制逃逸Th和Tc细胞溶解调控的免疫。其中之一就是在肿瘤微环境(tumor microenvironment,TME)中释放高浓度的犬尿氨酸(kynurenine)及其它潜在的AHR配体。In order to establish an effective anti-tumor immune response, antigen presenting cells (APCs) need to be processed, presented, and subsequently activated to helper CD4+T-cells (Th) and cytotoxic CD8+T- cells (cytotoxic CD8+T-cells, Tc), these cells work together to effectively dissolve tumor cells. Tumor cells have developed several mechanisms to escape Th and Tc cytolytic regulation of immunity. One of them is the release of high concentrations of kynurenine and other potential AHR ligands in the tumor microenvironment (TME).
肿瘤微环境(TME)中高浓度的AHR配体可导致直接抑制APCs、Th和Tc,以及Treg和Th17的招募、产生和活化,从而进一步抑制Tc和Th的活性。肿瘤通过这些机理能够逃避抗肿瘤免疫应答。所以,AHR抑制剂可以阻断恶性肿瘤细胞采用的AHR依赖性免疫逃逸通路,从而恢复抗肿瘤免疫。High concentrations of AHR ligands in the tumor microenvironment (TME) can lead to direct inhibition of APCs, Th and Tc, as well as the recruitment, production and activation of Treg and Th17, thereby further inhibiting the activities of Tc and Th. Tumors can evade anti-tumor immune responses through these mechanisms. Therefore, AHR inhibitors can block the AHR-dependent immune escape pathways used by malignant tumor cells, thereby restoring anti-tumor immunity.
近年对肿瘤免疫生物学的研究表明,恶性肿瘤细胞采用一种复合免疫逃逸机制。临床前和临床研究证明,通过治疗应用的组合(如免疫检查点抑制和疫苗)阻断或者加强这些机制,可以提供抗肿瘤免疫应答的最佳恢复。虽然希望单独使用AHR调节剂会恢复抗肿瘤免疫,但是可以预期AHR抑制剂与检查点抑制剂以及疫苗联合,甚至与其它治疗方法协同作用将加强免疫治疗应答。Recent studies on tumor immunobiology have shown that malignant tumor cells adopt a complex immune evasion mechanism. Preclinical and clinical studies have demonstrated that blocking or enhancing these mechanisms through a combination of therapeutic applications, such as immune checkpoint inhibition and vaccines, can provide optimal restoration of anti-tumor immune responses. While it is hoped that AHR modulators alone will restore anti-tumor immunity, it is expected that AHR inhibitors combined with checkpoint inhibitors and vaccines, or even synergistically with other treatments, will enhance immunotherapy responses.
AHR调控的免疫机理与自身免疫和炎症性疾病相关,如多发性硬化症和炎症性肠
病。因此通过AHR激动剂激活AHR通路可能有利于治疗自身免疫和炎症性疾病。虽然本领域中AHR激动剂已有描述,但是通过调节AHR治疗自身免疫性和炎症性疾病的免疫调节的成分和方法任然需要改进。The immune mechanisms regulated by AHR are related to autoimmune and inflammatory diseases, such as multiple sclerosis and inflammatory bowel disease. sick. Therefore, activating the AHR pathway through AHR agonists may be beneficial in the treatment of autoimmune and inflammatory diseases. Although AHR agonists have been described in the art, there remains a need for improvement in immunomodulatory components and methods for treating autoimmune and inflammatory diseases by modulating the AHR.
例如在中国专利申请CN101466363A、CN108239083A、CN113480530A、TWI752155B、CN114181208、WO2022078356等文件中都已公开了部分芳香烃受体类化合物。但临床仍然急需开发或改进用于治疗与AHR通路紊乱相关疾病的AHR抑制剂。For example, some aromatic hydrocarbon receptor compounds have been disclosed in Chinese patent applications CN101466363A, CN108239083A, CN113480530A, TWI752155B, CN114181208, WO2022078356 and other documents. However, there is still an urgent clinical need to develop or improve AHR inhibitors for the treatment of diseases related to AHR pathway disorders.
发明内容Contents of the invention
因此,根据本发明的第一个方面,本发明的一个目的在于提供一类由以下式Ⅰ表示的2-氮取代嘧啶类化合物,其各自旋光异构体,氘代物,前药或药学上可接受的盐:
Therefore, according to the first aspect of the present invention, an object of the present invention is to provide a class of 2-nitrogen-substituted pyrimidine compounds represented by the following formula I, each of which is an optical isomer, a deuterated product, a prodrug or a pharmaceutically acceptable compound. Salt accepted:
Therefore, according to the first aspect of the present invention, an object of the present invention is to provide a class of 2-nitrogen-substituted pyrimidine compounds represented by the following formula I, each of which is an optical isomer, a deuterated product, a prodrug or a pharmaceutically acceptable compound. Salt accepted:
其中,in,
A环为C6-10芳基或者含有杂1~3个选自N、O和S杂原子的5~10元杂芳基;Ring A is a C 6-10 aryl group or a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S heteroatoms;
R1和R2各自独立地为氢、饱和或不饱和的取代或未取代的C1-C8烷基、饱和或不饱和的取代或未取代的C3-C8环烷基、-OC(=O)C1-8烷基、-OC(=O)C3-C8环烷基、-C(=O)OC1-C8烷基、-C(=O)C3-C8环烷基、-S(O)mRc、饱和或不饱和的取代或未取代的C1-C8酰基、C6-C14芳基、含有1至3个选自N、O和S的杂原子的4至14元杂环烷基或含有1至3个选自N、O和S的杂原子的5至14元杂芳基,含有基团的饱和或不饱和的卤代或者未卤代的C1-8烷基,含有基团的饱和或不饱和的卤代或者未卤代的C3-8环烷基,其中所述“取代”是指选择性地被1至10个氘取代,或者选择性地含有1至4个选自羟基、卤素、氰基、-S(O)mRc、-NRdRe、饱和或不饱和的C1-C8烷基、饱和或不饱和的C3-C8环烷基、饱和或不饱和的C1-C8烷氧基、饱和或不饱和的C3-C8环烷氧基、-OC(=O)C1-C8烷基、-OC(=O)C3-C8环烷基、-C(=O)OC1-8烷基、-C(=O)OC3-C8环烷基、含有基团的饱和或不饱和的卤代或者未卤代的C1-8烷基,含有基团的饱和或不饱和的卤代或者未卤代的C3-8环烷基,饱和或不饱和的C1-C8酰基、饱和或不饱和的C1-C8烷氧基羰基、C6-C14芳基、含有1至3个选自N、O和S的杂原子的4至14元杂环烷基或含有1至3个选自N、O和S的杂原子的5至14元杂芳基的取代基;R 1 and R 2 are each independently hydrogen, saturated or unsaturated substituted or unsubstituted C 1 -C 8 alkyl, saturated or unsaturated substituted or unsubstituted C 3 -C 8 cycloalkyl, -OC (=O)C 1-8 alkyl, -OC(=O)C 3 -C 8 cycloalkyl, -C(=O)OC 1 -C 8 alkyl, -C(=O)C 3 -C 8 cycloalkyl, -S(O) m R c , saturated or unsaturated substituted or unsubstituted C 1 -C 8 acyl, C 6 -C 14 aryl, containing 1 to 3 selected from N, O and A 4- to 14-membered heterocycloalkyl group containing a heteroatom of S or a 5- to 14-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-8 alkyl group, containing The group is a saturated or unsaturated halogenated or unhalogenated C 3-8 cycloalkyl group, wherein "substituted" means optionally substituted by 1 to 10 deuterons, or optionally containing 1 to 4 Each one is selected from hydroxyl, halogen, cyano, -S(O) m R c , -NR d Re , saturated or unsaturated C 1 -C 8 alkyl, saturated or unsaturated C 3 -C 8 cycloalkyl base, saturated or unsaturated C 1 -C 8 alkoxy group, saturated or unsaturated C 3 -C 8 cycloalkoxy group, -OC(=O)C 1 -C 8 alkyl group, -OC(=O )C 3 -C 8 cycloalkyl, -C(=O)OC 1-8 alkyl, -C(=O)OC 3 -C 8 cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-8 alkyl group, containing The group is a saturated or unsaturated halogenated or unhalogenated C 3-8 cycloalkyl group, a saturated or unsaturated C 1 -C 8 acyl group, a saturated or unsaturated C 1 -C 8 alkoxycarbonyl group, C 6 -C 14 aryl, 4 to 14 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S, or 5 containing 1 to 3 heteroatoms selected from N, O, and S to 14-membered heteroaryl substituents;
或者R1和R2与连接它们的N原子一起形成取代或未取代的含有1至3个选自N、O和S的杂原子的4至14元杂环烷基,其中所述“取代”是指被1至10个氘取代,或者选择性地含有1至4个选自羟基,卤素,氰基,磺酰基,羧基-S(O)mRc、-NRdRe,
C1~C8烷基,C3~C8环烷基,C1~C8烷氧基,C3~C8环烷氧基,-OC(=O)C1-8烷基,-OC(=O)C3~C8环烷基,-C(=O)OC1-8烷基,-C(=O)OC3~C8环烷基,含有基团的饱和或不饱和的卤代或者未卤代的C1-8烷基,含有基团的饱和或不饱和的卤代或者未卤代的C3-8环烷基,被Rf取代的C1~C8烷基、C3~C8环烷基、C1~C8烷氧基、C3~C8环烷氧基的取代基;Or R 1 and R 2 together with the N atom connecting them form a substituted or unsubstituted 4 to 14 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, wherein said "substituted" Refers to being substituted by 1 to 10 deuterium, or optionally containing 1 to 4 selected from hydroxyl, halogen, cyano, sulfonyl, carboxyl -S(O) m R c , -NR d R e , C 1 to C 8 alkyl, C 3 to C 8 cycloalkyl, C 1 to C 8 alkoxy, C 3 to C 8 cycloalkoxy , -OC(=O)C 1-8 alkyl, - OC(=O)C 3 ~C 8 cycloalkyl, -C(=O)OC 1-8 alkyl, -C(=O)OC 3 ~C 8 cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-8 alkyl group, containing Saturated or unsaturated halogenated or unhalogenated C 3-8 cycloalkyl group, C 1 to C 8 alkyl group substituted by R f , C 3 to C 8 cycloalkyl group, C 1 to C 8 Substituents of alkoxy and C 3 to C 8 cycloalkoxy;
R3选自氘、卤素、硝基、氰基、羧基、羟基、-NRdRe、-ORg、-CO2Rg、-S(O)mRc,或被1至3个Rh取代的C1-8烷基、C3-8环烷基、C1-8烷氧基、C3-8环烷氧基、C1-8烷氧基羰基、C1-8烷基羰基、C1-8烷基羧基、3-10元环烷基、3-10元杂环烷基、6-10元芳基、5-10元杂芳基。R 3 is selected from deuterium, halogen, nitro, cyano, carboxyl, hydroxyl, -NR d R e , -OR g , -CO 2 R g , -S(O) m R c , or is replaced by 1 to 3 R h -substituted C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 3-8 cycloalkoxy, C 1-8 alkoxycarbonyl, C 1-8 alkyl Carbonyl group, C 1-8 alkylcarboxyl group, 3-10 membered cycloalkyl group, 3-10 membered heterocycloalkyl group, 6-10 membered aryl group, 5-10 membered heteroaryl group.
R4为H或D。R 4 is H or D.
L为化学键或者-NHRi。L is a chemical bond or -NHR i .
Ra、Rb各自独立地选自饱和或不饱和的取代或未取代的C3-C8环烷基,饱和或不饱和的取代或未取代的C1-C8烷基,取代或未取代的6~10元芳基或者取代或未取代的含有杂1~3个选自N、O和S杂原子的4~10元杂芳基,其中所述“取代”是指选择性地被1至10个氘取代,或者选择性地含有1至4个选自羟基、卤素、氰基、-S(O)mRc、-NRdRe、饱和或不饱和的C1-C8烷基、饱和或不饱和的C3-C8环烷基、饱和或不饱和的C1-C8烷氧基、饱和或不饱和的C3-C8环烷氧基、-OC(=O)C1-C8烷基、-OC(=O)C3-C8环烷基、-C(=O)OC1-8烷基、-C(=O)OC3-C8环烷基、饱和或不饱和的C1-C8酰基、饱和或不饱和的C1-C8烷氧基羰基、含有基团的饱和或不饱和的卤代或者未卤代的C1-8烷基,含有基团的饱和或不饱和的卤代或者未卤代的C3-8环烷基,C6-C14芳基、含有1至3个选自N、O和S的杂原子的4至14元杂环烷基或含有1至3个选自N、O和S的杂原子的5至14元杂芳基的取代基;R a and R b are each independently selected from saturated or unsaturated substituted or unsubstituted C 3 -C 8 cycloalkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted Substituted 6- to 10-membered aryl groups or substituted or unsubstituted 4- to 10-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S, wherein the "substituted" refers to selectively substituted by 1 to 10 deuterium substitutions, or optionally containing 1 to 4 selected from hydroxyl, halogen, cyano, -S(O) mRc , -NRdRe , saturated or unsaturated C1 - C8 Alkyl, saturated or unsaturated C 3 -C 8 cycloalkyl, saturated or unsaturated C 1 -C 8 alkoxy, saturated or unsaturated C 3 -C 8 cycloalkoxy, -OC(= O)C 1 -C 8 alkyl, -OC(=O)C 3 -C 8 cycloalkyl, -C(=O)OC 1-8 alkyl, -C(=O)OC 3 -C 8 ring Alkyl, saturated or unsaturated C 1 -C 8 acyl, saturated or unsaturated C 1 -C 8 alkoxycarbonyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-8 alkyl group, containing The group is saturated or unsaturated halogenated or unhalogenated C 3-8 cycloalkyl, C 6 -C 14 aryl, 4 to 14 containing 1 to 3 heteroatoms selected from N, O and S A substituent of a 5- to 14-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S;
或者Ra和Rb与连接它们的N原子一起形成取代或未取代的含有1至3个选自N、O和S的杂原子的4至14元杂环烷基,取代或未取代的含有1至3个选自N、O和S的杂原子的5至14元杂芳基,其中所述“取代”是指被1至10个氘取代,或者选择性地含有1至4个选自羟基,卤素,氰基,磺酰基,羧基-S(O)mRc、-NRdRe,C1~C8烷基,C3~C8环烷基,C1~C8烷氧基,C3~C8环烷氧基,-OC(=O)C1-8烷基,-OC(=O)C3~C8环烷基,-C(=O)OC1-8烷基,-C(=O)OC3~C8环烷基,含有基团的饱和或不饱和的卤代或者未卤代的C1-8烷基,含有基团的饱和或不饱和的卤代或者未卤代的C3-8环烷基,被Rf取代的C1~C8烷基、C3~C8环烷基、C1~C8烷氧基、C3~C8环烷氧基的取代基。Or R a and R b together with the N atom connecting them form a substituted or unsubstituted 4 to 14-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted containing 5 to 14 membered heteroaryl groups with 1 to 3 heteroatoms selected from N, O and S, wherein "substituted" means substituted with 1 to 10 deuterons, or optionally containing 1 to 4 selected from Hydroxy, halogen, cyano, sulfonyl, carboxyl -S(O) m R c , -NR d R e , C 1 to C 8 alkyl, C 3 to C 8 cycloalkyl, C 1 to C 8 alkoxy Base, C 3 to C 8 cycloalkoxy group, -OC(=O)C 1-8 alkyl group, -OC(=O)C 3 to C 8 cycloalkyl group, -C(=O)OC 1-8 Alkyl, -C(=O)OC 3 ~ C 8 cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-8 alkyl group, containing Saturated or unsaturated halogenated or unhalogenated C 3-8 cycloalkyl group, C 1 to C 8 alkyl group substituted by R f , C 3 to C 8 cycloalkyl group, C 1 to C 8 Alkoxy group and substituent of C 3 to C 8 cycloalkoxy group.
n为0、1、2、3、4或5的整数。n is an integer of 0, 1, 2, 3, 4 or 5.
n1为0、1或2的整数。
n1 is an integer of 0, 1 or 2.
m为0、1或2的整数。m is an integer of 0, 1 or 2.
Rc、Rg、Rh和Ri各自独立地选自氢、羟基、氨基、饱和或不饱和的取代或未取代的C1-C8烷基、饱和或不饱和的取代或未取代的C1-C8烷基、C3-C8环烷基、-C(=O)C1-8烷基、-C(=O)C3-C8环烷基、-C(=O)OC1-C8烷基、-C(=O)OC3-C8环烷基、-C(=O)NC1-C8烷基、-C(=O)NC3-C8环烷基、饱和或不饱和的取代或未取代的C1-C8磺酰基、C6-C14芳基、C7-C14芳基烷基、含有1至3个选自N、O和S的杂原子的4至14元杂环烷基或含有1至3个选自N、O和S的杂原子的5至14元杂芳基,其中所述“取代”是指被1至10个氘取代,或者选择性地含有1至4个选自羟基、卤素、氰基、磺酰基、-NRdRe、饱和或不饱和的C1-C8烷基、饱和或不饱和的C3-C8环烷基、饱和或不饱和的C1-C8烷氧基、饱和或不饱和的C3-C8环烷氧基、-OC(=O)C1-C8烷基、-OC(=O)C3-C8环烷基、-C(=O)OC1-8烷基、-C(=O)O C3-C8环烷基、饱和或不饱和的C1-C8磺酰基、饱和或不饱和的C1-C8酰基、饱和或不饱和的C1-C8烷氧基羰基、C6-C14芳基、含有1至3个选自N、O和S的杂原子的4至14元杂环烷基或含有1至3个选自N、O和S的杂原子的5至14元杂芳基的取代基,其中Rc不为氢;R c , R g , Rh and R i are each independently selected from hydrogen, hydroxyl, amino, saturated or unsaturated substituted or unsubstituted C 1 -C 8 alkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, -C(=O)C 1-8 alkyl, -C(=O)C 3 -C 8 cycloalkyl, -C(=O )OC 1 -C 8 alkyl, -C(=O)OC 3 -C 8 cycloalkyl, -C(=O)NC 1 -C 8 alkyl, -C(=O)NC 3 -C 8 cyclo Alkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 8 sulfonyl, C 6 -C 14 aryl, C 7 -C 14 arylalkyl, containing 1 to 3 selected from N, O and A 4- to 14-membered heterocycloalkyl group containing a heteroatom of S or a 5- to 14-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substituted" means substituted by 1 to 10 deuterium substituted, or optionally containing 1 to 4 selected from hydroxyl, halogen, cyano, sulfonyl, -NR d Re , saturated or unsaturated C 1 -C 8 alkyl, saturated or unsaturated C 3 -C 8 cycloalkyl, saturated or unsaturated C 1 -C 8 alkoxy, saturated or unsaturated C 3 -C 8 cycloalkoxy, -OC(=O)C 1 -C 8 alkyl , -OC(=O)C 3 -C 8 cycloalkyl, -C(=O)OC 1-8 alkyl, -C(=O)OC 3 -C 8 cycloalkyl, saturated or unsaturated C 1 -C 8 sulfonyl group, saturated or unsaturated C 1 -C 8 acyl group, saturated or unsaturated C 1 -C 8 alkoxycarbonyl group, C 6 -C 14 aryl group, containing 1 to 3 selected from N , a 4- to 14-membered heterocycloalkyl group with heteroatoms of O and S or a 5- to 14-membered heteroaryl substituent containing 1 to 3 heteroatoms selected from N, O and S, wherein R c is not hydrogen ;
Rd和Re各自独立地选自氢、卤素、氰基、羟基、饱和或不饱和的C1~C3烷基、C3~C6环烷基、饱和或不饱和的被卤素或羟基取代C1~C3烷基,被卤素或羟基取代的C3~C6环烷基,饱和或不饱和的C1~C3烷氧基,C3~C6环烷氧基,饱和或不饱和的被卤素或羟基取代C1~C3烷氧基,被卤素或羟基取代的C3~C6环烷氧基。R d and R e are each independently selected from hydrogen, halogen, cyano, hydroxyl, saturated or unsaturated C 1 to C 3 alkyl, C 3 to C 6 cycloalkyl, saturated or unsaturated halogen or hydroxyl Substituted C 1 to C 3 alkyl, C 3 to C 6 cycloalkyl substituted by halogen or hydroxyl, saturated or unsaturated C 1 to C 3 alkoxy, C 3 to C 6 cycloalkoxy, saturated or Unsaturated C 1 to C 3 alkoxy group substituted by halogen or hydroxyl group, C 3 to C 6 cycloalkoxy group substituted by halogen or hydroxyl group.
优选地,A环为C6~10芳基或者含有杂1~3个选自N、O和S杂原子的5~8元杂芳基。Preferably, ring A is a C 6-10 aryl group or a 5-8 membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S heteroatoms.
优选地,R1和R2各自独立地为氢、饱和或不饱和的取代或未取代的C1-C6烷基、饱和或不饱和的取代或未取代的C3-C6环烷基、-OC(=O)C1-6烷基、-OC(=O)C3-C6环烷基、-C(=O)OC1-C6烷基、-C(=O)C3-C6环烷基、-S(O)mRc、饱和或不饱和的取代或未取代的C1-C6酰基、C6-C10芳基、含有1至3个选自N、O和S的杂原子的5至10元杂环烷基或含有1至3个选自N、O和S的杂原子的5至10元杂芳基,含有基团的饱和或不饱和的卤代或者未卤代的C1-6烷基,含有基团的饱和或不饱和的卤代或者未卤代的C3-6环烷基,其中所述“取代”是指被1至10个氘取代,或者选择性地含有1至4个选自羟基、卤素、氰基、-S(O)mRc、-NRdRe、饱和或不饱和的C1-C6烷基、饱和或不饱和的C3-C6环烷基、饱和或不饱和的C1-C6烷氧基、饱和或不饱和的C3-C6环烷氧基、-OC(=O)C1-C6烷基、-OC(=O)C3-C6环烷基、-C(=O)OC1-6烷基、-C(=O)OC3-C6环烷基、含有基团的饱和或不饱和的卤代或者未卤代的C1-6烷基,含有基团的饱和或不饱和的卤代或者未卤代的C3-6环烷基,饱和或不饱和的C1-C6酰基、饱和或不饱和的C1-C6烷氧基羰基、C6-C10芳基、含有1至3个选自N、O和S的杂原子的5至10元杂环烷基或含有1至3个选自N、O和S的杂原子的5至10元杂芳基的取代基;Preferably, R 1 and R 2 are each independently hydrogen, saturated or unsaturated substituted or unsubstituted C 1 -C 6 alkyl, saturated or unsaturated substituted or unsubstituted C 3 -C 6 cycloalkyl , -OC(=O)C 1-6 alkyl, -OC(=O)C 3 -C 6 cycloalkyl, -C(=O)OC 1 -C 6 alkyl, -C(=O)C 3 -C 6 cycloalkyl, -S(O) m R c , saturated or unsaturated substituted or unsubstituted C 1 -C 6 acyl, C 6 -C 10 aryl, containing 1 to 3 selected from N , a 5- to 10-membered heterocycloalkyl group containing heteroatoms of O and S or a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-6 alkyl group, containing The group is a saturated or unsaturated halogenated or unhalogenated C 3-6 cycloalkyl group, wherein "substituted" means substituted by 1 to 10 deuterons, or optionally contains 1 to 4 selected from Hydroxy, halogen, cyano, -S(O) m R c , -NR d R e , saturated or unsaturated C 1 -C 6 alkyl, saturated or unsaturated C 3 -C 6 cycloalkyl, saturated Or unsaturated C 1 -C 6 alkoxy, saturated or unsaturated C 3 -C 6 cycloalkoxy, -OC(=O)C 1 -C 6 alkyl, -OC(=O)C 3 -C 6 cycloalkyl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3 -C 6 cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-6 alkyl group, containing The group is a saturated or unsaturated halogenated or unhalogenated C 3-6 cycloalkyl group, a saturated or unsaturated C 1 -C 6 acyl group, a saturated or unsaturated C 1 -C 6 alkoxycarbonyl group, C 6 -C 10 aryl, 5 to 10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S, or 5 to 3 heteroatoms selected from N, O, and S to 10-membered heteroaryl substituents;
或者R1和R2与连接它们的N原子一起形成取代或未取代的含有1至3个选自N、O和S的杂原子的5至10元杂环烷基,其中所述“取代”是指被1至10个氘取代,或
者选择性地含有1至4个选自羟基,卤素,氰基,-S(O)mRc、-NRdRe,C1~C6烷基,C3~C6环烷基,C1~C6烷氧基,C3~C6环烷氧基,-OC(=O)C1-6烷基,-OC(=O)C3~C6环烷基,-C(=O)OC1-6烷基,-C(=O)OC3~C6环烷基,含有基团的饱和或不饱和的卤代或者未卤代的C1-6烷基,含有基团的饱和或不饱和的卤代或者未卤代的C3-6环烷基,被Rf取代的C1~C6烷基、C3~C6环烷基、C1~C6烷氧基、C3~C6环烷氧基的取代基。Or R 1 and R 2 together with the N atom connecting them form a substituted or unsubstituted 5 to 10 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, wherein said "substituted" means replaced by 1 to 10 deuterium, or Those optionally contain 1 to 4 selected from hydroxyl, halogen, cyano, -S(O) m R c , -NR d R e , C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, C 1 to C 6 alkoxy group, C 3 to C 6 cycloalkoxy group, -OC(=O)C 1-6 alkyl group, -OC(=O)C 3 to C 6 cycloalkyl group, -C( =O)OC 1-6 alkyl, -C(=O)OC 3 ~C 6 cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-6 alkyl group, containing Saturated or unsaturated halogenated or unhalogenated C 3-6 cycloalkyl group, C 1 to C 6 alkyl group substituted by R f , C 3 to C 6 cycloalkyl group, C 1 to C 6 Alkoxy group and substituent of C 3 to C 6 cycloalkoxy group.
更优选地,R1和R2各自独立地为氢、饱和或不饱和的取代或未取代的C1-C4烷基、饱和或不饱和的取代或未取代的C3-C6环烷基、-OC(=O)C1-4烷基、-OC(=O)C3-C6环烷基、-C(=O)OC1-C4烷基、-C(=O)C3-C6环烷基、-S(O)mRc、饱和或不饱和的取代或未取代的C1-C4酰基、C6-C10芳基、含有1至3个选自N、O和S的杂原子的5至8元杂环烷基或含有1至3个选自N、O和S的杂原子的5至8元杂芳基,含有基团的饱和或不饱和的卤代或者未卤代的C1-4烷基,含有基团的饱和或不饱和的卤代或者未卤代的C3-6环烷基,其中所述“取代”是指被1至10个氘取代,或者选择性地含有1至3个选自羟基、卤素、氰基、-S(O)mRc、-NRdRe、饱和或不饱和的C1-C4烷基、饱和或不饱和的C3-C6环烷基、饱和或不饱和的C1-C4烷氧基、饱和或不饱和的C3-C6环烷氧基、-OC(=O)C1-C4烷基、-OC(=O)C3-C6环烷基、-C(=O)OC1-4烷基、-C(=O)OC3-C6环烷基、含有基团的饱和或不饱和的卤代或者未卤代的C1-4烷基,含有基团的饱和或不饱和的卤代或者未卤代的C3-6环烷基,饱和或不饱和的C1-C4酰基、饱和或不饱和的C1-C4烷氧基羰基、C6-C10芳基、含有1至3个选自N、O和S的杂原子的5至8元杂环烷基或含有1至3个选自N、O和S的杂原子的5至10元杂芳基的取代基;More preferably, R 1 and R 2 are each independently hydrogen, saturated or unsaturated substituted or unsubstituted C 1 -C 4 alkyl, saturated or unsaturated substituted or unsubstituted C 3 -C 6 cycloalkyl base, -OC(=O)C 1-4 alkyl, -OC(=O)C 3 -C 6 cycloalkyl, -C(=O)OC 1 -C 4 alkyl, -C(=O) C 3 -C 6 cycloalkyl, -S(O) m R c , saturated or unsaturated substituted or unsubstituted C 1 -C 4 acyl, C 6 -C 10 aryl, containing 1 to 3 selected from A 5- to 8-membered heterocycloalkyl group containing heteroatoms of N, O, and S or a 5- to 8-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-4 alkyl group, containing The group is a saturated or unsaturated halogenated or unhalogenated C 3-6 cycloalkyl group, wherein "substituted" means substituted by 1 to 10 deuterons, or optionally contains 1 to 3 selected from Hydroxy, halogen, cyano, -S(O) m R c , -NR d R e , saturated or unsaturated C 1 -C 4 alkyl, saturated or unsaturated C 3 -C 6 cycloalkyl, saturated Or unsaturated C 1 -C 4 alkoxy, saturated or unsaturated C 3 -C 6 cycloalkoxy, -OC(=O)C 1 -C 4 alkyl, -OC(=O)C 3 -C 6 cycloalkyl, -C(=O)OC 1-4 alkyl, -C(=O)OC 3 -C 6 cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-4 alkyl group, containing The group is a saturated or unsaturated halogenated or unhalogenated C 3-6 cycloalkyl group, a saturated or unsaturated C 1 -C 4 acyl group, a saturated or unsaturated C 1 -C 4 alkoxycarbonyl group, C 6 -C 10 aryl, 5 to 8 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S, or 5 to 3 heteroatoms selected from N, O, and S to 10-membered heteroaryl substituents;
或者R1和R2与连接它们的N原子一起形成取代或未取代的含有1至3个选自N、O和S的杂原子的5至8元杂环烷基,其中所述“取代”是指被1至10个氘取代,或者选择性地含有1至3个选自羟基,卤素,氰基,-S(O)mRc、-NRdRe,C1~C4烷基,C3~C6环烷基,C1~C4烷氧基,C3~C6环烷氧基,-OC(=O)C1-4烷基,-OC(=O)C3~C6环烷基,-C(=O)OC1-4烷基,-C(=O)OC3~C6环烷基,含有基团的饱和或不饱和的卤代或者未卤代的C1-4烷基,含有基团的饱和或不饱和的卤代或者未卤代的C3-6环烷基,被卤素、羟基、氨基或Rf取代的C1~C4烷基、C3~C6环烷基、C1~C4烷氧基、
C3~C6环烷氧基的取代基。Or R 1 and R 2 together with the N atom connecting them form a substituted or unsubstituted 5 to 8 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, wherein said "substituted" Refers to being substituted by 1 to 10 deuterium, or optionally containing 1 to 3 selected from hydroxyl, halogen, cyano, -S(O) m R c , -NR d R e , C 1 ~ C 4 alkyl , C 3 ~ C 6 cycloalkyl, C 1 ~ C 4 alkoxy, C 3 ~ C 6 cycloalkoxy, -OC(=O)C 1-4 alkyl, -OC(=O)C 3 ~C 6 cycloalkyl, -C(=O)OC 1-4 alkyl, -C(=O)OC 3 ~C 6 cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-4 alkyl group, containing Saturated or unsaturated halogenated or unhalogenated C 3-6 cycloalkyl group, C 1 to C 4 alkyl group, C 3 to C 6 cycloalkyl group substituted by halogen, hydroxyl, amino or R f , C 1 ~ C 4 alkoxy group, Substituent of C 3 to C 6 cycloalkoxy group.
优选地,R3选自氘、卤素、硝基、氰基、羧基、羟基、-NRdRe、-ORg、-CO2Rg、-S(O)mRc,或被1至3个Rh取代的C1-6烷基、C3-6环烷基、C1-6烷氧基、C3-6环烷氧基、C1-6烷氧基羰基、C1-6烷基羰基、C1-6烷基羧基、3-6元环烷基、3-6元杂环烷基、6-10元芳基、5-10元杂芳基。Preferably, R 3 is selected from deuterium, halogen, nitro, cyano, carboxyl, hydroxyl, -NR d R e , -OR g , -CO 2 R g , -S(O) m R c , or is replaced by 1 to 3 R h substituted C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 1-6 alkoxycarbonyl, C 1- 6- alkylcarbonyl, C 1-6 alkylcarboxyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl.
更优选地,R3选自氘、卤素、硝基、氰基、羧基、羟基、-NRdRe、-ORg、-CO2Rg、-S(O)mRc,或被1至3个Rh取代的C1-4烷基、C3-6环烷基、C1-4烷氧基、C3-6环烷氧基、C1-4烷氧基羰基、C1-4烷基羰基、C1-4烷基羧基、3-6元环烷基、3-6元杂环烷基、6-10元芳基、5-10元杂芳基。More preferably, R 3 is selected from deuterium, halogen, nitro, cyano, carboxyl, hydroxyl, -NR d R e , -OR g , -CO 2 R g , -S(O) m R c , or is replaced by 1 To 3 R h substituted C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 3-6 cycloalkoxy, C 1-4 alkoxycarbonyl, C 1 -4 alkylcarbonyl, C 1-4 alkylcarboxyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl.
优选地,Ra、Rb各自独立地选自饱和或不饱和的取代或未取代的C3-C6环烷基,饱和或不饱和的取代或未取代的C1-C6烷基,取代或未取代的6~10元芳基或者取代或未取代的含有杂1~3个选自N、O和S杂原子的5~8元杂芳基,其中所述“取代”是指被1至10个氘取代,或者选择性地含有1至3个选自羟基、卤素、氰基、-S(O)mRc、-NRdRe、饱和或不饱和的C1-C6烷基、饱和或不饱和的C3-C6环烷基、饱和或不饱和的C1-C6烷氧基、饱和或不饱和的C3-C6环烷氧基、-OC(=O)C1-C6烷基、-OC(=O)C3-C6环烷基、-C(=O)OC1-6烷基、-C(=O)OC3-C6环烷基、饱和或不饱和的C1-C6酰基、饱和或不饱和的C1-C6烷氧基羰基、含有基团的饱和或不饱和的卤代或者未卤代的C1-6烷基,含有基团的饱和或不饱和的卤代或者未卤代的C3-6环烷基,C6-C10芳基、含有1至3个选自N、O和S的杂原子的5至10元杂环烷基或含有1至3个选自N、O和S的杂原子的5至10元杂芳基的取代基;Preferably, R a and R b are each independently selected from saturated or unsaturated substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 6 alkyl, Substituted or unsubstituted 6- to 10-membered aryl groups or substituted or unsubstituted 5- to 8-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S heteroatoms, wherein the "substituted" refers to 1 to 10 deuterium substitutions, or optionally containing 1 to 3 selected from hydroxyl, halogen, cyano, -S(O) mRc , -NRdRe , saturated or unsaturated C1 - C6 Alkyl, saturated or unsaturated C 3 -C 6 cycloalkyl, saturated or unsaturated C 1 -C 6 alkoxy, saturated or unsaturated C 3 -C 6 cycloalkoxy, -OC(= O)C 1 -C 6 alkyl, -OC(=O)C 3 -C 6 cycloalkyl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3 -C 6 ring Alkyl, saturated or unsaturated C 1 -C 6 acyl, saturated or unsaturated C 1 -C 6 alkoxycarbonyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-6 alkyl group, containing The group is saturated or unsaturated halogenated or unhalogenated C 3-6 cycloalkyl, C 6 -C 10 aryl, 5 to 10 containing 1 to 3 heteroatoms selected from N, O and S A substituent of a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S;
或者Ra和Rb与连接它们的N原子一起形成取代或未取代的含有1至3个选自N、O和S的杂原子的4至10元杂环烷基,取代或未取代的含有1至3个选自N、O和S的杂原子的5至10元杂芳基,其中所述“取代”是指被1至10个氘取代,或者选择性地含有1至4个选自羟基,卤素,氰基,磺酰基,羧基-S(O)mRc、-NRdRe,C1~C6烷基,C3~C6环烷基,C1~C6烷氧基,C3~C6环烷氧基,-OC(=O)C1-6烷基,-OC(=O)C3~C6环烷基,-C(=O)OC1-6烷基,-C(=O)OC3~C6环烷基,含有基团的饱和或不饱和的卤代或者未卤代的C1-6烷基,含有基团的饱和或不饱和的卤代或者未卤代的C3-6环烷基,被Rf取代的C1~C6烷基、C3~C6环烷基、C1~C6烷氧基、C3~C6环烷氧基的取代基。Or R a and R b together with the N atom connecting them form a substituted or unsubstituted 4 to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted containing 5 to 10 membered heteroaryl groups with 1 to 3 heteroatoms selected from N, O and S, wherein "substituted" means substituted with 1 to 10 deuteriums, or optionally containing 1 to 4 selected from Hydroxy, halogen, cyano, sulfonyl, carboxyl -S(O) m R c , -NR d R e , C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, C 1 to C 6 alkoxy Base, C 3 to C 6 cycloalkoxy group, -OC(=O)C 1-6 alkyl group, -OC(=O)C 3 to C 6 cycloalkyl group, -C(=O)OC 1-6 Alkyl, -C(=O)OC 3 ~ C 6 cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-6 alkyl group, containing Saturated or unsaturated halogenated or unhalogenated C 3-6 cycloalkyl group, C 1 to C 6 alkyl group substituted by R f , C 3 to C 6 cycloalkyl group, C 1 to C 6 Alkoxy group and substituent of C 3 to C 6 cycloalkoxy group.
更优选地,Ra、Rb各自独立地选自饱和或不饱和的取代或未取代的C3-C6环烷基,饱和或不饱和的取代或未取代的C1-C4烷基,取代或未取代的6~10元芳基或者取代或未取代的含有杂1~3个选自N、O和S杂原子的5~8元杂芳基,其中所述“取代”是指被1至10个氘取代,或者选择性地含有1至3个选自羟基、卤素、氰基、-S(O)mRc、-NRdRe、饱和或不饱和的C1-C4烷基、饱和或不饱和的C3-C6环烷基、饱和或不饱和的C1-C4烷
氧基、饱和或不饱和的C3-C6环烷氧基、-OC(=O)C1-C4烷基、-OC(=O)C3-C6环烷基、-C(=O)OC1-4烷基、-C(=O)OC3-C6环烷基、饱和或不饱和的C1-C4酰基、饱和或不饱和的C1-C4烷氧基羰基、含有基团的饱和或不饱和的卤代或者未卤代的C1-4烷基,含有基团的饱和或不饱和的卤代或者未卤代的C3-6环烷基,C6-C10芳基、含有1至3个选自N、O和S的杂原子的5至10元杂环烷基或含有1至3个选自N、O和S的杂原子的5至10元杂芳基的取代基;More preferably, R a and R b are each independently selected from saturated or unsaturated substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 4 alkyl. , a substituted or unsubstituted 6 to 10-membered aryl group or a substituted or unsubstituted 5 to 8-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S heteroatoms, wherein the "substituted" refers to Substituted with 1 to 10 deuterium, or optionally containing 1 to 3 selected from hydroxyl, halogen, cyano, -S(O) mRc , -NRdRe , saturated or unsaturated C1- C 4 alkyl, saturated or unsaturated C 3 -C 6 cycloalkyl, saturated or unsaturated C 1 -C 4 alkyl Oxygen group, saturated or unsaturated C 3 -C 6 cycloalkoxy group, -OC(=O)C 1 -C 4 alkyl group, -OC(=O)C 3 -C 6 cycloalkyl group, -C( =O)OC 1-4 alkyl, -C(=O)OC 3 -C 6 cycloalkyl, saturated or unsaturated C 1 -C 4 acyl, saturated or unsaturated C 1 -C 4 alkoxy carbonyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-4 alkyl group, containing The group is saturated or unsaturated halogenated or unhalogenated C 3-6 cycloalkyl, C 6 -C 10 aryl, 5 to 10 containing 1 to 3 heteroatoms selected from N, O and S A substituent of a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S;
或者Ra和Rb与连接它们的N原子一起形成取代或未取代的含有1至3个选自N、O和S的杂原子的5至8元杂环烷基,取代或未取代的含有1至3个选自N、O和S的杂原子的5至6元杂芳基,其中所述“取代”是指被1至10个氘取代,或者选择性地含有1至3个选自羟基,卤素,氰基,磺酰基,羧基,-S(O)mRc、-NRdRe,C1~C4烷基,C5~C6环烷基,C1~C4烷氧基,C5~C6环烷氧基,-OC(=O)C1-4烷基,-OC(=O)C5~C6环烷基,-C(=O)OC1-4烷基,-C(=O)OC5~C6环烷基,含有基团的饱和或不饱和的卤代或者未卤代的C1-4烷基,含有基团的饱和或不饱和的卤代或者未卤代的C3-6环烷基,被卤素、羟基、氨基或Rf取代的C1~C4烷基、C5~C6环烷基、C1~C4烷氧基、C5~C6环烷氧基的取代基。Or R a and R b together with the N atom connecting them form a substituted or unsubstituted 5- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted containing A 5- to 6-membered heteroaryl group with 1 to 3 heteroatoms selected from N, O and S, wherein "substituted" means substituted with 1 to 10 deuteriums, or optionally containing 1 to 3 selected from Hydroxy, halogen, cyano, sulfonyl, carboxyl, -S(O) m R c , -NR d R e , C 1 to C 4 alkyl, C 5 to C 6 cycloalkyl, C 1 to C 4 alkyl Oxygen group, C 5 to C 6 cycloalkoxy group, -OC(=O)C 1-4 alkyl group, -OC(=O)C 5 to C 6 cycloalkyl group, -C(=O)OC 1- 4 alkyl, -C(=O)OC 5 ~ C 6 cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-4 alkyl group, containing Saturated or unsaturated halogenated or unhalogenated C 3-6 cycloalkyl group, C 1 to C 4 alkyl group, C 5 to C 6 cycloalkyl group substituted by halogen, hydroxyl, amino or R f , C 1 to C 4 alkoxy group, C 5 to C 6 cycloalkoxy group substituent.
优选地,Rc、Rf、Rg、Rh和Ri各自独立地选自氢、羟基、氨基、饱和或不饱和的取代或未取代的C1-C6烷基、饱和或不饱和的取代或未取代的C1-C6烷基、C3-C6环烷基、-C(=O)C1-6烷基、-C(=O)C3-C6环烷基、-C(=O)OC1-C6烷基、-C(=O)OC3-C6环烷基、-C(=O)NC1-C6烷基、-C(=O)NC3-C6环烷基、饱和或不饱和的取代或未取代的C1-C6磺酰基、C6-C10芳基、C7-C11芳基烷基、含有1至3个选自N、O和S的杂原子的5至10元杂环烷基或含有1至3个选自N、O和S的杂原子的5至10元杂芳基,其中所述“取代”是指被1至10个氘取代,或者选择性地含有1至4个选自羟基、卤素、氰基、磺酰基、C1-C6磺基、-NRdRe、饱和或不饱和的C1-C6烷基、饱和或不饱和的C3-C6环烷基、饱和或不饱和的C1-C6烷氧基、饱和或不饱和的C3-C6环烷氧基、-OC(=O)C1-C6烷基、-OC(=O)C3-C8环烷基、-C(=O)OC1-6烷基、-C(=O)OC3-C6环烷基、饱和或不饱和的C1-C6磺酰基、饱和或不饱和的C1-C6酰基、饱和或不饱和的C1-C6烷氧基羰基、C6-C10芳基、含有1至3个选自N、O和S的杂原子的5至10元杂环烷基或含有1至3个选自N、O和S的杂原子的5至10元杂芳基的取代基,其中Rc不为氢;Preferably, R c , R f , R g , Rh and R i are each independently selected from hydrogen, hydroxyl, amino, saturated or unsaturated substituted or unsubstituted C 1 -C 6 alkyl, saturated or unsaturated Substituted or unsubstituted C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, -C(=O)C 1-6 alkyl, -C(=O)C 3 -C 6 cycloalkyl , -C(=O)OC 1 -C 6 alkyl, -C(=O)OC 3 -C 6 cycloalkyl, -C(=O)NC 1 -C 6 alkyl, -C(=O) NC 3 -C 6 cycloalkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 6 sulfonyl, C 6 -C 10 aryl, C 7 -C 11 arylalkyl, containing 1 to 3 A 5- to 10-membered heterocycloalkyl group containing heteroatoms selected from N, O, and S or a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein the "substituted" Refers to being substituted by 1 to 10 deuterium, or optionally containing 1 to 4 selected from hydroxyl, halogen, cyano, sulfonyl, C 1 -C 6 sulfo, -NR d R e , saturated or unsaturated C 1 -C 6 alkyl, saturated or unsaturated C 3 -C 6 cycloalkyl, saturated or unsaturated C 1 -C 6 alkoxy, saturated or unsaturated C 3 -C 6 cycloalkoxy , -OC(=O)C 1 -C 6 alkyl, -OC(=O)C 3 -C 8 cycloalkyl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3 -C 6 cycloalkyl, saturated or unsaturated C 1 -C 6 sulfonyl, saturated or unsaturated C 1 -C 6 acyl, saturated or unsaturated C 1 -C 6 alkoxycarbonyl, C 6 -C 10 aryl, 5 to 10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S, or 5 to 10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S A substituent of a heteroaryl group, wherein R c is not hydrogen;
更优选地,Rc、Rf、Rg、Rh和Ri各自独立地选自氢、羟基、氨基、饱和或不饱和的取代或未取代的C1-C4烷基、饱和或不饱和的取代或未取代的C1-C4烷基、C4-C6环烷基、-C(=O)C1-4烷基、-C(=O)C4-C6环烷基、-C(=O)OC1-C4烷基、-C(=O)OC4-C8环烷基、-C(=O)NC1-C4烷基、-C(=O)NC4-C6环烷基、饱和或不饱和的取代或未取代的C1-C4磺酰基、C6-C10芳基、C7-C11芳基烷基、含有1至3个选自N、O和S的杂原子的5至8元杂环烷基或含有1至3个选自N、O和S的杂原子的5至10元杂芳基,其中所述“取代”是指被1至10个氘取代,或者选择性地含有1至3个选自羟基、卤素、氰基、磺
酰基、C1-C4磺基、-NRdRe、饱和或不饱和的C1-C4烷基、饱和或不饱和的C4-C6环烷基、饱和或不饱和的C1-C4烷氧基、饱和或不饱和的C4-C6环烷氧基、-OC(=O)C1-C4烷基、-OC(=O)C4-C6环烷基、-C(=O)OC1-4烷基、-C(=O)OC4-C6环烷基、饱和或不饱和的C1-C4磺酰基、饱和或不饱和的C1-C4酰基、饱和或不饱和的C1-C4烷氧基羰基、C6-C10芳基、含有1至3个选自N、O和S的杂原子的5至8元杂环烷基或含有1至3个选自N、O和S的杂原子的5至10元杂芳基的取代基,其中Rc不为氢。More preferably, R c , R f , R g , Rh and R i are each independently selected from hydrogen, hydroxyl, amino, saturated or unsaturated substituted or unsubstituted C 1 -C 4 alkyl, saturated or unsaturated Saturated substituted or unsubstituted C 1 -C 4 alkyl, C 4 -C 6 cycloalkyl, -C(=O)C 1-4 alkyl, -C(=O)C 4 -C 6 cycloalkyl base, -C(=O)OC 1 -C 4 alkyl, -C(=O)OC 4 -C 8 cycloalkyl, -C(=O)NC 1 -C 4 alkyl, -C(=O )NC 4 -C 6 cycloalkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 4 sulfonyl, C 6 -C 10 aryl, C 7 -C 11 arylalkyl, containing 1 to 3 A 5- to 8-membered heterocycloalkyl group containing a heteroatom selected from N, O, and S or a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein the "substituted ” refers to being substituted by 1 to 10 deuterium, or optionally containing 1 to 3 selected from hydroxyl, halogen, cyano, sulfonate Acyl group, C 1 -C 4 sulfo group, -NR d R e , saturated or unsaturated C 1 -C 4 alkyl group, saturated or unsaturated C 4 -C 6 cycloalkyl group, saturated or unsaturated C 1 -C 4 alkoxy, saturated or unsaturated C 4 -C 6 cycloalkoxy, -OC(=O)C 1 -C 4 alkyl, -OC(=O)C 4 -C 6 cycloalkyl , -C(=O)OC 1-4 alkyl, -C(=O)OC 4 -C 6 cycloalkyl, saturated or unsaturated C 1 -C 4 sulfonyl, saturated or unsaturated C 1 - C 4 acyl, saturated or unsaturated C 1 -C 4 alkoxycarbonyl, C 6 -C 10 aryl, 5 to 8 membered heterocycloalkane containing 1 to 3 heteroatoms selected from N, O and S group or a substituent of a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, wherein R c is not hydrogen.
更优选,Rf选自氘,卤素,氰基,羟基,氨基,饱和或不饱和的C1~C6烷基,饱和或不饱和的C3~C6环烷基,-S(O)mRc、NRdRe,饱和或不饱和的被氘、卤素、羟基或氨基取代C1~C6烷基,被氘、卤素、羟基或氨基取代的C3~C6环烷基,饱和或不饱和的C1~C6烷氧基,C3~C6环烷氧基,饱和或不饱和的被氘、卤素、羟基或氨基取代C1~C6烷氧基,被氘、卤素、羟基或氨基取代的C3~C6环烷氧基。More preferably, R f is selected from deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 6 alkyl, saturated or unsaturated C 3 to C 6 cycloalkyl, -S(O) m R c , NR d Re , saturated or unsaturated C 1 to C 6 alkyl group substituted by deuterium, halogen, hydroxyl or amino group, C 3 to C 6 cycloalkyl group substituted by deuterium, halogen, hydroxyl group or amino group, Saturated or unsaturated C 1 to C 6 alkoxy group, C 3 to C 6 cycloalkoxy group, saturated or unsaturated C 1 to C 6 alkoxy group substituted by deuterium, halogen, hydroxyl or amino group, substituted by deuterium, Halogen, hydroxyl or amino substituted C 3 to C 6 cycloalkoxy group.
更优选地,式Ⅰ中R1和R2与连接它们的N原子一起形成的结构选自以下基团中:
More preferably, the structure formed by R 1 and R 2 in formula I together with the N atom connecting them is selected from the following groups:
More preferably, the structure formed by R 1 and R 2 in formula I together with the N atom connecting them is selected from the following groups:
更优选地,式Ⅰ中Ra和Rb与连接它们的N原子一起形成的结构选自以下基团中:
More preferably, the structure formed by R a and R b in formula I together with the N atom connecting them is selected from the following groups:
More preferably, the structure formed by R a and R b in formula I together with the N atom connecting them is selected from the following groups:
其中,Rj和Rk每次出现时各自独立地为羟基,卤素,氰基,磺酰基,氨基,C1~C8烷基,C3~C8环烷基,C1~C8烷氧基,C3~C8环烷氧基,-OC(=O)C1-8烷基,-OC(=O)C3~C8环烷基,-C(=O)OC1-8烷基,-C(=O)OC3~C8环烷基,被Rf取代的C1~C8烷基、C3~C8环烷基、C1~C8烷氧基、C3~C8环烷氧基的取代基,其中Rf选自氘,卤素,氰基,羟基,氨基,饱和或不饱和的C1~C6烷基,饱和或不饱和的C3~C6环烷基,饱和或不饱和的被氘、卤素、羟基或氨基取代C1~C6烷基,被氘、卤素、羟基或氨基取代的C3~C6环烷
基,饱和或不饱和的C1~C6烷氧基,C3~C6环烷氧基,饱和或不饱和的被氘、卤素、羟基或氨基取代C1~C6烷氧基,被氘、卤素、羟基或氨基取代的C3~C6环烷氧基;n2为0、1、2、3、4或5的整数。Wherein, each occurrence of R j and R k is independently hydroxyl, halogen, cyano, sulfonyl, amino, C 1 to C 8 alkyl, C 3 to C 8 cycloalkyl, C 1 to C 8 alkyl Oxygen group, C 3 to C 8 cycloalkoxy group, -OC(=O)C 1-8 alkyl group, -OC(=O)C 3 to C 8 cycloalkyl group, -C(=O)OC 1- 8 alkyl, -C(=O)OC 3 ~ C 8 cycloalkyl, C 1 ~ C 8 alkyl substituted by R f , C 3 ~ C 8 cycloalkyl, C 1 ~ C 8 alkoxy, Substituents of C 3 to C 8 cycloalkoxy groups, wherein R f is selected from deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 6 alkyl, saturated or unsaturated C 3 ~ C 6 cycloalkyl, saturated or unsaturated C 1 to C 6 alkyl substituted by deuterium, halogen, hydroxyl or amino, C 3 to C 6 cycloalkyl substituted by deuterium, halogen, hydroxyl or amino group, saturated or unsaturated C 1 to C 6 alkoxy group, C 3 to C 6 cycloalkoxy group, saturated or unsaturated C 1 to C 6 alkoxy group substituted by deuterium, halogen, hydroxyl or amino group, substituted by C 3 to C 6 cycloalkoxy substituted by deuterium, halogen, hydroxyl or amino; n2 is an integer of 0, 1, 2, 3, 4 or 5.
优选地,Rj和Rk每次出现时各自独立地为羟基,卤素,氰基,磺酰基,氨基C1~C6烷基,C3~C6环烷基,C1~C6烷氧基,C3~C6环烷氧基,-OC(=O)C1-6烷基,-OC(=O)C3~C6环烷基,-C(=O)OC1-6烷基,-C(=O)OC3~C6环烷基,被Rf取代的C1~C6烷基、C3~C6环烷基、C1~C6烷氧基、C3~C6环烷氧基的取代基,其中Rf选自氘,卤素,氰基,羟基,氨基,饱和或不饱和的C1~C4烷基,饱和或不饱和的C3~C6环烷基,饱和或不饱和的被氘、卤素、羟基或氨基取代C1~C4烷基,被氘、卤素、羟基或氨基取代的C3~C6环烷基,饱和或不饱和的C1~C4烷氧基,C3~C6环烷氧基,饱和或不饱和的被氘、卤素、羟基或氨基取代C1~C4烷氧基,被氘、卤素、羟基或氨基取代的C3~C6环烷氧基。Preferably, each occurrence of R j and R k is independently hydroxyl, halogen, cyano, sulfonyl, amino C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, C 1 to C 6 alkyl Oxy group, C 3 to C 6 cycloalkoxy group, -OC(=O)C 1-6 alkyl group, -OC(=O)C 3 to C 6 cycloalkyl group, -C(=O)OC 1- 6 alkyl, -C(=O)OC 3 ~ C 6 cycloalkyl, C 1 ~ C 6 alkyl substituted by R f , C 3 ~ C 6 cycloalkyl, C 1 ~ C 6 alkoxy, Substituents of C 3 to C 6 cycloalkoxy, wherein R f is selected from deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 4 alkyl, saturated or unsaturated C 3 ~ C 6 cycloalkyl, saturated or unsaturated C 1 to C 4 alkyl substituted by deuterium, halogen, hydroxyl or amino, C 3 to C 6 cycloalkyl substituted by deuterium, halogen, hydroxyl or amino, saturated or unsaturated Saturated C 1 to C 4 alkoxy group, C 3 to C 6 cycloalkoxy group, saturated or unsaturated C 1 to C 4 alkoxy group substituted by deuterium, halogen, hydroxyl or amino group, substituted by deuterium, halogen, hydroxyl group Or amino-substituted C 3 to C 6 cycloalkoxy group.
更优选地,Rj和Rk每次出现时各自独立地为羟基,卤素,氰基,磺酰基,氨基C1~C4烷基,C4~C6环烷基,C1~C4烷氧基,C4~C6环烷氧基,-OC(=O)C1-4烷基,-OC(=O)C4~C6环烷基,-C(=O)OC1-4烷基,-C(=O)OC4~C6环烷基,被Rf取代的C1~C4烷基、C4~C6环烷基、C1~C4烷氧基、C4~C6环烷氧基的取代基,其中Rf选自氘,卤素,氰基,羟基,氨基,饱和或不饱和的C1~C3烷基,饱和或不饱和的C5~C6环烷基,饱和或不饱和的被氘、卤素、羟基或氨基取代C1~C3烷基,被氘、卤素、羟基或氨基取代的C5~C6环烷基,饱和或不饱和的C1~C3烷氧基,C5~C6环烷氧基,饱和或不饱和的被氘、卤素、羟基或氨基取代C1~C3烷氧基,被氘、卤素、羟基或氨基取代的C5~C6环烷氧基。More preferably, each occurrence of R j and R k is independently hydroxyl, halogen, cyano, sulfonyl, amino C 1 to C 4 alkyl, C 4 to C 6 cycloalkyl, C 1 to C 4 Alkoxy group, C 4 to C 6 cycloalkoxy group, -OC(=O)C 1-4 alkyl group, -OC(=O)C 4 to C 6 cycloalkyl group, -C(=O)OC 1 -4 alkyl, -C(=O)OC 4 ~ C 6 cycloalkyl, C 1 ~ C 4 alkyl substituted by R f , C 4 ~ C 6 cycloalkyl, C 1 ~ C 4 alkoxy , C 4 to C 6 cycloalkoxy substituents, wherein R f is selected from deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 3 alkyl, saturated or unsaturated C 5 ~C 6 cycloalkyl, saturated or unsaturated C 1 ~ C 3 alkyl substituted by deuterium, halogen, hydroxyl or amino. C 5 ~ C 6 cycloalkyl substituted by deuterium, halogen, hydroxyl or amino, saturated or Unsaturated C 1 to C 3 alkoxy group, C 5 to C 6 cycloalkoxy group, saturated or unsaturated C 1 to C 3 alkoxy group substituted by deuterium, halogen, hydroxyl or amino group, substituted by deuterium, halogen, Hydroxyl or amino-substituted C 5 to C 6 cycloalkoxy group.
更优选地,根据式Ⅰ表示的2-氮取代嘧啶类化合物,其各自旋光异构体,氘代物,前药或药学上可接受的盐选自以下化合物中:
More preferably, according to the 2-nitrogen-substituted pyrimidine compound represented by formula I, each of its optical isomers, deuterated products, prodrugs or pharmaceutically acceptable salts is selected from the following compounds:
More preferably, according to the 2-nitrogen-substituted pyrimidine compound represented by formula I, each of its optical isomers, deuterated products, prodrugs or pharmaceutically acceptable salts is selected from the following compounds:
根据本发明的第二个方面,本发明的另一目的在于提供一种药物组合物,所述药物组合物包含治疗有效量的根据本发明的由式Ⅰ表示的2-氮取代嘧啶类化合物,其各自旋光异构体,氘代物,前药或药学上可接受的盐和药学上可接受的赋形剂或载体。According to the second aspect of the present invention, another object of the present invention is to provide a pharmaceutical composition, said pharmaceutical composition comprising a therapeutically effective amount of a 2-nitrogen-substituted pyrimidine compound represented by Formula I according to the present invention, Each of its optical isomers, deuterated products, prodrugs or pharmaceutically acceptable salts and pharmaceutically acceptable excipients or carriers.
根据本发明的第三个方面,本发明的另一目的在于提供根据本发明的由式Ⅰ表示的2-氮取代嘧啶类化合物,其各自旋光异构体,氘代物,前药或药学上可接受的盐在制备AHR紊乱抑制剂中的用途。According to the third aspect of the present invention, another object of the present invention is to provide 2-nitrogen-substituted pyrimidine compounds represented by formula I according to the present invention, each of which is an optical isomer, a deuterated product, a prodrug or a pharmaceutically acceptable compound. Use of the accepted salts in the preparation of inhibitors of AHR disorders.
根据本发明的第四个方面,本发明的另一目的在于提供根据本发明的由式Ⅰ表示的2-氮取代嘧啶类化合物,其各自旋光异构体,氘代物,前药或药学上可接受的盐在制备治疗与AHR紊乱相关的肿瘤的药物中的应用。According to the fourth aspect of the present invention, another object of the present invention is to provide 2-nitrogen-substituted pyrimidine compounds represented by formula I according to the present invention, each of which is an optical isomer, a deuterated product, a prodrug or a pharmaceutically acceptable compound. Use of the salts accepted for the preparation of a medicament for the treatment of tumors associated with AHR disorders.
根据本发明的第五个方面,本发明的另一目的在于提供一种治疗与AHR紊乱相关的肿瘤的方法,所述方法包括向需要其的受试者施用有效量的根据本发明的由式Ⅰ表示的2-氮取代嘧啶类化合物,其各自旋光异构体,氘代物,前药或药学上可接受的盐或根据本发明的所述药物组合物。According to the fifth aspect of the present invention, another object of the present invention is to provide a method for treating tumors associated with AHR disorders, the method comprising administering to a subject in need thereof an effective amount of a compound according to the present invention represented by the formula The 2-nitrogen-substituted pyrimidine compound represented by I, each of its optical isomers, deuterated products, prodrugs or pharmaceutically acceptable salts or the pharmaceutical composition according to the present invention.
根据本发明的第六个方面,本发明的另一目的在于提供根据本发明的由式Ⅰ表示的2-氮取代嘧啶类化合物,其各自旋光异构体,氘代物,前药或药学上可接受的盐的制备方法,所述方法选自如下反应式1或反应式2所示:
According to the sixth aspect of the present invention, another object of the present invention is to provide 2-nitrogen-substituted pyrimidine compounds represented by formula I according to the present invention, each of which is an optical isomer, a deuterated product, a prodrug or a pharmaceutically acceptable compound. The preparation method of the accepted salt, the method is selected from the following reaction formula 1 or reaction formula 2:
According to the sixth aspect of the present invention, another object of the present invention is to provide 2-nitrogen-substituted pyrimidine compounds represented by formula I according to the present invention, each of which is an optical isomer, a deuterated product, a prodrug or a pharmaceutically acceptable compound. The preparation method of the accepted salt, the method is selected from the following reaction formula 1 or reaction formula 2:
反应式1Reaction 1
在反应式1中,式III的化合物与式II的化合物经过酯化反应形成式I表示的化合物,其中取代基R1、R2、R3、R4、Ra、Rb、环A、L的定义与式I中相同;
In reaction formula 1, the compound of formula III and the compound of formula II undergo an esterification reaction to form a compound represented by formula I, in which the substituents R 1 , R 2 , R 3 , R 4 , R a , R b , ring A, The definition of L is the same as in Formula I;
In reaction formula 1, the compound of formula III and the compound of formula II undergo an esterification reaction to form a compound represented by formula I, in which the substituents R 1 , R 2 , R 3 , R 4 , R a , R b , ring A, The definition of L is the same as in Formula I;
反应式2Reaction 2
在反应式2中,式III的化合物与式IV的肼化合物经过酯化反应形成式I-a中间体化合物,然后I-a中间体化合物与含取代基R2的化合物(例如酸酐类化合物)反应形成式I表示的化合物,其中取代基R1、R2、R3、R4、Ra、Rb、环A、L的定义与式I中相同。In reaction formula 2, the compound of formula III and the hydrazine compound of formula IV undergo an esterification reaction to form an intermediate compound of formula Ia, and then the intermediate compound Ia reacts with a compound containing substituent R 2 (such as an acid anhydride compound) to form formula I represents a compound in which the definitions of the substituents R 1 , R 2 , R 3 , R 4 , R a , R b , and rings A and L are the same as those in Formula I.
在反应式1和2中,化合物III可以按照如下方法之一制备得到,以下仅为举例说明。In reaction formulas 1 and 2, compound III can be prepared according to one of the following methods, and the following is only an example.
方法A
Method A
Method A
步骤1)中间体X-A的制备Step 1) Preparation of intermediate X-A
向尿素和含A环结构的二羰基化合物V的乙醇溶液中加入浓盐酸,搅拌过夜,冷却至室温,过滤,用冷乙醇洗涤,干燥得化合物VI。Concentrated hydrochloric acid was added to the ethanol solution of urea and the dicarbonyl compound V containing the A ring structure, stirred overnight, cooled to room temperature, filtered, washed with cold ethanol, and dried to obtain compound VI.
步骤2)中间体VII的制备Step 2) Preparation of Intermediate VII
化合物VI加入到三氯氧磷中,氮气保护下加热搅拌,减压浓缩至干,加入乙酸乙酯和冰水,搅拌后过滤,干燥得化合物VII。Compound VI was added to phosphorus oxychloride, heated and stirred under nitrogen protection, concentrated to dryness under reduced pressure, added with ethyl acetate and ice water, stirred, filtered, and dried to obtain compound VII.
步骤3)中间体VIII的制备Step 3) Preparation of Intermediate VIII
化合物VII和氨基化合物NHRaRb溶解在二甲基亚砜中,加K2CO3,加热到70℃,搅拌过夜,冷却到室温,加入冰水,过滤,水洗,干燥得化合物VIII;Dissolve compound VII and amino compound NHR a R b in dimethyl sulfoxide, add K 2 CO 3 , heat to 70°C, stir overnight, cool to room temperature, add ice water, filter, wash with water, and dry to obtain compound VIII;
步骤4)化合物III的制备Step 4) Preparation of Compound III
将化合物VIII溶解在混合溶剂中,加入氢氧化锂,室温搅拌过夜,减压浓缩,加冰水,搅拌,乙酸乙酯萃取,水相用盐酸调pH至6~7,过滤,干燥得化合物III,所述混合溶剂为THF/MeOH/H2O(体积比:1/1/1)。Dissolve compound VIII in the mixed solvent, add lithium hydroxide, stir at room temperature overnight, concentrate under reduced pressure, add ice water, stir, extract with ethyl acetate, adjust the pH of the aqueous phase to 6-7 with hydrochloric acid, filter and dry to obtain compound III , the mixed solvent is THF/MeOH/H 2 O (volume ratio: 1/1/1).
方法B
Method B
Method B
步骤1)中间体X的制备Step 1) Preparation of intermediate X
2,6-二氯嘧啶-4-羧酸乙酯和含有A环结构的硼酸化合物IX溶解在二氧六环中,加饱和碳酸钠,四(三苯基磷)钯,脱气,氮气保护性下加热,搅拌过夜,冷却到室温,减压浓缩,加入冰水,乙酸乙酯萃取,干燥,纯化得化合物X;2,6-Dichloropyrimidine-4-carboxylic acid ethyl ester and the boric acid compound IX containing the A ring structure are dissolved in dioxane, add saturated sodium carbonate, tetrakis (triphenylphosphorus) palladium, degassed, and protected by nitrogen Heated at room temperature, stirred overnight, cooled to room temperature, concentrated under reduced pressure, added ice water, extracted with ethyl acetate, dried, and purified to obtain compound X;
步骤2)中间体XI的制备Step 2) Preparation of intermediate XI
化合物X和氨基化合物NHRaRb溶解在二甲基亚砜中,加K2CO3,加热到70℃,搅拌过夜,冷却到室温,加入冰水,过滤,水洗,干燥得化合物XI; Compound _ _ _
步骤3)化合物III的制备
Step 3) Preparation of Compound III
将化合物XI溶解在混合溶剂中,加入氢氧化锂,室温搅拌过夜,减压浓缩,加冰水,搅拌,乙酸乙酯萃取,水相用盐酸调pH至6~7,过滤,干燥得化合物III,所述混合溶剂为THF/MeOH/H2O(体积比:1/1/1)。Dissolve compound XI in the mixed solvent, add lithium hydroxide, stir at room temperature overnight, concentrate under reduced pressure, add ice water, stir, extract with ethyl acetate, adjust the pH of the aqueous phase to 6~7 with hydrochloric acid, filter and dry to obtain compound III , the mixed solvent is THF/MeOH/H 2 O (volume ratio: 1/1/1).
方法C
Method C
Method C
步骤1)中间体XII的制备Step 1) Preparation of intermediate XII
2,6-二氯嘧啶-4-羧酸乙酯和和氨基化合物NHRaRb溶解在二甲基亚砜中,加K2CO3,加热到70℃,搅拌过夜,冷却到室温,加入冰水,过滤,水洗,干燥得化合物XII;Dissolve 2,6-dichloropyrimidine-4-carboxylic acid ethyl ester and amino compound NHR a R b in dimethyl sulfoxide, add K 2 CO 3 , heat to 70°C, stir overnight, cool to room temperature, add Ice water, filtered, washed, and dried to obtain compound XII;
步骤2)中间体XIII的制备Step 2) Preparation of intermediate XIII
化合物XII和含有A环结构的硼酸化合物IX溶解在二氧六环中,加饱和碳酸钠,四(三苯基磷)钯,脱气,氮气保护性下加热,搅拌过夜,冷却到室温,减压浓缩,加入冰水,乙酸乙酯萃取,干燥,纯化得化合物XIII;compound Concentrate under pressure, add ice water, extract with ethyl acetate, dry and purify to obtain compound XIII;
步骤3)中间体III的制备Step 3) Preparation of Intermediate III
将化合物XIII溶解在混合溶剂中,加入氢氧化锂,室温搅拌过夜,减压浓缩,加冰水,搅拌,乙酸乙酯萃取,水相用盐酸调pH至6~7,过滤,干燥得化合物III,所述混合溶剂为THF/MeOH/H2O(体积比:1/1/1)。Dissolve compound XIII in the mixed solvent, add lithium hydroxide, stir at room temperature overnight, concentrate under reduced pressure, add ice water, stir, extract with ethyl acetate, adjust the pH of the aqueous phase to 6~7 with hydrochloric acid, filter and dry to obtain compound III , the mixed solvent is THF/MeOH/H 2 O (volume ratio: 1/1/1).
以下,将详细地描述本发明。在进行描述之前,应当理解的是,在本说明书和所附的权利要求书中使用的术语不应解释为限制于一般含义和字典含义,而应当在允许发明人适当定义术语以进行最佳解释的原则的基础上,根据与本发明的技术方面相应的含义和概念进行解释。因此,这里提出的描述仅仅是出于举例说明目的的优选实例,并非意图限制本发明的范围,从而应当理解的是,在不偏离本发明的精神和范围的情况下,可以由其获得其他等价方式或改进方式。Hereinafter, the present invention will be described in detail. Before proceeding to the description, it is to be understood that the terms used in this specification and the appended claims should not be construed to be limited to ordinary and dictionary meanings, but rather to allow the inventor to appropriately define the terms for best interpretation. On the basis of the principles, explanations are made according to the meanings and concepts corresponding to the technical aspects of the present invention. Accordingly, the descriptions set forth herein are preferred examples for illustrative purposes only and are not intended to limit the scope of the invention, so that it will be understood that others may be derived therefrom without departing from the spirit and scope of the invention. price or improvement methods.
在本文中,所有以数值范围或百分比范围形式界定的特征或条件仅是为了简洁及方便。据此,数值范围或百分比范围的描述应视为已涵盖且具体公开所有可能的次级范围及范围内的个别数值,特别是整数数值。举例而言,“1至8”的范围描述应视为已经具体公开如1至7、2至8、2至6、3至6、4至8、3至8等等所有次级范围,特别是由所有整数数值所界定的次级范围,且应视为已经具体公开范围内如1、2、3、4、5、6、7、8等个别数值。除非另有指明,否则前述解释方法适用于本发明全文的所有内容,不论范围广泛与否。In this article, all characteristics or conditions defined in the form of numerical ranges or percentage ranges are for brevity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges shall be deemed to cover and specifically disclose all possible subranges and individual values within the ranges, in particular integer values. For example, a range description of "1 to 8" should be deemed to have specifically disclosed all sub-ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., particularly is a secondary range defined by all integer values and shall be deemed to have been specifically disclosed as individual values within the range such as 1, 2, 3, 4, 5, 6, 7, 8, etc. Unless otherwise indicated, the foregoing method of interpretation applies to all contents of the present invention, whether broad or not.
若数量或其他数值或参数是以范围、较佳范围或一系列上限与下限表示,则其应理解成是本文已特定公开了由任一对该范围的上限或较佳值与该范围的下限或较佳值构成的所有范围,不论这些范围是否有分别公开。此外,本文中若提到数值的范围时,除非另有说明,否则该范围应包括其端点以及范围内的所有整数与分数。If a quantity or other numerical value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that any pairing of the upper limit of the range or the preferred value and the lower limit of the range has been specifically disclosed herein. or all ranges consisting of better values, whether or not these ranges are separately disclosed. In addition, when reference is made herein to a range of values, such range shall include its endpoints and all integers and fractions within the range, unless otherwise stated.
在本文中,在可实现发明目的的前提下,数值应理解成具有该数值有效位数的精确度。举例来说,数字40.0则应理解成涵盖从39.50至40.49的范围。In this document, numerical values shall be understood to have an accuracy of 100 significant digits, provided that the object of the invention is achieved. For example, the number 40.0 should be understood to cover the range from 39.50 to 40.49.
在本文中,对于使用马库什群组(Markush group)或选项式用语以描述本发明特征或实例的情形,本领域技术人员应了解马库什群组或选项列表内所有要素的次级群组或任
何个别要素亦可用于描述本发明。举例而言,若X描述成“选自于由X1、X2及X3所组成的群组”,亦表示已经完全描述出X为X1的主张与X为X1及/或X2的主张。再者,对于使用马库什群组或选项式用语以描述本发明的特征或实例的情况,本领域技术人员应了解马库什群组或选项列表内所有要素的次级群组或个别要素的任何组合亦可用于描述本发明。据此,举例而言,若X描述成“选自于由X1、X2及X3所组成的群组”,且Y描述成“选自于由Y1、Y2及Y3所组成的群组”,则表示已经完全描述出X为X1或X2或X3而Y为Y1或Y2或Y3的主张。In this article, when Markush groups or alternative terms are used to describe features or examples of the present invention, those skilled in the art will understand that Markush groups or subgroups of all elements in the alternative list group or any Any individual elements may also be used to describe the invention. For example, if X is described as “selected from the group consisting of X1, X2, and X3,” it also means that the claim that X is X1 and the claim that X is X1 and/or Furthermore, when Markush groups or optional terms are used to describe features or examples of the present invention, those skilled in the art should understand the sub-groups or individual elements of all elements in the Markush group or option list. Any combination of may also be used to describe the invention. Accordingly, for example, if X is described as "selected from the group consisting of X1, Indicates that the claim that X is X1 or X2 or X3 and Y is Y1 or Y2 or Y3 has been fully described.
定义definition
“烷基”是指具有1至8个碳原子的直链或支链饱和烃基的基团(“C1–8烷基”)。在一些实施方案中,烷基具有1至7个碳原子(“C1-7烷基”)。在一些实施方案中,烷基具有1至6个碳原子(“C1-6烷基”)。在一些实施方案中,烷基具有1至5个碳原子(“C1-5烷基”)。在一些实施方案中,烷基具有1至4个碳原子(“C1-4烷基”)。在一些实施方案中,烷基具有1至3个碳原子(“C1-3烷基”)。在一些实施方案中,烷基具有1至2个碳原子(“C1-2烷基”)。在一些实施方案中,烷基具有1个碳原子(“C1烷基”)。在一些实施方案中,烷基具有1至6个碳原子(“C1-6烷基”)。C1–6烷基的实例包括甲基(C1),乙基(C2),丙基(C3)(例如,正丙基、异丙基),丁基(C4)(例如正丁基、叔丁基、仲丁基、异丁基),戊基(C5)(例如,正戊基、3-戊基、新戊基、3-甲基-2-丁基、叔戊基)和己基(C6)(例如,正己基)。烷基的另外的实例包括正庚基(C7)、正辛基(C8)等。除非另有说明,烷基的每个实例独立地未被取代(“未取代的烷基”)或被一个或多个取代基(例如,卤素,如F)所取代(“取代的烷基”)。在某些实施方案中,烷基是未取代的C1-8烷基(例如未取代的C1烷基,如-CH3)。在某些实施方案中,烷基为取代的C1-8烷基(例如取代的C1烷基,如-CF3)。"Alkyl" refers to a straight or branched chain saturated hydrocarbon radical having 1 to 8 carbon atoms ("C 1-8 alkyl"). In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1-7 alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 alkyl"). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2 alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("C 1 alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 alkyl"). Examples of C 1-6 alkyl groups include methyl (C 1 ), ethyl (C 2 ), propyl (C 3 ) (e.g., n-propyl, isopropyl), butyl (C 4 ) (e.g., n-propyl) Butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C 5 ) (for example, n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl group) and hexyl (C 6 ) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents (e.g., halogen, such as F) ("substituted alkyl" ). In certain embodiments, alkyl is unsubstituted C 1-8 alkyl (eg, unsubstituted C 1 alkyl, such as -CH 3 ). In certain embodiments, alkyl is substituted C 1-8 alkyl (eg, substituted C 1 alkyl, such as -CF 3 ).
“烷氧基”表示单价‐O‐烷基,其中所述烷基部分具有指定数目的碳原子。本公开中烷氧基通常含有1‐8个碳原子(“C1至C8烷氧基”),1‐6个碳原子(“C1至C6烷氧基”),或1‐4个碳原子(“C1‐C4烷氧基”)。例如,C1‐C4烷氧基,包括甲氧基、乙氧基、异丙氧基、叔丁基氧基等。除非另有说明,烷氧基的每个实例独立地任选被取代,即未取代(“未取代的烷氧基”)或被一个或多个取代基所取代(“取代的烷氧基”)。在某些实施方案中,烷氧基是未取代的C1至C6烷氧基。在某些实施方案中,烷氧基是取代的C1至C6烷氧基。"Alkoxy" means a monovalent -O-alkyl group, wherein the alkyl moiety has the specified number of carbon atoms. In this disclosure, alkoxy groups generally contain 1-8 carbon atoms ("C1 to C8 alkoxy"), 1-6 carbon atoms ("C1 to C6 alkoxy"), or 1-4 carbon atoms ( "C1-C4 alkoxy"). For example, C1-C4 alkoxy groups include methoxy, ethoxy, isopropoxy, tert-butyloxy, etc. Unless otherwise specified, each instance of alkoxy is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkoxy") or substituted with one or more substituents ("substituted alkoxy" ). In certain embodiments, alkoxy is unsubstituted C1 to C6 alkoxy. In certain embodiments, alkoxy is substituted C1 to C6 alkoxy.
“环烷基”是指非芳族环系中具有3至8个环碳原子(“C3-8环烷基”)和零个杂原子的非芳族环烃基的基团。在一些实施方案中,环烷基团具有3至8个环碳原子(“C3-8环烷基”)。在一些实施方案中,环烷基团具有3至6个环碳原子(“C3-6环烷基”)。在一些实施方案中,环烷基具有5至8个环碳原子(“C5-8环烷基”)。示例性的C3-6环烷基团包括但不限于环丙基(C3)、环丙烯基(C3)、环丁基(C4)、环丁烯基(C4)、环戊基(C5)、环戊烯基(C5)、环己基(C6)、环己烯基(C6)、环己二烯基(C6)等。示例性的C3-8环烷基团包括但不限于上述C3-6环烷基团以及环庚基(C7)、环庚烯基(C7)、环庚二烯基(C7)、环庚三烯基(C7)、环辛基(C8)、环辛烯基(C8)等。除非另有说明,环烷基的每个实例独立地任选被取代,即未取代(“未取代的环烷基”)或被一个或多个取代基所取代(“取代的环烷基”)。在某些实施方案中,环烷基是未取代的C3-8环烷基;在某些实施方案中,环烷基是取代的C3-8环烷基。"Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 8 ring carbon atoms ("C 3-8 cycloalkyl") and zero heteroatoms in a non-aromatic ring system. In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 8 ring carbon atoms ("C 5-8 cycloalkyl"). Exemplary C 3-6 cycloalkyl groups include, but are not limited to, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl group (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), etc. Exemplary C 3-8 cycloalkyl groups include, but are not limited to, the C 3-6 cycloalkyl groups described above as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), etc. Unless otherwise specified, each instance of cycloalkyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl" ). In certain embodiments, cycloalkyl is unsubstituted C 3-8 cycloalkyl; in certain embodiments, cycloalkyl is substituted C 3-8 cycloalkyl.
“杂环烷基”是指具有环碳原子和1至4个环杂原子的4至14元非芳族环系的基团,其中每个杂原子独立地选自氮、氧和硫(“4-14元杂环基团”)。在含有一个或多个氮原子的杂环基团中,只要化合价所允许,连接点可以是碳原子或氮原子。杂环基团可以是单环(“单环杂环基团”)或稠环、桥环或螺环系,例如双环系(“双环杂环基”),并且可以是饱和的或可以是部分不饱和的。“杂环基团”还包括其中如上所定义的杂环与一个或多个环
烷基基团稠合(其中连接点在环烷基团或杂环上)的环系,或其中如上所定义的杂环与一个或多个芳基或杂芳基基团稠合(其中连接点在杂环上)的环系,并且在这种情况下,环成员的数目继续指代杂环系中环成员的数目。除非另有说明,杂环基团的每个实例独立地任选地被取代,即未取代(“未取代的杂环烷基”)或被一个或多个取代基所取代(“取代的杂环烷基”)。在某些实施方案中,杂环烷基是未取代的4-14元杂环烷基。在某些实施方案中,杂环烷基取代的4-14元杂环烷基。"Heterocycloalkyl" means a group of 4 to 14 membered non-aromatic ring systems having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen and sulfur (" 4-14 membered heterocyclic group"). In heterocyclic groups containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom, as long as the valency permits. Heterocyclic groups may be monocyclic ("monocyclic heterocyclyl") or fused, bridged or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl"), and may be saturated or may be partially Unsaturated. "Heterocyclic group" also includes a heterocyclic group as defined above combined with one or more cyclic A ring system in which an alkyl group is fused (wherein the point of attachment is on a cycloalkyl group or a heterocycle), or in which a heterocycle as defined above is fused with one or more aryl or heteroaryl groups (wherein the attachment point on a heterocyclic ring), and in this case, the number of ring members continues to refer to the number of ring members in the heterocyclic ring system. Unless otherwise specified, each instance of a heterocyclic group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocycloalkyl") or substituted with one or more substituents ("substituted heterocycloalkyl"). Cycloalkyl"). In certain embodiments, heterocycloalkyl is unsubstituted 4-14 membered heterocycloalkyl. In certain embodiments, heterocycloalkyl substituted 4-14 membered heterocycloalkyl.
“芳基”或“芳香环”或“芳香环基”是指具有在芳环系中提供的6-14个环碳原子和零个杂原子的单环或多环(例如,二环或三环)4n+2芳族环系(例如,具有在环状阵列中共享的6、10或14个π电子)的基团(“C6-14芳基”)。在一些实施方案中,芳基具有6个环碳原子(“C6芳基”;例如,苯基)。在一些实施方案中,芳基具有10个环碳原子(“C10芳基”;例如,萘基,如1-萘基和2-萘基)。在一些实施方案中,芳基具有14个环碳原子(“C14芳基”;例如,蒽基)。“芳基”还包括其中如上定义的芳基环与一个或多个环烷基或杂环基团稠合(其中连接点在芳环上)的环系,并且在这种情况下,碳原子的数目继续以指代芳环系中的碳原子数目。除非另有说明,芳基的每个实例独立地任选被取代,即未取代(“未取代的芳基”)或被一个或多个取代基所取代(“取代的芳基”)。在某些实施方案中,芳基是未取代的C6-14芳基。在某些实施方案中,芳基是取代的C6-14芳基。"Aryl" or "aromatic ring" or "aromatic ring group" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic ring) having 6 to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system. Ring) A group of 4n+2 aromatic ring systems (eg, having 6, 10, or 14 π electrons shared in a cyclic array) ("C 6-14 aryl"). In some embodiments, an aryl group has 6 ring carbon atoms ("C 6 aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 aryl"; for example, anthracenyl). "Aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more cycloalkyl or heterocyclic groups, wherein the point of attachment is on the aromatic ring, and in this case, the carbon atom The number continues to refer to the number of carbon atoms in the aromatic ring system. Unless otherwise specified, each instance of aryl is independently optionally substituted, ie, unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, aryl is unsubstituted C 6-14 aryl. In certain embodiments, aryl is substituted C 6-14 aryl.
“杂芳基”是具有在芳族环系中提供的环碳原子和1-4个环杂原子的5-10元芳族环系,其中每个杂原子独立地选自氮、氧和硫(“5-10元杂芳基”)。在一些实施方案中,杂芳基是具有在芳族环系中提供的环碳原子和1-4个环杂原子的5-8元芳族环系,其中每个杂原子独立地选自氮、氧和硫(“5-8元杂芳基”)。在一些实施方案中,杂芳基是具有在芳族环系中提供的环碳原子和1-4个环杂原子的5-6元芳族环系,其中每个杂原子独立地选自氮、氧和硫(“5-6元杂芳基”)。在一些实施方案中,5-6元杂芳基具有1-3个选自氮、氧和硫的环杂原子。在一些实施方案中,5-6元杂芳基具有1-2个选自氮、氧和硫的环杂原子。在一些实施方案中,5-6元杂芳基具有1个选自氮、氧和硫的环杂原子。除非另有说明,杂芳基的每个实例独立地任选被取代,即未取代(“未取代的杂芳基”)或被一个或多个取代基所取代(“取代的杂芳基”)。在某些实施方案中,杂芳基是未取代的5-10元杂芳基。在某些实施方案中,杂芳基是取代的5-10元杂芳基。"Heteroaryl" is a 5-10 membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In some embodiments, heteroaryl is a 5-8 membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen , oxygen and sulfur ("5-8 membered heteroaryl"). In some embodiments, heteroaryl is a 5-6 membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen , oxygen and sulfur ("5-6 membered heteroaryl"). In some embodiments, a 5-6 membered heteroaryl group has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl group has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl group has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of heteroaryl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl" ). In certain embodiments, heteroaryl is unsubstituted 5-10 membered heteroaryl. In certain embodiments, heteroaryl is a substituted 5-10 membered heteroaryl.
“卤素”或“卤代”是指氟(氟,-F)、氯(氯,-Cl)、溴(溴,-Br)或碘(碘,-I)。"Halogen" or "halo" refers to fluorine (fluorine, -F), chlorine (chlorine, -Cl), bromine (bromine, -Br) or iodine (iodine, -I).
“取代的”或“任选取代的”是指基团中的原子,例如氢原子被取代。在某些实施方案中,烷基、环烷基、杂环基、芳基和杂芳基被取代(例如“取代的”烷基、“取代的”环烷基、“取代的”杂环烷基、“取代的”芳基,或“取代的”杂芳基)。通常,术语“取代的”,无论之前是否有术语“任选地”,意指存在于基团(例如,碳或氮原子)上的至少一个氢被可允许的取代基取代,例如,取代基在取代后会形成稳定的化合物,例如,不会(如通过重排、环化、消除或其他反应)自发地发生转化的化合物。除非另外指明,否则“取代的”基团在该基团的一个或多个可取代的位置上具有取代基,并且当任何给定结构中的多于一个位置被取代时,取代基在每个位置处相同或不同。预期术语“取代的”包括用有机化合物的所有可允许的取代基、任何导致形成稳定化合物的本文所述的取代基所取代。本公开预期任何和所有这些组合以获得稳定的化合物。为了本公开的目的,如氮的杂原子可以具有氢取代基和/或如本文所述的满足杂原子的化合价并导致形成稳定的部分的任何合适的取代基。在某些实施方案中,取代基是碳原子取代基。在某些实施方案中,取代基是氮原子取代基。在某些实施方案中,取代基是氧原子取代基。在某些实施方案中,取代基是硫原子取代基。"Substituted" or "optionally substituted" means that an atom, such as a hydrogen atom, in the group is substituted. In certain embodiments, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted (e.g., "substituted" alkyl, "substituted" cycloalkyl, "substituted" heterocycloalkyl radical, "substituted" aryl, or "substituted" heteroaryl). Generally, the term "substituted", whether or not preceded by the term "optionally", means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced by a permissible substituent, e.g. Substitution results in the formation of stable compounds, eg, compounds that do not undergo spontaneous transformation (eg, by rearrangement, cyclization, elimination, or other reactions). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions on the group, and when more than one position in any given structure is substituted, the substituent is present at each The location is the same or different. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, any substituent described herein that results in the formation of a stable compound. This disclosure contemplates any and all of these combinations to obtain stable compounds. For purposes of this disclosure, a heteroatom such as nitrogen may have a hydrogen substituent and/or any suitable substituent as described herein that satisfies the valency of the heteroatom and results in the formation of a stable moiety. In certain embodiments, the substituents are carbon atom substituents. In certain embodiments, the substituents are nitrogen atom substituents. In certain embodiments, the substituents are oxygen atom substituents. In certain embodiments, the substituent is a sulfur atom substituent.
“不饱和的”或“部分不饱和的”是指包含至少一个双键或三键的基团。“部分不饱和的”环系还旨在涵盖具有多个不饱和位点的环,但不旨在包括芳香族基团(例如,芳基或杂芳基)。同样,“饱和”是指不含双键或三键的基团,即全部含单键。
"Unsaturated" or "partially unsaturated" refers to a group containing at least one double or triple bond. "Partially unsaturated" ring systems are also intended to encompass rings having multiple sites of unsaturation, but are not intended to include aromatic groups (eg, aryl or heteroaryl). Likewise, "saturated" refers to a group that contains no double or triple bonds, that is, all single bonds.
本文中,当定义的取代基中存在多重取代时,这种多重取代的文字描述中可能存在重复定义的情况,但这种描述应理解为至少符合一般药物化学的基本规律,例如当取代基出现重复定义时,本领域技术人员可以按照一般药物化学常识确定这种重复是可行的或不可行的,并作出合理的选择。In this article, when there are multiple substitutions in a defined substituent, there may be repeated definitions in the text description of such multiple substitutions, but this description should be understood as at least consistent with the basic laws of general medicinal chemistry. For example, when a substituent appears When repeating a definition, those skilled in the art can determine whether such repeating is feasible or unfeasible based on common common sense in medicinal chemistry, and make a reasonable choice.
本文中采用的术语“药学上可接受的”,是针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症,与合理的利益/风险比相称。As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指本发明化合物的盐,由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐(即药学上可接受的盐),实例包括无机酸盐以及有机酸盐,所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸,碳酸氢根,磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等;所述有机酸包括如苯甲酸、2-羟基乙磺酸、氨基磺酸、苯磺酸、苯乙酸、扁桃酸、丙二酸、丙酸、草酸、对氨基苯磺酸、对甲苯磺酸、多聚半乳糖醛酸、泛酸、富马酸、谷氨酸、琥珀酸、甲烷磺酸、酒石酸、抗坏血酸、邻苯二甲酸、马来酸、柠檬酸、苹果酸、葡庚糖酸、葡糖酸、羟乙磺酸、乳酸、乳糖酸、十二烷基磺酸、双羟萘酸、水杨酸、辛二酸、亚叶酸、依地酸、乙醇酸、乙酸、乙烷磺酸、异丁酸、硬脂酸等类似的酸;还包括氨基酸(如精氨酸等)的盐,以及如葡糖醛酸等有机酸的盐(参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977))。本发明的某些特定的化合物含有碱性和酸性的官能团,从而可以被转换成任一碱或酸加成盐。化合物的母体形式与其各种盐的形式的不同之处在于某些物理性质,例如在极性溶剂中的溶解度不同。The term "pharmaceutically acceptable salts" refers to salts of compounds of the present invention prepared from compounds having specific substituents found in the present invention and relatively non-toxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts (i.e., pharmaceutical Acceptable salts above), examples include inorganic acid salts and organic acid salts, the inorganic acid includes, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid , hydrogen sulfate, hydriodic acid, phosphorous acid, etc.; the organic acids include benzoic acid, 2-hydroxyethanesulfonic acid, sulfamic acid, benzenesulfonic acid, phenylacetic acid, mandelic acid, malonic acid, propionic acid, Oxalic acid, p-aminobenzenesulfonic acid, p-toluenesulfonic acid, polygalacturonic acid, pantothenic acid, fumaric acid, glutamic acid, succinic acid, methane sulfonic acid, tartaric acid, ascorbic acid, phthalic acid, maleic acid, Citric acid, malic acid, glucoheptonic acid, gluconic acid, isethionic acid, lactic acid, lactobionic acid, dodecyl sulfonic acid, pamoic acid, salicylic acid, suberic acid, leucovorin, idetamine Acid, glycolic acid, acetic acid, ethanesulfonic acid, isobutyric acid, stearic acid and similar acids; also includes salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977)). Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts. The parent form of a compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.
如本文所用,修饰词术语“约”是指可能发生的数值变化,例如,通过常规测试和处理;通过此类测试和处理中的无意错误;通过本发明所用成分的制造,来源或纯度上的差异;等等。如本文所用,“约”特定值还包括该特定值,例如,“约10%”包括10%。不论是否被术语“约”修饰,权利要求均包括所列举数量的等同形式。在一个实施方式中,术语“约”是指在所报告的数值的20%以内。As used herein, the modifier term "about" refers to numerical variations that may occur, e.g., through routine testing and handling; through inadvertent errors in such testing and handling; through variations in the manufacture, source, or purity of the ingredients used in the invention. Difference; etc. As used herein, "about" a particular value also includes that particular value, for example, "about 10%" includes 10%. Whether or not modified by the term "about," the claims include equivalents of the recited quantities. In one embodiment, the term "about" means within 20% of the reported value.
如本文所用,术语“治疗”是指消除,减轻或改善疾病或病症和/或与其相关的症状。尽管没有排除,但是治疗疾病或病症并不需要完全消除与其相关的疾病,病症或症状。如本文所用,术语“治疗”等可以包括“预防性治疗”,是指在没有或有患上或易患疾病或病症或疾病或病症复发的风险的受试者中,降低疾病或病症的再发展或先前控制的疾病或病症的复发的可能性。术语“治疗”和同义词考虑向需要这种治疗的受试者施用治疗有效量的本文所述的化合物。As used herein, the term "treating" means eliminating, alleviating or ameliorating a disease or condition and/or symptoms associated therewith. Although not excluded, treatment of a disease or condition does not require the complete elimination of the disease, condition or symptoms associated with it. As used herein, the term "treatment" and the like may include "preventive treatment" which refers to reducing the recurrence of a disease or condition in a subject who does not have or is at risk of developing or susceptible to the disease or condition or the recurrence of the disease or condition. The possibility of development or recurrence of a previously controlled disease or condition. The term "treatment" and synonyms contemplate the administration of a therapeutically effective amount of a compound described herein to a subject in need of such treatment.
针对药物或药理学活性剂而言,术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型,组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异,取决于受体的年龄和一般情况,也取决于具体的活性物质,个案中合适的有效量可以由本领域技术人员根据常规试验确定。The term "effective amount" or "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a non-toxic amount of the drug or agent sufficient to achieve the desired effect. For the oral dosage form of the present invention, the "effective amount" of an active substance in the composition refers to the amount required to achieve the desired effect when combined with another active substance in the composition. The determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
根据本发明的所述AHR通路相关的疾病包括但不限于与AHR通路相关的肿瘤。The AHR pathway-related diseases according to the present invention include, but are not limited to, tumors related to the AHR pathway.
以下实施例仅是作为本发明的实施方案的例子列举,并不对本发明构成任何限制,本领域技术人员可以理解在不偏离本发明的实质和构思的范围内的修改均落入本发明的保护范围。除非特别说明,以下实施例中使用的试剂和仪器均为市售可得产品。
The following examples are merely examples of embodiments of the present invention and do not constitute any limitation to the present invention. Those skilled in the art can understand that modifications within the scope that do not deviate from the essence and concept of the present invention fall within the protection of the present invention. scope. Unless otherwise stated, the reagents and instruments used in the following examples are all commercially available products.
实施例1:中间体III-AExample 1: Intermediate III-A
方法A
Method A
Method A
步骤1)2,4-二羰基-4-(4-(三氟甲基)苯基)丁酸乙酯的制备Step 1) Preparation of 2,4-dicarbonyl-4-(4-(trifluoromethyl)phenyl)butyric acid ethyl ester
将草酸二乙酯(15.2g,104mmol)的无水乙醇(250ml)和乙醇钠(10.9g,160mmol)混合溶液冷却至10度以下,搅拌30min,滴加三氟甲基苯甲酮(18.8g,100mmol)的无水乙醇溶液(80ml),撤去冰浴,室温搅拌过夜,反应液几乎固化,过滤,少量乙醇洗涤,干燥,得2,4-二羰基-4-(4-(三氟甲基)苯基)丁酸乙酯(28g,收率97%)。LC/MS(ESI):m/z 289[M+1]+。Cool the mixed solution of diethyl oxalate (15.2g, 104mmol) in absolute ethanol (250ml) and sodium ethoxide (10.9g, 160mmol) below 10 degrees, stir for 30 minutes, and add trifluoromethylbenzophenone (18.8g) dropwise , 100mmol) absolute ethanol solution (80ml), remove the ice bath, stir at room temperature overnight, the reaction solution is almost solidified, filter, wash with a small amount of ethanol, and dry to obtain 2,4-dicarbonyl-4-(4-(trifluoromethyl Ethyl)phenyl)butyrate (28g, yield 97%). LC/MS(ESI): m/z 289[M+1] + .
步骤2)中间体VI-A的制备Step 2) Preparation of intermediate VI-A
向尿素(66mg,1.1mmol)和2,4-二羰基-4-(4-(三氟甲基)苯基)丁酸乙酯(288.2mg,1mmol)的乙醇溶液(4ml)中加入1ml的浓盐酸,在80℃搅拌过夜,冷却至室温,过滤,用冷乙醇洗涤,干燥得VI-A。LC/MS(ESI):m/z 313[M+1]+。To an ethanol solution (4 ml) of urea (66 mg, 1.1 mmol) and ethyl 2,4-dicarbonyl-4-(4-(trifluoromethyl)phenyl)butyrate (288.2 mg, 1 mmol) was added Concentrated hydrochloric acid, stir at 80°C overnight, cool to room temperature, filter, wash with cold ethanol, and dry to obtain VI-A. LC/MS(ESI): m/z 313[M+1] + .
步骤3)中间体VII-A的制备Step 3) Preparation of intermediate VII-A
化合物VI-A(78mg,0.25mmol)加入到2ml三氯氧磷中,氮气保护下加热到85℃,搅拌6h,减压浓缩至干,加入乙酸乙酯(EA)(50ml)和20g碎冰块,搅拌20min,过滤,干燥得化合物VII-A。LC/MS(ESI):m/z 331[M+1]+。Compound VI-A (78 mg, 0.25 mmol) was added to 2 ml of phosphorus oxychloride, heated to 85°C under nitrogen protection, stirred for 6 hours, concentrated to dryness under reduced pressure, and added ethyl acetate (EA) (50 ml) and 20 g of crushed ice. block, stir for 20 min, filter and dry to obtain compound VII-A. LC/MS(ESI): m/z 331[M+1] + .
步骤4)中间体III-A的制备Step 4) Preparation of intermediate III-A
化合物VII-A(56mg,0.16mmol)和咪唑(55mg,0.8mmol)溶解在二甲基亚砜(DMSO)(5ml)中,加K2CO3(150mg,1.09mmol),加热到70℃,搅拌过夜。冷却到室温,加入20ml冰水,过滤,水洗,干燥得化合物III-A。LC/MS(ESI):m/z 335[M+1]+,333[M-1]+。1H NMR(400MHz,DMSO-d6):δ11.5(brs,1H),9.00(s,1H),8.66(d,2H),8.50(s,1H),7.96(m,3H),7.20(s,1H)。Compound VII-A (56 mg, 0.16 mmol) and imidazole (55 mg, 0.8 mmol) were dissolved in dimethyl sulfoxide (DMSO) (5 ml), added K 2 CO 3 (150 mg, 1.09 mmol), and heated to 70°C. Stir overnight. Cool to room temperature, add 20 ml of ice water, filter, wash with water, and dry to obtain compound III-A. LC/MS(ESI): m/z 335[M+1] + , 333[M-1] + . 1 H NMR (400MHz, DMSO-d 6 ): δ11.5(brs,1H),9.00(s,1H),8.66(d,2H),8.50(s,1H),7.96(m,3H),7.20 (s,1H).
按照中间体III-A同样的方法可以制备下面表1中的中间体I-B至I-ZIntermediates I-B to I-Z in Table 1 below can be prepared according to the same method as Intermediate III-A.
表1
Table 1
Table 1
实施例2:中间体III-AA的制备 Example 2: Preparation of intermediate III-AA
方法C
Method C
Method C
步骤1)中间体XII-AA的制备Step 1) Preparation of intermediate XII-AA
2,6-二氯嘧啶-4-羧酸乙酯(2.21g,10mmol)和咪唑(1.02g,15mmol)溶解在DMSO(25ml)中,加K2CO3(4.14g,30mmol),加热到70℃,搅拌过夜。冷却到室温,加入200ml冰水,过滤,硅胶柱层析纯化得化合物XII-AA(533mg,收率21%)。LC/MS(ESI):m/z 253[M+1]+。2,6-Dichloropyrimidine-4-carboxylic acid ethyl ester (2.21g, 10mmol) and imidazole (1.02g, 15mmol) were dissolved in DMSO (25ml), added K 2 CO 3 (4.14g, 30mmol), and heated to 70°C and stir overnight. Cool to room temperature, add 200 ml of ice water, filter, and purify by silica gel column chromatography to obtain compound XII-AA (533 mg, yield 21%). LC/MS(ESI): m/z 253[M+1] + .
步骤2)中间体XII-AA的制备Step 2) Preparation of intermediate XII-AA
化合物XII-AA(506mg,2mmol)和6-(三氟甲基)吡啶-3-基硼酸(480mg,2.5mmol)溶解在二氧六环(10ml)中,加饱和碳酸钠(1ml),四(三苯基磷)钯(115mg,0.1mmol),脱气,氮气保护性下加热到100℃,搅拌过夜。冷却到室温,减压浓缩,加入50ml冰水,乙酸乙酯萃取,干燥,粗品硅胶柱层析纯化得化合物XIII-AA(568mg,收率78%)。LC/MS(ESI):m/z 364[M+1]+。Compound XII-AA (506 mg, 2 mmol) and 6-(trifluoromethyl)pyridin-3-ylboronic acid (480 mg, 2.5 mmol) were dissolved in dioxane (10 ml), and saturated sodium carbonate (1 ml) was added. (Triphenylphosphine)palladium (115 mg, 0.1 mmol), degassed, heated to 100°C under nitrogen protection, and stirred overnight. Cool to room temperature, concentrate under reduced pressure, add 50 ml of ice water, extract with ethyl acetate, dry, and purify the crude product by silica gel column chromatography to obtain compound XIII-AA (568 mg, yield 78%). LC/MS(ESI): m/z 364[M+1] + .
步骤3)中间体I-AA的制备Step 3) Preparation of intermediate I-AA
化合物XIII-AA(500mg,1.37mmol)溶解在THF/MeOH/H2O(1/1/1)的混合溶剂(15ml)中,加入氢氧化锂(220mg,9.2mmol),室温搅拌过夜,减压浓缩,加冰水20g,搅拌,乙酸乙酯萃取,水相用6N盐酸调pH至6~7,过滤,干燥得化合物I-AA(380mg,收率83%)LC/MS(ESI):m/z 336[M+1]+,334[M-1]。Compound XIII-AA (500 mg, 1.37 mmol) was dissolved in a mixed solvent (15 ml) of THF/MeOH/H 2 O (1/1/1), lithium hydroxide (220 mg, 9.2 mmol) was added, and the mixture was stirred at room temperature overnight. Concentrate under pressure, add 20g of ice water, stir, extract with ethyl acetate, adjust the pH of the aqueous phase to 6~7 with 6N hydrochloric acid, filter, and dry to obtain compound I-AA (380 mg, yield 83%) LC/MS (ESI): m/z 336[M+1] + , 334[M-1].
按照中间体I-AA同样的方法可以制备下面表2中的中间体I-BB至I-GGIntermediates I-BB to I-GG in Table 2 below can be prepared according to the same method as Intermediate I-AA.
表2
Table 2
Table 2
实施例3:中间体II-1盐酸盐的制备 Example 3: Preparation of intermediate II-1 hydrochloride
方法D
Method D
Method D
步骤1)中间体XIV-1的制备Step 1) Preparation of intermediate XIV-1
将BocNHNH2(13.2g,100mmol)溶解在100ml丙酮和50ml的甲醇中,加入无水硫酸镁(12g,100mmol),室温搅拌过夜,过滤除去硫酸镁,滤液减压浓缩至干,加100ml甲醇溶解,室温下分批加入硼氢化钠(15.2g,400mmol),搅拌1h,减压浓缩至干,加入200ml蒸馏水,用二氯甲烷萃取100ml×3次,合并有机相,无水硫酸钠干燥,过滤,减压浓缩至干。硅胶柱层析纯化(20%乙酸乙酯/石油醚)得XIV-1(15.1g,收率87%)。LC/MS(ESI):m/z 175[M+1]+。Dissolve BocNHNH 2 (13.2g, 100mmol) in 100ml acetone and 50ml methanol, add anhydrous magnesium sulfate (12g, 100mmol), stir at room temperature overnight, filter to remove magnesium sulfate, concentrate the filtrate to dryness under reduced pressure, add 100ml methanol to dissolve , add sodium borohydride (15.2g, 400mmol) in batches at room temperature, stir for 1 hour, concentrate to dryness under reduced pressure, add 200ml of distilled water, extract 100ml × 3 times with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, and filter , concentrated to dryness under reduced pressure. Purification by silica gel column chromatography (20% ethyl acetate/petroleum ether) gave XIV-1 (15.1 g, yield 87%). LC/MS(ESI): m/z 175[M+1] + .
步骤2)中间体XV-1的制备Step 2) Preparation of intermediate XV-1
将中间体XIV-1(1.74g,10mmol)、环氧丙烷(2.9g,50mmol)、DIEA(2.58g,20mmol)溶于20ml乙醇中,在密封的反应瓶中,80℃搅拌过夜。减压浓缩至干,硅胶柱层析纯化(20%-50%乙酸乙酯/石油醚)得XV-1(1.82g,收率78%)。LC/MS(ESI):m/z233[M+1]+。Intermediate XIV-1 (1.74g, 10mmol), propylene oxide (2.9g, 50mmol), and DIEA (2.58g, 20mmol) were dissolved in 20 ml of ethanol, and stirred at 80°C overnight in a sealed reaction bottle. Concentrate to dryness under reduced pressure and purify by silica gel column chromatography (20%-50% ethyl acetate/petroleum ether) to obtain XV-1 (1.82g, yield 78%). LC/MS(ESI):m/z233[M+1] + .
步骤3)中间体II-1盐酸盐的制备Step 3) Preparation of intermediate II-1 hydrochloride
将1.82g化合物XV-1溶解在10ml甲醇中,加入HCl的甲醇溶液(过量),室温搅拌过夜,40℃减压浓缩至干,得中间体II-1盐酸盐(2.3g,收率95%)。LC/MS(ESI):m/z 133[M+1]+。Dissolve 1.82g of compound XV-1 in 10 ml of methanol, add HCl methanol solution (excess), stir at room temperature overnight, and concentrate to dryness under reduced pressure at 40°C to obtain intermediate II-1 hydrochloride (2.3g, yield 95 %). LC/MS(ESI): m/z 133[M+1] + .
实施例4:中间体II-2盐酸盐的制备
Example 4: Preparation of intermediate II-2 hydrochloride
方法E
Method E
Method E
步骤1)中间体XIV-2的制备Step 1) Preparation of intermediate XIV-2
向500ml的圆底烧瓶中依次加入BocNHNH2(30g,227mmol)、300ml甲醇、20.4g羟基丙酮和无水硫酸镁(68g),室温搅拌3.5h,过滤除去硫酸镁,滤饼用无水甲醇洗涤,0℃下分批向滤液中加硼氢化钠(15.2g,400mmol),加毕,室温搅拌1h,减压浓缩至干,加入200ml蒸馏水,用二氯甲烷萃取100mlx3次,合并有机相,无水硫酸钠干燥,过滤,减压浓缩至干。硅胶柱层析纯化(20-40%乙酸乙酯/石油醚)得XIV-2(36g,收率84%)。LC/MS(ESI):m/z 191[M+1]+。Add BocNHNH 2 (30g, 227mmol), 300ml methanol, 20.4g hydroxyacetone and anhydrous magnesium sulfate (68g) to a 500ml round-bottomed flask in sequence, stir at room temperature for 3.5h, filter to remove magnesium sulfate, and wash the filter cake with anhydrous methanol. , add sodium borohydride (15.2g, 400mmol) to the filtrate in batches at 0°C, complete the addition, stir at room temperature for 1 hour, concentrate to dryness under reduced pressure, add 200ml of distilled water, extract 100mlx3 times with dichloromethane, combine the organic phases, no Dry over sodium sulfate, filter, and concentrate to dryness under reduced pressure. Purification by silica gel column chromatography (20-40% ethyl acetate/petroleum ether) gave XIV-2 (36 g, yield 84%). LC/MS(ESI): m/z 191[M+1] + .
步骤2)中间体XV-2的制备Step 2) Preparation of intermediate XV-2
向1L的圆底烧瓶中加入中间体XVI-2(19.0g,100mmol)、丙酮(17.4g,300mmol)、甲醇300ml,1ml醋酸,室温下加入氰基硼氢化钠(15.7g,250mmol),反应混合物室温搅拌过夜。减压浓缩至干,加入蒸馏水,用乙酸乙酯萃取,干燥,过滤,浓缩。硅胶柱层析纯化(10%-50%乙酸乙酯/石油醚)得白色固体XV-2(14.1g,收率61%)。LC/MS(ESI):m/z 233[M+1]+。Add intermediate XVI-2 (19.0g, 100mmol), acetone (17.4g, 300mmol), 300ml of methanol, and 1ml of acetic acid to a 1L round-bottomed flask. Add sodium cyanoborohydride (15.7g, 250mmol) at room temperature and react. The mixture was stirred at room temperature overnight. Concentrate to dryness under reduced pressure, add distilled water, extract with ethyl acetate, dry, filter and concentrate. Purification by silica gel column chromatography (10%-50% ethyl acetate/petroleum ether) gave white solid XV-2 (14.1g, yield 61%). LC/MS(ESI): m/z 233[M+1] + .
步骤3)中间体II-2盐酸盐的制备Step 3) Preparation of intermediate II-2 hydrochloride
按照中间体II-1盐酸盐的制备方法的步骤3)制备中间体II-2盐酸盐,收率90%。LC/MS(ESI):m/z 133[M+1]+。Intermediate II-2 hydrochloride was prepared according to step 3) of the preparation method of intermediate II-1 hydrochloride, with a yield of 90%. LC/MS(ESI): m/z 133[M+1] + .
实施例5:中间体II-3的制备
Example 5: Preparation of intermediate II-3
Example 5: Preparation of intermediate II-3
步骤1)中间体XV-3的制备Step 1) Preparation of intermediate XV-3
在0℃下,向2-羟基乙基肼(5g,65mmol)的甲醇(100ml)溶液中,加入13ml三乙胺、Boc2O(17.2g,78mmol),氮气保护下室温搅拌16h,减压浓缩至干,加柠檬酸溶液,乙酸乙酯萃取,无水硫酸钠干燥,过滤,减压浓缩至干。硅胶柱层析纯化(20-40%乙酸乙酯/石油醚)得XV-3(6.8g,收率89%)。LC/MS(ESI):m/z 177[M+1]+。To a solution of 2-hydroxyethylhydrazine (5g, 65mmol) in methanol (100ml) at 0°C, add 13ml of triethylamine and Boc 2 O (17.2g, 78mmol), stir at room temperature for 16h under nitrogen protection, and reduce the pressure. Concentrate to dryness, add citric acid solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, and concentrate to dryness under reduced pressure. Purification by silica gel column chromatography (20-40% ethyl acetate/petroleum ether) gave XV-3 (6.8 g, yield 89%). LC/MS(ESI): m/z 177[M+1] + .
步骤2)中间体II-3的制备Step 2) Preparation of intermediate II-3
将中间体XV-3(2g,11.2mmol)溶解在50ml的THF中,加入氢化铝锂(LAH)(1.7g,44.8mmol),氮气保护下回流5h,冷却至0℃下,分批加入Na2SO4·10H2O,过滤,滤饼用THF洗涤,滤液无水硫酸镁干燥,浓缩得II-3粗品,无需纯化直接用于下一步。LC/MS(ESI):m/z 91[M+1]+。Dissolve intermediate XV-3 (2g, 11.2mmol) in 50 ml of THF, add lithium aluminum hydride (LAH) (1.7g, 44.8mmol), reflux under nitrogen protection for 5 hours, cool to 0°C, and add Na in batches 2 SO 4 ·10H 2 O, filter, wash the filter cake with THF, dry the filtrate over anhydrous magnesium sulfate, and concentrate to obtain crude II-3, which can be used directly in the next step without purification. LC/MS(ESI): m/z 91[M+1] + .
实施例6:中间体II-4的制备
Example 6: Preparation of intermediate II-4
Example 6: Preparation of intermediate II-4
步骤1)中间体XV-4的制备Step 1) Preparation of intermediate XV-4
在0℃下,将2-羟基乙基肼(7.6g,100mmol)加入甲醇(100ml)和丙酮(50ml)混合溶剂中,加入无水硫酸镁(12g,100mmol),室温搅拌过夜,过滤除去硫酸镁,滤液减压浓缩至干,加100ml二氯甲烷溶解,加三乙胺(20.2g,200mmol),在0℃下滴加醋酸酐(10.7g,105mmol),室温搅拌过夜,加入200ml蒸馏水,用二氯甲烷萃取,合并有机相减压浓缩至干,加入四氢呋喃(50ml)和5ml盐酸,室温搅拌12h,减压浓缩至干得XV-4,不纯化直接用于下一步。LC/MS(ESI):m/z 119[M+1]+。At 0°C, add 2-hydroxyethylhydrazine (7.6g, 100mmol) to a mixed solvent of methanol (100ml) and acetone (50ml), add anhydrous magnesium sulfate (12g, 100mmol), stir at room temperature overnight, and filter to remove sulfuric acid. Magnesium, the filtrate was concentrated to dryness under reduced pressure, added 100ml dichloromethane to dissolve, added triethylamine (20.2g, 200mmol), added acetic anhydride (10.7g, 105mmol) dropwise at 0°C, stirred at room temperature overnight, added 200ml distilled water, Extract with dichloromethane, combine the organic phases and concentrate to dryness under reduced pressure. Add tetrahydrofuran (50ml) and 5ml of hydrochloric acid, stir at room temperature for 12 hours, and concentrate to dryness under reduced pressure to obtain XV-4, which is used directly in the next step without purification. LC/MS(ESI): m/z 119[M+1] + .
步骤2)中间体II-4的制备Step 2) Preparation of intermediate II-4
将中间体XV-4(1.2g,10mmol)溶解在50ml的THF中,加入四氢铝锂(LAH)(1.5g,44.8mmol),氮气保护下回流4h,冷却至0℃以下,分批加入Na2SO4·10H2O淬灭反应,过滤,滤饼用THF洗涤,滤液用无水硫酸镁干燥,过滤,减压浓缩至干得II-4。LC/MS(ESI):m/z 105[M+1]+。Dissolve intermediate XV-4 (1.2g, 10mmol) in 50ml of THF, add lithium aluminum tetrahydride (LAH) (1.5g, 44.8mmol), reflux under nitrogen protection for 4 hours, cool to below 0°C, and add in batches Na 2 SO 4 ·10H 2 O quenched the reaction, filtered, the filter cake was washed with THF, the filtrate was dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain II-4. LC/MS(ESI): m/z 105[M+1] + .
实施例7:中间体II-5的制备
Example 7: Preparation of Intermediate II-5
Example 7: Preparation of Intermediate II-5
步骤1)中间体XVI-5的制备Step 1) Preparation of intermediate XVI-5
中间体XVI-1(12.8g,73.5mmol),溴乙酸乙酯(36.6g,219mmol),无水碳酸钾(30.2g,219mmol),溶解在250ml DMF中,氮气保护下,加热到80℃,搅拌过夜,冷至室温,加水,乙酸乙酯萃取,无水硫酸钠干燥,过滤,减压浓缩至干得XVI-5粗品18g。LC/MS(ESI):m/z 261[M+1]+。Intermediate XVI-1 (12.8g, 73.5mmol), ethyl bromoacetate (36.6g, 219mmol), and anhydrous potassium carbonate (30.2g, 219mmol) were dissolved in 250ml DMF and heated to 80°C under nitrogen protection. Stir overnight, cool to room temperature, add water, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, and concentrate to dryness under reduced pressure to obtain 18 g of crude XVI-5. LC/MS(ESI): m/z 261[M+1] + .
步骤2)中间体XV-5的制备Step 2) Preparation of intermediate XV-5
在2L的圆底烧瓶中依次加入380ml乙醇、NaBH4(7.2g,189mmol)及LiCl(7.9g,188mmol),然后室温下滴加XVI-5(18g,69mmol)的THF溶液(380ml),搅拌6h,减压浓缩除去大量溶解,加水,乙酸乙酯萃取,合并后的有机相用无水Na2SO4干燥,过滤,减压浓缩至干得XV-5(12.9g,收率86%)。LC/MS(ESI):m/z 219[M+1]+。Add 380 ml of ethanol, NaBH 4 (7.2 g, 189 mmol) and LiCl (7.9 g, 188 mmol) in sequence to a 2L round-bottomed flask, then add a THF solution (380 ml) of XVI-5 (18 g, 69 mmol) dropwise at room temperature, and stir 6h, concentrate under reduced pressure to remove a large amount of dissolved matter, add water, extract with ethyl acetate, dry the combined organic phase with anhydrous Na 2 SO 4 , filter, and concentrate to dryness under reduced pressure to obtain XV-5 (12.9g, yield 86%) . LC/MS(ESI): m/z 219[M+1] + .
步骤3)中间体IV-5的制备Step 3) Preparation of intermediate IV-5
将XV-5(12.9g)溶解在50ml二氧六环中,加入HCl的二氧六环溶液(6N,30ml),室温搅拌过夜,减压浓缩至干,得中间体II-5(12.8g)。LC/MS(ESI):m/z 119[M+1]+。Dissolve XV-5 (12.9g) in 50ml of dioxane, add HCl in dioxane (6N, 30ml), stir at room temperature overnight, and concentrate to dryness under reduced pressure to obtain intermediate II-5 (12.8g ). LC/MS(ESI): m/z 119[M+1] + .
实施例8:中间体IV-6的制备
Example 8: Preparation of intermediate IV-6
Example 8: Preparation of intermediate IV-6
步骤1)中间体XVII-6的制备Step 1) Preparation of intermediate XVII-6
向3-甲基吗啉(1.0g,10mmol)的THF溶液(15ml)中,加入亚硝酸叔丁酯(1.1g,11mmol),回流12h,减压浓缩至干,得到XVII-6,不纯化直接用于下一步。LC/MS(ESI):m/z 131[M+1]+。To a THF solution (15 ml) of 3-methylmorpholine (1.0 g, 10 mmol), add tert-butyl nitrite (1.1 g, 11 mmol), reflux for 12 h, and concentrate to dryness under reduced pressure to obtain XVII-6 without purification. used directly in the next step. LC/MS(ESI): m/z 131[M+1] + .
步骤2)中间体II-6的制备Step 2) Preparation of intermediate II-6
将上一步的中间体XIX-6(80mmol)溶解在200ml的THF中,在0℃下分批加入LAH(6.1g,160mmol),室温搅拌过夜,冷却下,分批加入Na2SO4·10H2O,过滤,滤饼用THF洗涤,滤液无水硫酸镁干燥,过滤,减压浓缩得化合物的II-6(收率72%)。
LC/MS(ESI):m/z 117[M+1]+。Dissolve the intermediate XIX-6 (80mmol) from the previous step in 200 ml of THF, add LAH (6.1g, 160mmol) in batches at 0°C, stir at room temperature overnight, cool, and add Na 2 SO 4 ·10H in batches 2 O, filtered, the filter cake was washed with THF, the filtrate was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain compound II-6 (yield 72%). LC/MS(ESI): m/z 117[M+1] + .
按照化合物II-6同样的方法可以制备下面表3中的肼。The hydrazine in Table 3 below can be prepared according to the same method as compound II-6.
表3
table 3
table 3
实施例9:6-(4-三氟甲基苯基)-N-(1-羟基丙基-2-基)-N-异丙基-2-(1H-咪唑1-基)嘧啶-4-酰肼(化合物1)的制备
Example 9: 6-(4-trifluoromethylphenyl)-N-(1-hydroxypropyl-2-yl)-N-isopropyl-2-(1H-imidazol 1-yl)pyrimidine-4 -Preparation of hydrazide (compound 1)
Example 9: 6-(4-trifluoromethylphenyl)-N-(1-hydroxypropyl-2-yl)-N-isopropyl-2-(1H-imidazol 1-yl)pyrimidine-4 -Preparation of hydrazide (compound 1)
将实施例1中制备的I-A(36mg,0.1mmol)、肼盐酸盐(20mg,0.12mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)(57mg,0.15mmol)溶解在2ml的二甲基甲酰胺(DMF)中,加入N,N-二异丙基乙胺(DIPEA)(47mg,0.36mmol),在氮气下搅拌过夜,用乙酸乙酯稀释,水洗,有机相用无水硫酸钠干燥,过滤,减压浓缩至干,制备硅胶层析纯化(PE/EA,1:1),得化合物1(23mg,收率50%)。LC/MS(ESI):m/z 449[M+1]+。1H NMR(400MHz,DMSO-d6):δ10.15(s,1H),9.00(s,1H),8.66(d,2H),8.56(s,1H),7.96(m,3H),7.19(s,1H),4.34-4.37(m,1H),3.40-3.48(m,1H),3.28-3.35(m,1H),3.16-3.23(m,2H),1.14-1.20(m,6H),0.98(d,J=6.8Hz,3H)。
IA prepared in Example 1 (36 mg, 0.1 mmol), hydrazine hydrochloride (20 mg, 0.12 mmol), 2-(7-azobenzotriazole)-N,N,N',N'- Tetramethylurea hexafluorophosphate (HATU) (57mg, 0.15mmol) was dissolved in 2ml of dimethylformamide (DMF), and N,N-diisopropylethylamine (DIPEA) (47mg, 0.36mmol) was added ), stir overnight under nitrogen, dilute with ethyl acetate, wash with water, dry the organic phase with anhydrous sodium sulfate, filter, concentrate to dryness under reduced pressure, and purify by silica gel chromatography (PE/EA, 1:1) to obtain the compound 1 (23 mg, yield 50%). LC/MS(ESI): m/z 449[M+1] + . 1 H NMR (400MHz, DMSO-d 6 ): δ10.15(s,1H),9.00(s,1H),8.66(d,2H),8.56(s,1H),7.96(m,3H),7.19 (s,1H),4.34-4.37(m,1H),3.40-3.48(m,1H),3.28-3.35(m,1H),3.16-3.23(m,2H),1.14-1.20(m,6H) ,0.98(d,J=6.8Hz,3H).
按照化合物1同样的方法可以制备下表4中的化合物。The compounds in Table 4 below can be prepared according to the same method as Compound 1.
表4
Table 4
Table 4
实施例10化合物29的制备
Example 10 Preparation of Compound 29
Example 10 Preparation of Compound 29
化合物27(39mg,0.1mmol)溶解在5ml的DCM中,加入DIPEA(0.1ml),冷却至0℃,滴加0.06ml的乙酸酐,加毕,室温搅拌反应过夜,水洗三次,无水硫酸钠干燥,过滤、减压浓缩至干,硅胶柱层析纯化(PE/EA,1:1)的化合物29。收率77%。LC/MS(ESI):m/z 433[M+1]+。1HNMR(400MHz,DMSO-d6):δ10.13(s,1H),8.98(s,1H),8.66(d,2H),8.56(s,1H),7.96(m,3H),7.19(s,1H),3.27-3.18(m,1H),2.09(s,3H),1.14(d,J=6.8Hz,6H)。Compound 27 (39 mg, 0.1 mmol) was dissolved in 5 ml of DCM, added DIPEA (0.1 ml), cooled to 0°C, dropwise added 0.06 ml of acetic anhydride, completed the addition, stirred at room temperature overnight, washed three times with water, and anhydrous sodium sulfate Dry, filter, and concentrate to dryness under reduced pressure. Compound 29 is purified by silica gel column chromatography (PE/EA, 1:1). The yield is 77%. LC/MS(ESI): m/z 433[M+1] + . 1 HNMR (400MHz, DMSO-d 6 ): δ10.13(s,1H),8.98(s,1H),8.66(d,2H),8.56(s,1H),7.96(m,3H),7.19( s,1H),3.27-3.18(m,1H),2.09(s,3H),1.14(d,J=6.8Hz,6H).
按照化合物29同样的方法可以制备下表5中的化合物。The compounds in Table 5 below can be prepared according to the same method as compound 29.
表5
table 5
table 5
实施例11化合物33的制备
Example 11 Preparation of Compound 33
Example 11 Preparation of Compound 33
按照实施例1相似的制备方法,由中间体III-J和(S)-N-(2-氨基丙基)-1-甲基环丙烷基-1-磺酰胺基反应得化合物33。LC/MS(ESI):m/z 455[M+H]+。According to a preparation method similar to Example 1, compound 33 was obtained by reacting intermediate III-J and (S)-N-(2-aminopropyl)-1-methylcyclopropanyl-1-sulfonamide group. LC/MS(ESI): m/z 455[M+H] + .
效果实施例1 人源细胞系中研究化合物与AHR拮抗作用测试Effect Example 1 Test of antagonism between research compounds and AHR in human cell lines
测试使用内源表达AHR蛋白的人肝癌HepG2细胞系(由中国科学院干细胞库提供)。CYP1A1基因表达受到AHR活性的调控,AHR激活后能结合CYP1A1增强子上称为
外源反应元件(xenobiotic response element,XRE)的序列并引发CYP1A1基因表达。为了定量测量化合物对AHR活性的影响,CYP1A1基因启动子上游1200bp(-1143至+57)的调控序列通过基因合成后插入包含萤火虫荧光素酶的质粒载体中。质粒随后经过单酶切线性化后通过脂质体转染(Lipofectamine3000)进HepG2细胞,转染后的HepG2细胞通过嘌呤霉素筛选得到稳定表达的细胞系。在测量化合物和AHR的拮抗作用时,用AHR激动剂(如L-Kynurenine,Kynurenic acid,indirubin,TCDD,ITE(2-(1H-Indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester))等引发萤火虫荧光素酶的表达,同时用不同浓度的化合物来处理细胞,然后测量化合物对荧光素酶表达的抑制。The test used the human liver cancer HepG2 cell line that endogenously expresses AHR protein (provided by the Stem Cell Bank of the Chinese Academy of Sciences). CYP1A1 gene expression is regulated by AHR activity. After AHR is activated, it can bind to the CYP1A1 enhancer called The sequence of the xenobiotic response element (XRE) triggers CYP1A1 gene expression. In order to quantitatively measure the effect of compounds on AHR activity, the 1200 bp (-1143 to +57) regulatory sequence upstream of the CYP1A1 gene promoter was synthesized and inserted into a plasmid vector containing firefly luciferase. The plasmid was then linearized by single enzyme digestion and transfected into HepG2 cells via lipofectamine 3000. The transfected HepG2 cells were screened with puromycin to obtain stable expression cell lines. When measuring the antagonism between compounds and AHR, use AHR agonists (such as L-Kynurenine, Kynurenic acid, indirubin, TCDD, ITE (2-(1H-Indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester)), etc. Expression of firefly luciferase is elicited while cells are treated with different concentrations of compounds, and the inhibition of luciferase expression by the compounds is measured.
稳定转染的HepG2细胞在Eagle最低必须培养基(Minimum Eagle’s medium,MEM)中,37℃,5%二氧化碳的环境下传代培养。MEM培养基中补充了1mM丙酮酸钠,2mM GlutaMax,1×非必需氨基酸,10%澳洲胎牛血清,100U/mL的青链霉素以及5ug/mL的嘌呤霉素。测试前,HepG2细胞通过传代以5~8×104/孔的密度种植到96孔板中并生长24~48h以便在进行药物处理前达到~90%的汇合度(培养基中不含嘌呤霉素)。在药物处理前,先用相同培养基配制包含AHR激动剂的2×不同浓度的化合物溶液,然后将96孔板中的细胞培养基的一半替换成2×化合物溶液。阴性对照组设为仅包含对应浓度DMSO的AHR激动剂溶液,而阳性对照组设为对应浓度的CH223191,BAY2416964。
Stably transfected HepG2 cells were subcultured in Minimum Eagle's medium (MEM) at 37°C in a 5% carbon dioxide environment. MEM medium was supplemented with 1mM sodium pyruvate, 2mM GlutaMax, 1× non-essential amino acids, 10% Australian fetal calf serum, 100U/mL penicillin and 5ug/mL puromycin. Before testing, HepG2 cells were seeded into 96-well plates at a density of 5 to 8 × 10 4 /well and grown for 24 to 48 h to reach ~90% confluence before drug treatment (the culture medium did not contain puromyces white). Before drug treatment, 2× compound solutions containing AHR agonists at different concentrations were prepared with the same culture medium, and then half of the cell culture medium in the 96-well plate was replaced with 2× compound solution. The negative control group was set to the AHR agonist solution containing only corresponding concentrations of DMSO, while the positive control group was set to the corresponding concentrations of CH223191 and BAY2416964.
Stably transfected HepG2 cells were subcultured in Minimum Eagle's medium (MEM) at 37°C in a 5% carbon dioxide environment. MEM medium was supplemented with 1mM sodium pyruvate, 2mM GlutaMax, 1× non-essential amino acids, 10% Australian fetal calf serum, 100U/mL penicillin and 5ug/mL puromycin. Before testing, HepG2 cells were seeded into 96-well plates at a density of 5 to 8 × 10 4 /well and grown for 24 to 48 h to reach ~90% confluence before drug treatment (the culture medium did not contain puromyces white). Before drug treatment, 2× compound solutions containing AHR agonists at different concentrations were prepared with the same culture medium, and then half of the cell culture medium in the 96-well plate was replaced with 2× compound solution. The negative control group was set to the AHR agonist solution containing only corresponding concentrations of DMSO, while the positive control group was set to the corresponding concentrations of CH223191 and BAY2416964.
每个化合物(包括阳性对照及阴性对照)做2组独立重复测试。HepG2细胞在化合物处理24h后通过Promega公司的Steady-Glo荧光素酶检测系统进行裂解,并用Tecan公司的InfiniteM1000Pro酶标仪测量荧光素酶信号。Each compound (including positive control and negative control) was tested in two independent sets. HepG2 cells were lysed by Promega's Steady-Glo luciferase detection system 24 hours after compound treatment, and the luciferase signal was measured using Tecan's InfiniteM1000Pro microplate reader.
数据处理上,对每一个化合物的每组重复测试,以化合物浓度为0的孔信号作为100%,以未处理激动剂的细胞信号作为0,依次计算不同化合物浓度下的AHR活性抑制百分比,将2组重复数据的平均值通过非线性拟合按照公式计算化合物对应的IC50,其中y是抑制百分比,x是对应化合物的浓度。In terms of data processing, each compound was tested repeatedly for each group. The well signal with a compound concentration of 0 was taken as 100%, and the cell signal with untreated agonist was taken as 0. The AHR activity inhibition percentage at different compound concentrations was calculated in turn. The average value of 2 sets of repeated data is calculated by nonlinear fitting according to the formula Calculate the IC 50 corresponding to the compound, where y is the percent inhibition and x is the concentration of the corresponding compound.
参考文献:Buckley,S.M.K.et al.In vivo bioimaging with tissue-specific transcription factor activated luciferase reporters.Sci.Rep.5:11842(2015).Reference: Buckley, S.M.K.et al.In vivo bioimaging with tissue-specific transcription factor activated luciferase reporters.Sci.Rep.5:11842(2015).
各化合物的IC50如表6所示,其中A表示IC50≤100nM,B表示100nM<IC50≤1.0μM,C表示1μM<IC50≤5.0μM,D表示IC50>5.0μMThe IC 50 of each compound is shown in Table 6, where A means IC 50 ≤100nM, B means 100nM<IC 50 ≤1.0μM, C means 1μM<IC 50 ≤5.0μM, and D means IC 50 >5.0μM.
表6 各化合物的EC50
Table 6 EC 50 of each compound
Table 6 EC 50 of each compound
由表6可知,根据本发明的上述各化合物可抑制由AHR控制的那些功能和信号通路,进而可影响癌细胞的生长与增殖以及肿瘤细胞的侵袭力,因此本发明的式Ⅰ表示的2-氮取代嘧啶类化合物,其各自旋光异构体,氘代物,前药或药学上可接受的盐可用于抑制癌细胞生长,抑制肿瘤细胞的转移和侵袭。As can be seen from Table 6, the above-mentioned compounds according to the present invention can inhibit those functions and signaling pathways controlled by AHR, thereby affecting the growth and proliferation of cancer cells and the invasiveness of tumor cells. Therefore, 2- represented by Formula I of the present invention Nitrogen-substituted pyrimidine compounds, their respective optical isomers, deuterated products, prodrugs or pharmaceutically acceptable salts can be used to inhibit the growth of cancer cells and inhibit the metastasis and invasion of tumor cells.
以上所述仅为本发明的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内,可轻易想到变化或替换,都应涵盖在本发明的保护范围之内。因此,本发明的保护范围应所述以权利要求的保护范围为准。
The above are only specific embodiments of the present invention, but the protection scope of the present invention is not limited thereto. Any person familiar with the technical field can easily think of changes or replacements within the technical scope disclosed by the present invention. are covered by the protection scope of the present invention. Therefore, the protection scope of the present invention should be determined by the protection scope of the claims.
Claims (10)
- 一类由以下式Ⅰ表示的2-氮取代嘧啶类化合物,其各自旋光异构体,氘代物,前药或药学上可接受的盐:
A class of 2-nitrogen-substituted pyrimidine compounds represented by the following formula I, each of which is an optical isomer, deuterated product, prodrug or pharmaceutically acceptable salt:
其中,in,A环为C6-10芳基或者含有杂1~3个选自N、O和S杂原子的5~10元杂芳基;Ring A is a C 6-10 aryl group or a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S heteroatoms;R1和R2各自独立地为氢、饱和或不饱和的取代或未取代的C1-C8烷基、饱和或不饱和的取代或未取代的C3-C8环烷基、-OC(=O)C1-8烷基、-OC(=O)C3-C8环烷基、-C(=O)OC1-C8烷基、-C(=O)C3-C8环烷基、-S(O)mRc、饱和或不饱和的取代或未取代的C1-C8酰基、C6-C14芳基、含有1至3个选自N、O和S的杂原子的4至14元杂环烷基或含有1至3个选自N、O和S的杂原子的5至14元杂芳基,含有基团的饱和或不饱和的卤代或者未卤代的C1-8烷基,含有基团的饱和或不饱和的卤代或者未卤代的C3-8环烷基,其中所述“取代”是指选择性地被1至10个氘取代,或者选择性地含有1至4个选自羟基、卤素、氰基、氨基、-S(O)mRc、-NRdRe、饱和或不饱和的C1-C8烷基、饱和或不饱和的C3-C8环烷基、饱和或不饱和的C1-C8烷氧基、饱和或不饱和的C3-C8环烷氧基、-OC(=O)C1-C8烷基、-OC(=O)C3-C8环烷基、-C(=O)OC1-8烷基、-C(=O)OC3-C8环烷基、含有基团的饱和或不饱和的卤代或者未卤代的C1-8烷基,含有基团的饱和或不饱和的卤代或者未卤代的C3-8环烷基,饱和或不饱和的C1-C8酰基、饱和或不饱和的C1-C8烷氧基羰基、C6-C14芳基、含有1至3个选自N、O和S的杂原子的4至14元杂环烷基或含有1至3个选自N、O和S的杂原子的5至14元杂芳基的取代基;R 1 and R 2 are each independently hydrogen, saturated or unsaturated substituted or unsubstituted C 1 -C 8 alkyl, saturated or unsaturated substituted or unsubstituted C 3 -C 8 cycloalkyl, -OC (=O)C 1-8 alkyl, -OC(=O)C 3 -C 8 cycloalkyl, -C(=O)OC 1 -C 8 alkyl, -C(=O)C 3 -C 8 cycloalkyl, -S(O) m R c , saturated or unsaturated substituted or unsubstituted C 1 -C 8 acyl, C 6 -C 14 aryl, containing 1 to 3 selected from N, O and A 4- to 14-membered heterocycloalkyl group containing a heteroatom of S or a 5- to 14-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-8 alkyl group, containing The group is a saturated or unsaturated halogenated or unhalogenated C 3-8 cycloalkyl group, wherein "substituted" means optionally substituted by 1 to 10 deuterons, or optionally containing 1 to 4 Each one is selected from hydroxyl, halogen, cyano, amino, -S(O) m R c , -NR d R e , saturated or unsaturated C 1 -C 8 alkyl, saturated or unsaturated C 3 -C 8 Cycloalkyl, saturated or unsaturated C 1 -C 8 alkoxy, saturated or unsaturated C 3 -C 8 cycloalkoxy, -OC(=O)C 1 -C 8 alkyl, -OC( =O)C 3 -C 8 cycloalkyl, -C(=O)OC 1-8 alkyl, -C(=O)OC 3 -C 8 cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-8 alkyl group, containing The group is a saturated or unsaturated halogenated or unhalogenated C 3-8 cycloalkyl group, a saturated or unsaturated C 1 -C 8 acyl group, a saturated or unsaturated C 1 -C 8 alkoxycarbonyl group, C 6 -C 14 aryl, 4 to 14 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S, or 5 containing 1 to 3 heteroatoms selected from N, O, and S to 14-membered heteroaryl substituents;或者R1和R2与连接它们的N原子一起形成取代或未取代的含有1至3个选自N、O和S的杂原子的4至14元杂环烷基,其中所述“取代”是指被1至10个氘取代,或者选择性地含有1至4个选自羟基,卤素,氰基,-S(O)mRc、-NRdRe,C1~C8烷基,C3~C8环烷基,C1~C8烷氧基,C3~C8环烷氧基,-OC(=O)C1-8烷基,-OC(=O)C3~C8环烷基,-C(=O)OC1-8烷基,-C(=O)OC3~C8环烷基,含有基团的饱和或不饱和的卤代或者未 卤代的C1-8烷基,含有基团的饱和或不饱和的卤代或者未卤代的C3-8环烷基,被Rf取代的C1~C8烷基、C3~C8环烷基、C1~C8烷氧基、C3~C8环烷氧基的取代基;Or R 1 and R 2 together with the N atom connecting them form a substituted or unsubstituted 4 to 14 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, wherein said "substituted" Refers to being substituted by 1 to 10 deuterium, or optionally containing 1 to 4 selected from hydroxyl, halogen, cyano, -S(O) m R c , -NR d R e , C 1 to C 8 alkyl , C 3 ~ C 8 cycloalkyl, C 1 ~ C 8 alkoxy, C 3 ~ C 8 cycloalkoxy, -OC(=O)C 1-8 alkyl, -OC(=O)C 3 ~C 8 cycloalkyl, -C(=O)OC 1-8 alkyl, -C(=O)OC 3 ~C 8 cycloalkyl, containing Saturated or unsaturated halogenated or unsaturated groups Halogenated C 1-8 alkyl, containing Saturated or unsaturated halogenated or unhalogenated C 3-8 cycloalkyl group, C 1 to C 8 alkyl group substituted by R f , C 3 to C 8 cycloalkyl group, C 1 to C 8 Substituents of alkoxy and C 3 to C 8 cycloalkoxy;R3选自氘、卤素、硝基、氰基、羧基、羟基、-NRdRe、-ORg、-CO2Rg、-S(O)mRc,或被1至3个Rh取代的C1-8烷基、C3-8环烷基、C1-8烷氧基、C3-8环烷氧基、C1-8烷氧基羰基、C1-8烷基羰基、C1-8烷基羧基、3-10元环烷基、3-10元杂环烷基、6-10元芳基、5-10元杂芳基。R 3 is selected from deuterium, halogen, nitro, cyano, carboxyl, hydroxyl, -NR d R e , -OR g , -CO 2 R g , -S(O) m R c , or is replaced by 1 to 3 R h -substituted C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 3-8 cycloalkoxy, C 1-8 alkoxycarbonyl, C 1-8 alkyl Carbonyl group, C 1-8 alkylcarboxyl group, 3-10 membered cycloalkyl group, 3-10 membered heterocycloalkyl group, 6-10 membered aryl group, 5-10 membered heteroaryl group.R4为H或D;R 4 is H or D;L为化学键或者-NHRi;L is a chemical bond or -NHR i ;Ra、Rb各自独立地选自饱和或不饱和的取代或未取代的C3-C8环烷基,饱和或不饱和的取代或未取代的C1-C8烷基,取代或未取代的6~10元芳基或者取代或未取代的含有杂1~3个选自N、O和S杂原子的4~10元杂芳基,其中所述“取代”是指选择性地被1至10个氘取代,或者选择性地含有1至4个选自羟基、卤素、氰基、-S(O)mRc、-NRdRe、饱和或不饱和的C1-C8烷基、饱和或不饱和的C3-C8环烷基、饱和或不饱和的C1-C8烷氧基、饱和或不饱和的C3-C8环烷氧基、-OC(=O)C1-C8烷基、-OC(=O)C3-C8环烷基、-C(=O)OC1-8烷基、-C(=O)OC3-C8环烷基、饱和或不饱和的C1-C8酰基、饱和或不饱和的C1-C8烷氧基羰基、含有基团的饱和或不饱和的卤代或者未卤代的C1-8烷基,含有基团的饱和或不饱和的卤代或者未卤代的C3-8环烷基,C6-C14芳基、含有1至3个选自N、O和S的杂原子的4至14元杂环烷基或含有1至3个选自N、O和S的杂原子的5至14元杂芳基的取代基;R a and R b are each independently selected from saturated or unsaturated substituted or unsubstituted C 3 -C 8 cycloalkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted Substituted 6- to 10-membered aryl groups or substituted or unsubstituted 4- to 10-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S, wherein the "substituted" refers to selectively substituted by 1 to 10 deuterium substitutions, or optionally containing 1 to 4 selected from hydroxyl, halogen, cyano, -S(O) mRc , -NRdRe , saturated or unsaturated C1 - C8 Alkyl, saturated or unsaturated C 3 -C 8 cycloalkyl, saturated or unsaturated C 1 -C 8 alkoxy, saturated or unsaturated C 3 -C 8 cycloalkoxy, -OC(= O)C 1 -C 8 alkyl, -OC(=O)C 3 -C 8 cycloalkyl, -C(=O)OC 1-8 alkyl, -C(=O)OC 3 -C 8 ring Alkyl, saturated or unsaturated C 1 -C 8 acyl, saturated or unsaturated C 1 -C 8 alkoxycarbonyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-8 alkyl group, containing The group is saturated or unsaturated halogenated or unhalogenated C 3-8 cycloalkyl, C 6 -C 14 aryl, 4 to 14 containing 1 to 3 heteroatoms selected from N, O and S A substituent of a 5- to 14-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S;或者Ra和Rb与连接它们的N原子一起形成取代或未取代的含有1至3个选自N、O和S的杂原子的4至14元杂环烷基,取代或未取代的含有1至3个选自N、O和S的杂原子的5至14元杂芳基,其中所述“取代”是指被1至10个氘取代,或者选择性地含有1至4个选自羟基,卤素,氰基,磺酰基,羧基-S(O)mRc、-NRdRe,C1~C8烷基,C3~C8环烷基,C1~C8烷氧基,C3~C8环烷氧基,-OC(=O)C1-8烷基,-OC(=O)C3~C8环烷基,-C(=O)OC1-8烷基,-C(=O)OC3~C8环烷基,含有基团的饱和或不饱和的卤代或者未卤代的C1-8烷基,含有基团的饱和或不饱和的卤代或者未卤代的C3-8环烷基,被Rf取代的C1~C8烷基、C3~C8环烷基、C1~C8烷氧基、C3~C8环烷氧基的取代基,其中Rf选自氘,卤素,氰基,羟基,氨基,饱和或不饱和的C1~C6烷基,饱和或不饱和的C3~C6环烷基,-S(O)mRc、NRdRe,饱和或不饱和的被氘、卤素、羟基或氨基取代C1~C6烷基,被氘、卤素、羟基或氨基取代的C3~C6环烷基,饱和或不饱和的C1~C6烷氧基,C3~C6环烷氧基,饱和或不饱和的被氘、卤素、羟基或氨基取代C1~C6烷氧基,被氘、卤素、羟基或氨基取代的C3~C6环烷氧基;Or R a and R b together with the N atom connecting them form a substituted or unsubstituted 4 to 14-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted containing 5 to 14 membered heteroaryl groups with 1 to 3 heteroatoms selected from N, O and S, wherein "substituted" means substituted with 1 to 10 deuterons, or optionally containing 1 to 4 selected from Hydroxy, halogen, cyano, sulfonyl, carboxyl -S(O) m R c , -NR d R e , C 1 to C 8 alkyl, C 3 to C 8 cycloalkyl, C 1 to C 8 alkoxy Base, C 3 to C 8 cycloalkoxy group, -OC(=O)C 1-8 alkyl group, -OC(=O)C 3 to C 8 cycloalkyl group, -C(=O)OC 1-8 Alkyl, -C(=O)OC 3 ~ C 8 cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-8 alkyl group, containing Saturated or unsaturated halogenated or unhalogenated C 3-8 cycloalkyl group, C 1 to C 8 alkyl group substituted by R f , C 3 to C 8 cycloalkyl group, C 1 to C 8 Alkoxy, C 3 to C 8 cycloalkoxy substituents, wherein R f is selected from deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 6 alkyl, saturated or unsaturated C 3 ~ C 6 cycloalkyl, -S(O) m R c , NR d R e , saturated or unsaturated substituted by deuterium, halogen, hydroxyl or amino group C 1 ~ C 6 alkyl, substituted by deuterium, halogen , C 3 ~ C 6 cycloalkyl substituted by hydroxyl or amino, saturated or unsaturated C 1 ~ C 6 alkoxy, C 3 ~ C 6 cycloalkoxy, saturated or unsaturated substituted by deuterium, halogen, hydroxyl Or C 1 to C 6 alkoxy group substituted by amino group, C 3 to C 6 cycloalkoxy group substituted by deuterium, halogen, hydroxyl group or amino group;n为0、1、2、3、4或5的整数;n is an integer of 0, 1, 2, 3, 4 or 5;n1为0、1或2的整数; n1 is an integer of 0, 1 or 2;m为0、1或2的整数;m is an integer of 0, 1 or 2;Rc、Rg、Rh和Ri各自独立地选自氢、羟基、氨基、饱和或不饱和的取代或未取代的C1-C8烷基、饱和或不饱和的取代或未取代的C3-C8环烷基、-C(=O)C1-8烷基、-C(=O)C3-C8环烷基、-C(=O)OC1-C8烷基、-C(=O)OC3-C8环烷基、-C(=O)NC1-C8烷基、-C(=O)NC3-C8环烷基、C1-C8磺基、饱和或不饱和的取代或未取代的C1-C8磺酰基、C6-C14芳基、C7-C14芳基烷基、含有1至3个选自N、O和S的杂原子的4至14元杂环烷基或含有1至3个选自N、O和S的杂原子的5至14元杂芳基,其中所述“取代”是指被1至10个氘取代,或者选择性地含有1至4个选自羟基、卤素、氰基、磺酰基、C1-C8磺基、-NRdRe、饱和或不饱和的C1-C8烷基、饱和或不饱和的C3-C8环烷基、饱和或不饱和的C1-C8烷氧基、饱和或不饱和的C3-C8环烷氧基、-OC(=O)C1-C8烷基、-OC(=O)C3-C8环烷基、-C(=O)OC1-8烷基、-C(=O)O C3-C8环烷基、饱和或不饱和的C1-C8磺酰基、饱和或不饱和的C1-C8酰基、饱和或不饱和的C1-C8烷氧基羰基、C6-C14芳基、含有1至3个选自N、O和S的杂原子的4至14元杂环烷基或含有1至3个选自N、O和S的杂原子的5至14元杂芳基的取代基,其中Rc不为氢;R c , R g , Rh and R i are each independently selected from hydrogen, hydroxyl, amino, saturated or unsaturated substituted or unsubstituted C 1 -C 8 alkyl, saturated or unsaturated substituted or unsubstituted C 3 -C 8 cycloalkyl, -C(=O)C 1-8 alkyl, -C(=O)C 3 -C 8 cycloalkyl, -C(=O)OC 1 -C 8 alkyl , -C(=O)OC 3 -C 8 cycloalkyl, -C(=O)NC 1 -C 8 alkyl, -C(=O)NC 3 -C 8 cycloalkyl, C 1 -C 8 Sulfo group, saturated or unsaturated substituted or unsubstituted C 1 -C 8 sulfonyl group, C 6 -C 14 aryl group, C 7 -C 14 arylalkyl group, containing 1 to 3 selected from N, O and A 4- to 14-membered heterocycloalkyl group containing a heteroatom of S or a 5- to 14-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substituted" means substituted by 1 to 10 Deuterium substitution, or optionally containing 1 to 4 selected from hydroxyl, halogen, cyano, sulfonyl, C 1 -C 8 sulfo, -NR d R e , saturated or unsaturated C 1 -C 8 alkane group, saturated or unsaturated C 3 -C 8 cycloalkyl group, saturated or unsaturated C 1 -C 8 alkoxy group, saturated or unsaturated C 3 -C 8 cycloalkoxy group, -OC(=O )C 1 -C 8 alkyl, -OC(=O)C 3 -C 8 cycloalkyl, -C(=O)OC 1-8 alkyl, -C(=O)OC 3 -C 8 cycloalkyl base, saturated or unsaturated C 1 -C 8 sulfonyl group, saturated or unsaturated C 1 -C 8 acyl group, saturated or unsaturated C 1 -C 8 alkoxycarbonyl group, C 6 -C 14 aryl group, Substitution of a 4- to 14-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S or a 5- to 14-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S Base, where R c is not hydrogen;Rd和Re各自独立地选自氢、卤素、氰基、羟基、饱和或不饱和的C1~C3烷基、C3~C6环烷基、饱和或不饱和的被卤素或羟基取代C1~C3烷基,被卤素或羟基取代的C3~C6环烷基,饱和或不饱和的C1~C3烷氧基,C3~C6环烷氧基,饱和或不饱和的被卤素或羟基取代C1~C3烷氧基,被卤素或羟基取代的C3~C6环烷氧基。R d and R e are each independently selected from hydrogen, halogen, cyano, hydroxyl, saturated or unsaturated C 1 to C 3 alkyl, C 3 to C 6 cycloalkyl, saturated or unsaturated halogen or hydroxyl Substituted C 1 to C 3 alkyl, C 3 to C 6 cycloalkyl substituted by halogen or hydroxyl, saturated or unsaturated C 1 to C 3 alkoxy, C 3 to C 6 cycloalkoxy, saturated or Unsaturated C 1 to C 3 alkoxy group substituted by halogen or hydroxyl group, C 3 to C 6 cycloalkoxy group substituted by halogen or hydroxyl group. - 根据权利要求1所述的式Ⅰ表示的2-氮取代嘧啶类化合物,其各自旋光异构体,氘代物,前药或药学上可接受的盐,其特征在于,The 2-nitrogen-substituted pyrimidine compound represented by formula I according to claim 1, each of which is an optical isomer, a deuterated product, a prodrug or a pharmaceutically acceptable salt, characterized in that,优选地,A环为C6~10芳基或者含有杂1~3个选自N、O和S杂原子的5~8元杂芳基。Preferably, ring A is a C 6-10 aryl group or a 5-8 membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S heteroatoms.
- 根据权利要求1所述的式Ⅰ表示的2-氮取代嘧啶类化合物,其各自旋光异构体,氘代物,前药或药学上可接受的盐,其特征在于,The 2-nitrogen-substituted pyrimidine compound represented by formula I according to claim 1, each of which is an optical isomer, a deuterated product, a prodrug or a pharmaceutically acceptable salt, characterized in that,优选地,R1和R2各自独立地为氢、饱和或不饱和的取代或未取代的C1-C6烷基、饱和或不饱和的取代或未取代的C3-C6环烷基、-OC(=O)C1-6烷基、-OC(=O)C3-C6环烷基、-C(=O)OC1-C6烷基、-C(=O)C3-C6环烷基、-S(O)mRc、饱和或不饱和的取代或未取代的C1-C6磺酰基、饱和或不饱和的取代或未取代的C1-C6酰基、C6-C10芳基、含有1至3个选自N、O和S的杂原子的5至10元杂环烷基或含有1至3个选自N、O和S的杂原子的5至10元杂芳基,含有基团的饱和或不饱和的卤代或者未卤代的C1-6烷基,含有基团的饱和或不饱和的卤代或者未卤代的C3-6环烷基,其中所述“取代”是指被1至10个氘取代,或者选择性地含有1至4个选自羟基、卤素、氰基、-S(O)mRc、-NRdRe、饱和或不饱和的C1-C6烷基、饱和或不饱和的C3-C6环烷基、饱和或不饱和的C1-C6烷氧基、饱和或不饱和的C3-C6环烷氧基、-OC(=O)C1-C6烷基、-OC(=O)C3-C6环烷基、-C(=O)OC1-6烷基、-C(=O)OC3-C6环烷基、含有基团的饱和或不饱和的卤代或者未卤代的C1-6烷基,含有基团的饱和或不饱和的卤代或者未卤代的C3-6环烷基,饱和或不饱和的 C1-C6酰基、饱和或不饱和的C1-C6烷氧基羰基、C6-C10芳基、含有1至3个选自N、O和S的杂原子的5至10元杂环烷基或含有1至3个选自N、O和S的杂原子的5至10元杂芳基的取代基;Preferably, R 1 and R 2 are each independently hydrogen, saturated or unsaturated substituted or unsubstituted C 1 -C 6 alkyl, saturated or unsaturated substituted or unsubstituted C 3 -C 6 cycloalkyl , -OC(=O)C 1-6 alkyl, -OC(=O)C 3 -C 6 cycloalkyl, -C(=O)OC 1 -C 6 alkyl, -C(=O)C 3 -C 6 cycloalkyl, -S(O) m R c , saturated or unsaturated substituted or unsubstituted C 1 -C 6 sulfonyl group, saturated or unsaturated substituted or unsubstituted C 1 -C 6 Acyl group, C 6 -C 10 aryl group, 5 to 10 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S or 1 to 3 heteroatoms selected from N, O and S 5- to 10-membered heteroaryl groups containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-6 alkyl group, containing The group is a saturated or unsaturated halogenated or unhalogenated C 3-6 cycloalkyl group, wherein "substituted" means substituted by 1 to 10 deuterons, or optionally contains 1 to 4 selected from Hydroxy, halogen, cyano, -S(O) m R c , -NR d R e , saturated or unsaturated C 1 -C 6 alkyl, saturated or unsaturated C 3 -C 6 cycloalkyl, saturated Or unsaturated C 1 -C 6 alkoxy, saturated or unsaturated C 3 -C 6 cycloalkoxy, -OC(=O)C 1 -C 6 alkyl, -OC(=O)C 3 -C 6 cycloalkyl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3 -C 6 cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-6 alkyl group, containing Saturated or unsaturated halogenated or unhalogenated C 3-6 cycloalkyl group, saturated or unsaturated C 1 -C 6 acyl, saturated or unsaturated C 1 -C 6 alkoxycarbonyl, C 6 -C 10 aryl, 5 to 10 yuan containing 1 to 3 heteroatoms selected from N, O and S Heterocycloalkyl or a 5- to 10-membered heteroaryl substituent containing 1 to 3 heteroatoms selected from N, O and S;或者R1和R2与连接它们的N原子一起形成取代或未取代的含有1至3个选自N、O和S的杂原子的5至10元杂环烷基,其中所述“取代”是指被1至10个氘取代,或者选择性地含有1至4个选自羟基,卤素,氰基,-S(O)mRc、-NRdRe,C1~C6烷基,C3~C6环烷基,C1~C6烷氧基,C3~C6环烷氧基,-OC(=O)C1-6烷基,-OC(=O)C3~C6环烷基,-C(=O)OC1-6烷基,-C(=O)OC3~C6环烷基,含有基团的饱和或不饱和的卤代或者未卤代的C1-6烷基,含有基团的饱和或不饱和的卤代或者未卤代的C3-6环烷基,被Rf取代的C1~C6烷基、C3~C6环烷基、C1~C6烷氧基、C3~C6环烷氧基的取代基;Or R 1 and R 2 together with the N atom connecting them form a substituted or unsubstituted 5 to 10 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, wherein said "substituted" Refers to being substituted by 1 to 10 deuterium, or optionally containing 1 to 4 selected from hydroxyl, halogen, cyano, -S(O) m R c , -NR d R e , C 1 to C 6 alkyl , C 3 ~ C 6 cycloalkyl, C 1 ~ C 6 alkoxy, C 3 ~ C 6 cycloalkoxy, -OC(=O)C 1-6 alkyl, -OC(=O)C 3 ~C 6 cycloalkyl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3 ~C 6 cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-6 alkyl group, containing Saturated or unsaturated halogenated or unhalogenated C 3-6 cycloalkyl group, C 1 to C 6 alkyl group substituted by R f , C 3 to C 6 cycloalkyl group, C 1 to C 6 Substituents of alkoxy and C 3 to C 6 cycloalkoxy;更优选地,R1和R2各自独立地为氢、饱和或不饱和的取代或未取代的C1-C4烷基、饱和或不饱和的取代或未取代的C3-C6环烷基、-OC(=O)C1-4烷基、-OC(=O)C3-C6环烷基、-C(=O)OC1-C4烷基、-C(=O)C3-C6环烷基、-S(O)mRc、饱和或不饱和的取代或未取代的C1-C4酰基、C6-C10芳基、含有1至3个选自N、O和S的杂原子的5至8元杂环烷基或含有1至3个选自N、O和S的杂原子的5至8元杂芳基,含有基团的饱和或不饱和的卤代或者未卤代的C1-4烷基,含有基团的饱和或不饱和的卤代或者未卤代的C3-6环烷基,其中所述“取代”是指被1至10个氘取代,或者选择性地含有1至3个选自羟基、卤素、氰基、-S(O)mRc、-NRdRe、饱和或不饱和的C1-C4烷基、饱和或不饱和的C3-C6环烷基、饱和或不饱和的C1-C4烷氧基、饱和或不饱和的C3-C6环烷氧基、-OC(=O)C1-C4烷基、-OC(=O)C3-C6环烷基、-C(=O)OC1-4烷基、-C(=O)OC3-C6环烷基、含有基团的饱和或不饱和的卤代或者未卤代的C1-4烷基,含有基团的饱和或不饱和的卤代或者未卤代的C3-6环烷基,饱和或不饱和的C1-C4酰基、饱和或不饱和的C1-C4烷氧基羰基、C6-C10芳基、含有1至3个选自N、O和S的杂原子的5至8元杂环烷基或含有1至3个选自N、O和S的杂原子的5至10元杂芳基的取代基;More preferably, R 1 and R 2 are each independently hydrogen, saturated or unsaturated substituted or unsubstituted C 1 -C 4 alkyl, saturated or unsaturated substituted or unsubstituted C 3 -C 6 cycloalkyl base, -OC(=O)C 1-4 alkyl, -OC(=O)C 3 -C 6 cycloalkyl, -C(=O)OC 1 -C 4 alkyl, -C(=O) C 3 -C 6 cycloalkyl, -S(O) m R c , saturated or unsaturated substituted or unsubstituted C 1 -C 4 acyl, C 6 -C 10 aryl, containing 1 to 3 selected from A 5- to 8-membered heterocycloalkyl group containing heteroatoms of N, O, and S or a 5- to 8-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-4 alkyl group, containing The group is a saturated or unsaturated halogenated or unhalogenated C 3-6 cycloalkyl group, wherein "substituted" means substituted by 1 to 10 deuterons, or optionally contains 1 to 3 selected from Hydroxy, halogen, cyano, -S(O) m R c , -NR d R e , saturated or unsaturated C 1 -C 4 alkyl, saturated or unsaturated C 3 -C 6 cycloalkyl, saturated Or unsaturated C 1 -C 4 alkoxy, saturated or unsaturated C 3 -C 6 cycloalkoxy, -OC(=O)C 1 -C 4 alkyl, -OC(=O)C 3 -C 6 cycloalkyl, -C(=O)OC 1-4 alkyl, -C(=O)OC 3 -C 6 cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-4 alkyl group, containing The group is a saturated or unsaturated halogenated or unhalogenated C 3-6 cycloalkyl group, a saturated or unsaturated C 1 -C 4 acyl group, a saturated or unsaturated C 1 -C 4 alkoxycarbonyl group, C 6 -C 10 aryl, 5 to 8 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S, or 5 to 3 heteroatoms selected from N, O, and S to 10-membered heteroaryl substituents;或者R1和R2与连接它们的N原子一起形成取代或未取代的含有1至3个选自N、O和S的杂原子的5至8元杂环烷基,其中所述“取代”是指被1至10个氘取代,或者选择性地含有1至3个选自羟基,卤素,氰基,-S(O)mRc、-NRdRe,C1~C4烷基,C3~C6环烷基,C1~C4烷氧基,C3~C6环烷氧基,-OC(=O)C1-4烷基,-OC(=O)C3~C6环 烷基,-C(=O)OC1-4烷基,-C(=O)OC3~C6环烷基,含有基团的饱和或不饱和的卤代或者未卤代的C1-4烷基,含有基团的饱和或不饱和的卤代或者未卤代的C3-6环烷基,被Rf取代的C1~C4烷基、C3~C6环烷基、C1~C4烷氧基、C3~C6环烷氧基的取代基,其中Rf选自氘,卤素,氰基,羟基,氨基,饱和或不饱和的C1~C4烷基,饱和或不饱和的C3~C6环烷基,-S(O)mRc、NRdRe,饱和或不饱和的被氘、卤素、羟基或氨基取代C1~C4烷基,被氘、卤素、羟基或氨基取代的C3~C6环烷基,饱和或不饱和的C1~C4烷氧基,C3~C6环烷氧基,饱和或不饱和的被氘、卤素、羟基或氨基取代C1~C4烷氧基,被氘、卤素、羟基或氨基取代的C3~C6环烷氧基;Or R 1 and R 2 together with the N atom connecting them form a substituted or unsubstituted 5 to 8 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, wherein said "substituted" Refers to being substituted by 1 to 10 deuterium, or optionally containing 1 to 3 selected from hydroxyl, halogen, cyano, -S(O) m R c , -NR d R e , C 1 ~ C 4 alkyl , C 3 ~ C 6 cycloalkyl, C 1 ~ C 4 alkoxy, C 3 ~ C 6 cycloalkoxy, -OC(=O)C 1-4 alkyl, -OC(=O)C 3 ~C 6 ring Alkyl, -C(=O)OC 1-4 alkyl, -C(=O)OC 3 ~ C 6 cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-4 alkyl group, containing Saturated or unsaturated halogenated or unhalogenated C 3-6 cycloalkyl group, C 1 to C 4 alkyl group substituted by R f , C 3 to C 6 cycloalkyl group, C 1 to C 4 Alkoxy, C 3 to C 6 cycloalkoxy substituents, where R f is selected from deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 4 alkyl, saturated or unsaturated C 3 ~ C 6 cycloalkyl, -S(O) m R c , NR d R e , saturated or unsaturated substituted by deuterium, halogen, hydroxyl or amino group C 1 ~ C 4 alkyl, substituted by deuterium, halogen , C 3 ~ C 6 cycloalkyl substituted by hydroxyl or amino, saturated or unsaturated C 1 ~ C 4 alkoxy, C 3 ~ C 6 cycloalkoxy, saturated or unsaturated substituted by deuterium, halogen, hydroxyl Or C 1 to C 4 alkoxy group substituted by amino group, C 3 to C 6 cycloalkoxy group substituted by deuterium, halogen, hydroxyl group or amino group;优选地,R3选自氘、卤素、硝基、氰基、羧基、羟基、-NRdRe、-ORg、-CO2Rg、-S(O)mRc,或被1至3个Rh取代的C1-6烷基、C3-6环烷基、C1-6烷氧基、C3-6环烷氧基、C1-6烷氧基羰基、C1-6烷基羰基、C1-6烷基羧基、3-6元环烷基、3-6元杂环烷基、6-10元芳基、5-10元杂芳基;Preferably, R 3 is selected from deuterium, halogen, nitro, cyano, carboxyl, hydroxyl, -NR d R e , -OR g , -CO 2 R g , -S(O) m R c , or is replaced by 1 to 3 R h substituted C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 1-6 alkoxycarbonyl, C 1- 6- alkylcarbonyl, C 1-6 alkylcarboxyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl;更优选地,R3选自氘、卤素、硝基、氰基、羧基、羟基、-NRdRe、-ORg、-CO2Rg、-S(O)mRc,或被1至3个Rh取代的C1-4烷基、C3-6环烷基、C1-4烷氧基、C3-6环烷氧基、C1-4烷氧基羰基、C1-4烷基羰基、C1-4烷基羧基、3-6元环烷基、3-6元杂环烷基、6-10元芳基、5-10元杂芳基;More preferably, R 3 is selected from deuterium, halogen, nitro, cyano, carboxyl, hydroxyl, -NR d R e , -OR g , -CO 2 R g , -S(O) m R c , or is replaced by 1 To 3 R h substituted C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 3-6 cycloalkoxy, C 1-4 alkoxycarbonyl, C 1 -4 alkylcarbonyl, C 1-4 alkylcarboxyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl;优选地,Ra、Rb各自独立地选自饱和或不饱和的取代或未取代的C3-C6环烷基,饱和或不饱和的取代或未取代的C1-C6烷基,取代或未取代的6~10元芳基或者取代或未取代的含有杂1~3个选自N、O和S杂原子的5~8元杂芳基,其中所述“取代”是指被1至10个氘取代,或者选择性地含有1至3个选自羟基、卤素、氰基、-S(O)mRc、-NRdRe、饱和或不饱和的C1-C6烷基、饱和或不饱和的C3-C6环烷基、饱和或不饱和的C1-C6烷氧基、饱和或不饱和的C3-C6环烷氧基、-OC(=O)C1-C6烷基、-OC(=O)C3-C6环烷基、-C(=O)OC1-6烷基、-C(=O)OC3-C6环烷基、饱和或不饱和的C1-C6酰基、饱和或不饱和的C1-C6烷氧基羰基、含有基团的饱和或不饱和的卤代或者未卤代的C1-6烷基,含有基团的饱和或不饱和的卤代或者未卤代的C3-6环烷基,C6-C10芳基、含有1至3个选自N、O和S的杂原子的5至10元杂环烷基或含有1至3个选自N、O和S的杂原子的5至10元杂芳基的取代基;Preferably, R a and R b are each independently selected from saturated or unsaturated substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 6 alkyl, Substituted or unsubstituted 6- to 10-membered aryl groups or substituted or unsubstituted 5- to 8-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S heteroatoms, wherein the "substituted" refers to 1 to 10 deuterium substitutions, or optionally containing 1 to 3 selected from hydroxyl, halogen, cyano, -S(O) mRc , -NRdRe , saturated or unsaturated C1 - C6 Alkyl, saturated or unsaturated C 3 -C 6 cycloalkyl, saturated or unsaturated C 1 -C 6 alkoxy, saturated or unsaturated C 3 -C 6 cycloalkoxy, -OC(= O)C 1 -C 6 alkyl, -OC(=O)C 3 -C 6 cycloalkyl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3 -C 6 ring Alkyl, saturated or unsaturated C 1 -C 6 acyl, saturated or unsaturated C 1 -C 6 alkoxycarbonyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-6 alkyl group, containing The group is saturated or unsaturated halogenated or unhalogenated C 3-6 cycloalkyl, C 6 -C 10 aryl, 5 to 10 containing 1 to 3 heteroatoms selected from N, O and S A substituent of a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S;或者Ra和Rb与连接它们的N原子一起形成取代或未取代的含有1至3个选自N、O和S的杂原子的4至10元杂环烷基,取代或未取代的含有1至3个选自N、O和S的杂原子的5至10元杂芳基,其中所述“取代”是指被1至10个氘取代,或者选择性地含有1至4个选自羟基,卤素,氰基,磺酰基,羧基,-S(O)mRc、-NRdRe,C1~C6烷基,C3~C6环烷基,C1~C6烷氧基,C3~C6环烷氧基,-OC(=O)C1-6烷基,-OC(=O)C3~C6 环烷基,-C(=O)OC1-6烷基,-C(=O)OC3~C6环烷基,含有基团的饱和或不饱和的卤代或者未卤代的C1-6烷基,含有基团的饱和或不饱和的卤代或者未卤代的C3-6环烷基,被Rf取代的C1~C6烷基、C3~C6环烷基、C1~C6烷氧基、C3~C6环烷氧基的取代基;Or R a and R b together with the N atom connecting them form a substituted or unsubstituted 4 to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted containing 5 to 10 membered heteroaryl groups with 1 to 3 heteroatoms selected from N, O and S, wherein "substituted" means substituted with 1 to 10 deuteriums, or optionally containing 1 to 4 selected from Hydroxy, halogen, cyano, sulfonyl, carboxyl, -S(O) m R c , -NR d R e , C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, C 1 to C 6 alkyl Oxygen group, C 3 to C 6 cycloalkoxy group, -OC(=O)C 1-6 alkyl group, -OC(=O)C 3 to C 6 Cycloalkyl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3 ~ C 6 cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-6 alkyl group, containing Saturated or unsaturated halogenated or unhalogenated C 3-6 cycloalkyl group, C 1 to C 6 alkyl group substituted by R f , C 3 to C 6 cycloalkyl group, C 1 to C 6 Substituents of alkoxy and C 3 to C 6 cycloalkoxy;更优选地,Ra、Rb各自独立地选自饱和或不饱和的取代或未取代的C3-C6环烷基,饱和或不饱和的取代或未取代的C1-C4烷基,取代或未取代的6~10元芳基或者取代或未取代的含有杂1~3个选自N、O和S杂原子的5~8元杂芳基,其中所述“取代”是指被1至10个氘取代,或者选择性地含有1至3个选自羟基、卤素、氰基、-S(O)mRc、-NRdRe、饱和或不饱和的C1-C4烷基、饱和或不饱和的C3-C6环烷基、饱和或不饱和的C1-C4烷氧基、饱和或不饱和的C3-C6环烷氧基、-OC(=O)C1-C4烷基、-OC(=O)C3-C6环烷基、-C(=O)OC1-4烷基、-C(=O)OC3-C6环烷基、饱和或不饱和的C1-C4酰基、饱和或不饱和的C1-C4烷氧基羰基、含有基团的饱和或不饱和的卤代或者未卤代的C1-4烷基,含有基团的饱和或不饱和的卤代或者未卤代的C3-6环烷基,C6-C10芳基、含有1至3个选自N、O和S的杂原子的5至10元杂环烷基或含有1至3个选自N、O和S的杂原子的5至10元杂芳基的取代基;More preferably, R a and R b are each independently selected from saturated or unsaturated substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 4 alkyl. , a substituted or unsubstituted 6 to 10-membered aryl group or a substituted or unsubstituted 5 to 8-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S heteroatoms, wherein the "substituted" refers to Substituted with 1 to 10 deuterium, or optionally containing 1 to 3 selected from hydroxyl, halogen, cyano, -S(O) mRc , -NRdRe , saturated or unsaturated C1- C 4 alkyl, saturated or unsaturated C 3 -C 6 cycloalkyl, saturated or unsaturated C 1 -C 4 alkoxy, saturated or unsaturated C 3 -C 6 cycloalkoxy, -OC( =O)C 1 -C 4 alkyl, -OC(=O)C 3 -C 6 cycloalkyl, -C(=O)OC 1-4 alkyl, -C(=O)OC 3 -C 6 Cycloalkyl, saturated or unsaturated C 1 -C 4 acyl, saturated or unsaturated C 1 -C 4 alkoxycarbonyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-4 alkyl group, containing The group is saturated or unsaturated halogenated or unhalogenated C 3-6 cycloalkyl, C 6 -C 10 aryl, 5 to 10 containing 1 to 3 heteroatoms selected from N, O and S A substituent of a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S;或者Ra和Rb与连接它们的N原子一起形成取代或未取代的含有1至3个选自N、O和S的杂原子的5至8元杂环烷基,取代或未取代的含有1至3个选自N、O和S的杂原子的5至6元杂芳基,其中所述“取代”是指被1至10个氘取代,或者选择性地含有1至3个选自羟基,卤素,氰基,磺酰基,羧基,-S(O)mRc、-NRdRe,C1~C4烷基,C5~C6环烷基,C1~C4烷氧基,C5~C6环烷氧基,-OC(=O)C1-4烷基,-OC(=O)C5~C6环烷基,-C(=O)OC1-4烷基,-C(=O)OC5~C6环烷基,含有基团的饱和或不饱和的卤代或者未卤代的C1-4烷基,含有基团的饱和或不饱和的卤代或者未卤代的C3-6环烷基,被Rf取代的C1~C4烷基、C5~C6环烷基、C1~C4烷氧基、C5~C6环烷氧基的取代基;Or R a and R b together with the N atom connecting them form a substituted or unsubstituted 5- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted containing A 5- to 6-membered heteroaryl group with 1 to 3 heteroatoms selected from N, O and S, wherein "substituted" means substituted with 1 to 10 deuteriums, or optionally containing 1 to 3 selected from Hydroxy, halogen, cyano, sulfonyl, carboxyl, -S(O) m R c , -NR d R e , C 1 to C 4 alkyl, C 5 to C 6 cycloalkyl, C 1 to C 4 alkyl Oxygen group, C 5 to C 6 cycloalkoxy group, -OC(=O)C 1-4 alkyl group, -OC(=O)C 5 to C 6 cycloalkyl group, -C(=O)OC 1- 4 alkyl, -C(=O)OC 5 ~ C 6 cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-4 alkyl group, containing Saturated or unsaturated halogenated or unhalogenated C 3-6 cycloalkyl group, C 1 to C 4 alkyl group substituted by R f , C 5 to C 6 cycloalkyl group, C 1 to C 4 Substituents of alkoxy and C 5 to C 6 cycloalkoxy;优选地,Rc、Rf、Rg、Rh和Ri各自独立地选自氢、羟基、氨基、饱和或不饱和的取代或未取代的C1-C6烷基、饱和或不饱和的取代或未取代的C1-C6烷基、C3-C6环烷基、-C(=O)C1-6烷基、-C(=O)C3-C6环烷基、-C(=O)OC1-C6烷基、-C(=O)OC3-C6环烷基、-C(=O)NC1-C6烷基、-C(=O)NC3-C6环烷基、饱和或不饱和的取代或未取代的C1-C6磺酰基、C6-C10芳基、C7-C11芳基烷基、含有1至3个选自N、O和S的杂原子的5至10元杂环烷基或含有1至3个选自N、O和S的杂原子的5至10元杂芳基,其中所述“取代”是指被1至10个氘取代,或者选择性地含有1至4个选自羟基、卤素、氰基、磺 酰基、C1-C6磺基、-NRdRe、饱和或不饱和的C1-C6烷基、饱和或不饱和的C3-C6环烷基、饱和或不饱和的C1-C6烷氧基、饱和或不饱和的C3-C6环烷氧基、-OC(=O)C1-C6烷基、-OC(=O)C3-C8环烷基、-C(=O)OC1-6烷基、-C(=O)OC3-C6环烷基、饱和或不饱和的C1-C6磺酰基、饱和或不饱和的C1-C6酰基、饱和或不饱和的C1-C6烷氧基羰基、C6-C10芳基、含有1至3个选自N、O和S的杂原子的5至10元杂环烷基或含有1至3个选自N、O和S的杂原子的5至10元杂芳基的取代基,其中Rc不为氢;Preferably, R c , R f , R g , Rh and R i are each independently selected from hydrogen, hydroxyl, amino, saturated or unsaturated substituted or unsubstituted C 1 -C 6 alkyl, saturated or unsaturated Substituted or unsubstituted C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, -C(=O)C 1-6 alkyl, -C(=O)C 3 -C 6 cycloalkyl , -C(=O)OC 1 -C 6 alkyl, -C(=O)OC 3 -C 6 cycloalkyl, -C(=O)NC 1 -C 6 alkyl, -C(=O) NC 3 -C 6 cycloalkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 6 sulfonyl, C 6 -C 10 aryl, C 7 -C 11 arylalkyl, containing 1 to 3 A 5- to 10-membered heterocycloalkyl group containing heteroatoms selected from N, O, and S or a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein the "substituted" Refers to being substituted by 1 to 10 deuterium, or optionally containing 1 to 4 selected from hydroxyl, halogen, cyano, sulfonate Acyl group, C 1 -C 6 sulfo group, -NR d R e , saturated or unsaturated C 1 -C 6 alkyl group, saturated or unsaturated C 3 -C 6 cycloalkyl group, saturated or unsaturated C 1 -C 6 alkoxy, saturated or unsaturated C 3 -C 6 cycloalkoxy, -OC(=O)C 1 -C 6 alkyl, -OC(=O)C 3 -C 8 cycloalkyl , -C(=O)OC 1-6 alkyl, -C(=O)OC 3 -C 6 cycloalkyl, saturated or unsaturated C 1 -C 6 sulfonyl, saturated or unsaturated C 1 - C 6 acyl, saturated or unsaturated C 1 -C 6 alkoxycarbonyl, C 6 -C 10 aryl, 5 to 10 membered heterocycloalkane containing 1 to 3 heteroatoms selected from N, O and S group or a substituent of a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, wherein R c is not hydrogen;更优选地,Rc、Rf、Rg、Rh和Ri各自独立地选自氢、羟基、氨基、饱和或不饱和的取代或未取代的C1-C4烷基、饱和或不饱和的取代或未取代的C1-C4烷基、C4-C6环烷基、-C(=O)C1-4烷基、-C(=O)C4-C6环烷基、-C(=O)OC1-C4烷基、-C(=O)OC4-C8环烷基、-C(=O)NC1-C4烷基、-C(=O)NC4-C6环烷基、饱和或不饱和的取代或未取代的C1-C4磺酰基、C6-C10芳基、C7-C11芳基烷基、含有1至3个选自N、O和S的杂原子的5至8元杂环烷基或含有1至3个选自N、O和S的杂原子的5至10元杂芳基,其中所述“取代”是指被1至10个氘取代,或者选择性地含有1至3个选自羟基、卤素、氰基、磺酰基、C1-C4磺基、-NRdRe、饱和或不饱和的C1-C4烷基、饱和或不饱和的C4-C6环烷基、饱和或不饱和的C1-C4烷氧基、饱和或不饱和的C4-C6环烷氧基、-OC(=O)C1-C4烷基、-OC(=O)C4-C6环烷基、-C(=O)OC1-4烷基、-C(=O)OC4-C6环烷基、饱和或不饱和的C1-C4磺酰基、饱和或不饱和的C1-C4酰基、饱和或不饱和的C1-C4烷氧基羰基、C6-C10芳基、含有1至3个选自N、O和S的杂原子的5至8元杂环烷基或含有1至3个选自N、O和S的杂原子的5至10元杂芳基的取代基,其中Rc不为氢;More preferably, R c , R f , R g , Rh and R i are each independently selected from hydrogen, hydroxyl, amino, saturated or unsaturated substituted or unsubstituted C 1 -C 4 alkyl, saturated or unsaturated Saturated substituted or unsubstituted C 1 -C 4 alkyl, C 4 -C 6 cycloalkyl, -C(=O)C 1-4 alkyl, -C(=O)C 4 -C 6 cycloalkyl base, -C(=O)OC 1 -C 4 alkyl, -C(=O)OC 4 -C 8 cycloalkyl, -C(=O)NC 1 -C 4 alkyl, -C(=O )NC 4 -C 6 cycloalkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 4 sulfonyl, C 6 -C 10 aryl, C 7 -C 11 arylalkyl, containing 1 to 3 A 5- to 8-membered heterocycloalkyl group containing a heteroatom selected from N, O, and S or a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein the "substituted ” means substituted by 1 to 10 deuterium, or optionally containing 1 to 3 selected from hydroxyl, halogen, cyano, sulfonyl, C 1 -C 4 sulfo, -NR d R e , saturated or unsaturated C 1 -C 4 alkyl, saturated or unsaturated C 4 -C 6 cycloalkyl, saturated or unsaturated C 1 -C 4 alkoxy, saturated or unsaturated C 4 -C 6 cycloalkoxy base, -OC(=O)C 1 -C 4 alkyl, -OC(=O)C 4 -C 6 cycloalkyl, -C(=O)OC 1-4 alkyl, -C(=O) OC 4 -C 6 cycloalkyl, saturated or unsaturated C 1 -C 4 sulfonyl, saturated or unsaturated C 1 -C 4 acyl, saturated or unsaturated C 1 -C 4 alkoxycarbonyl, C 6 -C 10 aryl, 5- to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S, or 5- to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S A substituent for a 10-membered heteroaryl group, where R c is not hydrogen;更优选,Rf选自氘,卤素,氰基,羟基,氨基,饱和或不饱和的C1~C6烷基,饱和或不饱和的C3~C6环烷基,-S(O)mRc、NRdRe,饱和或不饱和的被氘、卤素、羟基或氨基取代C1~C6烷基,被氘、卤素、羟基或氨基取代的C3~C6环烷基,饱和或不饱和的C1~C6烷氧基,C3~C6环烷氧基,饱和或不饱和的被氘、卤素、羟基或氨基取代C1~C6烷氧基,被氘、卤素、羟基或氨基取代的C3~C6环烷氧基。More preferably, R f is selected from deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 6 alkyl, saturated or unsaturated C 3 to C 6 cycloalkyl, -S(O) m R c , NR d Re , saturated or unsaturated C 1 to C 6 alkyl group substituted by deuterium, halogen, hydroxyl or amino group, C 3 to C 6 cycloalkyl group substituted by deuterium, halogen, hydroxyl group or amino group, Saturated or unsaturated C 1 to C 6 alkoxy group, C 3 to C 6 cycloalkoxy group, saturated or unsaturated C 1 to C 6 alkoxy group substituted by deuterium, halogen, hydroxyl or amino group, substituted by deuterium, Halogen, hydroxyl or amino substituted C 3 to C 6 cycloalkoxy group.
- 根据权利要求1所述的式Ⅰ表示的2-氮取代嘧啶类化合物,其各自旋光异构体,氘代物,前药或药学上可接受的盐,其特征在于,The 2-nitrogen-substituted pyrimidine compound represented by formula I according to claim 1, each of which is an optical isomer, a deuterated product, a prodrug or a pharmaceutically acceptable salt, characterized in that,更优选地,式Ⅰ中R1和R2与连接它们的N原子一起形成的结构选自以下基团中:
More preferably, the structure formed by R 1 and R 2 in formula I together with the N atom connecting them is selected from the following groups:
- 根据权利要求1所述的式Ⅰ表示的2-氮取代嘧啶类化合物,其各自旋光异构体,氘代物,前药或药学上可接受的盐,其特征在于,The 2-nitrogen-substituted pyrimidine compound represented by formula I according to claim 1, each of which is an optical isomer, a deuterated product, a prodrug or a pharmaceutically acceptable salt, characterized in that,更优选地,式Ⅰ中Ra和Rb与连接它们的N原子一起形成的结构选自以下基团中:
More preferably, the structure formed by R a and R b in formula I together with the N atom connecting them is selected from the following groups:
其中,Rj和Rk每次出现时各自独立地为羟基,卤素,氰基,磺酰基,氨基,C1~C8烷基,C3~C8环烷基,C1~C8烷氧基,C3~C8环烷氧基,-OC(=O)C1-8烷基,-OC(=O)C3~C8环烷基,-C(=O)OC1-8烷基,-C(=O)OC3~C8环烷基,被Rf取代的C1~C8烷基、C3~C8环烷基、C1~C8烷氧基、C3~C8环烷氧基的取代基;n2为0、1、2、3、4或5的整数;Wherein, each occurrence of R j and R k is independently hydroxyl, halogen, cyano, sulfonyl, amino, C 1 to C 8 alkyl, C 3 to C 8 cycloalkyl, C 1 to C 8 alkyl Oxygen group, C 3 to C 8 cycloalkoxy group, -OC(=O)C 1-8 alkyl group, -OC(=O)C 3 to C 8 cycloalkyl group, -C(=O)OC 1- 8 alkyl, -C(=O)OC 3 ~ C 8 cycloalkyl, C 1 ~ C 8 alkyl substituted by R f , C 3 ~ C 8 cycloalkyl, C 1 ~ C 8 alkoxy, C 3 to C 8 cycloalkoxy substituents; n2 is an integer of 0, 1, 2, 3, 4 or 5;优选地,Rj和Rk每次出现时各自独立地为羟基,卤素,氰基,磺酰基,氨基C1~C6烷基,C3~C6环烷基,C1~C6烷氧基,C3~C6环烷氧基,-OC(=O)C1-6烷基,-OC(=O)C3~C6环烷基,-C(=O)OC1-6烷基,-C(=O)OC3~C6环烷基,被Rf取代的C1~C6烷基、C3~C6环烷基、C1~C6烷氧基、C3~C6环烷氧基的取代基;Preferably, each occurrence of R j and R k is independently hydroxyl, halogen, cyano, sulfonyl, amino C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, C 1 to C 6 alkyl Oxy group, C 3 to C 6 cycloalkoxy group, -OC(=O)C 1-6 alkyl group, -OC(=O)C 3 to C 6 cycloalkyl group, -C(=O)OC 1- 6 alkyl, -C(=O)OC 3 ~ C 6 cycloalkyl, C 1 ~ C 6 alkyl substituted by R f , C 3 ~ C 6 cycloalkyl, C 1 ~ C 6 alkoxy, Substituents of C 3 to C 6 cycloalkoxy;更优选地,Rj和Rk每次出现时各自独立地为羟基,卤素,氰基,磺酰基,氨基C1~C4烷基,C4~C6环烷基,C1~C4烷氧基,C4~C6环烷氧基,-OC(=O)C1-4烷基,-OC(=O)C4~C6环烷基,-C(=O)OC1-4烷基,-C(=O)OC4~C6环烷基,被卤素、羟基、氨基或Rf取代的C1~C4烷基、C4~C6环烷基、C1~C4烷氧基、C4~C6环烷氧基的取代基。 More preferably, each occurrence of R j and R k is independently hydroxyl, halogen, cyano, sulfonyl, amino C 1 to C 4 alkyl, C 4 to C 6 cycloalkyl, C 1 to C 4 Alkoxy group, C 4 to C 6 cycloalkoxy group, -OC(=O)C 1-4 alkyl group, -OC(=O)C 4 to C 6 cycloalkyl group, -C(=O)OC 1 -4 alkyl, -C(=O)OC 4 to C 6 cycloalkyl, C 1 to C 4 alkyl, C 4 to C 6 cycloalkyl, C 1 substituted by halogen, hydroxyl, amino or R f Substituents of ~C 4 alkoxy and C 4 ~C 6 cycloalkoxy. - 根据权利要求1至5中任意一项所述的式Ⅰ表示的2-氮取代嘧啶类化合物,其各自旋光异构体,氘代物,前药或药学上可接受的盐,其特征在于,所述2-氮取代嘧啶类化合物选自以下化合物中:
The 2-nitrogen-substituted pyrimidine compound represented by formula I according to any one of claims 1 to 5, each of which is an optical isomer, a deuterated product, a prodrug or a pharmaceutically acceptable salt, characterized in that: The 2-nitrogen-substituted pyrimidine compounds are selected from the following compounds:
- 一种药物组合物,所述药物组合物包含治疗有效量的根据权利要求1至6中任意一项所述的式Ⅰ表示的2-氮取代嘧啶类化合物,其各自旋光异构体,氘代物,前药或药学上可接受的盐和药学上可接受的赋形剂或载体。A pharmaceutical composition comprising a therapeutically effective amount of a 2-nitrogen-substituted pyrimidine compound represented by formula I according to any one of claims 1 to 6, each of its optical isomers and deuterated products , a prodrug or a pharmaceutically acceptable salt and a pharmaceutically acceptable excipient or carrier.
- 根据权利要求1至6中任意一项所述的式Ⅰ表示的2-氮取代嘧啶类化合物,其各自旋光异构体,氘代物,前药或药学上可接受的盐在制备AHR紊乱抑制剂中的用途。According to the 2-nitrogen-substituted pyrimidine compound represented by formula I according to any one of claims 1 to 6, each of its optical isomers, deuterated products, prodrugs or pharmaceutically acceptable salts is used in the preparation of AHR disorder inhibitors uses in.
- 根据权利要求1至6中任意一项所述的式Ⅰ表示的2-氮取代嘧啶类化合物,其各自旋光异构体,氘代物,前药或药学上可接受的盐在制备治疗与AHR紊乱相关的肿瘤的药物中的应用。According to the 2-nitrogen-substituted pyrimidine compound represented by formula I according to any one of claims 1 to 6, each of its optical isomers, deuterated products, prodrugs or pharmaceutically acceptable salts is used in the preparation and treatment of AHR disorders. Applications related to oncology drugs.
- 一种治疗与AHR紊乱相关的肿瘤的方法,所述方法包括向需要其的受试者施用有效量的根据权利要求1至6中任意一项所述的式Ⅰ所示的2-氮取代嘧啶类化合物,其各自旋光异构体,氘代物,前药或药学上可接受的盐或根据权利要求7所述的药物组合物。 A method of treating tumors associated with AHR disorders, the method comprising administering an effective amount of a 2-nitrogen-substituted pyrimidine represented by Formula I according to any one of claims 1 to 6 to a subject in need thereof compounds, their respective optical isomers, deuterated products, prodrugs or pharmaceutically acceptable salts or a pharmaceutical composition according to claim 7.
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CN115093400A (en) * | 2021-09-18 | 2022-09-23 | 重庆华森制药股份有限公司 | AhR inhibitor and application and preparation method thereof |
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